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Malignant Syphilis as an Initial Presentation of Underlying HIV Infection: A Case report

Authors
Ashok R Devkota, Rabindra Ghimire, Mirela Sam and Oo Aung
Article Citation and PDF Link
BJMP 2015;8(2):a816
Abstract / Summary
Abstract: 

There is a higher rate of HIV coinfection among men who have sex with men (MSM) infected with syphilis. HIV positive patients present more often with secondary syphilis and disease course is more aggressive. Here we present a patient, with diffuse papulo-nodular and ulcerative skin lesion and newly diagnosed human immunodeficiency virus. Biopsy of skin lesions confirmed the diagnosis of malignant syphilis, supported by serology results and he responded very well to doxycycline. It is important to recognize and diagnose malignant syphilis early and institute appropriate treatment as complete cure can be achieved.

Keywords: 
Malignant syphilis, human immunodeficiency virus (HIV), MSM

Introduction

The rate of primary and secondary syphilis reported in the United States is gradually increasing. Reported cases of syphilis decreased during the 1990s, were lowest in 2000, after which it gradually increased annually during 2001-20091. In a recent report published by CDC, primary and secondary syphilis rates have increased among men of all ages, races and ethnicities, largely among MSM, from 5.1 cases per 100,000 population in 2005 to 9.8 in 2013. Rates of 50%–70% HIV coinfection among MSM infected with primary and secondary syphilis have been reported2.  Syphilis and the behaviours associated with acquiring it, increase the likelihood of acquiring and transmitting HIV. Although the incidence of HIV has remained stable, the incidence of syphilis has been increasing disproportionately possibly due to adaptive behaviour like serosorting among HIV concordant couples and oral sex that decrease transmission of HIV but not syphilis3

Syphilis may manifest differently in patients with HIV. HIV positive patients present more often with secondary syphilis and the disease course is more aggressive4. Malignant syphilis also known as lues maligna or ulceronodular syphilis is a severe form of secondary syphilis and is more common among HIV infected persons5. Although HIV patients present with varied clinical symptoms, it is uncommon to present with florid secondary syphilitic skin lesions. Here we present a case report of a patient, who presented with diffuse ulceronodular skin lesions, whose serology and skin biopsy confirmed syphilis and was subsequently found to have HIV. 

Case report

A 20-year-old African American man was admitted to Interfaith Medical Center with a generalised body rash for a month. He noticed a rash on his chest, which in few days spread centrifugally to his whole body, face and arms, including palms and soles. The rash was non-pruritic, painless, progressive in size and gradually oozed and crusted (Figure 1a). Besides significant unintentional weight loss of 26 pounds in the last two months, he did not report any other systemic complaints. He denied any travel or unwell contacts. He is a homosexual man and has had two male sexual partners in the last two years; one of them was treated for syphilis two years ago. He denied smoking, alcohol or drug use.


Figure 1a - Skin lesions reveal papulosquamous nodular and ulcerative changes in upper limbs

On admission, he was afebrile with normal vital signs.  His physical examination revealed widespread papulonodular and ulcerated lesions on his whole body including the scalp and oral mucosa, and measured up to 2-3 cm. Skin lesions were prominent on his face, some with sero-purulent discharge and some covered with crusts and scabs, which would bleed on removal of crusts and scabs. No skin lesions were noted in genital area. Besides bilateral enlarged axillary lymph nodes, nosignificant lymphadenopathy was noted. Other systemic examinations were within normal limits.

His full blood count showed microcytic hypochromic anaemia with a mean corpuscular volume of 77.2 fL (normal reference range, 80-100 fL) and thrombocytosis with platelets of 546 per microliter (reference range, 130-400 per microliter). Renal and hepatic function tests were normal.  He tested positive for HIV using serum enzyme linked immunosorbent assay (ELISA), rapid plasma reagin was 1:128 (reference range, nonreactive), fluorescent treponemal antibody absorption test was reactive (reference range, nonreactive) and neurosyphilis was ruled out with negative spinal fluid studies.  Hepatitis B and Cserologieswere negative. Nucleic acid amplification test of the urine sample was negative for Neisseria gonorrhea and Chlamydia trachomatis. The patient was treated with doxycycline100 mg every 12 hours for secondary syphilis as he was allergic to penicillin.

The patient developed chills, fever, sweating, tachycardia and hypotension 18 hours after treatment with doxycycline. A Jarisch-Herxheimer reaction was suspected, which was managed with observation, intravenous hydration and a single dose of methylprednisone. Despite being on antibiotics, he had intermittent fever for two weeks, possibly related to the syphilis and its treatment. Further investigations included blood and urine culture, chest x-ray, CT scan of the head, chest, abdomen and pelvis and a gallium scan, which were unremarkable. Brucella IgM antibody, Q fever phase I and II antibodies, coccidioides antibody, histoplasma urine antigen,  cryptococcal antigen and blood culture for acid fast bacilliwere all negative. His EBVserologies suggested past infection and CMV serologies for IgG and IgM were positive. Wound culture taken from the purulent skin lesions grew methicillin sensitive Staphylococcus aureus (MSSA)which was treated with antibiotics. His HIV-1 RNA was 1050118 (reference range, <20) and CD4 was 276 cells per microlitre (reference range, 317-1868 cells per microlitre), CD4 was 17.4% (reference range, 25.7-62.8%) and CD4:CD8 ratio was 0.32 (reference range, 0.20-3.50). Skin biopsy from the left forearm lesion showed lichenoid lymphohistiocytic infiltrate with plasma cells (Figure 1b). Immunochemical stain was positive for spirochetes, which confirmed secondary syphilitic skin lesions (Figure 1c). After three weeks of doxycycline therapy, significant clinical improvement in the skin lesions were noted.  The skin lesions healed well with hyperpigmentation.  Combination anti-retroviral therapy was initiated upon discharge and on follow-up a month later, the skin lesions had resolved and the RPR titre was 1:32; showing a four-fold reduction. 


Figure 1b - A lymphocyhistiocytic infiltrate was present in the dermis and extended around blood vessels.


Figure 1c - Immunohistochemical stain showing delicate and spiral shaped spirochaetes, highly specific and sensitive of Treponema pallidum

Discussion

Skin lesions of secondary syphilis in patients with HIV may have varied appearance that mimic other diseases like cutaneous lymphomas, mycobacterial infections, bacillary angiomatosis, fungal infections or Kaposi’s sarcoma6.  Detail workup was done in our patient and systemic fungal and bacterial infections were ruled out. He had secondary infection of the skin lesions due to MSSA and was treated with doxycycline. Skin biopsy confirmed secondary syphilitic skin lesions. Histology showed abundant plasma cells and lymphocytesandtreponomes were demonstrated in the special immuno-histochemical stains.  Fisher’s diagnostic criteria for lues maligna include strongly positive RPR titre, a severe Jarisch-Herxheimer reaction, characteristic gross and microscopic morphology and rapid resolution of the lesions with antibiotics7.  Our patient had all of these features. Because of variable presentation of skin lesions and increased rate of false negative serological tests due to prozone phenomenon in patients with HIV, alternative diagnostic techniques like biopsy of skin lesions and special stains should be performed8,9.  The relative paucity of spirochetes in the biopsy of skin lesions makes the demonstration of microorganisms difficult. Yanagishawa et al were able to find 6 published cases of pathologically confirmed malignant syphilis with the demonstration of spirochetes10. Treatment of secondary syphilis in HIV infected patient is the same as that of HIV non infected patients. Benzathine penicillin is first line therapy and doxycycline is an alternative drug for penicillin allergic patients11. A severe Jarish-Herxheimer reaction occurred in our patient, which might not be observed in some cases with HIV and syphilis due to concurrent immunosuppression10. Experience from case reports have shown that malignant syphilitic skin lesions respond very well to antibiotics regardless of CD4 count12. With the increasing incidence of syphilis in HIV infected patients, it is important to recognise and diagnose malignant syphilis early and institute appropriate treatment as complete cure can be achieved.

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
We acknowledge our pathologist Dr Shamah Iqbal, MD for providing the histopathology and immunostain photographs.
Competing Interests: 
None declared
Details of Authors: 
ASHOK R DEVAKOTA, MBBS, MD: Internal Medicine Resident, Interfaith Medical Center, Brooklyn, NY, USA. RABINDRA GHIMIRE, MBBS, MD: Infectious Disease Fellow, The Dr. James J. Rahal, Jr. Division of Infectious Diseases, New York Hospital Queens, NY, USA. MIRELA SAM, MD: Attending and Chief-Infectious Diseases, Interfaith Medical Center, Brooklyn, NY, USA. OO AUNG, MD: Internal Medicine Resident, Interfaith Medical Center, Brooklyn, NY, USA.
Corresponding Author Details: 
drrabindraghimire@gmail.com
Corresponding Author Email: 
drrabindraghimire@gmail.com
References
References: 
  1. Division of STD prevention. Sexually Transmitted Disease Surveillance. C.D.C, 2012.  Jan 2014:2.
  2. Patton, M.E., et al. Primary and secondary syphilis--United States, 2005-2013. MMWR Morb Mortal Wkly Rep, 2014;63(18):402-6.
  3. Mayer, K.H. and M.J. Mimiaga. Resurgent syphilis in the United States: urgent need to address an evolving epidemic. Ann Intern Med, 2011; 155(3):192-3.
  4. Lynn, W.A. and S. Lightman. Syphilis and HIV: a dangerous combination. Lancet Infect Dis, 2004;4(7):456-66.
  5. Zetola, N.M., et al. Syphilis in the United States: an update for clinicians with an emphasis on HIV coinfection. Mayo Clin Proc, 2007; 82(9):1091-102.
  6. Yayli, S., et al. Late secondary syphilis with nodular lesions mimicking Kaposi sarcoma in a patient with human immunodeficiency virus. Int J Dermatol, 2014;53(1):  e71-3.
  7. Fisher, D.A., L.W. Chang, and D.L. Tuffanelli. Lues maligna. Presentation of a cas and a review of the literature. Arch Dermatol, 1969; 99(1):70-3.
  8. Pialoux, G., et al. Effect of HIV infection on the course of syphilis. AIDS Rev, 2008;10(2):85-92.
  9. Tucker, J.D., et al., Lues maligna in early HIV infection case report and review of the literature. Sex Transm Dis, 2009;36(8):512-4.
  10. Yanagisawa, N., et al. Pathologically confirmed malignant syphilis in an HIV-infected patient. Intern Med, 2011;50(20):2423-6.
  11. Zetola, N.M. and J.D. Klausner, Syphilis and HIV infection: an update. Clin Infect Dis, 2007;44(9):1222-8.
  12. Rallis, E. and V. Paparizos, Malignant syphilis as the first manifestation of HIV infection. Infect Dis Rep, 2012;4(1): e15.

Phytochemicals in cancer prevention and management?

Authors
Robert Thomas, Elizabeth Butler, Fabio Macchi and Madeine Williams
Article Citation and PDF Link
BJMP 2015;8(2):a815
Abstract / Summary
Abstract: 

Phytochemicals are compounds found in plants, which are responsible for the colour, taste and aroma of foods. Over and above these pleasant attributes, they protect us from environmental and ingested carcinogens by arming our antioxidant enzymes, enhancing DNA repair pathways and have direct effects on the fundamental hallmarks of cancer progression and metastasis. It is not a surprise then that analysis from the World Cancer Research Fund and other academic bodies, report that individuals eating phytochemical-rich foods have a lower risk of cancer or relapse after treatments.  The debate lies in whether concentrating these foods, or elements of these foods, into nutritional supplements may boost their health attributes. One notable randomised controlled trial (RCT) has demonstrated benefits for men with prostate cancer, but other trials of extracted chemicals have shown no benefit or even an increased cancer risk. This article provides a clinical overview, for medical practitioners, of the major classes of phytochemicals with examples of their common food sources. It reviews the international evidence for their anti-cancer mechanisms of action and their clinical benefits, as well as discussing the pros and cons of concentrating them into nutritional supplements. 

Keywords: 
Cancer, diet, phytochemicals, polyphenols

Introduction

Phytochemicals, are not regarded as essential nutrients in humans although an increasing number of well-conducted studies are linking higher intake with a lower risk of developing cancer, as well as lower relapse after initial treatment completion 1,2,3. There is a wide range of dietary phytochemicals, but one of the largest and well-known groups being the polyphenols [Table.1]. The average total dietary intake of polyphenols is reported to be over 1g per day, which is up to ten times higher than that of all other classes of phytochemicals and known dietary antioxidants4. The health benefits of phytochemical rich foods or concentrated nutritional supplements are often being highlighted in the medical and popular media and hence they are an increasing topic of conversation between medical practitioners and their patients especially those with cancer who have a particular interest in over the counter self help strategies 5,6. This article provides an overview of the major classes of phytochemicals with examples of their common food sources. It highlights the international evidence for their anti-cancer mechanisms of action, their clinical benefits, as well as discuss the pros and cons of concentrating them and, into nutritional supplements in an attempt to harness and boost their health benefits. Hopefully this review will provide some useful learning points to aid communication between patients and clinicians [Table. 2].

Classification

There are three major groups of phytochemicals: the polyphenols which can be subcategorized as the flavonoids, phenolic acids and other non-flavonoid polyphenols; the terpenoids, which can be subcategorized as the carotenoids and non-carotenoid terpenoids; and the thiols, which includes the glucosinolates, allylic sulfides and non-sulphur containing indoles (Table. 1). There are other phytochemical group, which although have some properties within these groups, have been classified within a miscellaneous category and examples of these include the betaines, chlorophylls and capsaicin.

Table.1 Classification of phytochemicals with notable food rich sources

Polyphenols

1. Flavonoids

o Flavonols:quercetin, kaempferol (onions, kale, leeks, broccoli, buckwheat, red grapes, tea, apples)

o Flavones: apigenin, luteolin (celery, herbs, parsley, chamomile, rooibos tea, capsicum pepper)

o Isoflavones: genistein, daidzein, glycitein (soya, beans, chick peas, alfalfa, peanuts)

o Flavanones: naringenin, hesperitin (citrus fruit)

o Anthocyanidins (red grapes, blueberries, cherries, strawberries, blackberries, raspberries, tea)

o Flavan-3-ols (tannins): catechins, epicatechin, epigallocatechin gallate (tea, chocolate, grapes)

o Flavanolols: silymarin, silibinin, aromadedrin (milk thistle, red onions)

o Dihydrochalcones: phloridzin, aspalathin (apples, rooibos tea)

2. Phenolic acids

o Hydrobenzoic acids: gallic acid, ellagic acid, vanillic acid (rhubarb, grape seed, raspberries, blackberries, pomegranate, vanilla, tea)

o Hydroxycinnamic acids: ferulic acid, P-coumaric acid, caffeic acid, sinapic acid (wheat bran, cinnamon, coffee, kiwi fruit, plums, blueberries)

3. Other non-flavonoid polyphenols

o Other tannins (cereals, fruits, berries, beans, nuts, wine, cocoa)

o Curcuminoids: curcumin (turmeric)

o Stilbenes: cinnamic acid, resveratrol (grapes, wine, blueberries, peanuts, raspberries)

o Lignans: secoisolariciresinol, enterolactone, sesamin (grains, flaxseed, sesame seeds)

Terpenoids

1. Carotenoid terpenoids

o Alpha, beta and gamma carotene (sweet potato, carrots, pumpkin, kale)

o Lutein (corn, eggs, kale, spinach, red pepper, pumpkin, oranges, rhubarb, plum, mango, papaya)

o Zeaxanthin (corn, eggs, kale, spinach, red pepper, pumpkin, oranges)

o Lycopene (tomatoes watermelon, pink grapefruit, guava, papaya)

o Astaxanthin (salmon, shrimp, krill, crab)

2. Non-carotenoid terpenoids

o Saponins (chickpeas, soya beans)

o Limonene (the rind of citrus fruits)

o Perillyl Alcohol (cherries, caraway seeds, mint)

o Phytosterols: natural cholesterols, siosterol, stigmasterol, campesterol (vegetable oils, cereal grains, nuts, shoots, seeds and their oils, whole grains, legumes)

o Ursolic acid (apples, cranberries, prunes, peppermint, oregano, thyme)

o Ginkgolide and bilobalide (Ginkgo biloba)

Thiols

o Glucosinolates: isothiocyanates (sulforaphane) and dithiolthiones (cruciferous vegetables such as broccoli, asparagus, brussel sprouts, cauliflower, horseradish, radish and mustard)

o Allylic sulfides: allicin and S-allyl cysteine (garlic, leeks, onions)

o Indoles: Indole-3-carbinol (broccoli, Brussel sprouts)

Other phytochemicals

o Betaines found in beetroot

o Chlorophylls found in green leafy vegetables

o Capsaicin found in chilli

o Peperine in black peppers

Table. 2 learning points

Higher intake of phytochemical-rich foods such as colourful fruit, vegetables, herbs, pulses, spices and teas is associated with a lower risk of cancer and relapse after treatments.

Their anti-oxidant properties help to protect our DNA from ingested or environmental carcinogens.

Phytochemicals, particularly polyphenols have direct anti-cancer mechanism of action via inflammation, modulation of cellular and signalling events involved in growth, invasion and metastasis.

Concentrating element of foods such as minerals, vitamins and phytoestrogenic polyphenols to potentially boost their health effects have largely been unsuccessful in preventing cancer in clinical trials.

Whole food phytochemical-rich supplements have demonstrated significant benefits in phase II and well conducted RCT and their true potential is been evaluated in ongoing studies.

Clinical evidence for cancer prevention.

Although not all, many studies have linked a higher intake of phytochemical-rich foods, such as vegetables, fruit, legumes, nuts, herbs and spices, with a lower incidence of cancer as highlighted in the latest comprehensive review from the World Cancer Research Fund and other systemic reviews2,3.

More specifically, certain elements of food have been addressed within a number of cohort studies. Carotenoids found in leafy green vegetables and carrots have been linked with a lower risk of breast cancer in a recent meta-analysis demonstrated7 and a lower risk of ovarian and pancreatic cancers, especially among smokers in either questionnaire or serum-based studies8, 9, 10. Higher intake of cruciferous vegetables such as cabbage, cauliflower, Brussel sprouts, radishes and broccoli have been associated with a lower prostate cancer risk11, as have foods rich in isoflavones such as pulses and soy products12, lycopene rich colourful fruits and tomatoes13. Foods with abundant levels of flavonoids such as onions, rich in quercetin, have been shown to reduce the incidence of numerous cancers particularly those arising from the lung, especially amoung smokers14, 15. The anthoxanthins, in dark chocolate, have been reported to lower the risk of colon cancer16 and higher green tea intake lowers the risk of breast, prostate, ovarian and oesophageal cancer, again particularly among smokers and alcoholics17, 18. Finally, coffee consumption has been shown to reduce the risk of non-melanomatous skin cancers and melanoma, even after removing other factors such as ultraviolet radiation exposure, body mass index, age, sex, physical activity, alcohol intake and smoking history19,20.

Clinical evidence for a benefit after cancer

The benefits of healthy foods do not stop after a diagnosis, especially if combined with other healthy lifestyle habits. For example, breast cancer survivors who regularly consumed more than the government recommended five portions of fruit and vegetables a day, had a third lower breast cancer recurrence risk if combined with regular physical activity21. In another study, women with breast cancer who had the highest serum lignan levels, reflecting good intake of legumes, cereals, cruciferous vegetables and soya, were reported to have the lowest risk of death22. Likewise, a lignan and polyphenol rich diet was associated with a lower colorectal cancer relapse rate23.

The large Shanghai Breast Cancer Survival Study demonstrated that women with the highest intake of the phytoestrogenic polyphenols isoflavones and flavanone found in soya and other beans, had a 29% lower risk of relapse and death24. Similar findings were seen for green tea after breast25 and colorectal cancer23. Green tea also decreased the abnormal white cell count in 30% of patients with chronic leukaemia and reduced the levels of several markers of proliferation, as well as serum Prostate Specific Antigen (PSA) among men with prostate cancer26. A slowing of PSA progression has similarly been observed in other dietary studies, most notably the randomised trial involving a plant-based diet together with other lifestyle changes27 and a phase II study of pomegranate juice28.

Another cancer influenced by nutrition is skin cancer, as highlighted by a study of individuals who have been treated for basal cell carcinoma or squamous cell carcinoma, and who have a high risk of further lesions due to their on-going solar damage. Those who consumed the highest levels of lutein and zeaxanthin-rich foods, such as leafy green vegetables, had the lowest levels of new cancer formation29.

A number of other studies evaluating the impact of phytochemicals are underway, the largest and probably most comprehensive is the UK’s DietCompLyf prospective trial involving 3159 women treated for breast cancer30.

What are the likely anti-cancer mechanisms of phytochemicals?

The precise biochemical mechanisms through which phytochemicals exert their anti-cancer effects are still being explored, as their actions are wide-ranging and complex but significant advances have been made of late in the understanding the mode of action. The most quoted cancer prevention mechanism is via their antioxidant activity, elicited either through direct free radical absorption or through induction of antioxidant enzymes such as superoxide dismutase (SOD), catalase and glutathione via a variety of molecular mechanisms31, 32. One of these mechanisms is activation of Nrf2, which switches on genes that code for antioxidant as well as detoxification enzymes31, 32. Phytochemicals, particularly the thiol class such as sulforaphane,have also been shown to inhibit the conver­sion of procarcinogens to their electrophilic, DNA damaging, chemicals32,33.

A number studies involving known, common carcinogens have highlighted the antioxidant properties of phytochemicals. A good example of their protective effect was an experiment involving the known house-hold carcinogen triclocarban, commonly found in detergents and cleaning agents. Healthy cells exposed to triclocarban tend to mutate into pre-malignant cells, however, the amount and rate of carcinogenesiswas significantly reduced byadding curcumin to the petri dish culture feeds34. In another study, volunteers who ate a diet rich in kaempferol were found, on serum and urine analysis, to have improved SOD activity and higher urinary concentration of these polyphenols35. Rats exposed to cigarette smoke given indole-3-carbinol, a phytochemical rich in cruciferous vegetables, had a lower lung cancer rate than those not given idole-3-carbinol36. Subjects eating a meal of onions, which increased their serum levels of quercetin, demonstrated decreased levels of oxidative metabolites including 8-hydroxydeoxyguanosine (8-OHdG) a marker of DNA damage and repair1618, 37. Quercetin supplementation has also been shown to improving mitochondrial dysfunctions induced by the toxin 3-nitropropionic acid38. A clinical study in Singapore gave Chinese smokers 170g of watercress a day, rich in the indole-3-carbinol, and found a similar effect on urinary markers of DNA damage39. Finally, marinating meat in rosemary and thyme, has been reported to reduced the serum levels of carcinogenic heterocyclic amines (HCA) by 87% compared to subjects who eat the meat unseasoned40.

Another key anti-cancer mechanism of phytochemicals appears to be their ability to reduce inflammation. It is now well established that inappropriate inflammation is intimately involved in the cancer process, particularly in the promotion and progression stages of cancer. Inflammation is closely associated with oxidative stress and activation of NF-kappa B family of transcription fac­tors. These factors regulate more than 150 genes involved in mechanisms of cell survival and these target genes are not just pro-inflammatory but also oncogenic. Numerous phytochemicals have been shown to inhibit NF-kappa B signalling, particularly the green tea polyphenol epigallocatechin-3-gallate (EGCG), quercetin, curcumin, caffeic acid and caffeic acid phenethyl ester and the phytochemicals within bilberries31,41.

More recently, it has been reported mainly from laboratory studies that phytochemicals have an affect on several cancer process through modulation of cellular and signalling events involved in growth, invasion and metastasis32. Pomegranate, for example, rich in the polyphenol ellagic acid, has been shown to directly inhibit cell growth and induce apoptosis in androgen sensitive and aggressive human prostate cancer cells42. Pomegranate extract has also been reported to inhibit processes involved in cancer metastasis in a study involving oestrogen sensitive and resistant breast cancer cell lines, showing increased markers of cell adhesion and migration in cancer but not normal cells43. In another study it inhibited a chemokine that attracts breast cancer cells to the bone44. Curcumin slows cancer cell growth by blocking the cell cycle, increasing the rate of apoptosis and preventing the invasion and migration of cells45, 46, 47, 48. It has also been found to halt the growth of stem cells that give rise to breast cancer without harming normal breast stem cells49. Curcumin has been shown to modulate miRNA expression in breast cancer cells leading to a reduced expression of Bcl-250 and stabilisation of tumour suppressor gene in colorectal cancer cell lines52. Green tea, rich in epigallocatechin gallate (EGCG), has demonstrated significant reduction of several factors that promote cancer cell proliferation by inhibiting DNA synthesis, de-differentiation and angiogenesis26, 52, 53. It has also been shown to block ornithine decarboxylase, an enzyme which signals cells to proliferate faster and bypass apoptosis50, 54. Resveratrol has demonstrated epigenetic regulatory properties which influence regulate proliferation, cell survival and apoptosis in prostate cancer by global modulation of gene expression through deacetylation of FOXO transcription factor46. Caffeic acid and phenethyl ester, as well as inhibiting NF-κB signaling, also have been shown to inhibit cell motility in vitro and inhibit metastasis of tumour models in vivo47. Luteolin, as well as inhibiting tumour growth and metastasis, inhibits epithelial mesenchymal transition which is a basic biological process related to cancer initiation and development47.

Finally some polyphenols and other phytochemicals are also able to influence cancer via a hormonal mechanism. Phytoestrogenic compounds, most notably isoflavones and lignans found in soy products, legumes and some cruciferous vegetables, weakly bind to the oestrogen receptor without stimulating proliferation of the cells, yet at the same time blocking the binding of more harmful oestrogens, including those produced endogenously39. This explains why in the previously mentioned Shanghai Breast Cancer Survival Study, women with the highest intake of isoflavones and flavanones-rich foods had a lower risk of death24. In men, phytoestrogenic compounds have been shown to affect 5 alpha reductase lowering endogenous testosterone levels. This may partly explain why men who eat phytoestrogenic foods such as beans and pulses have a lower risk of prostate cancer.

Can concentrating foods into supplements enhance their anti-cancer effect?

If certain foods have anti-cancer effects, then it is not unreasonable to hypothesise that concentrating them into a pill may be a good way to supplement individuals with poor diets or further enhance the benefits in those whoes diets are already adequate. People living with and beyond cancer (PLWBC) are certainly attracted to the potential health benefits of food supplements, as over 65% report regular intake5,6. There are two main categories of supplements commercially available: the first involves chemicals extracted from food, or made synthetically, such as minerals and vitamins; the second involves purifying and concentrating whole foods:

Vitamins and mineral supplements: The majority of studies, to date, have evaluated extracted chemicals such as vitamins and minerals. Some have shown a benefit. For example, a recent meta-analysis of studies reported that women who took supplements providing an average daily intake of vitamin C over 100mg had a reduced risk of breast cancer relapse57. The SU.VI.MAX study randomised French adults to a single daily capsule of ascorbic acid, vitamin E, beta carotene, selenium and zinc, or a placebo, and found no reduction in mortality or cancer-specific mortality overall58, although a further analysis in men found a reduction in the risk of prostate cancer. The authors postulated that this difference between the sexes was related to French men having a lower baseline micro-nutrient status59. A major trial of selenium and vitamin supplements in a poor region of China, demonstrated reduced risks of oesophageal cancer; at the time this population was known to have widespread micro-nutrient deficiencies60.

Unfortunately, most other studies of vitamin, minerals and other extracted nutrients have shown no benefit, or have actually shown an increased risk of cancer. For example, the CARET study found that beta carotene and retinol increased the risk of lung cancer61. The Health Professionals Follow-up study (HPFS) which followed the lifestyle habits of 51,529 male professionals for over 15 years found that men who took very high doses of zinc (>100mg/day), or took it for long durations were more than twice as likely to develop advanced prostate cancer compared with controls62. The randomised SELECT study demonstrated an increased prostate cancer incidence with vitamin E and selenium supplementation63. A further analysis of the HPFS found that of the 4,459 men who had developed prostate cancer, those who took selenium supplementation of ≥ 140 μg/d after diagnosis were associated with a 2.60-fold greater risk of prostate cancer mortality64.

The negative effects of vitamin E and beta carotene were once again demonstrated in the ATBC study which found them to increase lung cancer risk, although subsequent analysis showed that men with pre-intervention low plasma levels of beta-carotene had a lower prostate cancer risk following supplementation, and that those with high levels had a higher risk, particularly in smokers65. This u-shaped distribution of risk was also observed in the EPIC study where those with folate-deficient diets and those with the highest intake both had a higher risk of cancer66. These data have prompted organisation such as the National Cancer Institute to issue statements stating that long term vitamin and mineral supplements should ideally be given to correct a known deficiency67, which is rarely routinely detected unless individuals have self funded micro-nutrient analysis (cancernet.co.uk).

Whole food supplements: More recently academic attention has turned towards the evaluation of concentrated whole food supplements, particularly foods rich in polyphenols and other phytochemicals such as herbs, spices, green vegetables, teas and colourful fruits which have appeared to be beneficial in environmental cohort studies. Despite some initial encouragement from smaller evaluations, studies of extracted lycopene or genistein given on their own in more scientifically robust analyses have not demonstrate a benefit for either prostate cancer or benign prostatic hypertophy68, 69, 70 neither were there links with the reduction in the risks of breast cancer with regular intake5. Of more concern, a randomised study from Memorial Sloan Kettering reported that serum taken from women who had take very high dose soy supplementation (25.8 g twice a day) added to laboratory tumour cells caused them to proliferate faster (Increased K67 expression) and overexpress the tumorigenic growth factor receptor FGFR271. This supports the notion that phytoestrogen foods are healthy, but concentrating them into strong supplements is not recommended.

On the other hand, no study of non-phytoestrogenic foods supplements has shown any detrimental effects on cancer outcomes and some have beneficially influenced progression rates. For example, a study carried out at John Hopkins involving pomegranate seed extract, found that men taking the supplements had a reduction in PSA progression rate72. A study conducted at the Mayo Clinic found that green tea concentrate decreased the abnormal white cell count in 30% of patients with chronic leukaemia, and a small study from Louisiana University reported that green tea concentrate significantly reduced levels of several cancer-promoting growth factors as well as PSA levels in participants26. In the Vitamins and Lifestyle (VITAL) cohort study, a regular intake of grapeseed extract was shown to be linked with a lower risk of prostate cancer70, and another small RCT found that a dietary supplement containing isoflavones, plus other phytochemicals and anti-oxidants delayed PSA progression73. Interestingly one of the most popular supplements, Saw Palmetto, despite an effect in early small studies, showed no benefit for prostate cancer or benign prostatic hypertrophy in the largest randomised evaluation74. Likewise, another popular supplement, lycopene, despite similar suggestions from smaller non-randomised trials68, 69, demonstrated no benefits in a more robust evaluation.

So far, the largest trial analysing phytochemical-rich food extracts was the National Cancer Research Network adopted Pomi-T study75. This study combined four different food types (pomegranate, green tea, broccoli and turmeric) in order to provide a wide spectrum of synergistically acting nutrients, whilst at the same time avoiding over-consumption of one particular phytochemical. It involved two hundred men, with localised prostate cancer managed with active surveillance or watchful waiting experiencing a PSA relapse, following initial radical interventions.

The results, presented as an oral presentation at the American Society of Clinical Oncology Conference (ASCO), Chicago, showed a statistically significant, 63% reduction in the median PSA progression rate compared to placebo in both men on active surveillance and experiencing a PSA relapse post-treatment. A further analysis of MRI images, demonstrated the cancers size and growth patterns correlated with PSA changes, excluding the possibility that this was just a PSA rather than tumour effect75. It was well tolerated, apart from some mild loosening of the bowels in 10% of men, and there was no effect on testosterone levels. At 6 months, significantly more men opted to remain on surveillance rather than proceeding to expensive radiotherapy, surgery or medical castration which can cause unpleasant effects such as depression, hot flushes, weight gain, osteoporosis and erectile dysfunction75.

A number of other RCT’s involving whole food phytochemical-rich supplement have demonstrated benefits for some of the distressing symptoms common after cancer treatments, such as fatigue76 and urinary infections77. There are currently over ten, on-going studies registered with the National Institute of Health. In the UK, the Institute of Preventative Medicine has plans to include the Pomi-T supplement into the next national prostate cancer prevention study. This study will be recruiting men with a higher genetic risk of prostate cancer identified in the national RAPPER study, co-ordinated by the Institute of Cancer Research. Further trials are being designed involving men with prostate cancer already on androgen deprivation therapy and individuals with skin, colorectal and bladder cancer. In the meantime, a trial is passing through the regulatory process to investigate whether the natural anti-inflammatory properties of these ingredients could help joint pains after breast cancer.

Conclusion

There is increasingly convincing evidence to show that plant phytochemicals, particularly polyphenols have significant benefits for humans. Not only do they improve our daily lives by helping our food taste, smell and look appetising, they also reduce our risk of cancer and help people living with and beyond treatments. Living well programmes, slowly being introduced in the UK, are beginning to highlight the importance of phytochemical-rich diets, along side other lifestyle factors, largely being driving by the National Survivorship Initiative and guidelines from influential organisations such as ASCO. Going a step further and concentrating these foods, or extracted elements of these foods, into nutritional supplements gives an opportunity to boost their beneficial anti-cancer effects, but have their pitfalls. Studies of concentrated minerals, vitamins and phytoestrogenic supplements have reported detrimental effects. No study has reported detrimental effects of whole, non-phytoestrogenic food supplements and some have reported significant advantages. Despite these potential benefits and reports that over 60% of patients living with and beyond cancer take nutritional supplements, oncologists have been reluctant to discuss their pros and cons due to a lack of RCTs from academic institutions55, 56. Hopefully this trend will change, particularly following the success of the Pomi-T study75 and ongoing studies registered with the National Cancer Institute.

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
None
Competing Interests: 
None declared
Details of Authors: 
ROBERT THOMAS, MRCP MD FRCR. Consultant Oncologist, Bedford & Addenbrooke’s Hospitals, Cambridge University NHS Trust c/o The Pimrose Oncology Unit, Bedford Hospital, Bedford, UK. ELIZABETH BUTLER, MSc Dip ION. Body Soul Nutrition, Level 2, 25 Petersham Road, Richmond, Surrey, UK. FABIO MACCHI, M.Sc. Head of Scientific & Clinical Development, Helsinn Healthcare S.A. PO Box 357 6915 Lugano/Pambio-Noranco, Switzerland. MADELEINE WILLIAMS, BA(Hons) PgDip. Research Manager, The Primrose Oncology Unit, Bedford Hospital, Bedford, UK.
Corresponding Author Details: 
ROBERT THOMAS, MRCP MD FRCR. Consultant Oncologist, Bedford & Addenbrooke’s Hospitals, Cambridge University NHS Trust c/o The Pimrose Oncology Unit, Bedford Hospital, Bedford, UK. MK42 9DJ.
Corresponding Author Email: 
rt@cancernet.co.uk
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Phenobarbital induced Pellagra

Authors
Youssef kort, Naziha Khamassi, Heykel Abdelhedi and Ouahida Cherif
Article Citation and PDF Link
BJMP 2015;8(2):a814
Abstract / Summary
Abstract: 

Background: Pellagra is a nutritional disorder due to an insufficiency in vitamin B3 also called vitamin PP for “pellagra preventing” vitamin. The disease was characterized by the “3D” consisting in dermatitis, dementia and diarrhea. The insufficiency can be due to drug use as anti epileptics. We describe a case of Phenobarbital-induced pellagra.
Observation: We report here a 61 years old woman who developed pellagra after a 45 years use of Phenobarbital. The diagnosis was suspected by the association of dermatological, neurological and gastro intestinal signs. It was confirmed by the good response to the niacin treatment and Phenobarbital discontinuation.
Conclusion: Pellagra should be considered in patients taking anti epileptic drugs because of its very good prognosis if treated and fatal issue if misdiagnosis.

Keywords: 
Pellagra, Phenobarbital, epilepsy

Introduction

Pellagra is a nutritional disorder due to an insufficiency in vitamin B3 also called vitamin PP (‘Pellagra preventing’). The disease was characterized by the following ‘3 D’s’: ‘Dermatitis’, ‘Dementia’ and ‘Diarrhoea’. When it is misdiagnosed, it can lead to the fourth ‘D’ which is ‘Death’.1 It was very common in past centuries, particularly in populations that had an exclusively maize diet. Nowadays, this diet problem is rare in developed countries, so the disease is less frequent. However, many recent studies suggest that the disease has not been eradicated and can be under-diagnosed. Alcohol, drugs and malabsorption seem to be the new aetiologies of the disease. So, it is important to recognize the ‘3 D’s’ triad in such situations to avoid fatalities.

Observation

A 61-year-old patient presented to the Internal Medicine Department with an 8-month history of deterioration in her general state. She had a medical history of Epilepsy treated by Phenobarbital since she was 16.

Review of systems revealed gastrointestinal symptomatology consisting of intermittent diarrhoea (6-7 watery stools a day without blood), dysphagia and diffuse abdominal pain. The patient also reported a skin photosensitive eruption affecting her hands and feet.

Physical examination showed a listless patient with a low Body Mass Index (17 kg/m²).

On dermatological examination, symmetric, well-defined, brown-coloured and scaly eruption was observed on the dorsa of her feet (Picture 1) and hands (Picture 2). The mucous examination showed a commissural Cheilitis and Glossitis.


Picture 1:
Brown well-defined patches on feet.


Picture 2:
Brown pigmentation and scales of hands.


Picture 3:
Hands aspect after treatment.

The nervous system examination revealed a pyramidal and cerebellar syndrome. The response to neurocognitive tests was altered suggesting Dementia.

The rest of physical examination was normal. In particular, there were neither peripheral lymph nodes, nor spleen or liver enlargements, nor abdominal mass.

The laboratory tests (glucose, calcaemia, creatinine, liver function tests, urine analysis, haemoglobin, hematocrit, sedimentation rate, C-reactive protein and protein electrophoresis) were within normal limits.

Oesogastroduodenal endoscopy was normal. The cranial, thoracic and abdominal CT scans were normal.

The diagnosis of Pellagra was made on dermatological, abdominal and neurological signs. The patient was treated by Niacin (1000 mg/day) and multivitamin complex. Phenobarbital was discontinued and switched to Clobazam. The patient’s symptoms started to improve quickly. Ten days after the treatment began the skin lesions (Picture 3) and gastrointestinal signs completely disappeared.

Discussion

Pellagra was diagnosed clinically in our patient based on the skin aspects. The skin lesions have been described since 1771 by Frapolli whose name was given to the disease: Pellagra which means rough skin in Italian.1 The typical lesions consist of a brown pigmentation and scales with a photosensitive distribution and well-defined borders as seen in our patient. The face, the neck and the dorsa of the hands are the preferential locations.2 The skin lesions are not always found, and cases of Pellagra Sine Pellagra have been described.3 The extra-cutaneous manifestations are less specific, but their association with pellagrous skin lesions are sufficient to reach a diagnosis. The neurological involvement is classically a Dementia syndrome, but ‘Pellagrous Encephalopathy’ can also consist of delirium, insomnia, depression, cerebellar and extrapyramidal syndrome.4 The gastrointestinal signs are non-specific; they can be Glossitis, dysphagia, nausea, vomiting and abdominal pain. An intractable diarrhoea may occur in advanced stages of disease and can quickly lead to death.5

In 1929, Goldberger attributed such clinical manifestations to a Niacin (vitamin B3 or PP) deficiency. Niacin is a precursor for two important coenzymes namely ‘Nicotinamide Adenine Dinucleotide (NAD)’ and ‘NAD-Phosphate’ which are essential for many oxidative reactions. This probably explains why Pellagra affects tissues with a high rate of cell turnover such as the skin and digestive tract.4

Niacin can be directly absorbed by the gastrointestinal tract or synthesized from Tryptophan.

Primary Pellagra occurs when the diet is deficient in Niacin or Tryptophan as in poor populations with an exclusive maize diet (which contain Niacin but in an indigestible form).

Despite sufficient dietary Niacin, Secondary Pellagra may be caused by a problem in Niacin absorption or metabolism. Many causes of Secondary Pellagra were identified as alcohol, intestinal malabsorption, carcinoid tumours, Hartnup’s Syndrome, Anorexia Nervosa and drugs (Table 1).5 Our patient did not consume alcohol and had no biological signs of malabsorption, but she was taking Phenobarbital for about 45 years. In the English literature, we found only two cases of Phenobarbital-induced Pellagra, and with a fatality in one case.6, 7 The underlying mechanism of Pellagra caused by Phenobarbital, or other antiepileptic drugs, is an alteration in Niacinamide synthesis due to an enzymatic induction.5

Table 1: List of drugs predisposing to Pellagra.

Predisposing Drugs
Antituberculosis agents:
Isoniazid
Pyrazinamide
Antiepileptic drugs:
Hydantoins
Ethionamide
Phenobarbital
Diazepam
Chemotherapy and immunosuppressive drugs
6-Mercaptopurine
5-Fluorouracil
Chlorambucil
Azathioprine
Chloramphenicol

The treatment is first based on correction of predisposing factors. In our patient, it consisted of using another antiepileptic drug instead of Phenobarbital. Second-line treatment is a vitamin therapy based on Niacin. There is no consensus on the doses, form and duration of the treatment, but the minimal dose is 300 mg of Niacin/day. A multivitamin complex containing other B-vitamins is often necessary because of the frequency of other deficits in such patients.2 With treatment, the skin lesions and gastrointestinal symptoms generally disappear within a few hours or days, as in the case of our patient, and it is a good argument for a retrospective diagnosis of pellagra.1 Testing for Niacin levels or urinary metabolites is not frequently available and it’s not necessary for the diagnosis.

Conclusion

We described a typical case of Pellagra in which the ‘3 D’s’ were present. In such a case, we should begin the treatment before the results of the laboratory investigations are known. The improvement of all symptoms within a few days is sufficient to confirm the diagnosis. However, the ‘3 D’s’ triad is not always present, and the clinician should consider the diagnosis in face of unexplained abdominal or neurological signs in certain patient groups.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
YOUSSEF KORT, Internal Medicine, Razi hospital, cité les orangers 2010, Tunis, Tunisia. NAZIHA KHAMMASSI, Internal Medicine, Razi hospital, cité les orangers 2010, Tunis, Tunisia. HEYKEL ABDELHEDI, Internal Medicine, Razi hospital, cité les orangers 2010, Tunis, Tunisia. OUAHIDA CHERIF, Internal Medicine, Razi hospital, cité les orangers 2010, Tunis, Tunisia.
Corresponding Author Details: 
YOUSSEF KORT, Razi hospital, cité les orangers 2010, Tunis, Tunisia.
Corresponding Author Email: 
y_kort@yahoo.fr
References
References: 
  1.  Sayyidou S. Pellagra: a non-eradicated old disease. Clin Pract. 2014; 28; 4(1): 637.
  2. Pitche PT. Pellagra. Sante. 2005; 15(3): 205-208.
  3. Ishii N, Nishihara Y. Pellagra among chronic alcoholics: Clinical and pathological study of 20 necropsy cases. Journal of Neurology Neurosurgery and Psychiatry. 1981; 44(3): 209-215.
  4. Oldham MA, Ivkovic A. Pellagrous encephalopathy presenting as alcohol withdrawal delirium: a case series and literature review. Addict Sci Clin Pract. 2012; 7: 12.
  5. Piqué-Duran E, Pérez-Cejudo JA, Cameselle D, Palacios-Llopis S, García-Vázquez O. Pellagra: A clinical, histolopathological and epidemiological study of 7 cases. Actas Dermosifiliogr. 2012; 103: 51-58.
  6. Stadler R, Orfanos CE, Immel C. Drug induced pellagra. Hautarzt. 33(5): 276-280.
  7. Pancar Yuksel E, Sen S, Aydin F and al. Phenobarbital-induced pellagra resulted in death. Cutan Ocul Toxicol. 2014; 33(1): 76-78. 

“The Culture palette”- a randomized intervention study for women with burnout symptoms in Sweden.

Authors
Christina Grape Viding, Walter Osika, Töres Theorell, Jan Kowalski, Johan Hallqvist and Eva Bojner Horwitz
Article Citation and PDF Link
BJMP 2015;8(2):a813
Abstract / Summary
Abstract: 

Burnout is common among women in Sweden. Cultural activities, i.e. arts, have benefitted different patient populations and may have potential for treating this group as well. 
Aim: To evaluate possible health effects of regular cultural activities for women with burnout symptoms with focus on exhaustion level.
Methods: 48 women (mean age 54) were randomly assigned either to a cultural activity group (intervention group) or to a control group. Four health care centers were the settings for a “Culture Palette” comprised of six different cultural activity packages: interactive theater, movie, vocal improvisation and drawing, dance, mindfulness training and musical show. The activity packages were offered once a week over a period of three months. Standardized questionnaires; the Karolinska Exhaustion Disorder Scale ( KEDS), Sense of Coherence (SOC), Toronto Alexithymia Scale (TAS)  and Self-rated health  were used at baseline, in month three and at follow-up in month six. Qualitative interviews with patients, cultural producers and health care staff were conducted at month three and month six.
Results: Burnout symptoms/exhaustion (P< .001) and alexithymia (P=0.007) as well as self-rated health (P<0.001) improved more in the intervention group than in the control group with clinically relevant effect variances. There was no statistical evidence of any difference in the development of SOC between the intervention and the control group. The healthcare staff were also positively affected although they did not participate in the cultural activities. Conclusion: Regular cultural activities affected this group of women beneficially with enhanced health and decreased levels of exhaustion.  

Keywords: 
arts, burnout, cultural activities, exhaustion symptoms, health care centers, self-rated health, women.

Introduction

Population studies in Norway are showing that taking part of (creative) or receiving (receptive) cultural activities, i.e. arts, is associated with good health and good satisfaction with life among other things,1. Cultural activities have the potential to affect individuals beneficially: physiologically, biologically and emotionally, and several studies show that cultural activities can stimulate emotions and behaviors that make life easier, 2–5. Cultural activities can enrich and enhance our memory, stimulate connections among brain networks and enable us to accelerate learning and differentiate feelings of meaning and context,6,7 Cultural activities have also improved both physical health, social function and vitality among health care staff,8.

In an analysis of data from a large longitudinal cohort-study of a working population (called the SLOSH study = Swedish longitudinal occupational survey of health), some interesting associations were revealed between access to cultural activities in the workplace and health. Participants reporting many cultural activities at work had a more favorable improvement of emotional exhaustion during a follow-up period of two years than those whose workplaces did not offer these amenities,9. Other studies in which cultural activities have been offered to patients on long-term sick leave confirm that cultural activities have beneficial effects on both self-confidence and pain,10,11.

In a new approach, an artistic leadership program, called “Shibboleth”, affects not only managers included in the study, but also their employees (who did not participate in the artistic program). This one year art-based program showed statistically significantly more improvement of mental health, covert coping and performance-based self-esteem than the comparison group (who participated in an ordinary leadership program). They also experienced less winter/fall deterioration in the serum concentration of DHEA-S (dehydroepiandrostereone-sulfate), a regenerative/anabolic hormone,12.

Studies on singers, both amateur and professional singers and choir singers, show positive effects on different biological markers such as oxytocin and testosterone,13–15. On the basis of results from another Swedish project, ”Prescribed Culture”, which aimed to evaluate the effects of prescribed cultural experiences in the treatment of patients on long term sick leave, it was claimed that cultural experiences have their best effects when used in health promotion and prevention , rather than when the individual is already sick,16. Multimodal stimulation seems to have particularly strong effects. For instance, concomitant visual and auditory stimulation gives rise to stronger activation of “visual” and “auditory” parts of the brain than separate visual and auditory stimulation,17.

A mixture of different cultural activities seems to optimize influence on the limbic system since a broader emotional perception is activated,7. Cultural activities offered to participants that would not have chosen them spontaneously, could enhance already existing pathways in the brain enabling deeper cognitive behavioral change,17–20.

Despite this knowledge regarding the potential benefit of cultural activities in different contexts on both individuals and groups there is still a missing accessible practical functioning link between producers of culture and different groups of practitioners within health-care.

Burnout is characterized by emotional exhaustion, detachment from work and decreased effectiveness at work. This can develop in situations with excessive workload and insufficient resources as well as lack of control and support,21. If the process of burnout is a reaction to long-term stress, without enough recovery, this can lead to the more severe exhaustion syndrome,22. Symptoms include fatigue, impaired emotional regulation, cognitive problems and sleeping disorders. Most of these patients have an increased sensitivity for stress even after recovery,22. In recent years, Swedish rates of sick leave due to minor psychiatric morbidity , and burnout symptoms, have increased dramatically,23-24 . Complaints usually include physical, emotional and cognitive exhaustion, which in most cases appear to be related to chronic stress without restitution,25–28. Today many women in Sweden have stress related symptoms, and some are diagnosed with exhaustion syndrome. If these women are detected at an early stage, the prognosis is good,22.

Alexithymia, (the difficulty to differentiate your own and others feelings), can be a silent but severe problem for persons suffering from this personality trait. Grabe et al.,29 conducted a study in which the questionnaire TAS-20 was used for the assessment of alexithymia. Medical examination was also performed. In this study alexithymia was related to hypertension and arteriosclerotic plaques. Alexithymic personality traits may increase the risk for CVD (cardio vascular disease).

The rationale behind choosing symptoms of exhaustion, SOC and alexithymia as main outcome variables was the intention to examine whether cultural activities in this form can change pattern of thought, feelings and behavior in participants with burnout symptoms. If cultural activities prove effective for this participant group, they could have considerable benefits both financially in terms of reducing sick leave and health care consumption and of reduced individual suffering.

Aim

The aim of the study was to assess to what extent symptoms of exhaustion, sense of coherence, alexithymia and self-rated health among women with burnout symptoms can be beneficially influenced by cultural activities organized in health care centers.

Method

Participants

Four health care centers in Stockholm County hosted the cultural activities. Medical doctors and social workers distributed information about the study to women diagnosed with exhaustion disorder or exhaustion symptoms. Women, native and foreign born, with burnout/exhaustion symptoms (fatigue syndrome or stress-related fatigue) who were curious about new clinical approaches were asked by the doctor to participate in the study and screened for inclusion and exclusion criteria. Participants (women age > 18) with burnout/exhaustion symptoms such as strong fatigue, cognitive problems, and sleep disturbances were enrolled. There was an inclusion criterion with a score above 2 on the KEDS scale. The diagnosis was made by the doctor.

Exclusion criteria: Participants with difficulty in speaking and understanding Swedish, participants with alcohol or drug abuse problems, or/and participants with severe depression or psychiatric borderline. Also excluded were participants with severe somatic diseases (such as serious angina pectoris or participants who had had a stroke). Randomization was done using a 3:1 allocation to intervention or control groups.

The randomization was done using a stratified randomization by center. Randomization was done by the statistician. The group allocations were sent in individual envelopes which were distributed to centers and blinded to the site staff. Envelopes were further drawn in a consecutive order with regard to recruitment of subjects at each of the four health care centers. Thirty-six participants were allocated to the intervention group (nine patients in each group) and twelve participants to the control group. The standard care that each participant received included physiotherapy such as relaxation and physical light training.

All randomized participants gave their written consent to participation in the study. Data were collected over a period of 6 months. The project includes evaluation of six different culture activities. In the selection of the health care centers socio- economic diversity and employment status were considered. We used regularly occurring structured cultural activities in cooperation with culture producers, i.e. actors, musicians, dance teachers. The Regional Research Ethics Committee of Uppsala has approved the study (Dnr. 2012/359).

The culture palette: six different cultural packages

The following cultural activities were included in the study; five of them have previously been presented in the literature with good evidence on other groups of patients. One package (the musical show), which has not been presented previously on groups of patients, was chosen as it represents a combination of different modalities of activities at the same time. The active mechanism of all six cultural activities was to stimulate different modalities of the senses such as the visual, motor, verbal, auditory, emotional and sensational, according to Downing’s levels of perception, 30. All participants were offered six cultural packages:

1. Interactive theater: An experienced actor introduced poetical lyrics and poems and then initiated and participated in discussions with the participants regarding thoughts, emotions, and experiences evoked by the texts.

2. Movie: After showing a movie, a film expert initiated discussions among the participants about experiences and thoughts evoked by the movie.

3. Vocal improvisation and drawing: After participating in a vocal improvisation session with an experienced performance artist and pianist, the participants painted a picture representing emotions, thoughts and pictures evoked during the improvisation

4. Exploring Dance: The participants improvised dance movements under the guidance of a dance movement pedagogue/music teacher. The dance movements were staged according to the situation in the room and with focus on bodily awareness. Afterwards the group discussed their experiences during the dance session.

5. Mindfulness and contemplation: The participants contemplated and practiced mindfulness together with an experienced mindfulness instructor. Attention was on breathing and body awareness. Thoughts, feelings, images and sensations were in focus and experiences were reflected in the group after the contemplation.

6. Musical show: after a musical show including music, song and dance focusing on bodily awareness, the participants discussed thoughts regarding the body with the actor.

Every session in each one of the six different cultural packages lasted for 90 minutes.

Evaluations

Three different standardized scales, and also self-rated health and self-figure drawing, were used.

KEDS - Karolinska Exhaustion Disorder Scale,31. Questions about concentration, memory, physical fatigue, endurance, recovery, sleep, hypersensitivity to sensory input, experience requirements and irritation and anger. Higher scores indicate worse disease activity/performance.

SOC - Sense of coherence,32. A key factor in being able to feel well-being and health. This factor has been shown to be crucial to helping individuals mobilize their self-healing systems. Higher scores indicate better performance.

TAS - Toronto Alexithymia Scale,33. Estimation of ability to recognize and interpret feelings in oneself and others. TAS contains three subscales; the inability to handle emotions due to emotions being poorly recognized (difficulty recognizing), the inability to describe feelings (difficulty describing), and mismatch between coping behavioral emotions (externally oriented thinking). This study used the full scale score, i.e. the summary of the three sub scores. Higher scores indicate worse performance.

Self-rated health (SRH) consists of a single item measure.

Procedures/implementation

The four different health care centers presented each activity on two consecutive occasions. After two weeks of one program, there was a new program on two consecutive occasions etc. Each participant has thus been offered 12 cultural packages during a three-month period, i.e. once a week. During the monitoring period between month 3 and month 6, there was no culture activity offered. The control group was monitored in parallel during the entire period monthly at 0, 3 and 6 months.

The participants evaluated the project individually with questionnaires prior to the sessions, after completion of the intervention at month 3, and at follow-up after 3 months i.e. month 6 (both intervention and control group). In-depth interviews with both participants and producers of culture, i.e. representatives for the various cultural activities and health care staff were conducted during the monitoring period (this data is not presented in this article).

Data analysis

The primary outcome efficacy end point/measure was mean change from baseline to three and six months in the KEDS summary score. The secondary outcome measures were mean change from baseline in the SOC summary score, the TAS summary score and the self-rated health, from baseline to three to six months.

All data were presented using descriptive statistics, i.e. mean and standard deviation for continuous variables and frequency and percentage for categorical variables. For all main outcome variables, data were further analyzed using the Linear Mixed Models, including group (intervention and control) and time (baseline, 3 month and 6 months) as fixed factors. Results were presented as marginal means, the estimated mean value adjusted for the factors included in the analyses model. The difference between intervention and control group with regard to the estimated and adjusted means are defined as the effect size, i.e. the mean difference between the intervention groups for each of the primary and secondary outcomes measures divided by the standard deviation. All tests were two-tailed and p<0.05 was regarded as statistically significant.

IBM SPSS version 22 was used for statistical calculations. In the presentation of the results from the statistical analyses, the measured effect size was used and derived as the absolute difference between active intervention and controls with regard to each of the outcome variables/endpoints used,34.

Results

There were 55 participants screened in this study, however seven participants who met the exclusion criteria of too serious/severe depression was not included into the study. In total, there were 48 participants randomized into the study, age between 41 and 70 years, mean 53.8 (SD= 8.15).

The results showed that for KEDS (exhaustion) there was a statistically significant two-way interaction (P<0.001) with a decreased mean from baseline to three and six month respectively in the intervention group whereas in the control group there was no change. The mean treatment effect size, i.e. the mean difference between groups, in favor of the intervention group was 9.9 (SE=3.0) at 6 months. See table 1 and figure 1a.

There was no difference in mean SOC - Sense of Coherence – scores between the groups. See figure 1b. Further, the results revealed a statistically significantly more pronounced decrease in the intervention group compared to the control group in the alexithymia items of total score, (P=0.007, mean treatment effect size=5.4 (SE=2.2) at 6 months in favor of the intervention group), difficulty describing (P=0.004, 2.4 (0.9)), difficulty identifying (P=0.051, 2.6 (1.3)) but not for external orientation (P=0.334 0.5 (0.8)). See table 1 and figure 1c. There was also a statistically significant difference between the groups with regard to self-rated health (P<0.001) where mean scores increased over time in the intervention group but decreased in the control group. See figure 1d.

Table 1

KEDS (Karolinska Exhaustion Disorder Scale) and TAS (Toronto Alexithymia Scale) and SRH (self-rated health) at baseline, month 3 and month 6.

  Control Group (n=12)   Intervention Group (n=36)
Count Mean Standard Deviation Count Mean Standard Deviation
KEDS
Baseline 12 32.7 8.2 35 31.7 8.4
Month 3 12 34.9 9.2 34 23.6 8.6
Month 6 12 33.9 8.7 33 23.7 10.1
Sense of Coherence
Baseline 12 117.2 29.9 33 118.0 28.0
Month 3 12 112.8 30.3 33 121.1 30.5
Month 6 12 115.1 24.2 34 123.9 28.2
Difficulty Describing
Baseline 12 14.8 4.3 34 14.2 4.6
Month 3 12 15.3 3.6 31 12.7 4.6
Month 6 12 15.2 4.1 34 11.8 3.9
Difficulty Identifying
Baseline 12 20.0 6.0 34 20.3 6.3
Month 3 12 20.6 6.5 31 19.0 6.9
Month 6 12 20.0 6.1 34 17.4 5.0
Externally Oriented
Baseline 12 14.9 4.2 34 13.8 4.4
Month 3 12 15.4 4.3 31 13.9 3.9
Month 6 12 14.6 4.8 34 13.2 3.5
TAS
Baseline 12 49.7 13.1 34 48.3 13.4
Month 3 12 51.3 13.3 31 45.6 13.9
Month 6 12 49.8 13.9 34 42.4 10.8
Self-rated Health
Baseline 12 5.2 1.5 36 4.8 1.9
Month 3 12 4.6 1.9 36 6.0 1.9
Month 6 12 3.6 1.6 35 6.4 1.9

Figure 1a

Marginal means and 95 % confidence intervals for the KEDS (exhaustion) scale by group and time. Results were based on the linear mixed models analysis adjusted for baseline.

Figure 1b

Marginal means and 95 % confidence intervals for the sense of coherence (SOC) scale by group and time. Results were based on the linear mixed models analysis adjusted for baseline.

Figure 1c

Marginal means and 95 % confidence intervals for the Toronto Alexithymia Scale (TAS) by group and time. Results were based on the linear mixed models analysis adjusted for baseline.

Figure 1d

Marginal means and 95 % confidence intervals for the self-rated health scale (SRH) by group and time. Results were based on the linear mixed models analysis adjusted for baseline.

Discussion

The results show that the different exhaustion factors measured by means of KEDS (Karolinska Exhaustion Disorder Scale) decreased in the intervention group compared to the control group. With regard to the total score of TAS (Toronto Alexithymic Scale) there was a statistically significant decrease in the intervention group compared to the controls, i.e. the participants started to improve their differentiation of feelings and emotions after three months with cultural activities. The same pattern was seen with regard to self-rated health, which improved in the intervention group. However, there was no significant difference between the groups with regard to the development of sense of coherence.

It seems that the different cultural activities have helped the participants become more aware of their feelings and sensations; to describe and to identify feelings. It is not easy to explain the positive results based on one clear paradigm. It is likely a mixture of psychological, neurological and social factors or changes that interact in a complex manner.

Previous studies have discussed the theory of the emotional brain - cultural modalities can “surprise” the cognitive brain unconsciously. LeDoux,20 discusses the upper/slower and the lower/faster pathway in the brain. Emotionally loaded visual and auditory stimuli are transmitted on both types of pathways. Music impulses are for example evoking activities in the emotional brain much more rapidly than in the cognitive brain. However, impulses spread secondarily from the emotional to the cognitive brain. This can trigger the participants awareness of different emotions and may start a process of differentiation, possibly initiating a change of life course. By using different cultural activities, that the participants normally would not try, the differentiation process may be amplified. This suggests that cultural activities can surpass automated thinking and create new "pathways '' with changes in behavior and increased well-being.

In other studies we have observed that a mixture of different cultural activities can increase the amount of stimuli affecting a broader network of emotional correlates, 14,16,18 . A very interesting long-term decrease in alexithymia, 35 was associated with lowered blood pressure and a decrease in sick leave. By allowing the participants to try new cultural stimuli we may have helped the participants change old habits. A hypothesis is that this may also have contributed to the observed decrease in exhaustion.

Why did we not see any increase in the sense of coherence in the intervention group? It is very difficult to change patterns of thought and behavior although we can argue that the participants in the control group also found a new sense of coherence just by being invited to answer questions about themselves and being focused upon. Many of the participants did not go out spontaneously because of their fear of socializing. Some of them described their situation as black or white, not wanting to change routines that made them feel less safe,36.

Despite the fact that the health care staff did not participate in the culture palette, they were also affected by the cultural activities 36. This may be a mirroring effect, or emotional contagiousness on health care staff, which may also play a role between the participants and their staff. The passive cultural activation phenomenon has previously been presented in the literature,37 and there seem to be possible well-being effects of just watching dance or visiting a theatre, 6,10 which may explain the positive health care staff response to the culture palette. The results of this study underscore the importance of regarding the health care system as a whole, where patients, health care staff and visiting relatives affect each other. Empathic behaviors contaminate in all directions and we need to be aware of how we project ourselves when working in a caring context.

Modified “culture palettes” and “train the trainer” programs and workshops are now in use in Sweden, inspiring cultural producers to further develop the health care system and a cultural health box - a box with six different books about cultural activities and the research behind this - have been distributed to all health care centers in Sweden, 38.

Developing and adapting cultural programs to fit other kind of groups of participants could cross-fertilize health care thru culture production.

Limitations

This study was limited to women with exhaustion symptoms and therefore further research on implementation of cultural activities within different groups of participants and sexes is needed before we can generalize the results to other groups of participants. Another limitation is that we did not control for outside activities, such as doing walks in nature. In this study we only presented indoor cultural activities.

Conclusion

The cultural activities in this study made exhausted women understand what makes them vital, confirmed, curious, healthy and creative. The study also illustrated that there could be synergistic effects when bringing cultural activities into the health care system36.

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
The authors thank all participants, health care staff and cultural producers who made this study possible. The authors also thank the Postal Code lottery, Sweden, for sponsoring this project.
Competing Interests: 
None declared
Details of Authors: 
CHRISTINA GRAPE VIDING, RN, PHD stud., Dept. of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden. WALTER OSIKA, MD, PHD, Center for Social Sustainability, Dept. of Neurobiology, Care Sciences and Society, Karolinska Institutet and Dept. of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. TÖRES THEORELL, MD, PHD,PROF., Stress Research Institute, Stockholm University, Stockholm, Sweden. JAN KOWALSKI, Biostatistician, Dept. of Science, Intervention and Technology, Pediatric Unit, Karolinska Institutet, Stockholm, Sweden. JOHAN HALLQVIST, MD, PHD, PROF. Dept. of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden. EVA BOJNER HORWITZ, PHD, PHT, Dept. of Public Health and Caring Sciences, Uppsala University, Uppsala and Center for Social Sustainability, Dept. of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
Corresponding Author Details: 
CHRISTINA GRAPE VIDING, BMC, Husargatan 3, Box 564, SE-751 22 Uppsala, Sweden.
Corresponding Author Email: 
tina.grape.viding@pubcare.uu.se
References
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Familial dilated cardiomyopathy linked with hearing loss in brothers: case report

Authors
Jing Lin, Jianhong Tao, Guangre Xu and Li Cai
Article Citation and PDF Link
BJMP 2015;8(2):a812
Abstract / Summary
Abstract: 

Dilated cardiomyopathy (DCM) is the third leading cause of severe heart failure and the most common cause of heart transplantation. Many cases (25–30%) of DCM are familial, indicating a genetic contribution to the etiology. The diagnosis of Familial dilated cardiomyopathy (FDC) is clinically based on the clinical manifestation, with at least two affected members from the same family. More than 30 genes associated with FDC have been identified, but still theses explain only a minority of the etiology of FDC. Here we present a strange case of FDC accompanied by hearing loss and rapid progressive course. The manifestations of FDC in this family was really rare and it is anticipated that more susceptibility genes may be discovered.

Keywords: 
familial dilated cardiomyopathy; hearing loss; rapid progressive course

Introduction

Dilated cardiomyopathy (DCM) is a cardiac muscle disease, characterized by dilatation and impaired contraction of the left ventricle or both ventricles, and leads to progressive heart failure and sudden or heart failure-related death [1]. The life expectancy is limited and varies according to the underlying etiology with a median survival time of about 5 years after diagnosis [2]. Although the pathogenesis of this disease has been extensively studied for decades, it remains ambiguous. Currently, myocarditis, immunological abnormalities, toxic myocardial damage, and persistent cardio-tropic viral infection are all assumed to be causes of DCM [3]. Dilated cardiomyopathy occurring in families, or the familial dilated cardiomyopathy (FDC) may occur in 25% to 35% of DCM cases, implicating a genetic contribution to the etiology [4-7].  More than 30 susceptibility genes have been shown to be associated with an increased risk of developing a DCM. Here we report three strange cases of FDC accompanied by hearing loss and rapid progressive course in brothers from Sichuan Province of China. The presentation of the family was really rare and it is anticipated that more susceptibility genes may be discovered.

Case report

The patient was a boy from Sichuan Province, and had lost his hearing when he was five years old. At the age of eight, the boy presented with cough and acute onset breathlessness. On examination, he had blood pressure (BP) of 90/60mmHg, heart rate (HR) 105/min, raised jugular venous pressure (JVP), crackles over the lung bases and a pansystolic murmur at the apex. A huge cardiomegaly was seen on chest X-ray (CXR), and the cardiothoracic ratio (CT ratio) was 0.721. ECG revealed primary atrioventricular block and left ventricular hypertrophy (LVH). Echocardiography (Echo) showed enlargement of both ventricles of the heart, a decreased left ventricular ejection fraction (LVEF), and severe mitral regurgitation (MR). The patient was treated in line with congestive cardiac failure (CCF). However, he died three months after the acute onset of breathlessness.

Surprisingly, the progression was nearly the same as two of his older brothers. Both of them also lost hearings at the age of five. Then presented with acute onset breathlessness and they were diagnosed with DCM aged seven to eight years. They also died three months later after the acute onset of breathlessness. Because of the terrible experience of his older brothers, the boys’ parents took him to hospital every year to be examined. ECG and Echo images were normal 6 months before the onset of breathlessness. Moreover, the boy had no symptoms 1 month before his presentation.

Discussion

The definition of FDC is clinically based on manifestation with at least two affected members from the same family [5]. The most common mode of inheritance is the autosomal dominant type, while X-linked, autosomal recessive and mitochondrial forms are less common [8, 9]. Although most people affected die in early adulthood, the age of onset, rate of progression, disease complications, as well as overall prognosis and outcome vary within families [5, 10]. Nevertheless, the age of onsets in this family were similar and with a rapid progressive course. All of the sons in the family suffered from DCM as well as hearing loss. The manifestation of the brothers haven’t been reported before. We traced back three generations of this family finding no other affected members.  As all the patients were male, we speculated that the possible mode of inheritance in this family is X-linked. Regrettably, the parents had no daughters and we were not able to investigate the possible association between gender and FDC of this kind. Because of the rapid progressive course, we hypothesize that autoimmune abnormalities might be the pathogenic factors for this disease, but we do not have any solid evidence yet. Fortunately, we were able to get the blood samples from the patient and the relatives. Further studies are needed to explore new susceptibility genes as well as the molecular mechanisms that are involved in the disease.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
JING LIN, Department of Cardiology, Sichuan Academy of Medical Sciences &Sichuan Provincial People’s Hospital, Chengdu 610072, PR China. JIANHONG TAO, Department of Cardiology, Sichuan Academy of Medical Sciences &Sichuan Provincial People’s Hospital, Chengdu 610072, PR China. GUANGRE XU, Department of digestive internal medicine, Sichuan Academy of Medical Sciences &Sichuan Provincial People’s Hospital, Chengdu 610072, PR China. LI CAI, Department of Cardiology, Sichuan Academy of Medical Sciences &Sichuan Provincial People’s Hospital, Chengdu 610072, PR China.
Corresponding Author Details: 
LI CAI, Sichuan Academy of Medical Sciences &Sichuan Provincial People’s Hospital, Chengdu 610041, PR China.
Corresponding Author Email: 
582301352@qq.com
References
References: 
  1. Richardson P, McKenna W, Bristow M, Maisch B, Mautner B, O'Connell J, Olsen E, Thiene G, Goodwin J, Gyarfas I, Martin I, Nordet P: Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of cardiomyopathies. Circulation 1996;93:841-842.
  2. Osterziel KJ, Hassfeld S, Geier C, Perrot A: [Familial dilated cardiomyopathy]. Herz 2005;30:529-534.
  3. Chen Y, Peng Y, Zhou B, Wang Y, Zhou C, Song Y, Li C, Zhang J, Rao L: Analysis of adiponectin gene polymorphisms in dilated cardiomyopathy in a Han Chinese population. DNA Cell Biol 2010;29:313-317.
  4. Ghosh N, Haddad H: Recent progress in the genetics of cardiomyopathy and its role in the clinical evaluation of patients with cardiomyopathy. Curr Opin Cardiol 2011;26:155-164.
  5. Pasotti M, Repetto A, Pisani A, Arbustini E: [Genetic diagnosis of familial dilated cardiomyopathy]. Ital Heart J Suppl 2002;3:386-393.
  6. Burkett EL, Hershberger RE: Clinical and genetic issues in familial dilated cardiomyopathy. J Am Coll Cardiol 2005;45:969-981.
  7. Hershberger RE, Siegfried JD: Update 2011: clinical and genetic issues in familial dilated cardiomyopathy. J Am Coll Cardiol 2011;57:1641-1649.
  8. Martins E, Cardoso JS, Abreu-Lima C: Familial dilated cardiomyopathy. Rev Port Cardiol 2002;21:1487-1503.
  9. Zheng DD, Yang JH, Tao Q, Geng M, Lin J, Yang XJ, Song JP, Li HX, Han LH, Jiang WP: Mutations in the beta-myosin heavy chain gene in southern Chinese families with hypertrophic cardiomyopathy. J Int Med Res 2010;38:810-820.
  10. Serio A, Narula N, Kodama T, Favalli V, Arbustini E: Familial dilated cardiomyopathy. Clinical and genetic characteristics. Herz 2012;37:822-829.

A Study On Clinical Features And Cost Incurred By Dengue Syndrome Patients Admitted To Tertiary Care Hospital

Authors
Manjunath M N, Chaithanya C Nair and Sharanya R
Article Citation and PDF Link
BJMP 2015;8(2):a811
Abstract / Summary
Abstract: 

Background: India is one of the seven identified countries in Southeast Asia regularly reporting dengue fever (DF)/dengue haemorrhagic fever (DHF) outbreaks. India may soon transform into a major niche for dengue infection in the future with more and more new areas being struck by dengue epidemics.

Objectives: 1) To study the clinical manifestations, trends and outcomes of all confirmed dengue cases admitted to a tertiary care hospital. 2) To study the cost incurred by these patients during hospital stay.

Materials and Methods: This record-based study was conducted on 757 serologically (NS1 Ag/ IgM/ IgG) positive dengue cases admitted to KIMS Hospital & Research Centre, Bangalore during January 2012 to December 2012. Required data from the entire laboratory confirmed cases were collected from the Medical Records Department (MRD) and analysed.

Results: The seropositive case rate for dengue was 61.5% with NS1 antigen\ IgM\ IgG. Males were commonly affected and the most vulnerable age group was found to be between 5 to15 years of age. The median age was 8 years. The percentage of cases presented as dengue fever without warning signs was 88.5%, the remaining being dengue with warning signs and severe dengue. Fever was the most common symptom seen followed by vomiting and abdominal pain. Haemorrhagic manifestations were seen in about 4.5% of cases of which majority presented with petechiae followed by haematemesis. The mortality rate was 8.6%.

Conclusion: Increased awareness, better transport facilities and case management according to the WHO guidelines is needed to further reduce mortality and cost burden of dengue cases.

Abbreviations: 
DF - Dengue Fever, DHF - Dengue Haemorrhagic Fever, DSS - Dengue Shock Syndrome, ARDS - Acute Respiratory Distress Syndrome, MODS - Multiple Organ Dysfunction Syndrome.

Introduction:

Dengue made its debut as early as 1780, when Benjamin Rush described the condition as “break bone fever”. This hitherto unfamiliar infection has now grown to demand the attention of all public health care providers. It is a mosquito borne, fast emerging, viral infection manifesting in four serotypes (1). Approximately 2.5 billion people, living mainly in urban areas of tropical and subtropical regions, are estimated to be at risk of acquiring dengue infection (2). While dengue is endemic in more than 100 countries, most cases are reported from Southeast Asia and the western Pacific regions. Around 50 million cases and 24,000 deaths are estimated to occur in these 100 endemic countries. This includes hospitalisation of nearly half a million cases of dengue haemorrhagic fever (DHF), of which 90% are children. Treated (DHF)/dengue shock syndrome (DSS) is associated with a 1% mortality rate while mortality rate among untreated cases escalates to 20%(3,4).

India is one of the seven identified countries in the Southeast Asia region regularly reporting incidence of DF/DHF outbreaks. The first confirmed report of dengue infection in India dates back to 1940s, and since then more and more new states have been reporting the disease which mostly strikes in epidemic proportions often inflicting heavy morbidity and mortality, in both urban and rural environments.(5)

The various manifestations of dengue may not have a distinct line of demarcation: apart from the classic features, reports of rare presentations have recently become more frequent (6,7). During recent outbreaks in India, the clinical manifestations which were shown by the patients were slightly different from those in previous years(8).. There have been many reports of difficulties in the use of the previous classification, which were summarised in a systematic literature review (9). Difficulties in applying the criteria for dengue haemorrhagic fever in the clinical situation, together with the increase in clinically severe dengue cases which did not fulfil the strict criteria, led to the request for the classification to be reconsidered .Hence, WHO revised the dengue case classification into dengue (with or without warning signs), and severe dengue (10).The present study was done to analyse the clinical features, complications, cost incurred and outcome of cases admitted to a tertiary care teaching hospital in Bangalore.

Methodology:

A record based descriptive study was conducted in paediatric patients admitted with signs and symptoms suggestive of dengue fever to KIMS hospital Bangalore, during the period between January 2012 to December 2012. SD BioLine kit was used for testing with NS1 antigen\ IgM\ IgG. The medical records were perused for collecting data about these cases using a pre-designed proforma. Data was analysed for the clinical presentations, outcome and direct cost incurred in respect to hospital charges and laboratory investigations.

Results:

Out of 1230 cases admitted with clinical signs and symptoms suggestive of dengue syndrome 757 (61.5%) cases were found to be NS1 antigen\ IgM\ IgG positive for dengue. Among the 757 positive cases, males were 499 (65.9%) and females 258 (34.1%). The majority of the cases were in the school going age group and this consisted of 310 cases (41%) and adolescent children which accounted for 249 cases (33%), the median age being 8 years of age. The least number of cases were seen in infants which accounted for 45 cases (6%).

Table 1. Sex distribution

Age group Male Female Total
Infant 31 14 45
Toddler 114 39 153
School going 208 102 310
Adolescent 146 103 249
TOTAL 499 (65.9%) 258(34.1%) 757

The majority, 88.5% of cases presented as dengue fever without warning signs, 6.34% with dengue fever with warning signs and 5.15% with severe dengue. Of the cases with warning signs 92.3% of cases had fever, 42.5% cases had vomiting and 38.2% cases had abdominal pain. Haemorrhagic manifestations were seen in about 4.5% of cases of which majority (87%) presented with petechiae followed by haematemesis (9%) and epistaxis (4%). Rashes were seen in 4% and arthralgia in 13% of cases. Pleural effusion was seen in 21% of cases and ascites was seen in 16% of cases. Complications in the form of acute respiratory distress syndrome (ARDS) was seen in 12.06% cases, 6% cases showed neurological manifestations in the form of encephalopathy and 1.3% cases had renal failure.

Table 2. Severity of dengue

SEVERITY PERCENTAGE
DF without warning signs 88.5
DF with warning signs 6.3
Severe dengue 5.15

Table 3. Presenting complaints

Presenting Complaints Number (%)
Fever 699(92.3)
Myalgia 148(19.5)
Haemorrhagic manifestations 34(4.5)
Vomiting 321(42.5)
Abdominal pain 289(38.1)
Headache 201(26.5)
Arthralgia 99(13)
Diarrhoea 80(10.5)
Others 121(16)

Fig 1 presenting complaints.

Haemoglobin level of > 12gm% was found in 73.4% cases, 9-12gm% in 23.4%, 6-9gm% in 2.1% and <6 gm% in 1.1% of cases. Platelet count of < 20,000 was found in 21.5% of cases, 20-50 thousand in 39.5% , 50,000 to 1.5 lakh in 36% of cases and >1.5 lakh was found in 3% of cases. Majority (65.5%) of cases were NS1 Ag positive alone or with IgM/ IgG/ or both positive.

Remaining were positive for either of the antibodies.13.7% cases werepositive for all the three i.e. Ag, IgM,& IgG. The mortality rate was found to be 8.6%

Figure 2: outcome

Cost incurred which includes direct cost (transporting patient to the hospital, diagnostic testing and laboratory investigations, medications, hospitalisation, food) was found to been average of Rs.12,611=00. The indirect cost loss of wages of patient &attendants) was found to be an average of Rs.3, 109=00. The hidden cost (out of pocket expenses) was found to be an average of Rs.50=00. The cost of treatment of other co-morbid conditions was found to be an average of Rs.2, 275=00. The total cost of treating dengue syndrome was 18,045=00

Discussion:

In the present study it was found that males were commonly affected and the most common age group was between 5 to 15 yrs of age. Similar results were reported in a study by Faridi et al, 76% of all cases of DHF /DSS were aged 6 years or more[11].

In the present study, the most common presenting symptoms was fever followed by vomiting and abdominal pain which is similar to study done by Kumar A et al showed fever in 99.2% followed by myalgia (64.6%), vomiting (47.6%), headache (47.6%) and abdominal pain (37.5%) (12).

In the present study, the most common bleeding manifestation was haematemesis and epistaxis. In a study by Ratageri et al, common bleeding manifestations were gastrointestinal bleeding (22%) and petechiae (18%) [13]. The gastrointestinal tract was reported as the commonest site of bleeding (61%) in a study by Ahmed et al [14].

In the present study majority of cases had platelet count between 20,000 to 50,000/mm3.In a study by Kamath et al, platelet counts less than 50,000/mm were noted in 62.3% [15]. In our study complicated cases showed ARDS and neurological manifestations in the form of encephalopathy. Almost all the cases which expired were found to have ARDS. Dengue associated ARDS is associated with a high mortality [16]. Dengue infection is found to cause neurological manifestation ranging from non-specific symptoms to encephalitis and rarely Guillain-Barre Syndrome [17]. In our study the mortality rate was found to be 8.6% , in the study by Anju et al overall mortality seen was 6% [18], compared to 3% by Ahmed et al [14].

Conclusion:

The seropositivity for dengue was 61.5% with NS1 antigen\ IgM\ IgG. Males were commonly affected and most vulnerable age group was found to be 5-15 year olds. The median age was 8 years. 88.5% of cases presented as dengue fever without warning signs, the remaining being dengue with warning signs and severe dengue. Fever was the most common symptom seen followed by vomiting and abdominal pain. Haemorrhagic manifestations were seen in about 4.5% of cases of which majority presented with petechiae followed by haematemesis. The mortality rate was 8.6%. Acute Respiratory Distress Syndrom (ARDS) and multiple organ dysfunction syndrome (MODS) was found to be the most dreadful complications with high rates of mortality .

In this study it was found that cost incurred which includes direct cost (transporting patient to the hospital, diagnostic testing and lab investigations, medications, hospitalisation, food) was found to bean average of Rs. 12,611=00. Thus dengue syndrome also causes significant economic burden on the patients.

In the recent few years, the world has seen varied clinical presentation of the dengue fever in different epidemics, even in the same regions and even with the period of time. Where some known features are still manifesting, few atypical features are noted from several parts of the world. A continuous seroepidemiological surveillance and timely interventions are needed to indentify the cases, so that its complications, outbreak and mortality can be minimised.

Moreover community awareness, early diagnosis and management and vector control measures need to be strengthened, especially during peri-monsoon period, in order to curb the increasing number of dengue cases.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
DR MANJUNATH M N, Fellow in Paediatric Critical Care, Narayana Hrudayalaya, Bangalore, India. DR CHAITANYA NAIR, Post Graduate, Kempegowda Institute of Medical Sciences, Bangalore, India. DR SHARANYA R, Post Graduate, Kempegowda Institute of Medical Sciences, Bangalore, India.
Corresponding Author Details: 
DR MANJUNATH M N, Fellow in Paediatric Critical Care, Narayana Hrudayalaya, Bangalore, India.
Corresponding Author Email: 
drmanju.drmanju@gmail.com
References
References: 
  1. Guzmán MG, Kourí G. Dengue: An update. Lancet Infect Dis. 2002;2:33 42. [PubMed]
  2. Halstead SB (2007) Dengue. Lancet 370: 1644-1652
  3. WHO (2009) Dengue Guidelines for Diagnosis, Treatment, Prevention and Control WHO (2009) http://whqlibdoc.who.int/publications/2009/9789241547871_eng.pdf. Last accessed 5 July 2012
  4. World Health Organization. Dengue and dengue haemorrhagic fever. Fact Sheet. No. 117, 2002. Available from: http//www.who.int/mediacentre/factsheets/fs117/en/ [last accessed on 2009 Dec 20]
  5. Dengue in Kerala: A critical review. ICMR Bulletin. 2006;36:13–22
  6. Gulati S and Maheshwari A (2007) Atypical manifestations of dengue. Trop Med Int Health 12: 1087-1095
  7. Misra UK, Kalita J, Syam UK, Dhole TN (2006) Neurological manifestations of dengue virus infection. J NeurolSci 244: 117-122
  8. SeemaA, SinghV, KumarS, KumarA, DuttaS. The Changing Clinical Spectrum of Dengue Fever in the 2009 Epidemic in North India: A Tertiary Teaching Hospital Based Study. Journal of Clinical and Diagnostic Research 2012 August; Vol-6(6): 999-1002
  9. Bandyopadhyay S, Lum LC, Kroeger A. Classifying dengue: a review of the difficulties in using the WHO case classification for dengue haemorrhagic fever. Tropical Medicine and International Health, 2006,11(8):1238–1255
  10. WHO Library Cataloguing-in-Publication Data Handbook for clinical management of dengue.1. Dengue – therapy. 2. Dengue – diagnosis. 3. Clinical medicine. 4. Handbooks. I. World Health Organisation. ISBN 978 92 4 150471 3 (NLM classification: WC 528)
  11. Faridi MMA, Aggarwal A, Kumar M, et al. Clinical and biochemical profile of Dengue haemorrhagic fever in children in Delhi. Trop Doct. 2008;38(1): 28-30
  12. Shah I, Deshpande GC, Tardeja PN. Outbreak of dengue in Mumbai and Predictive markers of dengue Shock Sydrome. J Trop Pediatr 2004; 50:301-305
  13. Ratageri VH, Shepur TA, Wari PK, et al. Clinical profile and outcome of dengue fever cases. Indian J Pediatr. 2005;72(8):705-6
  14. Ahmed S, Arif F, Yahya Y, et al. Dengue fever outbreak in Karachi 2006 - a study of profile and outcome of children under 15 years of age. J Pak Med Assoc. 2008;58(1): 4-8
  15. Kamath SR, Ranjit S. Clinical features, complications and atypical manifestations of children with severe forms of dengue hemorrhagic fever in South India. Indian J Pediatr. 2006;73(10):889-95
  16. Lum LC, Thong MK, Cheah YK et al. Dengue-associated adult respiratory distress syndrome. Ann Trop Pediatr.1995;15(4):335-9
  17. Garacia-Rivera EJ, Rigan-Perez JG. Encephalitis and dengue. Lancet 2002;360(9328):261
  18. Aggarwal A, Chandra J, Aneja S, et al. An epidemic of dengue hemorrhagic fever and dengue shock syndrome in children in Delhi. Indian Pediatr. 1998;35(8):727-32

Current Management of Achalasia – A Review

Authors
Hanna Winter, Rajeev Shukla, Mohamed Elshaer and Amjid Ali Riaz
Article Citation and PDF Link
BJMP 2015;8(2):a810
Abstract / Summary
Abstract: 

Introduction: Achalasia is a rare oesophageal motility disorder characterised by oesophageal aperistalsis and incomplete relaxation on swallowing of the lower oesophageal sphincter. This review aims to identify and critique literature detailing the available management options for these patients and provide an up to date account of current thoughts and controversies in the treatment of achalasia.

Methods: An extensive literature search was performed for articles and reviews published on the management of achalasia, using Ovid MEDLINE, Cochrane library and PubMed search databases.

Results: The management of achalasia is controversial. Simple options such as pharmacological treatments and Botulinum toxin A injections do not provide sufficient relief of symptoms but may serve to treat those not suitable for surgery or dilatation. However, in those who are deemed suitable, the literature suggests that the optimum treatment is laparoscopic transabdominal Heller myotomy which has demonstrated the best long term results with few complications or perforations.

Conclusion: It is not possible to treat the underlying cause of achalasia but only to improve symptoms. Whilst the literature may suggest that the Heller myotomy is the best method to achieve this, it is clear that the outcomes are dependent on surgeon or physician technique and experience. It is important therefore that these patients are treated in a specialist centre with experience with such procedures. Recent advances in surgical and endoscopic technologies, with robotic Heller myotomy and per-oral endoscopic myotomy, provide promising progress for the treatment for achalasia

Keywords: 
Achalasia, manometry

INTRODUCTION

Achalasia is a rare oesophageal motility disorder, typically presenting with symptoms of dysphagia, regurgitation of food and retrosternal chest pain made worse on eating. The annual incidence in the UK, Ireland and USA is between 0.5 to 1.2 per 100,0001 and seems to affect both sexes and all races equally.

The aetiology of achalasia remains largely unknown. However, suggested influences include a genetic predisposition, infection and autoimmunity2,3. The changes responsible for achalasia include a combination of both poor oesophageal contractility and impairment of relaxation of the lower oesophageal sphincter resulting in oesophageal distension and symptoms described above. Reaching a diagnosis relies on oesophageal manometry in addition to barium swallow and oesophagogastroduodenoscopy (OGD).

The condition was first described by a British physician in 1674, Sir Thomas Willis, and treated with dilatation using a sponge attached to a whale bone4. It was not until many years later in 1913 that a German surgeon, Heller, performed the first cardiomyotomy5. The optimal treatment for achalasia remains controversial with treatment largely dependent on the preference of the physician. Cases are few and far between and therefore large studies reviewing the optimal treatments are limited.

This review aims to identify and collaborate relevant literature detailing the management options available to treat achalasia.

METHODS

An extensive literature search was performed using Ovid MEDLINE, Cochrane library and PubMed databases for relevant articles relating to medical, endoscopic and surgical management of patients with achalasia. Keywords including achalasia, Heller’s myotomy and balloon dilatation were used and relevant articles included.

MANAGEMENT

Diagnosis

All patients presenting with dysphagia should initially be investigated with OGD to exclude a mitotic lesion. OGD has little value however in diagnosing achalasia but remains an essential component of the investigation of the upper gastrointestinal tract. The gold standard for diagnosing achalasia is oesophageal manometry6,7. This typically shows a high resting pressure in the lower oesophageal sphincter which fails to relax on swallowing with associated impaired oesophageal contractility. A barium swallow may show very little in early disease, but in more advanced disease may demonstrate a ‘bird’s beak’ appearance or a sigmoid oesophagus, distension due to longstanding obstruction at the gastro-oesophageal junction (GOJ)8.

Achalasia Subtypes

Whilst the diagnosis of achalasia is dependent upon the above, high resolution manometry can further classify achalasia into three subtypes dependent on the pattern of oesophageal peristaltic abnormalities and oesophageal pressure dynamics (Figure 1). The three subtypes differ in responsiveness to treatment and as such, can be used to guide the most appropriate treatment and counsel patients appropriately.

Figure 1: The Chicago classification for achalasia subtypes9

Type I (classic) Achalasia with minimal oesophageal pressurisation
Type II Achalasia with oesophageal compression
Type III Achalasia with oesophageal spasm

Treatment

The treatment for achalasia is aimed entirely at symptom control. The underlying pathological processes which lead to myenteric plexus neurodegeneration are not fully understood and as such, cannot as yet be prevented or reversed. Current treatment options exist therefore to reduce the contractility of the lower oesophageal sphincter and hence improve the obstruction to passage of food and symptoms of dysphagia.

Various options exist for this, including pharmacological therapies which are available in the form of nitrates, calcium channel blockers, anticholinergic agents and beta agonists. Endoscopic therapy is a preferable alternative, with pneumatic balloon dilatation or intrasphincteric Botulinum toxin injection being the most commonly used techniques. The ultimate and generally accepted optimal treatment, however, is the surgical Heller’s myotomy (Figure 2).

Figure 2: Treatment options available for the management of achalasia

Pharmacological options Oral nitrates (GTN, Isosorbide dinitrate)
Calcium channel blockers (Nifedipine, verapamil)
Anticholinergics
Opioids (loperamide)
Phosphodiesterase inhibitors
Β2 agonists
Nitric oxide agonists
Endoscopic techniques Pneumatic balloon dilatation
Botulinum toxin injections
Peroral endoscopic myotomy (POEM)
Surgical options Heller’s cardiomyotomy (transabdominal or transthoracic / open or laparoscopic)

Medical

Pharmacological therapies as treatment for achalasia have been largely superseded by improvements in both endoscopic and surgical techniques. However, their potential role still exists in those with early disease, in elderly patients unsuitable for surgery or dilatation and in whom Botulinum toxin injections have failed. They may also have potential use in patients awaiting surgery for interim symptom control10,11,12. Most trials reviewing the effect of drug therapy for achalasia are limited by small numbers and short follow up so long-term benefits remain poorly understood13.

As with all achalasia treatments, the aim of drug therapy is to relax the lower oesophageal sphincter. Nitrates have been used as vasodilators within cardiovascular disease since the 1970s. Within the smooth muscle of the gastrointestinal tract, they behave similarly by increasing the production of cyclic GMP and in turn, causing dephosphorylation of the myosin light chain and subsequent inhibition of smooth muscle contraction. It is with this concept in mind that medical treatment with nitrates can cause relaxation of the lower oesophageal sphincter. There are only two randomised controlled trials which have reviewed the effect of nitrates on patients with achalasia and compared them to alternative treatment modalities14,15. However, as a Cochrane review has established, the results of these studies cannot be reliably interpreted due to both the methodology and the limitations with regards to follow up13. Regardless, nitrates are not without side effects and can cause headaches and changes in blood pressure. In view of this, their routine use is not recommended.

Calcium channel blockers, including Nifedipine, are more commonly used and are given sublingual 15-30 minutes before meals16. These limit the intracellular uptake of calcium and hence reduce the contractility of muscle cells. Reports of success as high as 65-80% have been documented17,18,19. However, up to 30% experience significant side effects.

Additional agents that have been described include β2- agonists, anticholinergics and phosphodiesterase inhibitors, the latter of which induces nitric oxide release and thereby relaxation of lower oesophageal sphincter muscle but can also result in significant side effects, including angina, and so routine use is again not advised20,21. It is for these reasons, that progress has been encouraged elsewhere with developments in both endoscopic and surgical techniques for the treatment of achalasia.

Endoscopic

Endoscopic treatments are again aimed at reducing the contractility of the lower oesophageal sphincter and several options exist for this. Injection of Botulinum toxin A is the most commonly performed and has fewer associated side effects and complications than its alternatives, hence is often used as first line treatment and especially in patients not suitable for surgical intervention. Alternative options include pneumatic balloon dilatation and more recently, per-oral endoscopic myotomy (POEM).

Botulinum toxin A is used as an intrasphincteric injection and exerts its action by inhibiting the release of acetylcholine, necessary for muscular contractions. This in turn lowers the tone and pressure of the lower oesophageal sphincter. 80-100 units of Botulinum toxin A are injected in divided doses in all four quadrants at the level of the squamocolumnar junction via endoscopic guidance. Patients recover quickly and can go home the same day22, typically seeing improvements in symptoms between days 1-323. Results are variable. Certainly the side effects are minimal and it appears to be a safe procedure without the risk of perforation seen with other techniques24,25. Short term improvement in symptoms is described as high as 85%. However, over time this is seen to decrease significantly to only 30% at one year. Most will require further injections or alternative treatments such as pneumatic balloon dilatation or surgical myotomy24.

Pneumatic balloon dilatation includes inflating a 30mm balloon at the level of the GOJ26,27. This process fractures the muscular fibers of the lower oesophageal sphincter hence disrupting the sphincter mechanism. It can be performed under fluoroscopic or endoscopic guidance dependent on operator experience and preference. The major risk is oesophageal perforation, which in experienced hands occurs in 1.9% (range 1-16)28. In addition, gastro-oesophageal reflux post procedure can be troublesome, affecting 4-16% of patients29.

A Cochrane review compared outcomes with Botulinum toxin injections and pneumatic balloon dilatation30. Whilst little difference in short term improvement was noted, longer term remission rates were considerably higher in those treated with balloon dilatation. However, even with balloon dilatation, up to a quarter require further treatments at five years31,32.

An emerging endoscopic technique is the peroral endoscopic myotomy (POEM). This is performed by incising the mucosa endoscopically, dissecting and developing a plane in the submucosal layer and performing a myotomy inferiorly to beneath the gastro-oesophageal junction. The mucosa is thereafter closed with staples. Studies have shown it to be both safe and effective with short term results demonstrating similar relief in dysphagia and improvements in Eckardt scores as patients undergoing laparoscopic myotomy33,34. The added benefit of POEM is the potential for faster return to normal activities34 and with preserving the need for surgery, dissection at the hiatus can be avoided which may reduce symptoms of post-operative reflux. However, it is technically challenging and studies demonstrating long term outcomes are not yet available.

Surgical

The surgical treatment for achalasia involves performing a myotomy at the level of the gastro-oesophageal junction. There has been controversy regarding the most appropriate method of achieving this and experience includes open versus laparoscopic, transthoracic versus transabdominal. Further controversy exists in the importance of performing simultaneous antireflux surgery.

With the development of laparoscopic abdominal surgery, there is little doubt that this has lowered the complications and improved patient recovery and inpatient hospital stay35,36,37. Not only is the approach to the GOJ easier via the abdomen, also single lung ventilation is not required and so pulmonary complications are fewer.

Surgical myotomy offers superior long-term relief of achalasia-related symptoms compared to medical and endoscopic alternatives, alleviating dysphagia in 88%-94% at ten years following surgery36,38. Improvements have also been demonstrated in patient satisfaction and quality of life post operatively39. Performing a complete myotomy is essential to outcome and prevention of recurrent symptoms, hence accuracy and precision is paramount40. Where this is concerned, robotic surgery is becoming more accessible and early results would suggest improvements over conventional laparosopic surgery41.

The risk of perforation is small with laparoscopic myotomy42 and even smaller with robotic surgery. The main complication associated with performing a myotomy is symptomatic reflux. Controversy exists regarding simultaneous anti-reflux procedure and some would argue that in the absence of posterior dissection at the level of the GOJ, there is not the need43. A meta-analysis performed by Lyass et al reviewed patients undergoing surgery for achalasia44. The authors concluded that the rates of reflux post operatively were no different between those who had anti-reflux procedures and those who did not. Ultimately, the decision to proceed with anti-reflux surgery will vary surgeon to surgeon. However, what is generally accepted is that a complete 360 degree Nissen’s fundoplication is not required, and may serve only to give the patient ongoing symptoms of dysphagia. Therefore, Toupet (posterior 270 degrees) or Dor (anterior 180 degrees) fundoplication are more commonly used, the latter providing cover to the myotomy and thus potentially protecting any unidentified mucosal breach45.

Surveillance

Studies have demonstrated that patients with a diagnosis of achalasia have an increased risk of squamous cell carcinoma of the oesophagus46. For this reason, guidelines developed by the American Society for Gastrointestinal Endoscopy suggest surveillance oesophagogastroduodenoscopy every 1-3 years for 15-20 years47.

CONCLUSIONS

Achalasia is a difficult condition to diagnose and treat. All treatments are aimed at disrupting the lower oesophageal sphincter mechanism and none are without risk or complication. Treatment modalities vary in their short and long term success rates. Pharmacological treatments are of limited value and Botulinum toxin injections have limited long term results but both may play a role in patients who cannot tolerate more invasive procedures48. The main debate has historically lain between advocating the use of endoscopic dilatation versus laparoscopic Heller myotomy.

Studies looking at endoscopic dilatation versus myotomy have comparable initial symptomatic relief. Direct comparison between the long term outcomes does, however, favour laparoscopic myotomy49,50. Traditionally, endoscopic dilatation has been the first line treatment, with surgery reserved for those in whom dilatation has failed51. However, subsequent intervention is common and there are many studies examining outcomes of second treatment with either surgery or dilatation. In cases where initial treatment has failed and recurrent symptoms of dysphagia present, dilatation has been shown to be more effective in those who have had surgery rather than those who have had previous dilatations or Botulinum toxin injections52,53. Importantly, there is not a greater risk of perforation in these patients than in those who have not undergone myotomy54.

Performing a surgical myotomy after previous treatment with dilatation or injection may complicate the surgery slightly and has been shown to increase complications and failure of myotomy55,56, providing an argument for surgery as first line treatment. That said, surgery is still recommended in these patients as the most successful option57.

Ultimately, the optimal treatment will vary dependent on physician or surgeon technique and experience. Cases are limited and so it is recommended that these patients are treated in a specialist Upper GI unit where all options are presented to the patient and the risks and benefits of each counselled appropriately. It is an exciting time for achalasia as new treatment options including POEM come to light and robotic surgery becomes more available.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
Prof.A A RIAZ, Hunterian Professor and Consultant Upper GI, West Hertfordshire Hospitals NHS Trust, Hertfordshire, WD18 0HB, UK. HANNA WINTER, Surgical Registrar, West Hertfordshire Hospitals NHS Trust, Hertfordshire, WD18 0HB, UK. RAJEEV SHUKLA, Surgical Registrar, West Hertfordshire Hospitals NHS Trust, Hertfordshire, WD18 0HB, UK. MOHAMED ELSHAER, and Surgical Registrars, West Hertfordshire Hospitals NHS Trust, Hertfordshire, WD18 0HB, UK.
Corresponding Author Details: 
Professor A A Riaz, Hunterian Professor and Consultant Upper GI, Laparoscopic and General Surgeon, Department of Surgery, West Hertfordshire Hospitals NHS Trust, Vicarage Road, Hertfordshire, WD18 0HB.
Corresponding Author Email: 
mrariaz@hotmail.com
References
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  26. Annese V, Basciani M, Perri F, Lombardi G, Frusciante V, Simone P, Andriulli A, Vantrappen G. Controlled trial of botunilnum toxin injection versus placebo and pneumatic dilation in achalasia. Gastroenterology. 1996;111(6):1418-24.
  27. Ghoshal UC, Chaudhuri S, Pal BB, Dhar K, Ray G, Banerjee PK. Randomized controlled trial of intrasphincteric botulinum toxin A injection versus balloon dilatation in treatment of achalasia cardia. Dis Esophagus. 2001;14(3-4):227-31.
  28. Richer JE. Update on the management of achalasia: balloons, surgery and drugs. Expert Rev Gastroenterol Hepatol 2008;2:435–45.
  29. Gideon RM, Catel DO, Yarze J. Prospective randomized comparison of pneumatic dilatation technique in patients with idiopathic achalasia. Dig Dis Sci 1999;44:1853-1857. 
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  32. Hulselmans M, Vanuytsel T, Degreef T, Sifrim D, Coosemans W, Lerut T, et al. Long-term outcome of pneumatic dilation in the treatment of achalasia. Clin Gastroenterol Hepatol. 2010 Jan;8(1):30-5.
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  40. Litle VR. Laparoscopic Heller Myotomy for Achalasia: A review of the controversies. Ann Thorac Surg. 2008 Feb;85(2):S743-6.
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  49. Kostic S, Kjellin A, Ruth M, Lönroth H, Johnsson E, Andersson M,  et al. Pneumatic dilatation or laparoscopic cardiomyotomy in the management of newly diagnosed idiopathic achalasia. Results of a randomized controlled trial. World J Surg. 2007 Mar;31(3):470-8.
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BJMP March 2015 Volume 8 Number 1

BJMP March 2015 Volume 8 Number 1

Full Issue Booklet   PDF

Editorial

Research Articles

Cervical ripening balloon as an alternative for induction of labour: a randomized controlled trial
Toh Lick Tan, Grace Yang Huang Ng, Sheri Ee-Lin Lim, Shephali Tagore, Ei Ei Phyo Kyaw and George Seow Heong Yeo
Full Text  PDF
Trend of developing resistance among isolates of Acinetobacter spp.; Threat of hospital acquired infection
Sadia Zafar, Syed Baqir Shyum Naqvi, Tanveer Abbas, Faaiza Qazi and Rabia Sheikh
Full Text  PDF

Review Articles

Current management of oesophageal cancer
Naufal Rashid, Mohamed Elshaer, Michael Kosmin and Amjid Riaz.
Full Text  PDF
Legal Highs - Not so new and still growing in popularity
Francis J Dunne, Khalid Jaffar and Shazia Hashmi
Full Text  PDF

Case Reports/Series

Clinical Practice

A feasibility study to establish a Deliberate Self-harm Register in a state hospital in southern India.
Rajgopal Rajendra, Murali Krishna, Sumanth Majgi, Narendra Heggere, Catherine Robinson, ROb Poole
Full Text  PDF

Homeopathy: In God we trust, all others must bring data.

Authors
Nasseer A Masoodi MD, MBA, FACP
Article Citation and PDF Link
BJMP 2015;8(1):a809
Abstract / Summary
Keywords: 
Homeopathy, effectiveness, science based medicine

Effectiveness of homeopathic remedies continues to be a question of concern for public, policy makers and the other involved stakeholders. A recent systematic review of studies by Australian National Health and Medical Research Council (NHMRC) 1 heightened further the concerns about the perception of effectiveness of homeopathic treatments in general. After an exhaustive review, the authors found no good quality, or well-designed studies with adequate sample size to support claims made by homeopathic practitioners. They concluded that the homeopathic remedies are no better than a placebo. Authors of the report cited concerns about the designs of the most of the studies especially the ones that showed any beneficial effect. Authors noted that such studies either had smaller sample sizes, were conducted poorly and/or were insufficiently powered to detect a statistically significant outcome. NHMRC concluded that there is no evidence from systematic reviews regarding the effectiveness of homeopathy as a treatment for any clinical condition in humans. The NHMRC identified “claiming benefits for human health not based on evidence”1 as a major health issue in Australia.

NHRMC’s report comes as no surprise as many other exhaustive reviews had failed to show any objective benefits of such remedies. Authors of a 2009-10 UK report titled as Evidence Check 2: Homeopathy2, reached to a similar conclusion. They questioned the lack of homeopathic treatment trials and cited that there is plenty of evidence showing that it is not efficacious. Their conclusion was no different from NHRMC’s and proposed that “systematic reviews and meta-analyses conclusively demonstrate that homeopathic products perform no better than placebo”2. They further recommended stopping any public funding of Homeopathic remedies in UK. Although a Swiss report3 argued otherwise claiming that homeopathy is a “valuable addition to the conventional medical landscape”3; however its methodology was considered to be flawed, biased, misinterpreting and discrediting the current science based study methodologies4.

The homeopathic notion of successive dilution of its products in water increasing the potency of the final product and “like cures like” doesn’t only defy any science based medicine logic, it is also in contrast to other alternative systems of medicine. The paucity of good-quality studies of sufficient size that examine the effectiveness of homeopathy as a treatment for any clinical condition in humans does no favors to this notion either. As cited by many reports referenced above, the available evidence is not compelling and fails to demonstrate that homeopathy is an effective treatment for any of the reported clinical conditions in humans. In spite of these significant concerns about the legitimacy and efficacy of homeopathy, the industry continues to benefit from public’s increasingly favorable attitudes toward homeopathy. The National Institutes of Health5 in the United States, reports that there is little evidence to support homeopathy as an effective treatment for any specific condition however millions of American adults and thousands of children use homeopathy. Even in UK6 where there is no legal regulation of homeopathic practitioners, The National Institute of Health and Care Excellence (NICE)-that advises the NHS on proper use of treatments, doesn’t recommend that homeopathy should be used in the treatment of any health condition. However homeopathy has seen a significant increase in its market share not only in UK but many other European countries too7.

With its market share in USA and rest of the world markets reaching in billions of dollars with yearly incremental increase, its claims for its remedial effects albeit lacking any generally acceptable evidence, raises concern that a vulnerable person may choose an ineffective remedy that may actually worsen their clinical status. There is a clash between patient autonomy and informed consent in decision making by a vulnerable patient about the appropriateness of homeopathic remedies. The ethical and policy debate on the appropriate balance between public’s access to different remedies (autonomy) and government institutional duty of public’s protection from potentially harmful or ineffective medicines is a delicate balance.  An objective and thorough evaluation of homeopathic remedies is needed however how to decide what is an objective and accurate way to assess homeopathic research continues to be the bone of contention. Although from a science based medicine perspective, homeopathic remedies have no scientific explanation, its advocates3, 4 don’t agree that it has to fall or go through same process of research methodology for its effectiveness as do allopathic remedies. Though it is a valid logic that reasoning directly from data that is gathered by controlled structure, as is true of science based trials in allopathy, is not always accurate as it’s with many biases and confounders, however the statistical testing helps to get beyond mere correlation to cause-and-effect and eliminate most of these concerns. These trials also help to formulate conclusions that can be further validated or refuted by gathering real world data. The mainstream science considers the homeopathic notion of ultra-dilutions, particle leaving imprint of itself on water, and “likes cures like” to be scientifically implausible. Even though this notion of scientists may be considered as a bias towards evaluating any homeopathic remedy, the public health institutions have an ethical obligation to educate public especially the vulnerable ones, not to substitute a proven and effective treatment for the ones whose effectiveness has not been scientifically proven.

As the saying goes, “change the rule and you will get a new number”, the onus is on homeopathic advocates not only to design trials, gather data, and publish papers but also to collect real world data to further study the impact of treatments on outcomes. The real world data can further help to understand the effects of treatments on patient outcomes that was not generated from a clinical trial. It is also an obligation of the homeopathic practitioners and organizations to seek to create standards of medical treatment, that are objective, replicable, and that will be made broadly available to physicians, researchers, parents, policy makers, and others who want to improve the care of individuals. As recommended by many exhaustive reviews1,2, these studies should recruit larger samples of patients, utilize methodologies that eliminate the bias, better discoverable record keeping for proper reporting and follow up, an objective analysis of outcomes data and how they were measured, and better discussion of potential confounders or biases. Besides they have to adequately and accurately report study details including treatment regimens, length of follow up, outcomes studied and the clinical and statistical significance of results. 

Going by the logic of famous words attributed to the noted statistician and management scientist, W Edwards Deming, “In God we trust; all others must bring data,” the ball is in their court.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
NASSEER A MASOODI, MD, MBA,FACP, Senior Consultant, Department of Medicine, Hamad Medical Corporation, Qatar.
Corresponding Author Details: 
Dr Nasseer A Masoodi, Senior Consultant, Department of Medicine, Hamad Medical Corporation, Qatar.
Corresponding Author Email: 
haadin@yahoo.com
References
References: 
  1. Effectiveness of Homeopathy for Clinical Conditions: Evaluation of the Evidence. Overview Report. Prepared for the NHMRC Homeopathy Working Committee, October 2013. Available at http://www.nhmrc.gov.au/_files_nhmrc/file/your_health/complementary_medicines/nhmrc_homeopathy_overview_report_october_2013_140407.pdf, accessed on April 04, 2015. 
  2. House of Commons Science and Technology Committee. Evidence check 2: Homeopathy. 2009. Available at: http://www.publications.parliament.uk/pa/cm200910/cmselect/cmsctech/45/45.pdf, accessed on April 04, 2015.
  3. Bornhöft G, Matthiessen P, Eds (2012). Homeopathy in Healthcare: Effectiveness, Appropriateness, Safety, Costs: An HTA report on homeopathy as part of the Swiss Complementary Medicine Evaluation Programme. Springer-Verlag, New York. 
  4. Shaw D (2012). The Swiss report on homeopathy: a case study of research misconduct. Swiss Med Wkly 142:w13594.
  5. Homeopathy: An Introduction. Available at https://nccih.nih.gov/health/homeopathy, accessed on April 04, 2015.
  6. Homeopathy: Overview. Available at http://www.nhs.uk/Conditions/Homeopathy/Pages/Introduction.aspx, accessed on April 04, 2015.
  7. Homeopathy- a healthcare choice for everyone. Available at http://www.britishhomeopathic.org/what-is-homeopathy/facts/the-growing-demand-for-homeopathy/, accessed on April 2015.

Successful Anaesthetic Management of an Intra-tracheal Tumour

Authors
Harshal D Wagh
Article Citation and PDF Link
BJMP 2015;8(1):a808
Abstract / Summary
Abstract: 

We report a successful management of an intra-tracheal tumour in a 56 year old patient. The tumour was situated  about 4 cm above the carina.The case was managed without the need of cardiopulmonary bypass. An orotracheal tube placed above the tumour was used to ventilate the lungs before the trachea was opened. A smaller  tube was placed in the left bronchus to ventilate the left lung after the trachea was opened to facilitate sleeve resection and anastomosis of the trachea. The patient was extubated in the immediate postop period without any adverse effects. Careful preoperative planning and good team work made the procedure possible and without complications.

INTRODUCTION

Anaesthetic management of a patient with a tracheal tumour is challenging, as the airway is shared with the surgeon and patency must be maintained despite airway manipulation.

Several anaesthetic techniques have been used in patients requiring tracheal resection and reconstruction. Cardiopulmonary bypass standby after femoral artery and vein cannulation and then intravenous/inhalational induction while oxygenating the patient has been considered to be a reasonable approach. Intratracheal tumours are challenging to anaesthetists because of the difficulty in establishment of a patent airway before commencement of surgery. The principal anaesthetic consideration is ventilation and oxygenation in the face of an open airway.

CASE REPORT

A 56 year old male with no other co-morbidities presented to the Thoracic Oncology department with a history of progressive dyspnoea and orthopnoea.On examination he was found to have dyspnoea at rest and could not complete full sentences while talking. Change of position made no difference to his symptoms.

Routine blood investigations which included full blood count, renal and liver functions, coagulation profile, ECG and 2DEcho were within normal limits. PFT showed a typical intrathoracic obstructive picture.

His chest X-ray showed bilateral hyperinflated lungs suggesting airtrapping. CT of the chest showed an intratracheal growth about 4 cm above the carina almost completely obstructing the lumen. An awake flexible bronschoscopy confirmed the CT scan findings. A 2.7mm flexible bronschocope was passed with difficulty beyond the tumour to visualise the carina. Excision of the intratracheal tumour was planned with possible resection and anastomosis of the involved tracheal segment. A careful perioperative plan was  discussed and decided in agreement with the thoracic surgeons, anaesthetist, cardiovascular surgeons and the rest of the team members.

Flexible and rigid bronchoscope, a Sanders venturi, an additional anaesthesia machine and various sizes of reinforced and normal endotracheal tubes and tracheostomy tubes were kept ready.

Preoperatively the patient had incentive spirometry and bronchodilator nebulisation and intravenous steroids. An awake epidural at T9-10 level and radial artery cannulation were done under local anaesthesia without any problems. Two 16 gauge peripheral IV lines were sited under local anaesthesia.

After adequate preoxygenation anaesthesia was induced with IV propofol along with oxygen and sevoflurane with BIS monitoring.  As mask ventilation proved to be easy the patient was paralysed with suxamethonium. There was no difficulty in ventilation after muscle paralysis. An 8.5 number COETT portex tube was placed in  the trachea with the cuff just beyond the cords to avoid possible trauma to the tumour. Since there was preoperative evidence of airtrapping, ventilator settings were set to an I:E ration of 1:3 with a tidal volume of 550ml, respiratory rate of 12-14 per minute and PEEP of 4. At these ventilator settings the airway pressures were reaching up to 22 cm of  H20 and ETCO2 reaching a maximum of 40mmHg. Anaesthesia was maintained with oxygen: air with sevoflurane and atarcurium for muscle paralysis.

Flexible bronchoscopy was done to confirm the position of the endotracheal tube, which showed that the ETT was adequately above the tumour.

A laryngeal drop procedure was done in the supine position with neck extension to facilitate mobilisation of the trachea for resection anastomosis. After the laryngeal drop procedure a right thoracotomy was done in the left lateral position. At this point of the procedure, the patient was ventilated with low tidal volumes of 300 and respiratory rate of 16-20 to keep the ETCO2 at around 40.The right lung was surgically retracted and the trachea  was exposed up to the carina. A repeat bronchoscopy was done through the ETT to help identify the upper and lower extent of the tumour. The trachea was then opened below the tumour, after which a 6.5 reinforced tube was introduced through the left bronchus to aid ventilation of the left lung. This ETT was withdrawn intermittently to help visualisation and aid surgical excision of the tumour and  sleeve resection of the trachea. The left lung was ventilated till partial closure of the trachea. The left-sided tube was then removed. Ventilation resumed through the orotracheal tube with intermittent occlusion of the defect with gauze by the surgeon.  The orotracheal tube was adjusted under vision before closure of the trachea to position it above the anastomotic site. The trachea was sutured and the thoracotomy incision closed without any adverse event. The neck was kept in a flexed position to avoid tension on the tracheal anastomotic area.

The patient was then extubated in the immediate postoperative period without any problems and the recovery was uneventful.

DISCUSSION

Anaesthetic management of a patient with a tracheal tumor is challenging, as the airway is shared with the surgeon, and patency must be maintained despite airway manipulation1, 2. Several anaesthetic techniques have been used in patients requiring tracheal resection and reconstruction 3–5.

Primary tracheal masses are very rare and mostly malignant, occurring in 0.2 in 1,00,000 persons per year 6 and among these squamous cell carcinomas form the main bulk. Cardiopulmonary bypass standby after femoral artery and vein cannulation and then intravenous/inhalational induction while oxygenating the patient with the oxygen inhalation has been considered to be a reasonable approach 7. Byrne JG et al (2004) advocated planned use of CPB to facilitate complete resection of thoracic malignancies after careful patient selection 8.

These patients are often mistaken to have asthma and require treatment with inhaled corticosteroids and beta agonists 9. They are generally treated for many years for asthma or COPD, unless a CT scan or endoscopic procedure is done for the symptoms 10. Intratracheal masses usually start getting symptomatic when 75% or more of the tracheal lumen is obstructed. Tracheal lesions present at lower level can have more complicated management of airway, anaesthesia and surgery for successful and safe removal of the mass. 10

Intratracheal tumours are challenging to anaesthetists because of the difficulty in establishment of a patent airway before commencement of surgery. The principal anaesthetic consideration is ventilation and oxygenation in the face of an open airway. Ventilation can be managed in many ways, including manual jet ventilation, high frequency jet ventilation, distal tracheal intubation, tracheostomy, spontaneous ventilation and CPB.11

Knowledge of various techniques available for management of such cases is vital. In order to have a successful and safe outcome it is extremely important to have good communication between the anaesthetic, surgical and intensive care team.

The challenge in managing such cases lies in establishing and maintaining a patent airway and also preventing seepage of blood and tumour particles distally into the tracheobronchial tree during the surgery.

There is a possibility of total airway obstruction during ventilation attempts using positive pressure because airway obstruction has a fixed and dynamic component. Dislodgement of the tumour, possibly from trauma following intubation causing total obstruction, should also be considered.

Thus an intratracheal tumour was successfully removed without any complications and by avoiding CPB. This case report also highlights the importance of proper planning and good communication between team members to ensure a successful and safe outcome.

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
RAJESH MISTRY, Consultant and Head of the Department of Oncosurgery, Kokilaben Ambani Hospital, Mumbai, India.
Competing Interests: 
None declared
Details of Authors: 
DR.HARSHAL D WAGH, MBBS,DA,DNB,FCPS,FRCA(LON), Kokilaben Ambani Hospital, Mumbai, India.
Corresponding Author Details: 
DR HARSHAL WAGH, Kokilaben Ambani Hospital, Andheri, 4 Bungalows, Mumbai, 400053,INDIA.
Corresponding Author Email: 
drhdw@yahoo.com
References
References: 
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  2. Furimsky M, Aronson S, Ovassapian A.Perioperative management of a patient presenting for resection of a tracheal mass. J Cardiothorac Anesth 1998;12:701–4.
  3. Divatia JV, Sareen R, Upadhye SM, et al.Anaesthetic management of tracheal surgery using the laryngeal mask airway.Anaesth Intensive Care 1994;22:69 –73.
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  5. Mentzelopoulos SD, Romana CN, Hatzimichalis AG, et al. Anesthesia for tracheal resection: a new technique of airway management in a patient with severe stenosis of the midtrachea. Anesth Analg1999;89:1156–60.
  6. Azar T, Abdul-Karim FW, Tucker HM: Adenoid cystic carcinoma of the trachea. Laryngoscope 1998, 108(9):1297-300.
  7. Céline Pinsonneault, Joanne Fortier, François Donati: Tracheal resection and reconstruction. Can J Anesth 1999, 46(5):439-455.
  8. Byrne JG, Leacche M, Agnihotri AK, Paul S, Bueno R, Mathisen DJ, Sugarbaker DJ: The use of cardiopulmonary bypass during resection of locally advanced thoracic malignancies: a 10- year two-center experience. Chest 2004, 125(4):1581-6.
  9. Jones TM, Alderson D.Sheard JD,Swift AC.Tracheal paraganglioma: A diagnostic dilemma culminating in a complex airway management problem.J Laryngol Otol 2001;115:747-9.
  10. Azorin J, Lamberto JF, Personne C, Larmignat P, Khellaf M, Lmeny JL,et al. Adenoid cystic carcinoma of the trachea: Treatment by combined laser therapy and surgery.Rev Mal respire 1987;4:95-6.
  11. Pinsonneault C, Fortier J, Donati F. Tracheal resection and reconstruction.Can J Anaesth 1999;46:439-55

A feasibility study to establish a Deliberate Self-harm Register in a state hospital in southern India.

Authors
Rajgopal Rajendra, Murali Krishna, Sumanth Majgi, Narendra Heggere, Catherine Robinson and Rob Poole
Article Citation and PDF Link
BJMP 2015;8(1):a807
Abstract / Summary
Abstract: 

Background: Deliberate self harm (DSH) registers are the first step towards understanding self-harm in developing countries.
Aims: To determine the  feasibility of a DSH register in a state hospital in India.
Methods: For each individual presenting with DSH between February and July 2012, data was collected by interview and from records. Time taken for  complete data entry was recorded. The proportion of DSH patients correctly identified and traced after admission was recorded, indicating ‘representativeness’, the proportion for whom a full data set was captured was recorded,  indicating ‘completeness’, and the proportion willing to be included in the register and followed up was recorded, indicating ‘acceptability’.
Results: 1072 presented with deliberate self-harm. All inpatient survivors (817) were traced and none objected to their details being entered on the register. Of 1023 on the register, complete data was available for 740 (72.3%). Data was incomplete for 283 (27.7%). All 1023 had performed an act of self-harm necessitating medical intervention. The time between identification and completion of data entry ranged from 30 minutes to 2 hours.
Conclusions: It is feasible to establish an accurate, reliable and complete DSH register in a large Indian state hospital.The clinical and service implications are discussed.

Abbreviations: 
DSH : Deliberate Self Harm, ICD: International Classification of disorders
Keywords: 
Self-harm, Register, Feasibility, Developing Countries.

BACKGROUND

Suicide and deliberate self-harm (DSH) have been recognised as major public health problems in India for some time, but there are significant obstructions to effective intervention including difficulties in following Western models to understand these behaviours.1, 2, 3

The World Health Organisation (WHO) recognises suicide as one of the three leading causes of death in young adults globally.4 The greatest burden of suicide is now in low- and middle-income countries like India where annual suicide rates are 10-11 per 100,000.5, 6, 7 India is second only to China in the absolute number of annual deaths by suicide.5 The number of individuals who die by suicide each year in India alone is more than the total number of suicides in the four top ranked European countries combined.3, 5, 8

DSH, defined as intentional self-poisoning or self-injury, is a closely related public health problem.9WHO estimates that for every suicide there are at least 10-20 DSH acts.10 If this estimated proportion, based on Western research, is also true in India then there are 1-2 million DSH acts in India each year.

Official data for 2005 suggest that 19.6% (n=22,327) of India's 113,914 officially recorded suicides were self-poisonings with pesticides7 (predominately organophosphates, which are freely available and widely used in agriculture). The official suicide rate for India, 10.3 per 100,000 in 2005,7 is thought to be an under-estimate.3, 11 Studies from several regions suggest that India's suicide rates may be as high as 40 per 100,000 and that 30% or more of these deaths are due to pesticide self-poisoning.11 The studies reporting the highest suicide rates within India are from Tamil Nadu (>60 per 100,000 – three times higher than the official figure for the state).12, 13, 14, 15 Whilst some of the discrepancies between official statistics and findings in local studies may be due to urban-rural differences in the incidence of suicide, data collated by the Indian police suggest that around 90% of suicides in India occur in non-urban areas.7, 11, 15 Extrapolating from these figures, it is conservatively estimated that there may be up to 420,000 suicides per annum in India (126,000 from pesticide self-poisoning).

India's centrally collated self-harm and suicide data are unreliable owing to a number of factors. Death registration processes are below Western standards. Only about 25% of deaths are registered and only about 10% are medically certified.16, 17 Attempted suicide is a crime in India.18 Survivors are interviewed by the police. Fear of legal and social consequences following an act of self-harm probably influence willingness to acknowledge DSH and preparedness to seek medical intervention.

India contributes almost 20% to the world's population, and suicides rates are increasing particularly amongst the young.11, 19 Obtaining reliable and nationally representative data on DSH rates in India should be a priority for health-funding agencies over the next decade. In order to reduce fatalities following self-harm, information and investment are needed to improve quality, affordability and accessibility of health care close to the affected communities.20

If, as seems likely, self-harm (especially pesticide poisoning) occurs predominantly in rural areas of India,11 Western models of data collection and intervention aimed at reducing pesticide poisoning (which is predominately accidental in developed economies) are likely to require significant modification to be reliable and effective. The WHO's global suicide prevention strategy is largely based on findings from research and models of suicide prevention developed in the West.21 Health care resources in rural areas of India are thinly spread, and are often rudimentary compared to those in the West. There is an urgent need for research in low- and middle-income communities – particularly in rural areas of India – to provide the evidence base to underpin public health strategies for preventing pesticide suicides in these countries.

The establishment of DSH registers is a first step towards the systematic collection of data in relation to self-harm, both for epidemiological purposes and to understand pesticide self-poisoning at an individual level. If DSH registers can be shown to generate reliable information in India, in due course it may be possible to identify the factors that put individuals at risk of behaving in this way, and create relevant evidence-based policies to develop interventions for reducing mortality and morbidity associated with DSH (particularly pesticide poisoning).

This paper explores the feasibility of setting up a DSH register in a resource-poor large State hospital in south India, where rates of suicide and DSH are high.

METHODS

Setting

This study was carried out at Mysore Medical College and Research Institution (MMCRI), a State-run hospital in Mysore, southern India. The hospital serves a catchment area of 1,500,000 population and 135 primary health centres. The hospital has most specialities, with 1050 beds and a 10-bedded intensive care unit. 800-1000 patients attend the hospital outpatient department daily. Daily attendance to the casualty department for the purpose of medico-legal registration (which includes self-harm) is between 110 and 130. All other presentations including emergencies are managed through respective speciality outpatient departments.

Figure 1. Care Pathway for deliberate self-harm (DSH) at Mysore Medical College and Research Institution (MMCRI)

Setting up of the register

The flow diagram (Fig. 1) illustrates the care pathway of those presenting with DSH to MMCRI highlighting that only a few receive psychosocial assessment. A working group of psychiatrists, psychologists, social workers, casualty medical officers, statisticians and hospital managers was formed to arrive at a consensus on the minimum dataset that could be gathered from DSH survivors for the purpose of setting up a register. Literature on establishing self-harm registers was reviewed along with international guidelines in relation to self-harm assessment in the general hospital.22, 23 Opinion was sought from senior psychiatrists and public health personnel from the private and public sector in Mysore and from the United Kingdom (UK). The team was visited, supported and advised by the Centre for Mental Health and Society, Bangor, UK.

The items listed in Table 1 were considered as ‘minimal yet essential’ for informing clinical practice, service development and patient engagement in future research. The study was not externally funded and, due to time and resource implications, it was agreed that outcomes of mental health assessments would not be recorded in the register. The method of DSH was coded according to the International Classification of Diseases 10th Revision (ICD-10) criteria24 and socio-economic indicators were derived from a modified Kuppuswamy’s scale25 that is validated for the south Indian urban population.

Table 1. Contents of the deliberate self-harm (DSH) register.

An electronic DSH register was set up in February 2013 and is currently held in the Department of Psychiatry, MMCRI, and Mysore. Two pre-registration House Officers (junior resident equivalent) visited the casualty department daily and identified those cases registered as self-harm from both the standard patient register and medico-legal case registers. If the individual was discharged from casualty (condition necessitated no further treatment, no intensive care bed available, or patient chose admission in private sector after first aid) the available information is captured from the registers and medical records. If they admitted to the general hospital they were traced and personally contacted. Information (as in Table 1) was collected from DSH survivors and from medical records. The data was verified by a Consultant Psychiatrist before being entered in the register. DSH survivors are asked to provide two contact details (postal address and phone number) for future tracing if they consent to further contact either in person or by phone. Table 2 is a list of the sources of data for the DSH register in Mysore and their limitations.

Table 2. Sources of data for deliberate self harm (DSH) register in Mysore and their limitations.

Feasibility

A DSH register should be representative, complete and accurate. The register should be acceptable to the entrants and only take a minimal time for data collection and registration. For the purpose of this study the following were identified as indicators of feasibility:

· Time between identifying that the patient should be included in the register and completion of data entry in the register. This was recorded for 80 randomly chosen inpatient DSH survivors.

· The proportion of patients presenting with alleged DSH who were correctly identified and, if admitted to the general hospital, traced for the purpose of inclusion to the register (representativeness).

· Proportion of those included in the register for whom a full data set could be captured (completeness).

· Proportion of the DSH survivors who were willing to be included in the register and provided contact details for future follow-up (acceptability).

· Over a period of a week, every month during study period February 2013 to July 2013, a Consultant Psychiatrist independently collected data from casualty registers and checked against the total number registered on the DSH register for the corresponding month (accuracy).

RESULTS

Between February 2013 and July 2013, a total of 19,563 patients attended the casualty department. Of these, 1072 attended in relation to self-harm. 1041 of them were hospitalised for further intervention. All of those who were hospitalised and survived (n=817) were traced and contacted. None objected to their details being entered on the register. However, only 253 of the 817 (30.9%) agreed to be contacted for future follow-up. Of the 817, only 109 (13%) had been formally referred to the psychiatry department for an assessment prior to contact with the research team. None of the 817 had any involvement with Social Services.

Out of the 1023 on the register, complete data was available and/or obtained for 740 (72.3%) individuals and data was incomplete for 283 (27.7%) patients. Either by reviewing the medical records or interviewing the patient, it was confirmed in all 1023 cases that there had been an act of self-harm necessitating medical intervention. The time between identifying that the patient should be included in the register and completion of data entry in the register varied between 30 minutes and 2 hours. When the data collected was cross-verified (n=315) by a Consultant Psychiatrist (author RR), entries of 310 individuals were accurate, with a minor discrepancy in less than 3 items for another 5 individuals.

Various terminologies were used to report a case of DSH in the case records (for example, suicide attempt, failed suicide, self-harm, poisoning, deliberate harm).

DISCUSSION

This is the first description of a method of successfully setting up and maintaining a DSH register in an Indian setting. It was a labour-intensive exercise due of lack of electronic patient data management, administrative support and the absence of an agreed care pathway for DSH in the hospital. Despite these obstructions, we have illustrated that it is feasible to set up a DSH register in a busy tertiary care hospital in India. Results of our study indicate that the register details are accurate and representative of those who seek help from the specialist centre. However, it cannot capture those patients whose DSH was managed successfully within primary health centres, those individuals who failed to seek help and those who died before admission.

Clinical Implications

The experience of establishing a DSH register has lead to changes in local clinical practice. DSH is associated with increased morbidity and increased utilisation of health services.26 DSH survivors who were contacted (n=817) by the psychiatry residents were offered psychosocial assessments. Under normal circumstances, 708 (87%) of this group would not have received any psychosocial assessment. The process of setting up the register has helped to identify DSH cases so that an intervention can be offered before discharge from the general hospital. The register has also played a major role in the identification of people who harmed themselves but were discharged without admission to a ward. This group can also be helped. We have now developed an education and service information leaflet which includes emergency contact details (similar to a crisis card in the UK), which is given to DSH patients on discharge. These are known to decrease the repetition of DSH in the developed world.27 Deaths from suicide are largely preventable if knowledge and understanding of this maladaptive behaviour is used to ensure timely intervention.8

By auditing DSH data in a systematic way, clinical decision-making will be based on pooled experience, not just on each clinician’s recall. Comprehensive registers of DSH provide clinicians with the opportunity to review cases of suicide where they have had clinical involvement, using techniques such as psychological autopsy, improving clinical skills and judgements. Overall there is a need for an attitude of vigilance about suicide risk, and of enthusiasm about pursuing initiatives for suicide prevention based on evidence. Better understanding of self-harm will assist in devising means of reaching out to those at risk of dying without having had contact with health care services.

Reporting of DSH in case records was inconsistent. There is a need for uniform recording, medical coding and reporting of DSH. In the DSH register, the method of self-harm is recorded using an international recognised coding system (e.g. ICD-10).

If we continue to offer psychiatric assessment to all cases of DSH, the much higher rate of ascertainment arising from the DSH register will place further strain on an already stretched psychiatric service. Further investment in services specifically targeting self-harm in India is urgently needed.

Service Implications

Use of the register

The register creates an opportunity for a standing DSH audit, allowing for identification of trends over time and comparisons with other services that establish DSH registers using similar methods. Systematic collection of demographic and clinical data will allow calculation of admission rates, repetition rates and other indices of importance in service development. Collaboration with non-governmental organisations in the region who work with those who self-harm will allow development and evaluation of specific culturally appropriate interventions.

Where the register should be held?

In the developed world DSH registers are normally held on electronic systems in the Accident and Emergency department or liaison psychiatric services. In India, it is a mandatory obligation to hold a medico-legal register (which includes DSH) in casualty. Maintaining an additional DSH register risks unnecessary duplication, but modification of a medico-legal register creates an ethical problem and risks under-reporting. There are few liaison psychiatry services in India. On balance, we suggest that our practice of holding the DSH register within the department of adult psychiatry is the optimal arrangement in the Indian setting.

Confidentiality

Confidentiality must be respected. In the UK, when establishing a DSH register, it is necessary to discuss issues of confidentiality and legality with the local Data Protection Officer, and to register under the Data Protection Act. Use of the data for research purposes requires approval from local Research Ethics Committees. In India, there is little regulation of this sort. In order to establish our register it was only necessary to obtain consultant approval and consent through the local medical committee. We suggest that good practice would demand that standards of confidentiality and oversight should, as far as possible, match Western standards.

Manpower and resources

Setting up this register in Mysore required input by a Consultant Psychiatrist, for 2 sessions per week for 6 months, to negotiate with casualty medical officers, consultant physicians and reception staff. The resident from the psychiatry department spent at least 2 hours a day collating and updating the register. The absence of a patient electronic data system and lack of administrative support has placed additional strain on residents and has prolonged the time to identify a case of DSH from the casualty records and trace them on the medical wards. We believe that once the register is established, these tasks could be managed by a trained Social Worker spending 1 session per day collecting the data and 1 session per week editing the register. The work load might vary in other hospitals, depending on the number of daily hospital attendances for DSH.

Integration with other data sources

Linking this register with post mortem records, local civil registration of deaths and police records is desirable but this needs co-ordinated effort from several civil bodies and public health organisations. In the absence of any legislation or national record linkage systems, there are few motivators to drive this change or the allocation of resources. However, a unique person identification number system is presently being rolled out across India. The development of cross-agency electronic databases will facilitate easier record linkage in the future, which creates the opportunity for collection of reliable and representative data at a regional level.

None of those who were contacted during the study period had any formal input from Social Services. Though the models and mode of delivery by Social Services in India is radically different to those in Europe, DSH survivors form a stigmatised vulnerable group who are frequently in need of social assessment and support.

Future investment and development

There are good humanitarian reasons to seek the de-criminalisation of acts of self-harm in India, and there is presently strong lobbying to bring this about. It is reasonable to suppose that this might lead to readier help-seeking and better reporting of self-harm and suspected suicide. However, there are other measures that would be necessary to reduce rates of DSH and completed suicide. Regulating the supply of organophosphate insecticides, so that they are only available in dilutions that make fatal overdose more difficult, would be one such measure. There is also a need to develop liaison psychiatric services, offering psychosocial assessments to a higher proportion of those who present with features indicative of probable self-harm. Other necessary developments include investment in patient electronic records and systematic strategies for destigmatisation of DSH.

The register has provided us with a cohort of individuals who are willing to be contacted for future studies. The register has continued beyond the study period. We presently have 3720 individuals on the register. The unit has established formal links with research centres in the UK. We intend to carry out longitudinal studies to examine the patterns of DSH, rates of repetition, compliance with follow-up and suicide rates. This will help to identify the culture-specific access, adherence and prognostic factors, and will influence the development and validation of brief psychosocial interventions in a social, economic and cultural context that is radically different to the West.

CONCLUSIONS

We have illustrated that it is feasible to set up a DSH register in a busy tertiary care hospital in India where rates of self-harm are high. Results of our study indicate that the register details are accurate and representative of those who seek help from the specialist centre.

Very few were referred for psychosocial assessment following an act of self-harm and none of them had any formal input from Social Services. Though the models and mode of delivery by Social Services in India is radically different to those in Europe, DSH survivors form a stigmatised vulnerable group who are frequently in need of social assessment and support.

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
We thank Prof Raveesh, Head of the Department of Psychiatry MMCRI, Mysore, India and Prof Geeta Avadani Dean MMCRI Mysore for providing access to the hospital records, casualty and wards.
Competing Interests: 
None declared
Details of Authors: 
RAJAGOPAL RAJENDRA, Associate Professor, Department of Psychiatry, Mysore Medical College and Research Institute, Mysore, India. MURALI KRISHNA, Early Career Research Fellow, Wellcome Department of Biotechnology (DBT) Alliance and Consultant Psychiatrist at CSI Holdsworth Memorial Hospital, Mysore, India. SUMANTH M MAJGI, Assistant Professor, Department of Community Medicine , Mysore Medical College and Research Institute, Mysore, India. NARENDRA HEGGERE, Assistant Professor in Psychiatry, Department of Psychiatry, Mysore Medical College and Research Institute, Mysore, India. CATHERINE A. ROBINSON, Professor of Social Policy Research, Centre for Mental Health and Society, School of Social Sciences, Bangor University, United Kingdom. ROB POOLE, Professor of Social Psychiatry, Centre for Mental Health and Society, School of Social Sciences, Bangor University, United Kingdom.
Corresponding Author Details: 
DR MURALI KRISHNA, Early Career Research Fellow, Wellcome DBT Alliance and Consultant Psychiatrist at CSI Holdsworth Memorial Hospital, PO Bo 28 Mandi – Mohalla, Mysore, India PIN 570021
Corresponding Author Email: 
muralidoc@gmail.com
References
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3. Gunnell D, Eddleston M, Phillips MR, Konradsen F.  The global distribution of fatal pesticide self-poisoning: systematic review. BMC Public Health 2007; 7:357.

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9. Hawton K, van Heeringen K.  Suicide. Lancet 2009; 373(9672): 1372-1381.

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11. Radhakrishnan R, and Andrade C. Suicide: An Indian perspective. Indian J Psychiatry 2012; 54(4): 304-319.

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13. Bose A, Konradsen F, John J, Suganthy P, Muliyil J, Abraham S.  Mortality rate and years of life lost from unintentional injury and suicide in South India. Trop Med Int Health, 2006; 11:1553-1556.

14. Prasad J, Abraham VJ, Minz S, Abraham S, Joseph A, Muliyil J P, Jacob KS (2000).  Rates and factors associated with suicide in Kaniyambadi Block, Tamil Nadu, South India, 2000–2002. Int J Soc Psychiatry 2000; 52:65-71.

15. Gajalakshmi V, Peto R.  Suicide rates in rural Tamil Nadu, South India: Verbal autopsy of 39 000 deaths in 1997–98. Int J Epidemiol, 2007; 36(1): 203-207.

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Cervical ripening balloon as an alternative for induction of labour: a randomized controlled trial

Authors
Toh Lick Tan, Grace Yang Huang Ng, Sheri Ee-Lin Lim, Shephali Tagore, Ei Ei Phyo Kyaw and George Seow Heong Yeo
Article Citation and PDF Link
BJMP 2015;8(1):a806
Abstract / Summary
Abstract: 

Objective: To evaluate the use of cervical ripening balloon (CRB) for induction of labour (IOL) in Singapore.
Design: Prospective cohort randomised controlled study comparing CRB to Prostin (PGE) for IOL
Setting: Tertiary maternity hospital in Singapore.
Population: Women aged 21 to 40 years old for IOL in a singleton term pregnancy without major fetal anomaly suitable for vaginal delivery were recruited unless they were in labour, had cervical dilatation ³3 cm, ruptured membrane, abnormal CTG, scarred uterus or malpresentation.
Methods: Suitable women were recruited in the ante-natal period and randomized to receive either CRB or PGE on the day of IOL. Characteristics of the women, labour and birth outcomes, as well as their pain and satisfaction scores were obtained from case notes and by interviewing the women at IOL and after delivery.
Main Outcome Measures: Characteristics of participants, labour outcomes, birth outcomes.
Results: 98 women were enrolled for the study with 31 CRB and 52 PGE cases analysed. Both groups had similar maternal age, ethnic mix, proportion of primigravidae, weight, gestational age, cervical dilatation, indication for IOL, baby gender and birth weight. The induction to vaginal delivery time and vaginal delivery rate, as well as risk of low Apgar scores, meconium aspiration, pyrexia in labour, neonatal intensive care unit or intensive care unit admissions were also similar. Although only 1 (3.2%) in CRB arm failed to be induced compared with 9 (17.3%), this was not statistically significant (p = 0.082). Only 1 case of uterine hyperstimulation was observed and was from the PGE group.
Conclusions: Both CRB and PGE are effective and complementary methods for IOL. The availability of both methods in an obstetric unit will allow women and clinicians choice in their method of IOL.

Keywords: 
cervical ripening; Cook balloon; labour induction; mechanical ripening

Introduction

Increasing number of term deliveries undergo induction of labour (IOL). This figure is as high as 1 in 4 in developed countries, making it one of the most common procedures a woman may experience in pregnancy. 1 IOL may be achieved with pharmacological, mechanical or surgical methods. 1, 2 Mechanical methods were the first methods used to ripen the cervix and induce labour. The National Institute of Clinical Excellence (NICE) does not recommend the routine use of mechanical methods for IOL as only heterogeneous small studies were available at their time of publication more than half a decade ago. 2 However, since then there is increasing evidence of safety and efficacy of mechanical IOL. Subsequent publications including those from World Health Organization (WHO) and Cochrane Database of Systematic Reviews support the use of balloon catheter for IOL. 1, 3 It is therefore important to revisit the role of mechanical methods of IOL.

The Cochrane Database of Systematic Reviews concluded that mechanical methods of induction of labour have a lower risk of uterine hyperstimulation with similar caesarean section rates and delivery within 24 hours as prostaglandins. Furthermore, mechanical methods reduce the risk of caesarean section when compared with oxytocin induction of labour. 3 This review is consistent with another earlier systematic review. 4

Both Pfizer’s Prostin (PGE) and Cook Medical’s Cervical Ripening Balloon (CRB) are licensed for IOL. While the use of Prostin is a standard care in Singapore, the CRB has not been used routinely. We therefore propose a study to evaluate the use of CRB for IOL in Singapore.

Methods

A prospective cohort randomised controlled study was conducted in a tertiary referral maternity unit in Singapore. Pregnant women aged 21 – 40 years old with a singleton pregnancy with no major fetal anomaly who were suitable for vaginal delivery and scheduled for a planned IOL at 37+0 to 41+6 weeks gestation were invited for the study. Cases were excluded if at the start of the planned IOL, they were in spontaneous labour, had a cervical dilatation of ³3 cm, had confirmed rupture of membrane, had abnormal cardiotocogram (CTG), had a scarred uterus such as previous caesarean section, had malpresentation in labour, or if caesarean section delivery was indicated. Women who were unable to give or had withdrawn their consent to participate in the trial were also excluded for the study.

All suitable pregnant women receiving team care who require elective IOL were identified in antenatal clinic, antenatal or labour wards by the attending doctor or clinical research coordinator (CRC). Following routine counselling for IOL by the attending doctor, the woman will be offered participation in the study and a member of the research team will counsel and obtain informed consent from her. The woman will be made to understand that participation in the study is voluntary, does not affect her medical care and consent for participation can be withdrawn at any stage of the study. Women who were uncertain in their participation were offered the opportunity to participate during her follow-up or on the day of IOL after further consideration. Patient information leaflet on IOL as well as information of the study were made available to the participants.

On the day of the IOL, the participants were reviewed for the appropriateness of the IOL and participation in the study. A presentation scan, vaginal examination for cervical dilatation and CTG were performed. If they were suitable, they were randomly allocated PGE or CRB IOL in labour ward. Randomization was achieved with third party sealed envelope allocation. A total of 75 envelopes containing a folded paper with the words “Cervical Ripening Balloon” and another 75 identical envelopes containing a folded paper with the word “Prostin” were prepared and shuffled after sealing. These randomized envelopes were then labelled sequentially with their randomization allocation number from 1 to 150. The participants who underwent randomization were allocated to the next randomization allocation numbered envelop which contain either allocation for CRB or PGE IOL.

Participants undergoing CRB IOL will have the CRB inserted after cleaning the vulva and vagina with Cetrimide solution. The uterine and vaginal balloons of the CRB will be gradually inflated with normal saline, initially 40 ml and 20 ml respectively, and a further 20 ml each hour later until each balloon is 80 ml. CTG monitoring was undertaken before and after each inflation for at least 20 minutes. If the participant was not in labour after complete inflation of the balloons, she would be transferred to the antenatal wards for rest before removing the CRB 12 hours after insertion in labour ward when possible.

Participants undergoing PGE IOL will have 3 mg Prostin tablet inserted in the posterior fornix after cleaning the vulva with Cetrimide solution. CTG monitoring was also undertaken for at least 40 minutes after PGE insertion. If the participant was not in labour, she would be transferred to the antenatal wards. If there was no response to the first PGE, a repeat dose was given after 6 hours in labour ward when possible.

Participants will undergo artificial rupture of membrane (ARM) and/or oxytocin infusion augmentation of labour as necessary. If the participant was not in labour or ARM was not possible after removing the CRB or 2 cycles of PGE, the participant would have been considered having a failed IOL and will leave the study protocol with her subsequent management determined by the specialist attending to her. This would typically involve insertion of a third or first PGE in the PGE or CRB arm respectively.

Upon delivery of the pregnancy, a member of the research team will interview the participant and obtain demographics, labour and delivery outcomes data from the clinical notes. Pain and maternal satisfaction scores and comments were also recorded by interviewing the participants in the post-natal period; these findings will however be discussed separately.

The data was collected on a pro forma and entered into an excel spreadsheet. The data was then analysed using IBM SPSS Statistics version 19.

This study was approved by the SingHealth centralised institutional review board with the reference number of 2013/553/D.

Results

A total of 138 women were approached to join the study but 40 (29.0%) women declined. There was no significant difference in maternal age (27.8 ± 5.4 vs 28.7 ± 5.2 years; p = 0.373), ethnicity, proportion of primigravidae (62.5% vs 53.1%; p = 0.349), weight (61.2 ± 15.4 vs 64.4 ± 13.8 kg; p = 0.228), BMI (24.8 ± 5.8 vs 25.3 ± 5.0 kg/m2; p = 0.646) and primary indication for IOL between women who declined and accepted enrolment to the study respectively.

The remaining 98 women were enrolled for the study. Eight-seven women were randomized after excluding 6 women in spontaneous labour, 1 woman with non-cephalic fetal presentation, and 1 woman had confirmed ruptured of membrane on admission for their IOL, as well as 3 other cases in which the women presented for IOL without the availability of the research team (figure 1).

Figure 1. Flow diagram of recruitment, randomisation and completion status

In the CRB arm, one woman withdrew from the study after 8 hours 55 minutes as she felt the discomfort was too unbearable. Another woman was excluded when she was found to have spontaneous version to breech in labour. One woman randomized to PGE did not receive it as she went into spontaneous labour prior to IOL. Another woman in the PGE arm was subsequently found to be only 36+3 weeks and was therefore excluded from analysis (figure 1). The remaining 83 cases were analysed and their characteristics are shown in table 1.

The induction to vaginal delivery time, as well as, vaginal delivery rate were similar in both arms of the study (table 2). Compared to PGE arm, participants undergoing CRB IOL were faster in achieving cervical dilatation ≥4 cm (14.4 ± 5.7 vs 23.5 ± 16.6 hr; p = 0.001) and requesting epidural (16.4 ± 5.4 vs 23.2 ± 15.8 hr; p = 0.040), as well as more likely to require oxytocin infusion for augmentation (77.4% vs 50.0%; p = 0.020). Uterine hyperstimulation defined as >5 contractions every 10 minutes was only found in PGE arm. Cervical dilatation from 0 – 2 cm to ≥4 cm was achieved without regular contractions in 2 (6.9%) cases in the CRB arm and 1 (2.4%) case in the PGE arm. The mean frequency of uterine contractions at cervical dilatation ≥4 cm was 2.5 ± 1.4 in 10 minutes for CRB arm compared to 3.8 ± 1.4 in 10 minutes for PGE arm (p <0.001). No case of uterine rupture was observed.

There was 1 (3.2%) case for failed CRB IOL where both uterine and cervical balloons were found in the vagina suggesting that either placement of the uterine balloon was not optimal or it was expelled after placement. The woman went on to have Prostin and delivered vaginally. In the 9 (17.3%) cases in the PGE group that did not respond after 2 cycles, all went on to have the third Prostin successfully except for 2 women who required Caesarean section for persistent failed IOL.

The birth outcomes of both arms of the study were also similar with no case of stillbirth (table 3). There were 2 case of neonatal intensive care unit admission in the PGE arm for continuous positive airway pressure therapy; both were discharged from NICU within 24 hours.

Table 1. Characteristics of participants undergoing cervical ripening balloon (CRB) and Prostin (PGE) induction of labour.

  CRB (n = 31) PGE (n = 52) p
Maternal age, years (83) 1 28.2 ± 5.3 28.7 ± 5.0 0.646
Ethnicity (83) 2         0.222
· Chinese 35.5% (11) 42.3% (22)  
· Malay 54.8% (17) 36.5% (19)  
· Indian 3.2% (1) 15.4% (8)  
· Others 6.5% (2) 5.8% (3)  
Primigravidae (83) 2 61.3% (19) 44.2% (23) 0.174
Weight, kg (83) 1 64.4 ± 15.0 63.9.4 ± 13.2 0.861
BMI, kg m-2 (83) 1 25.5 ± 5.0 25.0 ± 5.1 0.706
Pre delivery Hb, g dl-1 (80) 1 11.6 ± 1.8 12.0 ± 1.3 0.211
GBS positive (79) 2 22.6% (7) 21.2% (11) 0.204
Gestational age, weeks (83) 1 39.4 ± 1.1 39.2 ± 1.9 0.357
Cervical dilatation, cm (83) 1 1.0 ± 0.7 0.9 ± 0.7 0.954
Primary indication for IOL (83) 2         0.108
· Decreased fetal movement 3 -   11.5% (6) 0.082
· Post dates 3 54.8% (17) 32.7% (17) 0.065
· Gestational diabetes 3 16.1% (5) 13.5% (7) 0.756
· Impending macrosomia 3 -   1.9% (1) 0.526
· IUGR 3 3.2% (1) -   0.137
· Low amniotic fluid index 3 19.4% (6) 34.6% (18) 0.089
· Maternal request 3 3.2% (1) 5.8% (3) 0.489
· Pre-eclampsia 3 3.2% (1) -   0.373

1 Values are mean ± SD, p calculated with Student t-test; 2 Values are percentage (n), p calculated with Pearson chi-square test; 3 Values are percentage (n), p calculated with Fisher’s exact test.

Table 2. Labour outcomes of participants undergoing cervical ripening balloon (CRB) and Prostin (PGE) induction of labour.

  CRB (n = 31) PGE (n = 52) p
IOL to ≥4 cm dilatation, hr (78) 1 14.4 ± 5.7 23.5 ± 16.6 0.001
IOL to full dilatation, hr (66) 1 20.8 ± 6.1 24.8 ± 15.7 0.150
IOL to vaginal delivery, hr (63) 1 21.2 ± 6.8 25.6 ± 16.1 0.136
Duration of 2nd stage, hr (63) 1 0.9 ± 2.9 0.8 ± 0.9 0.741
Delivery within 24 hr (83) 2 77.3% (17) 61.0% (25) 0.265
Failed IOL (83) 3 3.2% (1) 17.3% (9) 0.082
Number of PGE used (83) 2         <0.001
· 0 96.8% (30) -    
· 1 3.2% (1) 53.8% (28)  
· 2 -   28.8% (15)  
· 3 -   17.3% (9)  
Augmentation use (83) 3 77.4% (24) 50.0% (26) 0.020
           
Epidural use (83) 3 58.1% (18) 55.8% (29) 1.000
· IOL to epidural use, hr (47) 1 16.4 ± 5.4 23.2 ± 15.8 0.040
· Epidural use to delivery, hr (47) 1 9.2 ± 4.1 7.0 ± 3.8 0.065
Contractions 1          
· At IOL (83) 0.2 ± 0.6 0.2 ± 0.5 0.579
· 3 hr after IOL (81) 2.0 ± 1.9 1.6 ± 1.9 0.451
Contractions >5 every 10 min 3          
· 30 min after IOL (81) -   -   -
· 3 hr after IOL (81) -   2.0% (1) 1.000
Vaginal delivery (83) 3 71.0% (22) 78.8% (41) 0.438
Indication for LSCS (20) 2         0.513
· Failed IOL -   18.2% (2)  
· FTP in 1st stage of labour 55.6% (5) 36.4% (4)  
· FTP in 2nd stage of labour 22.2% (2) 9.1% (1)  
· NRFS 11.1% (1) 27.3% (3)  
· FTP and NRFS 11.1% (1) 9.1% (1)  

1 Values are mean ± SD, p calculated with Student t-test; 2 Values are percentage (n), p calculated with Pearson chi-square test; 3 Values are percentage (n), p calculated with Fisher exact test.

Table 3. Birth outcomes of participants undergoing cervical ripening balloon (CRB) and Prostin (PGE) induction of labour.

  CRB (n = 31) PGE2 (n = 52) p
Male fetus (83) 2 51.6% (16) 42.3% (22) 0.496
Birth weight, g (83) 1 3,166 ± 478 3,094 ± 417 0.472
Apgar at 5 min <7 (83) -   -   -
Meconium aspiration (83) -   -   -
Pyrexia in labour (83) 3 6.5% (2) 5.8% (3) 1.000
NICU admission (83) 2 -   3.8% (2) 0.526
ITU admission (83) -   -   -

1 Values are mean ± SD, p calculated with Student t-test; 2 Values are percentage (n), p calculated with Pearson chi-square test; 3 Values are percentage (n), p calculated with Fisher exact test.

Discussion

To the best of our knowledge, this is the first randomized controlled study to assess the use of CRB for IOL in Singapore. Our study concur with the published literature that both CRB and PGE have similar rate of vaginal deliveries and rate of deliveries within 24 hours. Both methods are effective and safe with PGE having a higher risk of uterine hyperstimulation and need for Caesarean section for failed IOL.

Pharmacological induction of labour using PGE is the most established form of IOL. However, it is important to be able to offer alternative methods to women particularly in cases of hypersensitivity or allergy to PGE. PGE can cause bronchospasm complicating asthma, a medical condition which affects 4 – 12% of pregnant women. 5, 6 Similarly, caution should be exercised in the use of PGE in women with other common medical conditions such as hypertension and epilepsy.

In addition, women may not respond to PGE for IOL, or the PGE may only result in uterine tightenings which do not lead to cervical dilatation. In these situations the CRB may be considered as an adjunct for IOL to avoid Caesarean section of ‘failed IOL’.

The risk of uterine hyperstimulation and the need for a repeat dose in 6 to 8 hours for PGE typically require the women to be admitted for IOL. The use of CRB does not require planned intervention until 12 hours later. This potentially allows an outpatient IOL if further studies support its safety in this aspect.

The application of PGE is relatively straightforward and is already performed by both doctors and midwives. The insertion of CRB may however be considered too invasive for midwives thus limiting the type and hence availability of staff to commence IOL. We have explored the learning curve in the insertion of CRB and will discuss this separately.

Conclusion

Both CRB and PGE are effective methods for IOL at term. Each method has its own benefits and limitations. The availability of both methods in an obstetric unit will allow the clinician to choose the most appropriate form of IOL, provide a complementary method of IOL, as well as offer women choice in their IOL.

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
We are grateful for the supply of cervical ripening balloons for the study provided by Cook Medical.
Competing Interests: 
None declared
Details of Authors: 
TOH LICK TAN , MBBS MRCOG, Department of Obstetrics and Gynaecology, KK Women’s and Children’s Hospital, Singapore. GRACE YANG HUANG NG, MBChB, Department of Obstetrics and Gynaecology, KK Women’s and Children’s Hospital, Singapore. SHERI EE-LIN LIM, MBBS PhD MRCOG, Department of Obstetrics and Gynaecology, KK Women’s and Children’s Hospital, Singapore. SHEPHALI TAGORE, MBBS MRCOG, Department of Maternal Fetal Medicine, KK Women’s and Children’s Hospital, Singapore. EI EI PHYO KYAW, BDS, BSc (Hons) , Department of Maternal Fetal Medicine, KK Women’s and Children’s Hospital, Singapore. GEORGE SEOW HEONG YEO, MBBS FRCOG FAMS, Department of Maternal Fetal Medicine, KK Women’s and Children’s Hospital, Singapore.
Corresponding Author Details: 
Dr Tan Toh Lick, Department of Obstetrics and Gynaecology, KK Women’s and Children’s Hospital, 100 Bukit Timah Road, Singapore 229899, Singapore.
Corresponding Author Email: 
tan.toh.lick@kkh.com.sg
References
References: 
  1. WHO recommendations for Induction of labour. Geneva, World Health Organization, 2011.
  2. National Collaborating Centre for Women’s and Children’s Health. Induction of labour. London: RCOG Press; 2008.
  3. Jozwiak M, Bloemenkamp KW, Kelly AJ, Mol BW, Irion O, Boulvain M. Mechanical methods for induction of labour. Cochrane Database Syst Rev. 2012 Mar 14;3.
  4. Vaknin Z, Kurzweil Y, Sherman D. Foley catheter balloon vs locally applied prostaglandins for cervical ripening and labor induction: a systematic review and metaanalysis. 11. Am J Obstet Gynecol. 2010 Nov; 203(5): 418-29.
  5. Rey E, Boulet LP. Asthma in pregnancy. BMJ 2007; 334: 582–5.
  6. Kwon HL, Belanger K, Bracken MB. Asthma prevalence among pregnant and childbearing-aged women in the United States: estimates from national health surveys. Ann Epidemiol 2003; 13: 317–24.

25 years of Hallucinogen Persisting Perception Disorder- A diagnostic challenge

Authors
Fabida Noushad, Qutaiba Al Hillawi, Vasantha Siram and Muhammad Arif
Article Citation and PDF Link
BJMP 2015;8(1):a805
Abstract / Summary
Abstract: 

We present an interesting case of a forty eight year old man who took LSD in his early twenties. He continued to experience visual perceptual disturbances for 25 years following cessation of the hallucinogen.  This is a unique case, where symptoms of hallucinogen persisting perception disorder have persisted for over two decades after the cessation of Lysergic acid diethylamide. He was treated with clonazepam 1 mg four times a day with good effect. There is a need for raising awareness about this condition to prevent misdiagnosis and delay in appropriate treatment.

Abbreviations: 
EEG- electroencephalogram, MRI- magnetic resonance imaging, LSD- Lysergic acid diethylamide, DSM- Diagnostic and statistical manual, HPPD: Hallucinogen persisting perceptual disorder, SSRI- selective serotonin reuptake inhibitors.
Keywords: 
LSD- Lysergic acid diethylamide

Case report

A forty-eight year old man presented with unusual and distressing visual experiences with varying degrees of severity for over twenty years. Some of these included the following; red objects having a green shimmer around them like 3-D glasses, altered sense for distance estimation, people’s faces seeming to change shape when looked at, alteration of own reflection, anything patterned appearing to move all the time, words moving about while reading, things appearing to be multi-layered, bright lights throwing up shadows, vehicles appearing to stretch as they drive past, flying birds looking like animation and difficulty in focussing.

When present, his symptoms interfered markedly with his functioning. For example, he could not cross the road, could not read, and had to dim his lights. He struggled with knowing which visual perceptions were real and which were not. The patient felt his visual experiences were related to his past LSD use twenty-five years ago. He felt the drug had put him “in a coma” and he was “dreaming all of this”.

He specifically remembered a party with friends where he took a cocktail of illicit drugs, including LSD and marijuana, with alcohol. He said he would usually take drugs and alcohol in a binge pattern. The ‘trips’ would usually last twelve hours. He felt he experienced some memory loss of that particular night. When he woke up the next morning he was still experiencing the effects of LSD and said he has felt these effects ever since. He tried to explain that it was like drinking alcohol, waking up drunk and being drunk from that point on. After this incident he did not use illicit drugs again.

Prior to this particular night he said he may have used LSD about fifteen times, as Microdot tablets, usually one at a time, with cannabis. He said it was “like having a tripping switch in your brain”. When you took LSD, “the switch turned the tripping on and after a while it turned off”. He said his switch “was broken” and he therefore continued to re-experience the effects of the drug.

His other complaint was that of feeling he was “not real”; to the extent he even thought he should harm his family members so he could prove he was real.

He also complained of low mood, decreased concentration, anxiety and an inability to cope.

His first contact with mental health services was at the age twenty two years. He presented with symptoms of anxiety but it was not felt he had a mental illness. He was referred again a year later and was diagnosed to have Primary Depersonalization syndrome.

The patient himself reported that all his symptoms started after he had used LSD about fifteen times in six months. At the time he had described having undergone a complete personality change due to his experiences. He felt objects and experiences had a dream-like quality. His visual experiences caused so much distress he felt suicidal.

Over the next twenty-five years he has had various other diagnoses; LSD induced Depersonalisation Syndrome, Depersonalisation-Derealisation Syndrome, LSD induced Simple schizophrenia, depressive disorder and anxiety disorders. His visual disturbances had been interpreted as visual hallucinations. He had received treatment with antidepressants (Imipramine, Amitriptyline, and Venlafaxine); antipsychotics (Trifluperazine, Promazine); Benzodiazepines (Diazepam); Propranolol; and Fentazine. He was also prescribed Hydergine (which helped reduce symptoms briefly) at one point.

Investigations: EEG, MRI Brain, and Carotid ultrasound were normal.

He was admitted to a psychiatric hospital at the age of forty-eight years old where the admitting doctor described his symptoms as visual hallucinations and started him on Risperidone, which increased the intensity of his symptoms. He was also treated with Citalopram for his low mood. It was noted that his symptoms were different from common psychotic illnesses. Detailed history taking and assessment of his perceptual abnormalities over the following few weeks in hospital confirmed the diagnosis of hallucinogen persisting perception disorder (HPPD).

He was treated with Clonazepam 1 mg four times a day with good effect; as seen by the reduction of symptoms - see Table 1.

Table 1:

DSM IV/V Symptom Checklist Prior to treatment with Clonazepam 3 months after initiation of Clonazepam treatment
Geometric hallucinations Present Absent
False perception of movement in peripheral fields Present Absent
Flashes of colour Present Absent
Intensified colours Present Absent
Trails of images of moving objects Present Absent
Positive after images Present Absent
Halos around objects Present Present but reduced in intensity and frequency
Macropsia Present Absent
Micropsia Present Absent

After discharge he had .a depressive episode and was treated with Escitalopram. This was later changed to Reboxetine.

Discussion:

This is the first case that we are aware of where symptoms of HPPD have persisted for over two decades after the cessation of the use of Lysergic acid diethylamide. There is a need for raising awareness about this condition to prevent misdiagnosis and delay in appropriate treatment.

This patient presented to psychiatric services over twenty-five years ago and at that time he felt his symptoms were related to his use of LSD. He was given a variety of different diagnoses before the correct diagnosis was established and treatment initiated with good outcome.

The patient had also experienced migraines and used alcohol excessively on occasions in the past. Although we are not aware of any connection between this disorder and these factors, future reports and studies may help provide further knowledge in these areas.

HPPD is a recognised condition described in DSM V and DSM IV with a diagnostic code 292.89. In DSM III it was referred to as post hallucinogen perception disorder (PHPD). It is described in ICD 10 under the code F16.983.

LSD has been known to alter perception and mood in the presence of an unaltered sensorium. HPPD was first described by Eisner and Cohen, who observed spontaneous recurrences of LSD like states in subjects, days to weeks following cessation of drug use1.

Other authors have described more or less the same clinical picture; for example, Rosenthal described patients suffering from post drug visual hallucinations lasting as long as five months from the time of drug use2

In a survey of sixty five users of LSD, Holsten found fifty users who described post LSD disturbances eighteen months to four years later3.

Flashbacks have been suggested to be a misnomer as patients described cases of continuous rather than paroxysmal visual disturbances from LSD 4

It is not clear what made our patient re-experience these visual disturbances however the literature suggests that emerging into a dark environment can precipitate or exacerbate post LSD visual symptoms. Among other precipitating factors are intentional inductions, marijuana use, medications like: neuroleptics (phenothiazine), amphetamines, cold remedies, anti-Parkinson’s agents and SSRI’s5.

The patient mentioned that he had ingested LSD approximately fifteen times before he developed this condition. The data suggests that peak incidence occurs with fifteen exposures and second smaller peaks at around forty to fifty exposures 6.

A number of hypotheses have been formulated in order to understand the underlying aetiology. HPPD is related to the recreation of symptoms experienced in intoxication. LSD has been shown to be excitotoxic to neurons. It is also known to be a partial agonist at post synaptic 5HT2 receptors and enhances glutaminergic transmission.

The patient had suffered from these rather distressing visual disturbances for more than two decades, which have had considerable impact on his daily living. He was given different diagnoses which included Induced depersonalisation, depersonalisation-derealisation syndrome, LSD induced simple schizophrenia, depressive disorder and anxiety disorders.

The patient had been treated with different psychotropic medications including antidepressants, antipsychotics, benzodiazepines, propranolol, fentazine and hydergine. Some had little effect like hydergine, whilst others worsened symptoms, in particular antipsychotic medications.

A case series of three HPPD patients treated with Risperidone reported an exacerbation of LSD-like panic and visual symptoms. Thus from these reports and our case report Risperidone could be contraindicated in patients with HPPD 7.

There have been some published case reports on treatment of HPPD, including the use of Reboxetine, which suggest it is beneficial in the treatment of the visual disturbances and depressive features associated with HPPD. This is possibly due to its alpha 2 adrenoceptor modulating effect on both Noradrenaline and Serotonin release8. Another case report suggested the use of a combination of Fluoxetine and Olanzapine in the treatment of HPPD9.

Benzodiazepines seem to be the most beneficial treatment so far and Clonazepam is the most effective due to its high potency compared to low potency Benzos and its long action at the GABA receptors10.

Conclusion:

Hallucinogen Persisting Perception Disorder is one of the outcomes associated with the ingestion of LSD. Symptoms can be present for years as demonstrated by different case reports, and for over two decades as reported in this report. The effect could be devastating to the person experiencing extremely distressing and disturbing perceptual phenomenon. It can last up to twenty five years after the cessation of the hallucinogenic drug. Early diagnosis and appropriate treatment can significantly help improve the quality of life of patients with this condition.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
FABIDA NOUSHAD, MRCPsych, Consultant Psychiatrist, Leicestershire Partnership NHS Trust, UK. QUTAIBA AL HILLAWI, MRCPsych, Speciality Trainee ST6, Norfolk And Suffolk Foundation Trust, UK. VASANTHA SIRAM, MRCPsych, Specialty Trainee ST4, Leicestershire Partnership NHS Trust, UK. MUHAMMAD ARIF, MRCpsych, Consultant Psychiatrist, Leicestershire Partnership NHS Trust, UK.
Corresponding Author Details: 
DR MUHAMMAD ARIF, Consultant Psychiatrist, Bradgate Mental Health Unit, Groby Road, Leicester, LE3 9EJ, UK.
Corresponding Author Email: 
muhammad.arif@leicspart.nhs.uk
References
References: 
  1. Rosenthal, S. H. (1964) Persistent Hallucinosis following repeated administration of hallucinogenic drugs, American Journal of Psychiatry, 121, pp. 238-244
  2. Robbins, E., Frosch, W. A. and Stern, M. (1967) Further observations on Untoward Reactions to LSD, American Journal Of Psychiatry, 124, pp. 393-395
  3. Holsten, F. (1976) Flashbacks: Clinical and social significance 1 ½-4 years after the first admission , Journal of Norwegian Medical Association; 96: 875-878
  4. Anderson, WH, O’Malley, JE (1972) Trifluperazine for the “Trailing” phenomenon. Journal of American Medical Association, 220: 1244-1245
  5. Abraham, H.D. (1983) Visual Phenomenology of the LSD flashbacks, Archives of General Psychiatry, 40, pp. 884-889
  6. Abraham HD, Visual phenomenology of the LSD flashbacks. Archives of General Psychiatry. 1983; 40:884-889
  7. Abraham, Henry David MD, Mamen, Anita MD. LSD like Panic from Risperidone in post-LSD Visual Disorder. Journal of Clinical Psychopharmacology: June 1996; Volume 16; Issue 3: 238- 241
  8. Lerner AG, Shufman E, Kodesh A, Kretzmer G, Sigal M. LSD induced Hallucinogen Persisting Perception Disorder with depressive features treated with Reboxetine. Israel Journal of Psychiatry and Related Sciences; 2002; 39(2):100-3
  9. Aldurra, G; Crayton, J. Improvement of Hallucinogen-Induced Persistent Perception disorder by Treatment with a Combination of Fluoxetine and Olanzapine: Case report; letter to the editor; Journal of Clinical Psychopharmacology. June 2001- Volume 21- Issue 3- pp 343-344
  10. Lerner AG; Gelkopf M; Skladman I; Rudinski D; Nachshon; Bleich A. Clonazepam treatment of Lysergic acid diethylamide induced hallucinogen persisting perception disorder with anxiety features, International Clinical Psychopharmacology 2003, Volume 18- Issue 2 : 101-105

Current management of oesophageal cancer

Authors
Naufal Rashid, Mohamed Elshaer, Michael Kosmin and Amjid Riaz.
Article Citation and PDF Link
BJMP 2015;8(1):a804
Abstract / Summary
Abstract: 

Background: Oesophageal cancer is the eighth most common cancer and it’s the sixth leading cause of death in the world. The five years overall survival is reported to be between 15-20%. The aim of this review is to highlight the current trends of management of oesophageal cancer.

Methods: A literature search of PubMed/MEDLINE, EMBASE and Cochrane Library and Central Register of Controlled Trials (CENTRAL) databases up to November 2014 was conducted.

Results: Oesophageal cancer accounts for almost 3% of all cancers and is the ninth most common malignancy in the UK. Diagnosis is usually made by oesophago-gastro-duodenoscopy where multiple biopsy samples must be taken from any mucosal abnormality to exclude early tumours. The management of oesophageal cancers requires a multi-disciplinary team approach involving surgeons, oncologists, radiologists, pathologists, specialist nurses, dietitians and specialists from other specialties if required.

Conclusions: Treatment of oesophageal cancer is still a challenge however recent advances in surgery, endoscopic treatments and new therapeutic agents will hopefully improve prognosis.

Keywords: 
Oesophageal cancer, staging, Transhiatal oesophagectomy, Ivor-Lewis oesophagectomy, chemotherapy.

Introduction

Oesophageal cancer (OC) is the eighth most common cancer affecting an estimated 481,000 people worldwide with a rapidly rising incidence. Due to the poor prognosis of patients with these cancers it is the sixth leading cause of cancer related mortality with 406,000 deaths.1,2 Although the overall 5-year survival has increased from 4% in the 1970s3 to currently ranging between 15 to 20%4, it remains a challenge to treat as clinical presentation is often late and diagnosis is made at advanced stages. Incidence and mortality rates for OCs are two fold higher in males compared to females, however this ratio rises to up to 5-10:1 for oesophageal adenocarcinomas. Cohort studies have shown that the incidence of OC increases with age; the average of onset is between 65 to 70 years. 14 This article seeks to discuss the epidemiology, diagnosis and staging, prevention and current trends in the management of OC.

Methods

We searched PubMed/MEDLINE, EMBASE and Cochrane Library and Central Register of Controlled Trials (CENTRAL) databases up to November 2014. Our search strategy used a combination of MeSH, textwords, and appropriate words variants of “oesophagus”, “cancer”, “epidemiology”, “adenocarcinoma”, or “squamous cell carcinoma”, and “staging”, “transhiatal oesophagectomy”, “transthoracic oesophagectomy”, “chemotherapy”, “radiotherapy”. This was supplemented with selected systematic reviews, evidence based guidelines and consensus statements.

Epidemiology

There have been major changes in the epidemiology of OC over the last thirty years. The two key histological types of OC are adenocarcinoma and squamous cell carcinoma (SCC) and they differ significantly in their fundamental patterns of incidence and aetiological factors. Oesophageal SCC comprises the majority of cases worldwide and represents 90% of all OCs in most Eastern countries. However the incidence of adenocarcinoma has risen rapidly over the last three decades and it is now the predominant histological type in Western Europe, USA and Australia, particularly amongst white males.5, 6 There are other rare histological types, which include lymphoma, leiomyosarcoma, melanoma, rhabdomyosarcoma and small cell carcinoma.7 OC accounts for almost 3% of all cancers in the UK and is the ninth most common malignancy in the UK. There were 8,173 new cases in 2008; incidence rates have increased over the last thirty years in the UK and are now one of the highest in Europe.8 Incidence rates of OC differ markedly by geographical locations and between ethnic groups; overall, rates are twice as high in less developed regions compared with more-developed regions and the highest rates occur in Asia. In this region, especially in Iran, Turkey, Kazakhstan and China, a very high incidence of oesophageal SCC exists with greater than 100 cases per 100,000 population annually. A similar trend is also seen in South Africa.9-12 In contrast, the rate of rise in incidence of oesophageal adenocarcinoma in more-developed countries has exceeded that of oesophageal SCC, which has remained the same or decreased. Oesophageal adenocarcinoma now comprises approximately 50% of all OCs in these countries. 13

Who gets oesophageal cancer?

The aetiology of OC is multifactorial, with interactions between environmental risk exposures and genetic factors. These can be divided between the two different histological types of OC.

Pathology of oesophageal tumours

Oesophageal tumours are classified as epithelial and non epithelial. Epithelial tumours include papilloma, intraepithelial neoplasia, carcinoma and carcinoid tumours. Non epithelial tumours include leiomyoma, lipoma and gastrointestinal stromal tumours (Table 1).

Table 1: WHO histological classification of oesophageal tumours

Epithelial Non Epithelial
Squamous cell papilloma Intraepithelial neoplasia
· Squamous
· Glandular (adenoma)
Carcinoma
· Squamous cell carcinoma
· Verrucous (squamous) carcinoma
· Basaloid squamous cell carcinoma
· Spindle cell (squamous) carcinoma
· Adenocarcinoma
· Adenosquamous carcinoma
· Mucoepidermoid carcinoma
· Adenoid cystic carcinoma
· Small cell carcinoma
· Undifferentiated carcinoma
· Others
Carcinoid tumour
Leiomyoma Lipoma
Granular cell tumour
Gastrointestinal stromal tumour
· benign
· uncertain malignant potential
· malignant
Leiomyosarcoma
Rhabdomyosarcoma
Kaposi sarcoma
Malignant melanoma
Others
Secondary tumours

Oesophageal adenocarcinoma

Established risk factors for oesophageal adenocarcinoma (Fig. 1) include gastro-oesophageal reflux disease, Barrett’s oesophagus, obesity, male sex, tobacco smoking and a low intake of fruit and vegetables.15, 16 There is evidence to suggest that previous infection with Helicobacter Pylori and the use of non-steroidal anti-inflammatory drugs may decrease the risk of OC. 17

Fig. 1: Adenocarcinoma of the oesophagus (from Lewin et al. Gastrointestinal pathology and its clinical implications)

Barrett’s oesophagus (Fig. 2) occurs when there is metaplastic change in the lining of the oesophagus from normal stratified squamous mucosa to single layered columnar glandular mucosa with variable degrees of goblet cell differentiation.18 This transition usually occurs in the context of chronic gastro-oesophageal reflux disease, which causes exposure of the epithelium to refluxate. Gastro-oesophageal reflux disease is a major contributory factor and 5% of people with reflux disease develop Barrett’s oesophagus. The estimated prevalence of Barrett’s oesophagus is just under 2% amongst adults in the West and the annual incidence is approximately 0.1%. However, there is evidence to suggest that the rate of diagnosis is increasing by 2% annually.19 There has been a rise in the incidence of gastro-oesophageal reflux disease, which may be explained by a number of factors. The rise in the prevalence of obesity, specifically central and intra-abdominal obesity has been found to have a link with oesophageal adenocarcinoma. This can be explained by the fact that an increase in adiposity will cause a rise in intra-abdominal pressure thereby increasing reflux that may be asymptomatic. However, studies also suggest that obesity is a strong independent risk factor for oesophageal adenocarcinoma regardless of gastro-oesophageal reflux symptoms implying an underlying link. 20, 21 Another factor that may contribute to the rise in reflux disease is the increased use of drugs that relax the lower oesophageal sphincter. There is evidence to suggest that individuals with previous H. Pylori infections are less likely to develop oesophageal adenocarcinoma.22 This might be explained by the gastric atrophy that results from this infection, which will reduce the acidity and quantity of gastric secretions and thus decreasing the chances of gastro-oesophageal reflux. However, the prevalence of H. Pylori infections is decreasing in the Western population, which may contribute to the rising incidence of oesophageal adenocarcinoma. Gastro-oesophageal junction (GOJ) adenocarcinoma was classified by Siewert and Stein into three types. Type I arises from 1 to 5 cm proximal to the GOJ (tumours of the distal oesophagus), type II arises from 1 cm proximal to 2 cm distal to the GOJ (true cardiacarcinoma), and type III arises from 2 to 5 cm distal to the GOJ (subcardial gastric carcinoma). 61

Fig. 2: Barrett’s oesophagus (adapted from WHO classification of oesophageal tumours)

Oesophageal squamous cell carcinoma

The major risk factors for the development of oesophageal SCC (Fig. 3,4) are tobacco use and alcohol consumption; particularly a combination of both.23, 24 Nitrosamine exposure in tobacco smoking and the alcohol metabolite aldehyde, which is a known carcinogen, are probably the underlying reasons for these two risk factors. The high incidence of oesophageal SCC in Northern China, Iran and areas of Southern Africa may be related to a diet rich in nitrosamines and deficient in trace elements and vitamins A & C.

Other risk factors for oesophageal SCC in the Western world include low socioeconomic status, poor oral hygiene, achalasia, history of thoracic radiation, caustic injury, hereditary tylosis and Plummer-Vinson Syndrome.25

Fig. 3: Squamous cell carcinoma of the oesophagus

Fig. 4: Microscopic picture of squamous cell carcinoma (adapted from WHO classification of oesophageal tumours)

How does oesophageal cancer present clinically?

Patients presenting with symptoms of OC almost invariably have advanced disease. The most common presenting symptom is progressive dysphagia with 74% of patients reporting difficulty swallowing.26 This is graded according to the following: 27

  • Grade 1: Able to swallow most foods
  • Grade 2: Able to swallow soft foods only
  • Grade 3: Able to swallow liquids only
  • Grade 4: Unable to swallow anything

17% of patients will also report pain on swallowing food and liquids (odynophagia). 26 Typically, patients with oesophageal adenocarcinoma will be white males with a background of gastro-oesophageal reflux disease who have developed dysphagia. On the other hand, patients with oesophageal SCC will present with dysphagia, associated with weight loss and a history of smoking and increased alcohol intake may exist.

Other less common symptoms include dyspnoea, cough, hoarseness, acute haemorrhage and pain which may be retrosternal, back or right upper abdominal. These will usually represent the existence of metastatic disease.

Physical examination is often normal; positive clinical findings may include cachexia, lymphadenopathy and hepatomegaly in the presence of metastases.

How is oesophageal cancer diagnosed?

It is essential to have a low threshold if cancers are to be detected at an early, treatable stage. National Institute for Health and Clinical Excellence (NICE) guidelines state that a patient presenting with symptoms suggestive of upper gastrointestinal cancer should be referred to a team specialising in the management of these cancers. Specifically; patients of any age presenting with dyspepsia in association with alarm symptoms should be urgently referred for endoscopy or to a specialist. The classical ‘alarm’ symptoms associated with OC includes dysphagia, vomiting, anorexia, weight loss and symptoms associated with gastro-intestinal blood loss. Patients aged 55 or more with persistent, recent onset, and unexplained dyspepsia should be referred urgently for an endoscopy.

Diagnosis is usually made by oesophago-gastro-duodenoscopy where multiple biopsy samples must be taken from any mucosal abnormality to exclude early tumours. Suspicious lesions including oesophageal strictures may require repeated biopsies if initial results are negative.

Once diagnosis is made patients should be urgently referred to an Upper Gastro-intestinal team at a specialist centre for investigations to stage disease and further management.

Staging oesophageal cancers

It is essential to accurately stage disease to exclude patients with widespread metastatic disease for whom surgery will not be curative and to identify subgroups of patients who will require neo-adjuvant therapies. Whilst it is difficult to completely eliminate the possibility of ‘open and shut’ cases where tumours are found to be inoperable at the time of surgery; it is important to develop a staging strategy with investigations and procedures that help to minimise this risk. The TNM (Tumour, Node, Metastasis) staging system is used to classify the depth of tumour invasion into or through the oesophageal wall, the status of regional lymph nodes and metastases to distant sites. The TNM7 categories are shown in Tables 2 and the current stage groupings is shown in Table 3. 28

Table 2: TNM7 staging system

Primary Tumour (T)
TX Primary tumour cannot be assessed
T0 No evidence of primary tumour
Tis High-grade dysplasia
T1 Tumour invades lamina propria, muscularis mucosae, or submocusa
T1a Tumour invades lamina propria, muscularis mucosae
T1b Tumour invades submucosa
T2 Tumour invades muscularis propria
T3 Tumour invades adventitia
T4 Tumour invades adjacent strictures
T4a Resectable tumour invading pleura, pericardium, or diaphragm
T4b Unresectable tumour invading other adjacent structures, such as aorta, vertebral body, trachea etc.
Regional Lymph Nodes (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastases in 1-2 regional lymph nodes
N2 Metastases in 3-6 regional lymph nodes
N3 Metastases in ≥ 7 regional lymph nodes
Distant Metastasis (M)
M0 No distant metastasis
M1 Distant metastasis

Table 3: Stage classification for oesophageal cancer in the 2010 TNM7 staging system

Squamous-cell carcinoma
Stage Tumour Node Metastasis Grade Tumour location
0 Tis (HGD) N0 M0 1, X Any
IA T1 N0 M0 1, X Any
IB T1 N0 M0 2-3 Any
T2-3 N0 M0 1, X Lower, X
IIA T2-3 N0 M0 1, X Upper, middle
T2-3 N0 M0 2-3 Lower, X
IIB T2-3 N0 M0 2-3 Upper, middle
T1-2 N1 M0 Any Any
IIIA T1-2 N2 M0 Any Any
T3 N1 M0 Any Any
T4a N0 M0 Any Any
IIIB T3 N2 M0 Any Any
IIIC T4a N1-2 M0 Any Any
T4b Any M0 Any Any
Any N3 M0 Any Any
IV Any Any M1 Any Any
Adenocarcinoma  
Stage Tumour Node Metastasis Grade  
0 Tis (HGD) N0 M0 1, X  
IA T1 N0 M0 1-2, X  
IB T1 N0 M0 3  
T2 N0 M0 1-2, X  
IIA T2 N0 M0 3  
IIB T3 N0 M0 Any  
T1-2 N1 M0 Any  
IIIA T1-2 N2 M0 Any  
T3 N1 M0 Any  
T4a N0 M0 Any  
IIIB T3 N2 M0 Any  
IIIC T4a N1-2 M0 Any  
T4b Any M0 Any  
Any N3 M0 Any  
IV Any Any M1 Any  

Initial staging assessment includes Computed Tomography (CT) (Fig. 5) of the thorax, abdomen and pelvis and its major role will be in evaluating the T stage to detect local tumour invasion into adjacent structures and determining the presence or absence of metastatic disease. However CT will not be able to determine the depth of tumour invasion. Endoscopic ultrasound (EUS) (Fig. 6) is the main modality used to stage the primary tumour and primarily aids in distinguishing T1 lesions from T2-4 lesions. This method has an accuracy ranging from between 73% to 89% in tumour staging.29 Accurately distinguishing tumour stage will affect treatment as T1 lesions may be treated with endoscopic therapy or with oesophagectomy whereas T2-4 lesions may require neo-adjuvant chemo-radiotherapy prior to surgery. EUS is also used for evaluation of regional lymph nodes however although sensitivity is approximately 80%, the specificity is lower at approximately 70%. 30 It is best to perform a EUS-guided lymph node biopsy for confirmation of involvement.

Fig. 5: CT scan shows irregular wall thickening of the esophagus and enlarged metastatic lymph node.

Fig. 6: Endoscopic ultrasound (EUS) of oesophagus showing T3 tumour

FDG-PET (18F-fluoroudeoxyglucose PET) (Fig. 7) is a key modality for the detection of distant metastatic disease in OC.31, 32 PET may reveal previously occult distant metastases in nodal and non-nodal sites with a sensitivity of 67% and high specificity of 97%. 33 It can also reveal metastases to bone, which may not be detected using conventional methods. An investigation has shown PET to be the only modality that predicted intended curative resection and it may also be used to prevent unnecessary surgical explorations.34 The use of PET has been shown in a study to change the management of patients from curative to palliative due to detection of previously unknown metastases.35 It has also been used in a prospective study to assess response early after neo-adjuvant chemotherapy to determine the need for urgent surgery or further chemotherapy. The usage of CT and PET in combination has become increasingly available and is useful in selective cases.36

Fig. 7: FDG PET/CT image demonstrating increased uptake at the distal oesophagus and coeliac lymph node in oesophageal cancer case

Minimally invasive surgery is also used as a method to stage OC in many specialist centres.37 A staging laparoscopy can visualise the primary tumour, identify metastases such as hepatic and regional nodal and can accurately detect intraperitoneal dissemination of disease, which may not have been appreciated on other radiological staging investigations. Samples of peritoneal ascites or washings for cytology can also be obtained at this stage if present.

Endoscopic mucosal resection (EMR) can provide accurate histological staging for high grade dysplasia and intramucosal carcinomas. 38 In many cases EMR alone can be a therapeutic intervention depending on the depth of invasion on the specimen.

Treatment

The management of OCs requires a multi-disciplinary team approach involving surgeons, oncologists, radiologists, pathologists, specialist nurses, dietitians and specialists from other specialties if required. Patients considered for surgery or chemo-radiotherapy will require a fitness assessment. In addition to pulmonary function tests, ECG and echocardiogram, cardio-pulmonary exercise testing (CPEX/CPET) is now being increasingly used to assess fitness for major surgery.

OCs can be managed with surgery, chemotherapy or radiotherapy, a combination of the three or palliation in many cases. Disease that is locally advanced without signs of distant metastases is treated with an intention to cure and this will involve a multimodal approach. Metastatic, disseminated and recurrent disease will be treated with palliative intent with chemotherapy to increase survival or measures such as radiotherapy or stent placement for symptomatic relief.

Surgical

Surgical resection can be part of a multimodal approach or alone and is the main option for curative treatment. There are a number of surgical procedures that can be used however it is important to ensure removal of macroscopic and microscopic tumour in association with dissection of lymph nodes with either method as these are vital prognostic factors following surgery.

Open oesophagectomy (OO):

Options for resection include trans-hiatal oesophagectomy and transthoracic approaches and the choice of approach will depend on the location of the tumour, access to lymph nodes and surgeon preference. An Ivor Lewis oesophagectomy (also known as Lewis-Tanner oesophagectomy) involves abdominal mobilization of the stomach and right thoracic approach for resection of the oesophagus. The three-stage modified McKeown oesophagectomy involves a laparotomy, right thoracotomy and neck anastomosis. A resection margin 8-10 cm proximally and 7 cm distally is recommended to achieve an R0 resection (recommendation class IIB, level of evidence C). The next step is to construct a conduit for the anastomosis and this can be achieved by using a gastric tube, large or small bowel. A gastric tube is preferred due to the following factors; ease of use, tension free and longest term conduit survival (recommendation class IIA, level of evidence C). The anastomosis can be performed in the chest or the neck. This relies on multiple factors such as ease of the anastomosis, tension on the repair, ability to diagnose and treat complications and the oncological status. Circular staplers or hand sewn technique usually used with no significant differences in the outcomes. A drainage procedure such as pyloroplasty is recommended to avoid delayed gastric emptying (recommendation class I, level of evidence B). 62

Radical oesophagectomy using either approach has a perioperative mortality of 5-10% and morbidity of 30-40%. 39 Lymph node dissection plays an important role owing to the extensive submucosal lymphatic drainage of the oesophagus. This has meant that nearly 80% of patients undergoing surgery have positive lymph nodes and prognostically this is of importance.40, 41 However, there has been controversy with regards to the extent of lymph node dissection required. For optimal staging 10 lymph nodes for T1 and 20-30 lymph nodes for T2 and T3 tumours should be harvested. 62 In order to perform a curative resection for carcinoma of the middle and lower third of the oesophagus it is recommended to dissect the abdominal and mediastinal lymph nodes. Three-field lymphadenectomy in the abdomen, chest and neck, is performed in Japan for oesophageal SCC.42 Proponents of radical lymphadenectomy argue that it does allow optimal staging, improves loco-regional disease free survival improving the quality of life for these patients.

Minimally invasive oesophagectomy (MIO):

Minimally invasive approaches, which involve laparoscopic mobilisation of the stomach, thoracoscopic mobilisation of the oesophagus and hybrid or robotic approaches, are increasing in many specialist centres. Benefits of this approach include shorter recovery times, decreased post-operative pain and reduced cardiopulmonary complications without jeopardising the oncological outcomes. Luketich et al. reported a mortality rate of 1.7%, leak 5% and empyema 6% following MIO. 63Several randomised controlled trials (RCTs) and comparative studies were conducted to investigate the efficacy and outcomes of MIO. A study by Li et al was conducted on 407 patients underwent MIO and OO found that the overall incidence of complications was lower in the MIO patients. The incidence of pulmonary complications was 20.7% in contrast to 39.7% in the OO group. However, there was no difference in the overall survival among the groups. Another comparative retrospective study by Mu et al. didn’t reveal any difference in the morbidity, anastomotic leak rate, pulmonary complications and length of stay between the approaches and the authors concluded that both techniques are equivalent. 63, 64

Neo-adjuvant chemotherapy

This aims to improve operability; achieving this by shrinking the tumour prior to surgery, down-staging the disease as well as treating occult metastatic disease. Response to treatment can be assessed prior to surgery with repeat radiological investigations. It is now common for patients in the UK with locally advanced disease to undergo neo-adjuvant chemotherapy followed by resection. This is based on the results of a multi-centre study conducted by the Medical Research Council (OEO2), which showed a 9% improvement in two-year survival in patients given 2 cycles of Cisplatin and 5-Fluorouracil chemotherapy compared to those who were not. Five-year survival with surgery alone was 17%, compared with 23% with neoadjuvant chemotherapy.43 The MRC Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial randomized patients to chemotherapy with surgery or to surgery alone and it was found that patients in the chemotherapy group (who received Epirubicin, Cisplatin and infused 5-Fluorouracil, ‘ECF’) had a significant improvement in progression-free survival and a 13% increase in 5-year survival.45

In a meta-analysis of neoadjuvant chemotherapy, there was an overall all-cause absolute survival benefit of 7% at 2 years with the addition of chemotherapy. When analysed by subtype, chemotherapy had no significant effect on mortality for patients with squamous cell carcinoma; however, there was a significant survival benefit for patients with oesophageal adenocarcinoma (HR 0.78; p=0.014). 47

As a result of this evidence, neoadjuvant chemotherapy is a standard of care for patients with operable mid and lower oesophageal and GOJ adenocarcinoma. The ongoing MRC OEO5 trial is evaluating optimal neoadjuvant chemotherapy regimens: 4 cycles of chemotherapy with ‘ECX’ (Epirubicin, Cisplatin and Capecitabine) compared to two cycles Cisplatin and 5-Fluorouracil, as in OEO2.44

Patients who are deemed suitable for surgical management of mid or distal oesophageal (including GOJ) adenocarcinomas are referred to the GI oncology team to assess fitness for chemotherapy. Many of the criteria assessed are similar to those in the pre-operative assessment, particularly performance status and medical comorbidities. Significant history of renal disease or cardiovascular disease, especially ischaemic heart disease would be a relative contraindication to systemic chemotherapy. Toxicities from chemotherapy are wide-ranging and include gastrointestinal upset, hair loss, skin rash, neurotoxicity, renal toxicity, bone marrow suppression (with risk of neutropaenic sepsis, thrombocytopaenia, and anaemia), cardiovascular toxicity, and chemotherapy-related fatigue. In the MAGIC trial, three cycles of epirubicin, cisplatin and capecitabine (ECX) chemotherapy were given both before and after surgery, and approximately one quarter of patients had CTCAE grade 3 or 4 neutropaenia. 45

The REAL 2 trial 48 was a 2x2 factorial non-inferiority comparison of cisplatin versus oxaliplatin and 5-fluorouracil (5-FU) versus oral capectiabine in patients with oesophageal, gastro-oesophageal junction and gastric tumours. Treatment was given as triplet chemotherapy: epirubicin plus platinum agent (cisplatin or oxaliplatin) plus 5-FU or capecitabine. The trial results showed that oxaliplatin was at least as effective as cisplatin, and oral capectibine was at least as effective as intravenous 5-fluorouracil. There was less grade 3 and 4 neutropaenia with oxaliplatin versus cisplatin, but this was offset by an increase in neuropathy and diarrhoea. As a result of this trial, EOX chemotherapy can be used as an alternative to ECX in both the neoadjuvant and metastatic settings (Table 4).

Table 4: Efficacies of major combination chemotherapy drugs

Drug Histologic type No. of cases Response rate (%)
5-FU + cisplatin Squamous cell carcinoma 39 36
Cisplatin + paclitaxel Squamous cell carcinoma/adenocarcinoma 32 44
Cisplatin + irinotecan Squamous cell carcinoma/adenocarcinoma 35 57
Cisplatin + gemcitabine Squamous cell carcinoma/adenocarcinoma 32 45
5-FU + nedaplatin Squamous cell carcinoma 38 40

Neo-adjuvant chemo-radiotherapy

In contrast to the UK, patients in the USA commonly receive neo-adjuvant chemo-radiotherapy (CRT) for locally advanced oesophageal carcinoma. There is evidence that preoperative CRT is superior to surgery alone. A meta-analysis of ten randomised controlled trials showed a hazard ratio for all-cause mortality of 0.81 (95% CI 0.70 to 0.93; p=0.002). This corresponded to a 13% absolute survival benefit at 2 years.47 In the subgroup analysis of the Dutch CRT trial (which used paclitaxel and carboplatin combination chemotherapy), the beneficial effect was more pronounced in patients with squamous cell carcinoma (HR 0.34; 95% CI 0.17 to 0.65) compared to adenocarcinoma (HR 0.82; 95% CI 0.58 to 1.16).49

There has been no direct head-to-head comparison of neoadjuvant chemotherapy and neoadjuvant CRT in the context of a phase III randomised control trial. Concerns regarding the added morbidity of CRT have meant that chemotherapy alone is the standard neoadjuvant treatment of choice in the UK. However, the role of neoadjuvant CRT is currently being reassessed in the Neo-SCOPE trial.

Definitive chemo-radiotherapy (CRT)

According to current UK consensus guidelines, CRT is the definitive treatment of choice for localised squamous cell carcinoma of the proximal oesophagus. 50 Localised squamous cell carcinoma of the middle or lower oesophagus may be treated with CRT alone, or CRT plus surgery. 50

In a pivotal study, US Intergroup RTOG-8501 randomised 121 patients with squamous cell carcinoma or adenocarcinoma to receive CRT (cisplatin and 5-Fluorouracil with 50 Gray in 25 fractions), or radiotherapy alone (64 Gray in 32 fractions). This trial 46, together with a subsequent systematic review 55, demonstrated a survival superiority of CRT over radiotherapy alone (1-year mortality odds ratio 0.61; 95% CI 0.31 to 0.89; p<0.001). This was at the expense of increased toxicity.

This and similar studies 56-57 have demonstrated a remarkably consistent median survival of 14-18 months and 2 year overall survival of 30-40% with CRT.

CRT practice in the UK is somewhat varied, but within the authors’ multidisciplinary team Cisplatin and 5-Fluorouracil chemotherapy is given in weeks 1 and 5 of a five-and-a-half week course of radiotherapy. The radiation dose used is 50.4 Gray in 28 daily fractions, treating Mondays to Fridays. An alternative radiation dose-fractionation which is supported by the Royal College of Radiologists guidelines is 50 Gray in 25 daily fractions. 58

There are few trials directly comparing surgery alone with CRT. A study of 80 patients with squamous cell carcinoma randomised to surgery or CRT failed to show superiority of either strategy in terms of early disease free survival or overall survival. 51 Adding surgery to CRT can improve local control rates compared with CRT alone, but combined-modality therapy has not been shown to improve survival. It predictably also leads to significantly more treatment-related morbidity.52

The French FFCD 9102 trial recruited 444 patients with potentially resectable OC (90% squamous cell carcinoma) to receive induction CRT. Those patients who showed evidence of response to CRT were then randomised to further CRT or surgery. Median overall survival was 19.3 months in the CRT alone arm, and 17.7 months in those randomised to surgery. The trial met its endpoint of non-inferiority for 2 year overall survival. Again, toxicity was shown to be significantly higher in patients who received both CRT and surgery.53

Although definitive CRT is a current recommended standard of care for localised squamous cell carcinoma of the oesophagus, there is insufficient evidence to to support either a surgical or non-surgical approach 50. Surgery should be considered in patients who have histologically-confirmed residual disease at the end of CRT.

For patients deemed unsuitable for surgery with localised adenocarcinoma of the oesophagus, CRT is a valid option for treatment. An American case series of 25 patients with a median age of 77 years showed that CRT using two cycles of mitomycin-C and 5-fluorouracil in combination with radiation (dose 50.4Gy in 28 daily fractions) was effective and tolerable. 68% of these patients had no evidence of residual disease on post-treatment endoscopy. This small series of patients had a two year overall survival of 64%, with a median overall survival of 35 months.54

Salvage surgery after definitive CRT

Local recurrence occurs within the first year in 10-30% of patients treated with definitive CRT.50 Salvage curative oesophagectomy may be considered within a multidisciplinary team setting. Repeat staging investigations including a CT-PET and EUS are required before a final decision for salvage surgery is made. Survival benefit is limited, and such surgery is associated with an increased in-hospital mortality rate and increased morbidity.59 Informing patients of the potential high risks and poor outcomes is an integral part of the decision-making process for salvage surgery.

Palliation

The majority of patients diagnosed with OC are never treated with curative intent as a result of advanced disease or their physical fitness and comorbidities not allowing for radical treatment. It also includes patients who have developed recurrent or metastatic disease following resection. For this group of patients, there are a number of palliative treatments available for relief of symptoms, prolonging and maximising their quality of life. Once again, a multidisciplinary, holistic approach is required to provide the best treatment.

Treatments to provide symptomatic relief such as dysphagia can include intraluminal brachytherapy, endoscopic stenting using self-expanding metal stents or repeated endoscopic dilatations. Dysphagia can also be palliated by chemotherapy or external beam radiotherapy. Laser-thermal Nd-YAG endoluminal tumour destruction and photodynamic therapy can also be administered however this requires a number of treatments and may be more suitable for short exophytic tumours. It is essential to manage pain and nutrition and feeding options through a gastrostomy, jejunostomy or even intravenously can be provided to ensure adequate nutritional status. In addition to providing symptomatic relief it is important to also ensure that these patients receive social and psychological support by identifying and addressing the needs of the patients as well as their carers.

Palliative radiotherapy can be offered to patients with symptomatic primary oesophageal tumours in the context of metastatic or inoperable disease. Palliative dose and fractionation options are varied, but include 27 Gray in 6 fractions treating twice a week for 3 weeks; 30 Gray in 10 fractions treating daily for 2 weeks; 20 Gray in 5 fractions treating daily for 1 week.58 The aim of such radiation treatment is to palliate dysphagia. This effect is not immediate, and therefore patients with significant dysphagia are better served initially by endoscopic stenting.

Chemotherapy has been shown to be effective in improving symptoms and overall survival. Patients with good performance status are offered combination chemotherapy. This can be with EOX, as per the MAGIC trial, 45or with Cisplatin and 5-Fluorouracil, with or without the addition of Epirubicin (CF or ECF). 5-Fluorouracil can be substituted for oral Capecitabine (i.e. CX or ECX) without any adverse effects on outcomes.45

When choosing palliative systemic chemotherapy for patients with incurable OC, the primary aim should be about maximising quality of life. Improvements in outcome with more intensive chemotherapy regimens, such as docetaxel, cisplatin and 5-Fluorouracil, have been shown to be offset by significantly more toxicity.60 As a result, Docetaxel containing regimens are not approved in the UK for this indication.50

Conclusions

The incidence of oesophageal carcinoma is increasing and despite advances in management and treatment the overall prognosis remains poor. It is essential to recognize and diagnose early, to have a clear pathway for subsequent investigations to ensure accurate staging. This will allow appropriate therapy to be administered to ensure the best possible outcomes are achieved. Treatment of OC is still a challenge however recent advances in surgery, endoscopic treatments and new therapeutic agents will hopefully improve prognosis.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
NAUFAL RASHID, Department of Upper GI Surgery, West Hertfordshire Hospitals, England. MOHAMED ELSHAER, Department of Upper GI Surgery, West Hertfordshire Hospitals, England. MICHAEL KOSMIN, Department of Oncology, Mount Vernon Hospital, England. AMJID RIAZ, Department of Upper GI Surgery, West Hertfordshire Hospitals, England.
Corresponding Author Details: 
AMJID ALI RIAZ, Department of Upper GI Surgery, Watford General Hospital, Vicarage road, Watford, WD18 0HB, United Kingdom.
Corresponding Author Email: 
mrariaz@hotmail.com
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Refractory Disseminated Intravascular Coagulation Following Ovarian Torsion and Rupture in a Pregnant Patient

Authors
Joelle Williams, Amaju Ikomi, Chanaka Karunaratne and Preethi Angala
Article Citation and PDF Link
BJMP 2015;8(1):a803
Abstract / Summary
Abstract: 

This report describes a case of a 36 year old pregnant woman presenting at 33 weeks’ gestation with torsion and rupture of a malignant ovarian tumour. She undergoes an emergency laparotomy, Caesarean section and oophorectomy following which develops severe Disseminated Intravascular Coagulation (DIC) develops. Persistent blood loss warranted multiple surgical explorations, as well as, blood and blood product transfusions in excess of 100 units. Additional complications that arose included hyperkalaemia and VF cardiac arrest. The clinician should be alerted to the possibility of a deleterious coagulopathy which may be seen following a malignant ovarian tumour rupture and torsion.

Abbreviations: 
DIC- Disseminated Intravascular Coagulation,DVT - Deep vein thromboses, IABP -Invasive Arterial Blood Pressure, FFP - Fresh Frozen Plasma
Keywords: 
ovarian cancer, tumour, rupture, pregnancy, Disseminated Intravascular Coagulation, haemorrhage

Case report

A 36 year old multiparous woman presented to the Labour Ward at 33 weeks’ gestation with lower abdominal pain. She had mild asthma and her obstetric history included 2 previous normal vaginal deliveries.

At 16 weeks’ gestation she was found during antenatal scanning to have a right ovarian cystic lesion measuring 59x34x50mm. This was monitored and a repeat scan at 25 weeks’ showed it had increased in size to 73x55x47mm.

At 32 weeks’ she was diagnosed with a DVT and was commenced on therapeutic enoxaparin (stopped two days before current presentation). (D-Dimer > 4000micrograms/L). An inferior vena cava filter was inserted. The patient declined any surgical intervention of the cystic lesion during pregnancy and an early elective Caesarean Section with surgical management of the cyst at 34 weeks’ gestation was planned. She had no symptoms or signs suggestive of a PE and was not formally investigated for one prior her current presentation.

On this presentation at 33 weeks’ gestation, her pain suddenly worsened with associated hypotension and evidence of foetal distress and so an emergency exploratory laparotomy was performed.

Admission haematology results: haemoglobin 10g/dL, platelets 158 x 109 /L, INR 1.0, APTT 28.4 seconds, APTT ratio 1, fibrinogen 3g/L.

She underwent a rapid sequence induction in the supine wedged position using thiopentone and suxamethonium. She was a Grade 1 intubation and anaesthesia was maintained with oxygen/nitrous oxide/sevoflurane and muscle relaxation was achieved with atracurium. A ruptured, torted right ovarian mass containing an estimated one litre of altered blood was noted. At Caesarean section a live male infant was delivered. A right oophrectomy was then performed. The infant was subsequently intubated and transferred to the Neonatal Intensive Care Unit.

Oxytocin 5IU followed by a 40IU infusion over 4 hours was administered following delivery of the baby. Effective haemostats was achieved, the uterus appeared well-contracted and the patient’s abdomen was closed. Surgical blood loss was estimated as 600mls (excluding blood within the ovarian mass).

Thirty minutes following completion of surgery the patient, fresh blood was noted vaginally. A HemoCue* reading was taken as 5.9g/dL. Four units of blood and two units of FFP were transfused whilst a second laparotomy was performed. Fresh blood was noted intra-abdominally and the uterus was markedly atonic. Ergometrine 500mcg and carboprost trimethamine 250mcg were administered intramuscularly, as well as, misoprostol 800mg vaginally. A hysterectomy was performed due to the rate of bleeding and the evident haemodynamic instability.

Coagulation studies: platelets 27 x 109/L, INR 1.4, APTT 101.8 seconds, APTT ratio 3.6 and fibrinogen 1g/L.

A further 4 units of blood, 4 units of FFP, 1 pool of platelets and 2 units of cryoprecipitate were transfused. Factor VII was also administered on advice from the Haematologist.

An internal jugular central venous catheter was inserted and a noradrenaline infusion started. Initial attempts to insert an arterial cannula were unsuccessful as peripheral pulses were difficult to palpate. Venous blood gas readings revealed hyperkalaemia (K+ 6.4mmol/L) which was treated with sodium bicarbonate, 10mls 10% calcium chloride and a continuous 50% dextrose and insulin infusion. Her abdomen was packed and percutaneous drains were inserted. Anaesthesia, close monitoring and resuscitation continued.

Ongoing output from drains prompted a third exploration after an hour. There was generalised oozing particularly around the bed of the resected ovary in the pouch of Douglas.

Coagulation profile: platelets 50 x 109/L, INR 1.4, APTT 89.6 seconds, APTT ratio 3.1 seconds, fibrinogen 1.4g/dL.

A further 10 units of blood, 3 pools of platelets, 5 units of FFP and 3 units of cryoprecipitate were transfused. Sequential coagulation profiles and thromboelastography were used to guide transfusion.

During this exploration, ECG revealed a broad complex tachycardia with no palpable pulse confirming cardiac arrest likely secondary to hypovolaemia and/or hyperkalaemia. Return of spontaneous circulation was achieved after 3 cycles of continuous cardiac massage, 4 direct current shocks and adrenaline 1mg.

A femoral artery cut-down was performed and arterial cannula was inserted by a general surgeon. IABP monitoring commenced.

A fourth exploration was carried out around two hours later for ongoing blood loss. Again only generalised oozing was noted particularly from the oophrectomy site. Her abdomen was re-packed.

Coagulation profile: haemoglobin 7.4g/dL, INR 1.2, APTT 48.9 seconds, APTT ratio 1.7, fibrinogen 1.9g/dL, platelets 94 x 109/L.

She was transferred to the ICU eight hours from the start of the primary operation. Estimated total blood loss was 13,200mls. Transfusions continued and her abdomen was closed two days later. She received haemofiltration therapy for acute kidney injury. She recovered to her premorbid level with no neurological deficit before being discharged with her baby a few weeks later. In total, she was transfused 64 units of blood, 35 units of FFP, 10 pools of platelets and 11 units of cryoprecipitate. Histology of the ovarian mass revealed high grade clear cell carcinoma for which she received chemotherapy but unfortunately she died two years later.

Discussion

The association between cancer and thromboembolism has been well established for many decades.1Ovarian cancer patients have one of the highest incidences of VTE amongst cancer patients, particularly clear cell carcinoma (CCC). One study found the incidence of thromboembolic complications to be significantly higher in CCC when compared with other epithelial types of ovarian cancer (27.3% vs 6.8%).2

The pathological mechanism behind the hypercoaguable state induced in ovarian cancer patients appears to be largely multi-faceted. A variety of procoagulant subtances may be involved. Of particular interest is tissue factor (TF), a potent procoagulant found in endothelial and blood cells, as well as, in tumour cells. TF may play an important role in this hypercoaguable state through activation of the coagulation cascade.3 TF is frequently over-expressed in ovarian cancer tissue and there is research suggesting it influences tumour progression.3,4

A hyperviscosity syndrome may also be seen in association with ovarian cancer which favours thrombosis and may accelerate tumour progression and metastasis.DVT is a recognised complicating factor of ovarian cancer which may adversely affect the course of the disease possibly as a component of this hyperviscosity syndrome5,6 Ovarian cancer patients are also vulnerable to developing cerebrovascular complications and carry a higher risk of developing ischaemic strokes which has a significant impact on morbidity and mortality.7

The hypercoagulable state seen in cancer patients can have a spectrum of manifestations that ranges from DIC to massive thromboembolism. DIC in these instances is usually chronic and subclinical.8

The degree of coagulopathy which was seen in this case could not be attributed solely to dilutional effects incurred through fluid resuscitation. Instead we propose the acute severe coagulopathy was a consequence of procoagulant factors inherent to neoplastic tissue, including TF, which were suddenly released into the circulation following rupture and surgery to the ovarian tumour. The overall result would be widespread activation of the clotting cascade and a consumptive coagulopathy.

This case aims to increase awareness of a refractory coagulopathy which may be seen following rupture and/or surgical resection of a malignant ovarian tumour. The presence of an ovarian cyst especially in conjunction with evidence of vascular thrombosis in pregnancy should raise suspicion for an ovarian malignancy and hence vigilance for this potential complication. Anticipation of such a severe coagulopathy and associated significant blood loss should pre-empt early establishment of invasive monitoring, ample intravenous access and ensuring quick access to blood and blood products. Bedside coagulation tests such as thromboelastography are useful guides to blood product transfusion.9 Prompt mobilisation of resources, multi-disciplinary input and effective team work were crucial factors which facilitated the management of this case.

Acute, severe DIC associated with ovarian intratumoural bleed which resolves following resection of the tumour has been reported previously.10 This is the first case to the best of our knowledge occurring following ovarian cancer torsion and rupture during pregnancy.

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
Dr Niroshoni Rathnasiri for her role in information gathering.
Competing Interests: 
None declared
Details of Authors: 
JOELLE WILLIAMS(MBBS), Basildon Hospital, Nethermayne, Basildon, Essex, SS16 5NL, United Kingdom. AMAJU IKOMI(MSc FRCOG),Basildon Hospital, Nethermayne, Basildon, Essex, SS16 5NL, United Kingdom. CHANAKA KARUNARATNE (FRCA),Basildon Hospital, Nethermayne, Basildon, Essex, SS16 5NL, United Kingdom. PREETHI ANGALA(FRCOG), Basildon Hospital, Nethermayne, Basildon, Essex, SS16 5NL, United Kingdom.
Corresponding Author Details: 
JOELLE WILLIAMS, Basildon Hospital, Nethermayne, Basildon, Essex, SS16 5NL, United Kingdom.
Corresponding Author Email: 
joellesw011@gmail.com
References
References: 
  1. Trousseau A. Clinique Médicale de l'Hôtel-Dieu de Paris. Paris: Bailliere et Fils. 1865; 654-712
  2. Matsuura Y, Roberston G, Marsden D, et al. Thromboembolic complications in patients with clear cell carcinoma of the ovary. Gynecol Oncol. 2007;104(2):406-10
  3. Uno K, Homma S, Satoh T, et al. Tissue factor expression as a possible determinant of thromboembolism in ovarian cancer. Br J Cancer. 2007; 96:290–295
  4. Zhang Y, Deng Y, Luther T, et al. Tissue factor controls the balance of angiogenic and antiangiogenic properties of tumor cells in mice. J Clin Invest. 1994; 3:1320-1327
  5. Sorensen HT, Mellemkjær L, Olsen JH, et al. Prognosis of cancers associated with venous thromboembolism. N Engl J Med. 2000; 343:1846-1850
  6. Von Templehoff GF, Nieman F, Heilmann L, et al. Association between blood rheology, thrombosis and cancer survival in patients with gynecologic malignancy. Clin Hemorheol Microcirc. 2000;22:107-130
  7. Kuan A, Teng C, Wu H, et al. Risk of ischemic stroke in patients with ovarian cancer: a nationwide population-based study. BMC Medicine. 2014;12:53 
  8. Caine GJ, Stonelakey PS, Lip, et al. The Hypercoagulable State of Malignancy: Pathogenesis and Current Debate. Neoplasia. 2002;6:465-473.
  9. Trapani L. Thromboelastography: Current Applications, Future Directions. O J Anaes. 2013; 3(1):23-27.
  10. Matsushita H, Kurabayashi T, Tomita M, et al. Disseminated Intravascular Coagulation associated with Intratumoral Haemorrhage of Ovarian Cancer. Gynecol Obstet Invest. 2001; 51:274-276.

Trend of developing resistance among isolates of Acinetobacter spp.; Threat of hospital acquired infection

Authors
Sadia Zafar, Syed Baqir Shyum Naqvi, Tanveer Abbas, Faaiza Qazi and Rabia Sheikh
Article Citation and PDF Link
BJMP 2015;8(1):a802
Abstract / Summary
Abstract: 

Aim:  Acinetobacter sp. is a Gm-ve bacteria which is a major cause of serious infections. Today it has emerged as multidrug resistant organism. The  aim of current study was to evaluate the trend of sensitivity/resistance pattern of Acinetobacter spp. against broad spectrum antibiotics.
Method: Standard Kirby bauer Disc Diffusion method was adopted to conduct the study according to the CLSI 2013 Standards. Total 52 isolates were collected from different sites of inpatients admitted to renowned tertiary care hospital from Feb 2014-March 2014 and sensitivity/resistance pattern was observed against 08 broad spectrum antibiotics of different classes.
Result: It is observed that 61.5% of all samples were obtained from male patients while, the mean range of age group among both the gender frequently found infected was 51-75 yrs. The highest percentage of isolate was obtained from tracheal aspirate (55.76%) of both the genders. Both Colistin and Polymixin were found to be most effective against 98% isolates each while Imipenem was the least effective broad spectrum antibiotic. Thus, the isolates were highly resistant to 05 antibiotics traditionally used to treat infections caused by Acinetobacter spp. Surprisingly, more than 32% of isolates showed Intermediate sensitivity to Fosfomycin .
Conclusion: Due to emerging trend of  developing resistance among Acinetobacter spp. and  spread of hospital acquired infections, there is a serious need to take necessary steps by hospital officials to ensure cleanliness. Patients should also be educated about the proper use of antibiotics.

Abbreviations: 
CLSI :Clinical and Laboratory Standards Institute
Keywords: 
Acinetobacter sp. , Hospital acquired, Resistance Pattern.

Introduction

For decades the genus Acinetobacter has undergone several taxonomical modifications. Large number of non-fastidious, aerobic, Gram-negative bacteria (GNB) are included in this genus. In the last few years these organisms are genetically modifying into highly resistant forms resulting in untreatable nosocomial infections1 and health care associated infections.2 Acinetobacter is also a major cause of invasive type infections in children resulting in untreatable urinary tract infections (UTIs), skin infections and septicemia.3 One identified cause of the resistance mechanism in carbapenem resistant Acinetobacter spp. is the production of the MBL enzyme.4 It has been revealed through various published studies that Acinetobacter displays a specific type of mechanism of resistance against different antimicrobials. Some of them, for example β-lactam, are inhibited by enzymatic degradation, while quinolones are rendered ineffective due to a genetic mutation preventing the binding of an antibiotic to a distinct binding site. The same is true with aminoglycosides in which the resistant strains are noticed to acquire a gene involved in enzymatic modification.1

Although polymixin resistance in Acinetobacter spp. was reported the specific cause of resistance was unknown until 2008. In 2013, one study detected the presence of hetero-and adaptive resistance due to mutation in specific gene for the first time.1,21 Hence the aim of this current study was to evaluate the trend of sensitivity/resistance pattern of Acinetobacter spp. against broad spectrum antibiotics.

Method and Materials

The objective of the study was to evaluate the sensitivity of Acinetobacter spp. to 08 broad spectrum antibiotics. The Kirby Bauer Disc Diffusion method was used following the standard procedures as laid down by CLSI 2013.6 A total of 52 isolates were collected from Feb 2014-March 2014 from patients admitted to tertiary care hospitals in Karachi. The isolates were identified by routine lab procedures.

Antimicrobial agents and medium: Standard (Oxoid) discs of Amikacin (30 µg), Cefoperazone (75 µg), Ceftriaxone (30 µg), Ciprofloxacin (5 µg), Colistin (10µg), Fosfomycin (50 µg), imipenem (10 µg), Polymixin B (300units), Mueller Hinton Agar (Oxoid UK) and Mueller Hinton broth (Oxoid UK) were used.

0.5 McFarlan Standard: The inoculum was grown at 370C for 2-6 hrs. Turbidity Standard of 0.5 McFarland was achieved by incubating broth culture.

Inoculation of test plates:The plates were inoculated with the culture of Acinetobacter spp. by the help of sterile cotton swabs. The excess fluid was removed after the cotton swab was dipped into inoculum suspension. When the inoculum were dried the antibiotic discs were placed with sterile forceps onto the agar surface.15

Incubation of test plates: The isolates after application of antibiotic discs plates were incubated for 24 hours and results were interpreted according to CLSI standards 5,6. Interpretative standards for used antibiotics and Zone diameter of inhibition are shown in Table 25.

Control strain: Escherichia coli ATCC 25922was used as a control strain to maintain accuracy and precision of procedures.

Results

It is reported that out of all the samples 61.5% were obtained from male patients. Infections caused by Acinetobacter spp. had a high prevalence among both the genders among the age group 51-75 yrs. The most frequent site of isolate collection was tracheal aspirate (55.76%) among both genders and the second highest percentage of isolate was obtained from sputum (19.23%) as shown in Table 1. The Colistin and Polymixin B were found equally effective against Acinetobacter spp. by inhibiting 98% of isolates each and 19.23% isolates showed sensitivity against Amikacin. The isolate showed the highest degree of resistance against Imipenem (98%), followed by Cefoperazone (94.23%) and Ceftrioxone (92.3). Surprisingly 32.69% of isolates exhibited intermediate sensitivity (IS) against Fosfomycin as indicated in Table 3 and Figure 1.

Table 1: Age and gender specific distribution of Acinetobacter spp. among patients

Age Male n=32(61.5%) Female n=20(38.46%)
00-25 10 06
26-50 05 02
51-75 12 11
76-100 05 01

Table 2: Zone diameter interpretive standards for Acinetobacter spp. CLSI standards table of antibiotics for Acinetobacter spp.

Antibiotic Disc Content Zone of Inhibition (mm)
Resistance Intermediate Sensitive
Amikacin 30µg ≤14 15-16 ≥17
Cefoperazone 75 µg ≤15 16-20 ≥21
Ceftriaxone 30 µg ≤13 14-20 ≥21
Ciprofloxacin 5 µg ≤15 16-20 ≥21
Colistin٭ 10µg ≤11   ≥17
Fosfomycin٭ 50 µg ≤12 13-15 ≥16
Imipenem 10 µg ≤13 14-15 ≥16
Polymixin B٭ 300units ≤13   ≥19

 

*Since the interpretive standards for Colistin, Fosfomycin and Polymixin B against Acinetobacter spp. is not established in CLSI 2013 mannual zone diameter interpretative standards for Enterobacter spp. and E. coli were used.20

Figure 1: Susceptibility pattern of Acinetobacter spp. against broad spectrum antibiotics

Table 3: Total % efficacy of different antibiotics among Acinetobacter spp. isolated (N= 52)

S.No. Antibiotics Disc Code Resistance (%) Intermediate (%) Sensitivity (%)
1. Amikacin 30µg 42(80.76) 00 10(19.23)
2. Cefoperazone 75µg 49(94.23) 00 03(5.76)
3. Ceftriaxone 30µg 48(92.3) 00 04(7.69)
4. Ciprofloxacin 05µg 47(90.38) 01(1.9) 04(7.69)
5. Colistin 10µg 01(1.9) 00 51(98)
6. Fosfomycin 50µg 34(65.38) 17(32.69) 01(1.9)
7. Imipenem 10µg 51(98) 00 01(1.9)
8. Polymixin B 300 units 01(1.9) 00 51(98)

Discussion

Our present study shows that the Acinetobacter spp. were highly resistant to Cefoperazone (94.23%). This finding is further substantiated by research that observed Cefoperazone to be only effective when used in combination.7,8

We also observed that only 19% isolates were sensitive to Amikacin, which contradicts the findings of Liu et al 2013 3 who observed 100% efficacy. However, they also discovered that 82% were inhibited by Imipenem while Fluoroquinolone was also found to be effective against 70% of all isolated organisms and Cefoperazone as least effective.

Organisms isolated from sputum showed a high degree of resistance to most of antibiotics, Zheng W and Yuan S also observed such results9.Nwadike et al 201410 found a high prevalence of resistant Acinetobacter spp. isolates against Ciprofloxacin (100%) and Amikacin (50%).10

Polymixin inhibited 98% of isolates, which is similar to figures found by Haeili et al 20131 who observed 95.5% susceptibility to Polymixin B. The second most effective antibiotic was Colistin - Trottier et al 200712 also observed 100% susceptibility of A. baumanni to Colistin. Similarly, Vakilietal 201413 found a low rate (i.e, 11.6%) of Colistin resistance.

Colistin has emerged as a viable choice for treatment of multidrug resistant Acinetobacter strains. In several studies,13,14 where 98% of isolates were resistant to Imipenem these results support the work of Khajuria et al 201416 who also reported reduced efficacy. Our findings are in contradiction to the study by of Tripathi et al 201417 who reported that Imipenem was a highly effective drug in comparison to other broad spectrum antibiotics.Fosfomycin surprisingly exhibited unusual results in our study; 32% of Acinetobacter spp. were IS while 65% were resistant. However, previous studies showed that Fosfomycin were proved to be good option to treat infections caused by Acinetobacter spp.18 Zhang et al 201319 reported that Fosfomycin used alone was highly ineffective in treatment of Penicillin Drug Resistant-Acinetobacter baumannii (PDR-Ab).Another study revealed that Acinetobacter spp. has developed adaptive resistance against Polymixin.21

Acinetobacter spp. are emerging as a resistant bacteria and a common cause of nosocomial and hospital acquired infections. There is a serious need to take necessary measures by hospital administration in maintaining environmental and personnel cleanliness according to current Good Manufacturing Practices. Pharmacists should educate patients about the drawbacks of self-medication and not completing medication courses, which is resulting in development of resistant bacterial pathogens.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
SADIA ZAFAR , M.PHIL, Faculty of Pharmacy, Jinnah University for Women, Karachi, 5C, Nazimabad, Karachi , PAKISTAN. SYED BAQIR SHYUM NAQVI, PHD, Department of Pharmaceutics, Faculty of Pharmacy, University of Karachi,Main university road, PAKISTAN. TANVEER ABBAS, PHD, Department of Microbiology, University of Karachi,Main university road, PAKISTAN. FAAIZA QAZI, M.PHIL, Faculty of Pharmacy, Jinnah University for Women, Karachi, 5C, Nazimabad, Karachi , PAKISTAN. RABIA SHEIKH, B.PHARM, Nigehban Compounding Pharmacy, Karachi,Bangalow#46 C.P.Brar society, PAKISTAN.
Corresponding Author Details: 
SADIA ZAFAR,MUHAMMAD ZAFAR IQBAL, FACULTY OF PHARMACY, JINNAH UNIVERSITY FOR WOMEN, KARACHI, P.O.Box 74600, PAKISTAN.
Corresponding Author Email: 
sadiazafarnew@yahoo.com
References
References: 
  1. Peleg AY,  Seifert H and  Paterson DL. Acinetobacter baumannii: Emergence of a Successful Pathogen Clin. Microbiol. Rev.2008, 21: 3 538-582
  2. Tekin R, Dal T, Pirinccioglu H,  et al A 4-year surveillance of device-associated nosocomial infections in a neonatal intensive care unit.PediatrNeonatol. 2013,54:303-8. 
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Legal Highs - Not so new and still growing in popularity

Authors
Francis J Dunne, Khalid Jaffar and Shazia Hashmi
Article Citation and PDF Link
BJMP 2015;8(1):a801
Abstract / Summary
Abstract: 

Designer or synthetic drugs which include legal highs and other “club drugs” are substances which have a propensity to cause euphoria, central nervous system stimulation, and hallucinations. Based on chemical formulae for opioids, mescaline, and cannabis, they are created in laboratories under lax conditions for no defined medical purposes. Because they vary in composition from batch to batch they are potentially dangerous for users. Furthermore, the chemical structure is continually changing in order to avoid legislation and therefore users can never be sure what they are taking.

For the purpose of this article readers should use the terms legal highs, designer drugs, bath salts, herbal highs, ‘research’ chemicals, and novel psychoactive substances, interchangeably. Their main purpose is to induce psychoactive effects that mimic amphetamines, cannabinoids or psychedelic drugs.  The term ‘research’ only infers that very little is known about these substances and information on adverse effects is often sparse. The reader should also bear in mind that it is beyond the scope of this article to include many other agents. 

Keywords: 
legal highs, bath salts, designer drugs

Overview

The term ‘designer drug’, coined in the 1980s, generally referred to various synthetic opioids based mostly on the fentanyl molecule (α-methylfentanyl) and MDMA (methylenedioxymethamphetamine) commonly known as ecstasy. Fentanyl is an extremely potent analgesic, some 100 times more potent than morphine. MDMA and fentanyl compounds were the most popular synthetic drugs initially. The terminology is confusing because although the description ‘designer drug’ seems to imply the creation of new drugs, many are not new. For example, cathinone derivatives have been reported since the late 1920s. MDMA was first synthesised in 1912, methcathinone in 1928, and mephedrone in 1929. Cathinone is chemically similar to ephedrine, cathine, methcathinone and other amphetamines.

Legal highs generally comprise cathinone stimulants and synthetic cannabinoids. Hallucinogenic agents such as salvia divinorum are also included, the latter sometimes described as herbal ecstasy. Synthetic amphetamines are not regarded as hallucinogenic, though hallucinations are experienced by some users.

Thus, the term ‘designer drugs‘ covers an array of substances which are used recreationally, are not controlled under the Misuse of Drugs Act (1971), are not licensed for ‘legal’ use, and are not regulated under the Medicines Act (1968). They are chemicals produced by tweaking or altering the molecular structure of previous well-known psychoactive agents. By stating they are ‘not for human consumption’, or are just ‘bath salts’, they can be sold legally. Hundreds of such substances are now available, reflecting the ease at which chemists can produce them.

Availability and Consumption

The World Drug Report (available on the Internet) produced annually by the UN Office on Drugs and Crime (UNODC), provides information on the worldwide manufacture and marketing of illegal drugs. The 2013 report highlights a striking rise in the availability of new substances. Part of the challenge lies in their variety - some are derived from plants, for instance, the mint plant Salvia divinorum, native to Mexico, with synthetic cathinones and cannabinoids also being major contributors in other countries.

Ease of synthesis, low cost, and resourceful marketing have contributed to the problem. Information provided via the internet, combined with minimal difficulty in the manufacture and transport from distant regions, together with lax legal enforcement, creates an ideal opportunity for legal highs to flourish. The low cost is particularly attractive though ironically legal highs probably cost more these days: for example, 1g of mephedrone costs about £16.00 more than when legislation was introduced in 2010. On the other hand MDAI (methylenedioxy-2-aminoindane), a legal stimulant and club drug which is snorted or bombed, costs about half the price of cocaine (£20 per gm). It is sometimes cheaper to buy legal highs over the internet than from a drug dealer. Part of the increase in use of legal highs may be a result of decreasing purity of other ‘buzz’ drugs such as cocaine and MDMA.As with other illegal drugs regulatory measures drive the drugs ‘underground’ and into the hands of drug dealers and the price then varies with the purity of the drug and its ease of manufacture and availability.

Some users will revert to taking an illegal drug when the legal alternative is prohibited. There is also a certain curiosity to experiment with new drugs. Even so, to keep things in perspective, consumption of more harmful familiar illegal drugs (for example, cocaine, amphetamines) has not abated, with over 315 million people worldwide thought to be using them. More worrying is that millions of individuals inject more harmful drugs such as opiates with resultant increased rates of HIV, hepatitis B and hepatitis C infection. Readers are also likely to be aware of the violence and deaths associated with drug manufacturing and supplying within countries such as Latin America.

Government Control

The Medicines Act 1968 (UK) governs the control of medicines for human and veterinary use. It defines three categories of medicines: a) prescription only medicines (POM), available solely from a pharmacist and requiring an appropriate practitioner to issue, b) pharmacy medicines (P), available only from a pharmacist, without the need for a prescription, and c) general sales list (GSL) meaning medicines bought without a prescription. The Medicines Act 1968was set up to protect patients from unscrupulous suppliers of medicines. Safeguarding the public from illegal medicines or any inaccurate and misleading labelling of medicines isparamount. However, manufacturers have managed to sell legal highs by passing them off as bath salts or research chemicals.

Phenylalkylamines analogues such as amphetamine are widely misused and because of their simple structure hundreds of amphetamine analogues have been introduced for decades. This is the reason why so many legal highs are available. Amphetamine (phenylisopropolamine), a familiar central nervous system (CNS) stimulant, has effects which last for several hours after oral intake. Methamphetamine is closely related to amphetamine and ephedrine (a mixed-acting sympathomimetic). Ephedrine and pseudoephedrine (often used for relief of nasal congestion) undergo reduction to methamphetamine, or oxidation to methcathinone. As with methamphetamines, methcathinones can be readily ‘cooked’ in the laboratory and hence the term ‘synthetic’.

Background biochemistry

Morphine, the most abundant opiate alkaloid found in the poppy plant, papaver somniferum, was first isolated in 1804. The actual term alkaloid is derived from "alkaloide" introduced in 1819 by the German chemist Carl Friedrich Wilhelm Meisner, from the Latin root ‘alkali’, and the Arabic word al-qalwī meaning "ashes of plants".

Alkaloids are a group of naturally occurring organic nitrogen-containing bases, a base being a substance with a pH above 7 which turns red litmus paper blue. They include related compounds with neutral and even weakly acidic properties and more than 3,000 different types have been identified. In addition to nitrogen, hydrogen and carbon, most alkaloids contain oxygen, sulfur, and to a lesser extent, chlorine, bromine, and phosphorus. Generally, an alkaloid contains at least one nitrogen atom in an amine-type structure, i.e. one derived from ammonia (NH3) replacing the hydrogen atoms with hydrocarbons, for example, CH3 or CH2. Alkaloids generally are weak bases and some act as acid or base (amphoteric).

Alkaloids are produced primarily by flowering plants and organisms such as bacteria, fungi, and animals. Several alkaloids may be extracted from one plant.They can be purified from crude extracts by acid-base extraction and tend to have a bitter taste. Those containing a ring system are known as indole alkaloids (for example, terpenoids and steroids). Some are named after the biological species from which they are derived (morphine from the poppy plant Papaver somniferum, cocaine from erythroxolon coca, and so on). Other common examples include psilocin, caffeine, nicotine, vincristine, reserpine, atropine, quinidine, ephedrine,strychnine and quinine. Atropine is the tropane alkaloid isolated from the deadlynightshade plant Atropa belladonna, and strychnine is derived from the seeds of the Strychnos nux-vomica tree. Caffeine, cocaine, codeine (methylmorphine) and nicotine are water-soluble alkaloids. Morphine and yohimbine are highly water-soluble. Other alkaloids dissolve poorly in water yet readily in organic solvents such as chloroform or ether. The biological precursors of most alkaloids are amino acids, such as phenylalanine, tyrosine, tryptophan, histidine, and aspartic acid, among others. 1

How are they used?

The synthetic cathinones (usually mephedrone and methylone, or M-Cats) are most commonly used intranasally (insufflated) or ingested. “Bombing” is a method of ingestion whereby mephedrone powder is wrapped in cigarette paper and swallowed. Because sniffing the drug may cause nasal burns users will often resort to ‘bombing’. “Keying” is the practice of dipping a key into powder and then insufflating, with approximately five to eight “keys” per gram. Rectal administration, gingival delivery, inhalation, intramuscular and intravenous injection have also been described. Multiple concomitant routes of administration are reported. Self-reported doses range from a few milligrams to over 1 g of powder. A typical dose of mephedrone would be 100-200mg every 1-2 hours.

Users cannot be certain of the actual contents or indeed of the purity of the drug, therefore actual dosage and exposure is highly variable. For example, when MDAI (methylenedioxy-2-aminoindane) known as Sparkle (a granular, brownish powder) is snorted or bombed, it has an effect similar to ecstasy causing mood enhancement and hallucinations. Onset of action is usually within one hour and the effects are then almost immediate, perhaps a minute or so. The high lasts about six hours with a peak of two hours. It may cause hyperthermia, paranoid ideation and panic attacks.2

Cathinone is a naturally-occurring beta-ketone amphetamine analogue found in the leaves of the khat plant. Other synthetic cathinones such as methcathinone and MDVP (methylenedioxypyrovalerone) produce similar effects. Beta-ketone refers to the possession of a ketone group in the beta position of the aminoalkyl chain attached to the main molecular methylenedioxyphenyl ring.

Synthetic cannabinoids share some functional similarities with Δ9-tetrahydrocannabinol (THC), the active principle of cannabis. Like THC, they can have sedative, depressant and hallucinogenic effects. They have been detected in herbal smoking mixtures such as ‘Spice’ as well as resins that mimic cannabis resin.

Khat (Catha edulis)

Some knowledge of this plant is necessary in order to explain the background to many of the synthetic designer drugs. Khat is an evergreen shrub the leaves of which are chewed for their stimulant properties. An understanding of its chemical composition helps to explain the use of its constituents in the formation of designer drugs. Khat contains more than 40 alkaloids as well as many other compounds. The khat pheylalkylamines consist of cathinone, cathine and norephedrine: these alkaloids are structurally related to amphetamine and noradrenaline. Although similar to methylamphetamine, methcathinone (variously known as Cat, Kat, Qat, Ghat, and Chat) possesses a chemical structure resembling cathinone; its side effects and addictive properties are more potent.

The plant is chewed into a ball and kept in the cheek for a while. When khat leaves dry, cathinone (benzoylethanamine) decomposes within 48 hours leaving behind the milder chemical, cathine (a phenethylamine compound). Therefore, to maintain the potency of the drug, harvesters transport khat by packaging the leaves and stems in plastic bags or wrapping them in banana leaves to preserve moisture. It is common to sprinkle the plant with water or use refrigeration during transportation. Khat is therefore best used within 12-48 hours when the leaves are still moist.

Catha edulis is a flowering plant (one that produces seeds) native to the Horn of Africa (Eritrea, Djibouti, Ethiopia and Somalia) and the Arabian Peninsula. In these countries chewing the leaves and stalks is a social custom dating back thousands of years. It may take 7-8 years for the shrub to reach its full height (6-12 feet or more). Globally it is estimated that some 10 million males (usually) use khat on a daily basis.

Cathaedulis leaves containa beta-ketone amphetamine analogue. Ketones contain a carbonyl group (C=O) bonded to two other carbon atoms. Phenylalkylamines (derived from phenethylamine) are often termed “bk-amphetamines” for the beta-ketone moiety.

The principal active components in khat are cathinone and cathine. By chewing khat these substances are secreted into saliva. The effects are similar to amphetamine though less potent. Psychological dependence does occur in some though generally khat is not addictive. It is freely available in many countries and its production, sale and consumption are legal, including the Horn of Africa. In the Arab Peninsula it is known as Arabian tea and in South Africa it is referred to as Bushman’s tea.

Although its stimulant effect was originally attributed to cathine, extracts from fresh leaves of khat were shown to contain cathinone, isolated in 1975 and its properties recognized in 1978. Cathinone is not very stable and breaks down to produce cathine and norephedrine which belong to the phenylpropanolamine family, a subset of the phenethylamines and the catecholamines adrenaline and noradrenaline.

When the leaves are chewed the active ingredients are absorbed through the oral and gastric mucous membranes. The action of cathine and cathinone on the reuptake of adrenaline and noradrenaline results in the wakefulness associated with amphetamine derivatives. The effects of cathinone peak after 30 minutes, with nearly 98% of the substance metabolized by the liver into noradrenaline. Cathine has a half-life of about three hours in humans. Typically, an individual consumes 100–200 g of khat leaves (one bundle) in a session, and its effects last for several hours.

Symptoms are rather similar to the ingestion of strong coffee or amphetamines, for example, overtalkativeness and hyperactivity. The effects of oral cathinone occur more rapidly than those of amphetamine, 15 minutes compared to 30 minutes respectively. Khat causes constipation, dilated pupils (mydriasis), tachycardia and increased blood pressure, reflecting the sympathomimetic effects of the drug. Withdrawal symptoms, as would be expected, include mild depression and irritability, lethargy, rebound anxiety causing nightmares, tremulousness and loss of appetite. Long-term use may cause hepatic dysfunction, a permanent greenish tinge darkening of the teeth, and diminished libido. Rarely, dilated cardiomyopathy and myocardial infarction result from chronic use. 3

Mephedrone

Mephedrone (‘meow meow’) is a synthetic stimulant chemically related to cathinone, the psychoactive substance present in the khat plant. It is usually sold as a white crystalline or off-white-yellow powder (as a hydrochloride salt) for about £10 per gram. Consumption is usually oral or intranasal and rarely, by injection. Sellers avoid attracting the attention of regulatory bodies by labelling the substance “not for human consumption,” which means that no advice on safer use and dosing is provided.4

In one study the most commonly seen drug class were piperazines, followed by the cathinones, with significant variation in the content in one quarter of these compounds. The authors stated that it was relatively easy to purchase a number of legal highs from different Internet suppliers, though there times when not all of the products were available leading to the problem of users buying different active drugs to those they are used to, raising the prospect of potential toxicity to unknown agents.5A cross-sectional survey of 947 of mephedrone users found it to be the sixth most frequently used drug in the previous month after tobacco, alcohol, cannabis, cocaine and MDMA. Users typically were young males; 15% reported using weekly or more frequently; nearly 50% used between 0.5 and 1g during a typical session; intranasal use was the most common route of use (70%). Almost 55% of those who used cocaine reported that the ‘high’ obtained with mephedrone was better: intranasal use was also more likely addictive than oral use. Mephedrone appears to be the most widely abused synthetic cathinone in Europe, in contrast to the USA where MDVP and methylone are the most frequently abused. 6 7

Classification of mephedrone has had a limited effect on controlling its availability and use. Before the introduction of the legislation users generally obtained it via the internet. Now it is bought from street dealers, on average at double the price. Mephedrone was defined as a Class B drug under the Misuse of Drugs Act (1971) in the UK in April 2010. 4

Mephedrone produces similar effects to ecstasy, amphetamines and cocaine. It is detected in 20% of ecstasy tablets. It simulates the release of and inhibits the reuptake of monoamine neurotransmitters. The onset of psychoactive effects after insufflation is usually 10–20 minutes with an expected duration of effect of 1–2 hours; after oral ingestion onset is about 15–45 minutes with duration of 2–4 hours, and intravenous users report symptoms peaking at 10–15 minutes with a 30-minute duration of the desired effect.

Mephedrone users report that it has a better quality high than cocaine. It is speculated that mephedrone’s popularity reflects dissatisfaction with the purity and consistency of available cocaine and ecstasy. Concerns are also raised when it is considered that mephedrone is readily available from street dealers and may be taken by young people who have little previous experience of drug use.

Blood or plasma mephedrone concentrations are expected to be in a range of 50–100 μg/l in persons using the drug recreationally, >100 μg/l in intoxicated patients and >500 μg/l in victims of acute overdose.

Mephedroneinduces a greater increase in dopamine than serotonin release whereas MDMA (‘ecstasy’) induces a huge increase in serotonin with an insignificant rise in dopamine. Amphetamine results in a surge in dopamine release with an insignificant increase in serotonin. Mephedrone, amphetamine, and MDMA have decay values of 25, 50 and 300 minutes respectively. Therefore, the rapid rise and fall of dopamine levels could explain the addictive properties of mephedrone in some users. The effects are often described as somewhere between ecstasy and cocaine. As with cocaine, the ‘high’ generally lasts around an hour before wearing off. Furthermore, prolonged high –dose use of the substances can produce long-lasting neurotransmitter deficits in humans. 8 9

According to Mixmag (the online drug-use clubbing survey magazine for the UK) published in March 2012, 42% of clubbers had tried mephedrone the drug, and 34% had taken it in the last month. Some 30% of mephedrone users had reported using more ecstasy since the ban came into effect, while 19% reported using more cocaine. Blood or plasma mephedrone concentrations are expected to be in a range of 50–100 μg/l in persons using the drug recreationally, >100 μg/l in intoxicated patients and >500 μg/l in victims of acute overdose.

In 2011, Mixmag and the Guardian newspaper which draws on previous Mixmag surveys collected 15,500 responses from around the world, mostly the United Kingdom. In 2010/11, reported levels of use of mephedrone in the last year and last month were three times higher among clubbers (30 % and 13 %) than non-clubbers (10 % and 3 %).

Mephedronepredictably, causes increased alertness, restlessness, euphoria, excitement, the urge to talk, openness, time rushes, hot flushes, increased libido and elation. Hyperhidrosis, headache, palpitations, a Raynaud–type syndrome, and nausea are other relatively common unpleasant effects. Dizziness, hallucinations, panic attacks, and psychosis may occur. Other physical symptoms include dry mouth, blurred vision, and epistaxis. Symptoms of intoxication include agitation, aggression, violence, seizures and hyperthermia. Fatigue and insomnia are common residual effects. Mephedrone is generally used by nasal insufflation or ingestion of powder, liquid, capsule or tablets. The majority of users source mephedrone from street level dealers.10 Mephedrone induces strong feelings of craving in most users. If the unstable ecstasy market situation persists, the potential of mephedrone to substitute for MDMA might be substantial. Mephedrone, sold as ecstasy, is therefore more likely to be a cause for concern in the future.

Bath salts

This is the street name for substances which contain synthetic cathinone stimulants, such as methylenedioxypyrovalerone (MDPV) and mephedrone.11Bath salts components act synergistically at the dopamine transporter site and enhanced dopamine transmission may increase the potential for abuse. MDPV is consumed with other illicit drugs of abuse. It is the primary ingredient in "bath salts." Being a synthetic, cathinone-derivative it produces a high similar to cocaine or methamphetamine. It can be administered orally, by nasal insufflation, smoking, intravenously/intramuscularly, or per rectum, and intoxication lasts many hours.

MDPV may cause cardiac problems and disturbance of perception. During the withdrawal period after MDPV use, bone and muscle pain, and visual disturbances may occur. In the metabolism of MDPV, the most important catalyst is the CYP2C19 isoenzyme; the CYP1A2 and the CYP2D6 isoenzymes also play a role. The formed catechols are conjugated with either glucuronic acid or sulphate.

These compounds are not true bath salts in the traditional sense of household products. Cathinone is an amphetamine-like stimulant found naturally in the khat plant, described in more detail below. MDPV is much more potent than cocaine and its effect is longer lasting.12

Because of the sympathomimetic activity side effects are predictable and include cardiac arrhythmias, hypertension, arrhythmias, and hyperthermia. Chest pain, myocardial infarction, sweating, rhabdomyolysis, seizures, stroke, cerebral oedema, cardiorespiratory collapse, and rarely, death, have been reported. Psychiatric manifestations include hypersomnia, panic attacks, agitation, paranoia, suicidal ideation, self-mutilation, and aggressive behaviour.

The mode of action is thought to be the result of disruption and interference with central monoamine systems. In other words, synthetic cathinones increase extracellular monoamines by blocking transporter reuptake and increasing presynaptic neurotransmitter release. The dopamine (DA) transporter (DAT) and serotonin (5-HT) transporter (SERT) tightly regulate the amount of neurotransmitters within the synaptic cleft. Monoamine release also may be driven by presynaptic input from cholinergic or glutaminergic systems.12 7

Psychoactive bath salts are sold as tablets, capsules, or powder and purchased in places such as tobacco and convenience stores, gas stations, head shops, and the Internet. Bath salts may mimic cocaine, lysergic acid diethylamide (LSD), methamphetamine, or MDMA. The most common bath salts are the cathinone derivatives MDPV, mephedrone and methylone. The drugs have the potential for addiction because they cause intense stimulation, euphoria, elevated mood, and a pleasurable "rush". 13 14

In the United Kingdom (UK) to avoid being controlled by the Medicines Act, legal highs are sometimes described as bath salts, fertilizer (plant food), or incense, even though they have never been used for these purposes. In other words, legal highs are not covered by current drugs laws yet are used by individuals in the same way as illegal drugs such as cocaine or cannabis. The easy availability of legal highs marketed as "bath salts", ‘incense’ and ‘plant foods’, with the added proviso that they are not to be consumed by humans allows the drugs to circumvent current legislation. When legislation is changed the molecular structure is easily altered to produce a new legal high.

Synthetic cannabinoids

Marketed as ‘incense’ and labeled “not for human consumption”, these drugs were increasingly popular with students and young adults being initially legal and easily available from stores, online, head shops (outlets selling drug paraphernalia/counterculture magazines) and petrol stations. The structure of synthetic cannabinoids does not resemble that of tetrahydrocannabinol (THC] contained in marijuana or hashish, yet the drugs affect individuals in the same manner and are much more potent. Synthetic cannabinoids are sold under countless names such as ‘Mr Nice Guy,’ ‘Spice’, ‘Sabbaba’ and ‘Lemon Grass’, to name a few. Spice is a designer drug derived from herbs sprayed with synthetic chemicals which mimic the effects of cannabis. The ingredients are thus similar to but not identical to THC. Synthetic cannabis can precipitate psychosis, especially in individuals with a previous history and a chronic psychotic disorder may persist in some vulnerable patients.

A great variety of synthetic cannabinoids, most often cannabicyclohexanol, are used in an attempt to avoid prosecution. Some are sold in 'herbal' smoking mixtures and the latter have been found on occasion not to contain any synthetic cannabinoids at all. Cannabicyclohexanol is a cannabinoid receptor agonist drug. It has been sold under various brands such as Black Mamba, Bombay Blue, Fake Weed, Genie, Bliss, Blaze, Yucatan Fire. Spice products sometimes sold as “incense,” more closely resemble potpourri. Although Spice is usually smoked, sometimes individuals mix it with cannabis or prepare a herbal infusion for drinking.

To create the herbal products, synthetic cannabimimetics are dissolved in an organic solvent (e.g. acetone) and the resulting solution is sprayed on plant material. The doped plant material is then dried and smoked in a similar fashion to actual cannabis. Spice products typically have a pleasurable smell and taste. They are often referred to as herbal or legal highs because of their legal status and ‘natural’ herbal make-up. They are distributed in the form of dried leaves or resin, and powder, and are sold without age restriction in metal-foil sachets, usually containing 3 g of vegetable matter, to which one or more of the synthetic cannabinoids have been added. Spice is typically smoked, using a pipe or by rolling in a cigarette paper, and can also be ingested as an infusion, or inhaled.15 16

Table 1: Side effects of mephedrone

Common:
Hyperhidrosis
Headache
Palpitations
Nausea
Raynaud-type syndrome

Uncommon < 10%
Dizziness
Hallucinations
Psychosis
Dry mouth
Increased sociability
Chest pain
Blurred vision
Agitation, aggression, violence,
Hyponatraemia
Seizures and hyperthermia
Fatigue and insomnia

Drugs of the 2C family (phenethylamines containing methoxy groups attached to a benzene ring) have hallucinogenic and stimulant effects. The term ‘2C’' refers to the 2 carbon atoms between the benzene ring and the amino group in these compounds. The effects are a cross between MDMA and LSD. They are relatively new to the market and not widely available in the UK. An excited delirium presentation seems to be consistent in deaths attributed to 2C drugs and at least five deaths have been reported in the literature in patients intoxicated with 2C drugs. One agent known as 2C-1 or Smiles, which first appeared in 2003,has more potent effects than MDMA and LSD. Users report an intense energy with vivid visual and auditory hallucinations lasting hours to days.. Patients may exhibit symptoms consistent with serotonin toxicity. Doctors need to be vigilant as synthetic drugs do not show up on routine testing. Treatment of 2C intoxication is primarily supportive.17

Despite widespread Internet availability, many of these drugs remain unfamiliar to doctors and yet ‘bath salts’, have resulted in nationwide emergency department visits for severe agitation, sympathomimetic toxicity, and death. As with other illicit substances designer drugs may compromise cardiac function causing hypertension and tachycardia and users who inject run the well-known risks of contracting hepatitis C or HIV, thrombophlebitis and embolus formation.

Methoxetamine

Methoxetamine (also known as ‘mexxy’) is available on the Internet and marketed as ‘legal ketamine.’ It is an arylcyclohexylamine chemically related to ketamine and PCP (phencyclidine). Methoxetamine is longer acting and more potent than ketamine. The drug, a white powder, is usually taken sublingually, snorted, ‘bombed’, or injected intramuscularly. Doses are typically between 5mg-90mg orally. After snorting the drug it may take 30-90 minutes for its effects to become apparent. When injected the onset of action is usually within five to ten minutes. The overall duration of effect is within the range of 1–3 hours, sometimes longer. The drug induces feelings of detachment (dissociative state), paranoid symptoms, visual hallucinations, restlessness and increased energy in some. Other reported symptoms include confusion, catatonia, depression, tachycardia and hypertension. Methoxetamine is now a Class B drug under the Misuse of Drugs Act.18 19

Piperazine derivatives

The piperazine derivatives, a class of amphetamine-like compounds that includes BZP (benzylpiperazine) and TFMPP (trifluoromethylphenylpiperazine) are making a comeback as "legal ecstasy." Often perceived as safe by the public, adverse effects may range from minimal to life-threatening. Co-ingestion of BZP and TFMPP causes increased action of dopamine and serotonin, similar to MDMA. Severe symptoms include seizures, hyperthermia, hyponatremia, dystonic reactions, rhabdomyolysis, renal failure, metabolic acidosis, DIC, and respiratory failure. 20 Over the last few years piperazine derivatives are being sold as ecstasy pills, or under the names of “Frenzy”, “Bliss”, “Charge”, “Herbal ecstasy”, “A2”, “Legal X” and “Legal E”. Although piperazine designer drugs enjoy a market reputation of being safe, they may cause distorted perceptions after ingestion. There are several reports of toxic symptoms experienced by users after drug intake.The piperazinic compounds are derived from piperazine, a cyclic molecule containing two opposite nitrogen atoms and four carbon atoms distributed between the two and were originally used as anti-helminthic agents in the 1950s. Designer drugs of this class can be divided into the benzylpiperazines such as benzylpiperazine (BZP) and its methylenedioxy analogue methylenedioxybenzylpiperazine (MDBP), and phenylpiperazines such as chlorophenylpiperazine (CPP), trifluoromethylphenylpiperazine (TFMPP), and methoxyphenylpiperazine (MeOPP). A third group includes the thienylmethylpiperazines. Chlorophenylpiperazine is an active metabolite of drugs such as trazodone, and nefazodone used as antidepressants. A survey in the UK found that piperazines are among the most common active drugs in tablets purchased from internet supplier sites.Piperazine-derived compounds are therefore emerging designer drugs, whose abuse has increased remarkably worldwide.21

Naphyrone

Naphyrone(naphthylpyrovalerone) or NRG-1 (or Energy1) is a cathinone derivative available to buy on a number of websites and is gaining popularity. It is sold as an alternative to mephedrone. Belonging to the designer drugs class, it is similar in structure to pyrovalerone, a monoamine uptake inhibitor and as it is somewhat similar to other cathinone derivatives it has the potential to produce anxiety, paranoia, and cardiovascular side effects. Two products, both sold as NRG-2 from different internet suppliers, were found to contain the banned substituted cathinones - 4-methylethcathinone (4-MEC) and 4-methylmethcathinone (4-MMC), the latter being present in much smaller quantities. Although sold as research chemicals and labelled 'not for human consumption', they are essentially legal highs and are available online. 22 23

Table 2: Some commonly used psychoactive substances

Drug Mode of Action How used
MDMA (‘ecstasy’) ‘Molly’ is the pure crystalline powder form Releases and inhibits reuptake of dopamine, serotonin and noradrenaline Tablet or capsules

Sometimes one or more tablets taken at one time (‘bumping’)

Salvia divinorum Partial dopamine receptor agonist; also works on kappa receptors Smoked, inhaled, ingested, used sublingually
Mephedrone Effects similar to MDMA, cocaine and amphetamines Nasal insufflation, ingestion
MDVP (see text) Related to cathinone. Effects similar to ‘ecstasy’ Nasal insufflation, inhalation, ingestion
Spice Similar to THC Smoked; sometimes prepared as a herbal infusion for drinking
Naphyrone Effects similar to mephedrone Usually snorted, sometimes swallowed in paper wraps (‘bombing’)

Discussion

New designer drugs have increased in popularity over the past several years because of their euphoric effects. Understanding the pharmacology and toxicology of these agents is essential in order to provide the best medical care for patients. They are all potentially dangerous. For example, an excited delirium presentation seems to be consistent amongst deaths attributed to 2C drugs.

From the above description it can be seen that synthetic drugs fall into three broad categories: synthetic cathinones (bath salts), synthetic cannabinoids (spice or incense), and amphetamine-like drugs (methamphetamine, ephedrine, MDMA). Cathinones being related to the amphetamine family will cause dilated pupils, hypertension, hyperventilation, paranoia, agitation, hyperthermia, tremors and seizures. Many countries have made certain cathinones illegal, for example, mephedrone, methylone and MDPV. Indeed, the robust stimulation of dopamine transmission by MDPV predicts serious potential for abuse and may provide a mechanism to explain the adverse effects observed in humans taking high doses of 'bath salts' preparations. Furthermore, pyrovalerone is much more potent than cocaine at inhibiting the uptake of dopamine and norepinephrine.

Methcathinone was previously used in Russia as an antidepressant, also known as “Cat” and “Jeff” when used recreationally. Nowadays the drugs are sold as bath salts, plant food, insecticides, chicken feed additives, or research chemicals with names such as like NRG (Energy) and meow, meow. Bath salts are water-soluble, usually inorganic, solid products designed to be added to water during bathing. Numerous nicknames are used to describe them including Ivory Wave, Purple Wave, Red Dove, Zoom, Bloom, Cloud Nine, Ocean Snow, Lunar Wave, Vanilla Sky, White Lightning, and Hurricane Charlie.

Although ‘legal highs’ are commonly referred to as bath salts they are not Epsom salts (magnesium sulphate) or other water softeners within the usual meaning. In many cases the chemical ingredients are changed without the consumer knowing, making risks unpredictable. Some legal highs contain active ingredients controlled under the Misuse of Drugs Act 1971 (UK). Therefore any individual found in possession of these products would be liable to prosecution and the associated penalties, even if unaware that he/she has purchased a controlled drug. However, claiming a product to be "not intended for human consumption" can potentially circumvent the entire legal process. Drug designers are already showing skilful exploitation of the law and remain far ahead of criminalization efforts. Furthermore, the irony of prohibition is that the supply and slump in the market for cocaine and ecstasy in 2009 led to individuals resorting to untried and untested substances that are now easily available online. 24 25

Synthetic cathinones are mostly excreted via the urine and can be measured via gas or liquid chromatography-mass spectrometry in the blood, urine and stomach contents. They can also be analysed in hair. Unlike traditional cosmetic bath salts, which are packaged and sold for adding to bath water for soaking and cleaning, synthetic designer drugs sold as "bath salts" have no legitimate use for bathing and are intended for abuse. Baths salts contain one or more synthetic derivatives of the naturally-occurring stimulant cathinone. Low doses produce euphoria and increase alertness, but high doses or chronic use may cause serious adverse effects.26

Treatment

Treatment should be tailored to the specific drug of abuse. Medical and psychological needs require examining. Generally, treatment uses a combination of counselling and medication to reduce the need or desire (craving) for the drug and give the person the skills to refrain from future drug use. Other treatments might include cognitive behavioural therapy, detox, and relapse prevention techniques.

Supportive care is the mainstay of treatment for untoward serious side effects. Sedation with benzodiazepines is indicated for agitation, seizures, tachycardia, and hypertension. Extreme hypertension that persists despite benzodiazepines may be treated with vasodilators. Beta blockers should be avoided due to the potential to cause unopposed alpha-adrenergic stimulation, worsening the hypertension. Significant hyperthermia may require passive or active cooling. All moderately to severe symptomatic patients should have an electrocardiogram (ECG), be placed on a cardiac monitor, and receive serial temperature checks. Electrolytes, liver function tests, cardiac enzymes creatine, and toxicology should be carried out. Asymptomatic patients with no other suspected ingested drugs or psychiatric symptoms generally may be discharged.

Prevention

Banning legal highs is probably futile because it is impossible to keep up with newer drugs because they are synthesized as soon as the ‘illegal’ drug becomes banned. Some would argue that arresting users creates more harm for individuals, their families and society, as they are then caught up in the criminal system. Others may argue that ‘legal highs’ are not generally harmful and not as dangerous as opiates or their derivatives, or indeed alcohol. It might be more worthwhile making legal highs ‘uncool’, much in the same way that cigarette consumption is now frowned upon. However, it would require a great deal of public money to subsidise such an advertising venture.

Users of legal highs need to be made aware that such drugs purchased on-line may contain illegal substances and therefore may render them subject to prosecution if found in possession. 27

Pre-school family based programmes, and programmes involving the school and community, motivational interviewing for adolescents, and individual programmes, may be beneficial in reducing drug use and other harmful outcomes. Importantly, none of these approaches focus exclusively on particular substances or groups of substances, and although there have been relatively few investigations of intervention processes they most likely work by targeting a number of important precursors of drug use behaviour.28

Preventing designer drug abuse begins with understanding the warning signs of addiction which in many respects are similar to alcohol or more common street drugs.

Club drugs are now widely available and their harmful effects are increasingly becoming more evident. Their effects are unpredictable as they are often ‘contaminated’ with other harmful substances. It is unlikely that legislation will have a meaningful impact. Increasing public awareness about these drugs is paramount, and medical and nursing staff should consider intoxication in those patients who present with agitation and psychosis who have no previous history of mental health problems.

Pharmacists are in a pivotal position to observe changes in patterns of drug use and report worrying trends to health care practitioners. Counselling for young people especially and prevention programmes based in schools could prove useful in pointing out the dangers of these drugs to teenagers. Health care professional too should endeavour to keep up with recent information on these substances by attending hospital-based lectures or conferences as part of continuing professional education.

Urine drug testing will generally be unhelpful as many club drugs are undetectable on standard urine drug screens.29 Mental health staff should enquire about club drugs as part of routine drug and alcohol assessment and be aware that these patients may not fit the stereotype of a drug misuser.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
Dr Francis J Dunne, FRCPsych, Consultant Psychiatrist, Havering Community Recovery Team, 137-145 Church Road, Romford, Essex RM3 0SH. Dr Khalid Jaffar, MRCPsych, Specialist Registrar ST6, Havering Community Recovery Team, 137-145 Church Road, Romford, Essex RM3 0SH. Dr Shazia Hashmi, MRCPsych, Specialist Registrar ST6, Havering Community Recovery Team, 137-145 Church Road, Romford, Essex RM3 0SH.
Corresponding Author Details: 
Francis J Dunne, Thorpe Coombe Hospital, The Larkswood Centre, Walthamstow, E17 3HP.
Corresponding Author Email: 
dunnefrancis@googlemail.com
References
References: 
  1. Roberts MF, Wink M.  Alkaloids: biochemistry, ecology, and medicinal applications. Plenum Press; New York and London 1998. 
  2. Prosser JM, Nelson LS. The toxicology of bath salts: a review of synthetic cathinones. J Med Toxicol 2012; 8: 33-42.
  3. Wabe. Chemistry, pharmacology, and toxicology of khat (Catha edulis Forsk): a review. Addiction Health 2011; 3: 137-49.  
  4. Winstock A, Mitcheson L, Marsden J. Mephedrone: still available and twice the price.   Lancet 2010; 376: 1537
  5. Davies S, Wood DM, Smith G,  Button J, Ramsey J, Archer R, Holt DW, Dargon PI. Purchasing ‘legal highs’ on the Internet – is there consistency in what you get?  Q J Med 2010; 103: 489–93.
  6. Winstock AR, Mitcheson LR, Deluca P, Davey Z, Corazza  O, Schifano F. Mephedrone, new kid for the chop?  Addiction 2011; 106: 154-61. 
  7. German CL, Fleckenstein AE, Hanson GR. Bath salts and synthetic cathinones: an emerging designer drug phenomenon. Life Sciences 2014, 97: 2-8. Elsevier Inc.
  8. 8. Kehr J, Ichinose F, Yoshitake S, Goiny M, Sievertsson T, Nyberg F,   Yoshitake T. Mephedrone, compared to MDMA (ecstasy) and amphetamine, rapidly increases both dopamine and serotonin levels in nucleus accumbens of awake rats. B J Pharmacol 2011; 164 (8): 1949–58.
  9. Hadlock GC,  Webb KM,  McFadden LM, Chu PW, Ellis JD, Allen SC, Andrenyak DM et al. 4-methylmethcathinone (mephedrone): neuropharmacological effects of a designer stimulant of abuse. J Pharmacol Exp Ther 2011; 339(2): 530–36. 
  10. Dargan PI, Albert S, Wood DM. Mephedrone use and associated adverse effects in school and college/university students before the UK legislation change.     Quart J Med 2010; 103: 875-79
  11. Gunderson EW, Kirkpatrick MG, Willing LM, Holstege CP. Substituted cathinone products: a new trend in "bath salts" and other designer stimulant drug use. J Addict Med 2013; 7(3):153-62.
  12. Cameron KN, Kolanos R, Solis E Jr, Glennon RA, De Felice LJ. Bath salts components mephedrone and methylenedioxypyrovalerone (MDPV) act synergistically at the human dopamine transporter. Br J Pharmacol 2013; 168(7):1750-7. 
  13. Wieland DM1, Halter MJ, Levine C. Bath salts: they are not what you think.   J Psychosoc Nurs Ment Health Serv 2012; 50(2):17-21. 
  14. Gershman JA, Fass AD. Synthetic cathinones (‘Bath Salts’): legal and health care challenges. Pharmacy and Therapeutics 2012; 37(10): 571-72.  
  15. Fattor L, Fratta W.  Beyond THC: the new generation of cannabinoid designer drugs. Behav Neurosci 2011|doi: 10.3389/fnbeh.2011.00060.
  16. Zawilska JB, Wojcieszak J. Spice/K2 drugs – more than innocent substitutes for marijuana. Int J Neuropsychopharmacol 2014; 17: 509–25.
  17. Dean BV, Stellpflug SJ, Burnett AM, Engebretsen KM. 2C or not 2C: phenethylamine designer drug review.  J Med Toxicol 2013; 9: 172-78.
  18. Morris H, Wallach J. From PCP to MXE: a comprehensive review of the non‐medical use of dissociative drugs. Drug Test Anal 2014; 10.1002/dta.1620.
  19. Jonsson K, Kjelleren A. MethoxetaminE (MXE) – a phenomenological study of experiences induced by a ‘legal high’ from the Internet. J Psychoactive Drugs 2013; 45: 276-86.
  20. Schep LJ, Slaughter RJ, Vale JA, Beasley DM, Gee P. The clinical toxicology of the designer “party pills” benzylpiperazine and trifluoromethylphenylpiperazine. Clin Toxicol 2011; 49: 131-41. 
  21. Arbo MD, Bastos ML, Carmo HF. Piperazine compounds as drugs of abuse. Drug and Alcohol Dependence 2012; 122: 174– 85. 
  22. Brandt SD, Sumnall HR, Measham F, Cole J. Analyses of second-generation ‘legal highs’ in the UK: initial findings. Drug Test Anal 2010; 2: 377–82.
  23. Ayres TC, Bond JW. A chemical analysis examining the pharmacology of novel psychoactive substances freely available over the internet and their impact on public (ill) health. Legal highs or illegal highs? BMJ Open 2012; 2:e000977 doi: 10.1136/bmjopen-2012-000977
  24. Johnson LA, Johnson RL, Portier R-B. Current legal highs. J Emerg Med 2013 44: 1108-15.
  25. Measham F, Moore K, Newcombe R, Welch (nee Smith), Z. Tweaking, bombing, dabbing and stockpiling; the emergence of mephedrone and the perversity of prohibition. Drugs and Alcohol Today 2010; 10: 14-21.
  26. Baumann MH, Partilla JS, Lehner KR. Psychoactive ‘bath salts’: not so soothing. Eur J Pharmacol 2013, 698: 1-5.  
  27. Wood DM, Davies S, Cummins A, Button J, Holt DW, Ramsey J, Dargan PI. Energy-1 (‘NRG-1’): don't believe what the newspapers say about it being legal. BMJ Case Reports 2011; doi:10.1136/bcr.07.2010.3184 
  28. Sumnall H. Some thoughts on the tricky problem of ‘legal highs’ drugs education. Centre for Public Health, 2014, 2-9. (http://www.cph.org.uk/media).
  29. Bowden-Jones, O. Legal highs and other club drugs: why the song and dance?  Psychiatric Bulletin 2013; 37: 185-187.

BJMP December 2014 Volume 7 Number 4

BJMP December 2014 Volume 7 Number 4

Full Issue Booklet   PDF

Editorial

Research Articles

A Rapid Need Assessment Survey of Anaesthesia and Surgical Services in District Public Hospitals in Cross River State, Nigeria
Queeneth N. Kalu, Atim I. Eshiet, Essien I. Ukpabio, Anietimfon U. Etiuma and Emmanuel Monjok.
Full Text  PDF
Prevalence and implications of genital tattoos: A site not forgotten
Thomas Neluis, Myrna L. Armstrong, Cathy Young, Alden E. Roberts, LaMicha Hogan, and Katherine Rinard
Full Text  PDF
Association between plasma adiponectin and risk of myocardial infarction in Asian Indian patient with diabetes
Arun Narayan, Sanjay Kulkarni, Rahul Kothari, Telugu Seetharam Deepak, Punith Kempegowda
Full Text  PDF
Case Reports/Series
Cutaneous Polyarteritis Nodosa: A case report
Harish J, Manjunath M N and Chaithanya C Nair
Full Text  PDF
Case report: DiGeorge syndrome presenting with hypoparathyrodism and Learning Difficulties in adulthood.
Nawras Al-taie ,Sandra Scheuter-Mlaker , Michael Schlesinger , Heidemarie Abrahamian
Full Text  PDF

Clinical Practice

Chest pain and syncope in a middle-aged man
Deacon Zhao Jun Lee, Karan Saraf and Paul Sheridan
Full Text  PDF
Miscellaneous

"A girl with Anorexia" - A Poem by Dr Javed Latoo

Authors
Javed Latoo
Article Citation and PDF Link
BJMP 2014;7(4):a737

It all began when she was sixteen.

She started getting, increasingly,

Worried about her weight.

All day she dreamt of getting slim, getting lean.

 

Her days revolved around counting calories.

She made every effort to avoid fattening food, 

To survive on soup, toasts, coffee and berries.

Her fear of being judged, fat and ugly, was overwhelming.

 

Her life revolved around specific chores

Of excessive exercises, 

Of inducing vomiting, of taking 

Laxatives. All hidden from her family and friends.

 

Like a tree in the winter, bereft 

Of life, bereft of glow, she lost 

Her every feature, every playfulness,

That made her beautiful, that made her desirable.

 

She was slowly withering, like crops 

In a drought, until her family 

Alarmed her to see a doctor. A timely 

Intervention, timely support, raised

 

The hopes of a new dawn

The hopes of her recovery.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
JAVED LATOO MBBS DPM MRCPsych, Consultant Psychiatrist and Honorary Lecturer, 5 Borough Partnership NHS Foundation Trust, Warrington, United Kingdom.
Corresponding Author Details: 
Dr JAVED LATOO MBBS, Consultant Psychiatrist, 5 Borough Partnership NHS Foundation Trust, Hollins Park, Hollins Lane, Warrington, United Kingdom.
Corresponding Author Email: 
javedlatoo@gmail.com

Severe Presentation of Acute Upper Airway Obstruction – A Case Report

Authors
Adeel Majeed and Asquad Sultan
Article Citation and PDF Link
BJMP 2014;7(4):a736
Abstract / Summary
Abstract: 

Tongue swelling (glossitis) can be caused by many conditions. We present a case of severe tongue swelling leading to severe, acute upper airway obstruction and its anaesthetic management in the emergency setting.

Abbreviations: 
A+E - Accident and Emergency, IV - intravenous, IM - intramuscular, O2 - oxygen, GCS - Glasgow Coma Scale, ICU - Intensive Care Unit, ENT - Ears Nose and Throat, ALS - Advanced Life Support, CPR - Cardio-pulmonary Resuscitation, ETT - endotracheal tube
Keywords: 
Airway Obstruction, Angio-oedema, Anaphylaxis, Tracheostomy,

Case

A 74 year old female presented to the A&E department after waking with a swollen tongue. She called for an ambulance and the paramedic crew initially treated her for an allergic reaction with 200mg hydrocortisone IV, 20mg chlorphenamine IV and four doses of 0.5mg adrenaline 1 in 1,000 IM. She did not improve and was transferred to the local A&E.

In A&E, she was initially stable with no stridor or difficulty in breathing but noticeably swollen tongue. Saturations were 98% on 5L nasal O2. Blood pressure was stable at 135/75 mmHg. GCS was 15/15, but the patient was agitated from not being able to speak or retract the tongue. No further history was taken other than an allergy to shellfish, with no recent exposure. An obese habitus was noted.

A&E doctors called the anaesthetic on-call team, and on their request called the on-call ICU consultant and the on-call ENT consultant. Further adrenaline 100mcg IV, hydrocortisone 200mg IV and chlorphenamine 10mg IV were given. An attempt to look inside the mouth with a tongue depressor and torch was made by the anaesthetics/ICU team and it was quickly realised that the swelling continued into the mouth and larynx and was rapidly progressing. Given the lack of suitable equipment and the severity of the case, a decision was made to transfer to emergency theatres.

Once in emergency theatres, the on-call ENT consultant was scrubbed and ready. 100% oxygen via facemask and routine monitoring was instituted. At the request of the ENT consultant, a micro-tracheostomy was attempted with local anaesthesia but failed to pass into the trachea given the patient’s habitus. The ENT surgeons attempted an awake tracheostomy, but this was difficult due to her being agitated and unable to lie still, and a calcified trachea.

The rapidly progressing swelling compromised oxygen delivery to the lungs and the saturations began to drop quickly. The patient became bradycardic and lost consciousness. At this point, it became easier to attempt the tracheostomy. The ALS protocol was followed and CPR started. An attempt was made for direct laryngoscopy – a grade 3b view was obtained and a size four microlaryngeal tube was passed successfully. 100% O2, two doses of 1mg adrenaline IV, and 3mg atropine IV were given and the heart rate improved. Pulses were present and the defibrillator showed sinus rhythm; CPR was stopped and tracheostomy was continued. Due to abundant peri-tracheal fat, a number of tracheostomy tubes were tried before a secure tracheostomy was placed. However the microlaryngeal tube maintained airway patency.

An arterial line and larger cannula was secured. Propofol infusion and fentanyl IV were given to maintain anaesthesia and the patient was transferred to ICU.

On ICU, there was further difficulty in ventilation, with high airway pressures and saturations falling to the low 90s despite 100% O2. It was thought the tracheostomy tube was abutting the carina or posterior tracheal walls. The ENT surgeons were called urgently and in the interim the patient was re-intubated with a size 7 ETT to maintain the airway. The ENT team changed the size 8 cuffed non-fenestrated tracheostomy tube for a size 7 Shiley with a proximal extension. Despite the change, ventilation remained difficult. An urgent chest X-ray was performed which showed a right-sided pneumothorax. A chest drain was inserted and a ‘hiss’ was noted on insertion, indicating a possible tension pneumothorax. Ventilation then improved.

Further history was taken from previous notes and discharge letters. It was noted that the patient had allergies to shellfish, penicillin, erythromycin, and diclofenac, but no history of exposure. She had a background of hypertension, angina, chronic kidney disease and previous breast cancer. She was taking Lisinopril, Diltiazem, Nicorandil, Tamoxifen, Sertraline and Omeprazole. Her tongue swelling improved markedly over the next two days with antibiotic treatment and regular dexamethasone. She was awakened once appropriate and haemodynamically stable. A nasendoscopy was performed by the ENT team on day six and nothing remarkable was noted, with swelling having regressed totally. She was decannulated on day eight and transferred to the ward. Lisinopril was stopped.

Discussion

This case demonstrated a severe, acute presentation of tongue swelling (glossitis) leading to upper airway obstruction. Although a number of conditions may cause glossitis: infection, trauma, anaemia, liver disease, malnutrition. Acute glossitis is a hallmark of angio-oedema. This is a rare, but life threatening condition that requires prompt recognition and treatment.

Angio-oedema may result from anaphylactic, hereditary, acquired or idiopathic processes. Some 12-24% of anaphylaxis cases present with angio-oedema.1, 2 Hereditary and acquired cases usually result from a deficiency of C1 esterase inhibitor deficiency, which causes an accumulation of bradykinin, leading to soft tissue oedema. Such an increase in bradykinin may be caused by angiotensin converting enzyme inhibitors, leading to angio-oedema.3 If no cause can be found, it is termed idiopathic.

Management of angio-oedema requires rapid airway assessment and management; resuscitation; and treatment of the underlying cause. Anaphylaxis should respond to standard management as outlined by the AAGBI.4 Angio-oedema from other causes requires cessation of the suspected causative agent3, and in an emergency, nebulized adrenaline to reduce airway swelling. Infusion of plasma derived or recombinant C1 Esterase Inhibitor may also rapidly improve symptoms.1

Although airway support is the cornerstone of anaesthetic management, an acute, rapidly progressing case such as this requires a multi-disciplinary approach.5 Anaesthetists will require help from operating department practitioners and nurses to manage the initial airway compromise. A compromised airway presents a significant hazard to any form of anaesthesia, especially if it results in cardio-respiratory depression, which will expedite hypoxemia and impair tissue oxygenation. An awake, spontaneously ventilating approach to secure the airway needs to be undertaken. ENT staff should be scrubbed and ready to perform an emergency surgical tracheostomy if complete airway obstruction occurs or airway access cannot be secured.

An awake fibre-optic intubation can be attempted but this requires an experienced anaesthetist, timely access to equipment, preparation and a co-operative patient. These are unlikely to be provided in the resuscitation room. Fibre-optic manipulation causing bleeding or further swelling can lead to complete airway obstruction.

An inhalational induction to maintain spontaneous ventilation and then followed by direct laryngoscopy or fibre-optic intubation is another option and reduces the required co-operation of the patient. But this may cause haemodynamic instability in an already compromised patient and can lead to complete airway collapse.

An elective awake tracheostomy under local anaesthetic is the most likely route to ensure airway access without haemodynamic compromise.6 This will require a co-operative patient, senior help from trained operating department staff, and the ENT surgeons scrubbed and ready to perform a surgical tracheostomy if a percutaneous approach fails.

The Intensive Care Unit should be aware of the patient and ICU teams will be required to help with airway access as well as manage haemodynamic instability, secure arterial and central venous access. The patient will need further airway support and treatment in the Intensive Care Unit.

An acute upper airway obstruction therefore requires an emergent, yet controlled, approach to secure airway access and maintain oxygenation. Staff should have clear roles, ideally decided beforehand and practiced, with experience in the use of the equipment available. Senior ENT help should be available readily and again be versed in securing an emergency awake tracheostomy should other means fail or are not suitable.

As with any critical incident a debriefing should be undertaken to highlight points in the management of such patients that were handled well and those that were not, so that existing management plans can be improved and skills honed to improve management of future incidents.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
ADEEL MAJEED, MPHARM MBCHB FRCA, Anaesthetic Trainee (ST5), Kettering General Hospital, Rothwell Road, Kettering, UK. ASQUAD SULTAN, MBBS FFARCSI Dip ESRA, Anaesthetic Consultant, Kettering General Hospital, Rothwell Road, Kettering, UK.
Corresponding Author Details: 
ADEEL MAJEED, Anaesthetic Trainee (ST5), Anesthetic Department, Kettering General Hospital, Rothwell Road, Kettering, NN16 8UZ, UK.
Corresponding Author Email: 
adeel@majeed.org
References
References: 
  1. Hoyer C, Hill MR, Kaminski ER. Angio-oedema: an overview of differential diagnosis and clinical management. Contin Educ Anaesth Crit Care Pain. 2012; 12(6): 301-311
  2. Oxford Handbook of Anaesthesia, 3rd Edn. K. Allman and I. Wilson (editors). Published by Oxford University Press, Oxford, UK. 2012  p.948
  3. Chiu AG, Newkirk KA, Davidson BJ, et.al. Angiotensin-converting enzyme inhibitor-induced angioedema: a multicenter review and an algorithm for airway management. Ann Otol Rhinol Laryngol. 2001; 110(9): 834-840
  4. Association of Anaesthetists of Great Britain and Ireland. Suspected anaphylactic reactions associated with anaesthesia. 2009. AAGBI Safety Guideline.
  5. Cheng WY, Smith WB, Russell WJ. Acute upper airway obstruction from acquired angioedema. Emergency Medicine Australasia. 2007; 19: 65–67
  6. Jensen NF, Weiler JM. C1 Esterase Inhibitor Deficiency, Airway Compromise, and Anaesthesia. Anesth Analg. 1989; 87: 480-488

Chest pain and syncope in a middle-aged man

Authors
Deacon Zhao Jun Lee, Karan Saraf and Paul Sheridan
Article Citation and PDF Link
BJMP 2014;7(4):a735
Abstract / Summary
Abstract: 

A 46 year old man presented to the Emergency Department with chest pain and collapse with loss of consciousness. The history, examination and investigation findings are detailed below followed by five questions surrounding the pathophysiology, diagnosis and management of the condition.

Keywords: 
Brugada syndrome, channelopathy, sudden cardiac death, ventricular tachycardia, ventricular fibrillation, risk stratification, internal cardioverter defibrillator

Case history

A 46 year-old man presented to the Emergency department with chest pain and collapse, associated with loss of consciousness lasting several minutes. He had no significant past medical history and he had no risk factors for coronary artery disease. However, he did note a similar episode of collapse and loss of consciousness one year prior for which he did not seek medical attention. There was no known family history of heart disease or sudden death.

On examination he was haemodynamically stable with a blood pressure of 130/80 mmHg and heart rate of 85 beats per minute. Jugular venous pressure was measured at 2cm above the sternal angle and heart sounds were normal with no added sounds. His oxygen saturation was 98% on air and chest was clear to auscultation. Chest X-Ray demonstrated clear lung fields and laboratory investigations, including electrolytes and cardiac troponin T were within normal limits. Echocardiography showed a structurally normal heart. Figure 1 shows his 12-lead electrocardiogram (ECG) on admission.


Figure 1 
– 12 lead ECG on admission

Questions

1. What is the likely diagnosis based on the clinical presentation and ECG findings?

2. What life-threatening arrhythmias can arise from this condition?

3. What is the pathophysiology of this condition?

4. How is the diagnosis of this condition made?

5. What treatment options are available for patients with this condition?

Answers

1. What is the likely diagnosis based on the clinical presentation and ECG findings?

Short answer

Brugada syndrome

Long answer

The ECG shows coved Type 1 ST segment elevation in keeping with a diagnosis of Brugada syndrome.

First described in 1992, Brugada syndrome is a primary cardiac electrical disease or channelopathy that is accompanied a structurally normal heart and carries an association with sudden cardiac death1.

Presentation often occurs in the third or fourth decades of life, with a male preponderance of 8:1, however sudden cardiac death due to Brugada syndrome has also been seen in patients at the extremes of age. It is estimated that it accounts for up to 20% of all sudden cardiac deaths in patients without structural heart disease, ischaemia or electrolyte abnormalities2. It is most commonly seen in south-east Asia, especially Thailand, where its incidence is around 1%, and is much less common in western countries1.

2. What life-threatening arrhythmias can arise from this condition?

Short answer

Brugada syndrome is associated with increased risk of ventricular tachycardia (VT), often polymorphic, and ventricular fibrillation (VF).

Long answer

Brugada syndrome often manifests clinically in the form of syncope or sudden cardiac death. It is most commonly associated with polymorphic VT and VF, which may or may not terminate spontaneously. There are a large proportion of patients with Brugada syndrome who never experience any symptoms and indeed, may not ever even be identified as having the condition, unless they are found to have incidental ECG abnormalities as part of routine medical testing or are under investigation for another problem3.

3. What is the pathophysiology of this condition?

Short answer

Brugada syndrome is understood as a genetic cardiac channelopathy, a disorder produced by the dysfunction of a cardiac ion channel participating in the action potential which can result in electrical change favouring the development of arrhythmias. Inheritance of the condition occurs via an autosomal dominant mode of transmission with incomplete penetrance4.

Long answer

Brugada syndrome is a genetic disorder, with a loss-of-function mutation of the SCN5A gene implicated in about 30% of sufferers. This gene codes for the α-subunit of the cardiac sodium channel. Other mutations of sodium and calcium channels have also been found. In inherited cases, the gene is passed in an autosomal dominant fashion, though sporadic mutations are also seen.

There is increased susceptibility to ventricular arrhythmias, because of altered depolarisation within the right ventricle. In SCN5A mutations, the defect in sodium channels leads to decrease in the sodium current and a shortening of the cardiac action potential by blunting phase 0 depolarisation. Potassium channels are also affected, with an increased number of transient outward potassium channel currents. This imbalance in the myocytes between sodium and potassium concentrations means the overall effect is to shorten the refractory period, making the myocytes more prone to re-entrant circuits, leading to the development of VT and degeneration to VF2,5.

4. How is the diagnosis of this condition made?

Short answer

Brugada syndrome is characterised by electrocardiographic changes demonstrating coved ST segment elevation in the right precordial leads.

Long answer

Electrocardiographic abnormalities constitute the hallmark of Brugada syndrome. There are three different ECG patterns and in all three types, the ECG shows ≥2mm J point (junction between the termination of QRS complex and beginning of ST segment) elevation and a characteristically shaped ST segment in the right precordial leads6.

Type I has a ‘coved’ pattern ST segment elevation ≥2mm, with a descending terminal portion in at least one right precordial lead.

Type II has a ‘saddle-back’ ST segment elevation ≥1mm and has a high elevation in its initial portion.

Type III has either coved or saddleback ST elevation but is less accentuated than types I or II (<1mm).

Although all the 3 patterns can be present in patients with Brugada syndrome, only the presence of a type-1 ECG pattern defines the diagnosis of the condition2,7. The patterns for type II or III are not diagnostic, and carrying out a Class I anti-arrythmic drug (AAD) test to confirm the diagnosis is recommended. This can be done with AADs such as ajmaline, flecainide or procainamide, though currently ajmaline is preferred due to its higher sensitivity in revealing Brugada type ECG changes1.

It is worth noting that the resting ECG changes associated with Brugada syndrome (in particular type I) are often transient, and therefore, in someone in whom the diagnosis is suspected, an AAD test may be indicated even if there are no resting spontaneous ECG abnormalities evident6.

Differential diagnoses of Brugada syndrome must be approached with care as ST segment elevation is associated with a wide variety of benign and malignant pathophysiologic conditions3.

5. What treatment options are available for patients with this condition?

Short answer

Currently, the implantable cardioverter defibrillator is the only proven effective treatment in the prevention of sudden cardiac death.

Long answer

Management of Brugada syndrome is focused on risk stratification of patients to prevent arrhythmic death in high risk individuals. ICD implantation can prevent sudden cardiac death in these groups1. Newer devices are now also being used, including the subcutaneous ICD which is implanted in a subcutaneous pocket and does not require any endovascular leads in the heart or access to the central venous circulation8.

Pharmacological options are focused on rebalancing the ion channel current active during the early phases of the epicardial action potential in the right ventricle3,9. Some studies have evaluated the role of quinidine in the treatment of Brugada syndrome and found it to be effective in preventing polymorphic VT and VF in this condition10. Quinidine has also been proposed as an alternative to ICD implantation in children and infants too young to receive an ICD11,12.

Data relative to the use of cryosurgical treatments or ablation therapy in Brugada syndrome are very limited at this point in time3.

Patient outcome

The patient underwent successful implantation of a subcutaneous cardioverter defibrillator. Figure 2 and Figure 3 show chest radiographs of the leadless device.


Figure 2 
– Chest radiograph (PA view) showing the implanted subcutaneous ICD


Figure 3 
– Chest radiograph (lateral view) showing the implanted subcutaneous ICD

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
DEACON ZHAO JUN LEE, MBCHB MRCP, Sheffield Teaching Hospitals, UK. KARAN SARAF, MBCHB, Sheffield Teaching Hospitals, UK. PAUL SHERIDAN, MBCHB MRCP PhD, Sheffield Teaching Hospitals, UK.
Corresponding Author Details: 
DEACON ZHAO JUN LEE, Sheffield Teaching Hospitals, Northern General Hospital, Herries Road, Sheffield, S5 7AU.
Corresponding Author Email: 
deacon.lee.04@aberdeen.ac.uk
References
References: 
  1. Boussy T, Sarkozy A, Chierchia GB et al. The Brugada Syndrome: Facts and Controversies. Herz 2007;32:192-200
  2.  Antzelevitch C, Brugada P, Borggrefe M et al. Brugada syndrome: report of the second consensus conference: endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation 2005;111:659-70
  3. Antzelevitch C. Brugada Syndrome. PACE 2006;29:1130-59
  4. Benito B, Brugada R, Brugada J et al. Brugada Syndrome. Progress in Cardiovascular Diseases 2006;51(1):1-22
  5. Herbert E, Chahine M. Clinical aspects and physiopathology of Brugada Syndrome: a review of current concepts. Can J Physiol Pharmacol 2006;84:795-802
  6. Richter S, Sarkozy A, Chierchia GB et al. Variability of the diagnostic coved-type ECG during long-term follow-up of patients with Brugada syndrome and primary prophylactic ICD implantation. Eur Heart J 2006,27:Suppl 1:AB88662
  7. Wilde AAM, Antzelevitch C, Borggrefe M et al. Proposed diagnostic criteria for the Brugada syndrome. Eur Heart J 2002;23:1648-1654
  8. Weiss R, Knight BP, Gold MR et al. Safety and efficacy of a totally subcutaneous implantable-cardioverter defibrillator. Circulation 2013;128:944-953
  9. Márquez MF, Salica G, Hermosillo AG et al. Ionic basis of pharmacological therapy in Brugada syndrome. J Cardiovasc Electrophysiol. Feb 2007;18(2):234-40
  10. Belhassen B, Glick A, Viskin S. Efficacy of quinidine in high-risk patients with Brugada syndrome. Circulation 2004;110(13):1731–7
  11. Probst V, Evain S, Gournay V et al. Monomorphic ventricular tachycardia due to Brugada syndrome successfully treated by hydroquinidine therapy in a 3 year old child. J Cardiovasc Electrophyiol 2006;17:97-100
  12. Probst V, Denjoy I, Meregalli PG et al: Clinical aspects and prognosis of Brugada syndrome in children. Circulation 2007;115:2042-2048

Cutaneous Polyarteritis Nodosa: A case report

Authors
Harish J, Manjunath M N and Chaithanya C Nair
Article Citation and PDF Link
BJMP 2014;7(4):a734
Abstract / Summary
Abstract: 

Cutaneous polyarteritis nodosa is a rare vasculitis of childhood relating to small-to-medium-sized arteries. Its etiology is unknown. Clinical manifestations include tender subcutaneous nodules, livedo reticularis, cutaneous ulcers and necrosis. Although it is distinct from systemic polyarteritris nodosa in that it lacks significant internal organ involvement, extra-cutaneous manifestations may be evident. The diagnosis is by skin biopsy as there is no other specific serological tests and characteristic pathologic feature is a leukocytoclastic vasculitis in the small to medium-sized arterioles of the dermis with or without fibrinoid necrosis. Mild cases may resolve with nonsteroidal anti-inflammatory drugs. If more severe, treatment with systemic corticosteroids generally achieves adequate response.  We report a 10 year old girl with cutaneous PAN, who presented to us with arthralgia and swelling of left knee joint and both ankle joints and fever  , with  multiple tender subcutaneous nodules on both upper and lower limbs.

Abbreviations: 
cPAN- Cutaneous polyarteritis nodosa, PSM- pansystolic murmur. CRP- c reactive protein, ASLO- anti streptococcal lysin O
Keywords: 
Cutaneous polyarteritis nodosa, subcutaneous nodules, vasculitis.

Polyarteritis nodosa (PAN) is a rare vasculitis in childhood. Since first described by Kussmaul and Maier in 1866 1, there have been approximately 140 pediatric case reports in the literature. Traditionally, children were classified as having one of three forms: infantile, cutaneous, and systemic. Infantile PAN is now recognized as a severe form of Kawasaki disease. Criteria for a diagnosis of systemic PAN in childhood have been proposed but not validated2.

Cutaneous PAN (cPAN) is recognized as a separate entity but there are no diagnostic criteria for cPAN2. cPAN is characterized by disease affecting the skin with no major organ system involvement. The cutaneous symptoms are similar to systemic PAN and mild fever, muscle, joint, and peripheral nervous system involvement may also occur. Fever, rash, and musculoskeletal symptoms are common in children and cPAN needs to be differentiated from other diagnostic entities. Definitive diagnosis is by histopathologic evidence of necrotizing inflammation of the medium and small-sized arteries. There is a paucity of knowledge of the spectrum of clinical presentation and management of children with cPAN. Here we describe a case of cPAN and summarize the clinical manifestations, laboratory data and treatment regimens of our patient.

Case report

This 10 year old female adolescent presented with pain in both the elbow joints followed by pain in the left knee joint and both the ankle joints in a course of 8 days and fever for the past 2 days .On admission her vitals were stable, both the elbow joints were tender and the knee and ankle joints were swollen and tender .She had multiple subcutaneous nodules over extensor aspect of both her forearms, both her tibial shins and few on her thighs. Systemic examination showed presence of a soft PSM of grade 2 intensity over left sternal edge. Blood investigations showed leucocytosis, elevated CRP, elevated ASLO titres and 2Decho revealed a mild tricuspid regurgitation. An initial diagnosis of acute rheumatic fever was made and child was started on penicillin and Aspirin. But child continued to have excruciating arthralgia and hence a rheumatologist opinion was taken. Child was advised a skin biopsy from the nodular lesions which showed small and medium vessel vasculitis suggestive of cutaneous polyarteritis nodosa. Hence she was stopped with aspirin therapy , given pulse therapy with methyl prednisolone and continued with penicillin therapy .Her arthralgia subsided within a day of pulse therapy and the subcutaneous nodules gradually disappeared .On discharge child was put on oral steroid therapy and penicillin prophylaxis and advised regular follow up.


Fig1 showing segmental fibrinoid necrosis with inflammatory infiltrates of small artery.


Fig2 showing leukocystoclastic vasculitis with fragmentation of neutrophils in and around blood vessels.

DISCUSSION:

cPAN is not common in the pediatric population with approximately 140 cases reported in the literature. Disease is limited to skin, joints, and muscles in the majority with a minority having nerve involvement. Constitutional symptoms are common. Most children have a chronic and relapsing benign course.

The precise etiology of cPAN remains to be unknown. However, an immune mediated mechanism has been postulated. Several infectious and noninfectious conditions have been associated both to initiation and relapse of the disease3,4,5. Among them, streptococcal infection has been commonly implicated6,7. Although some evidence of streptococcal infection as an initiating factor for cPAN is present, caution must be exercised when interpreting elevations in the serologic markers of streptococcal infection in the absence of an appropriate clinical presentation.

Cutaneous and systemic PAN share the same histopathologic features of necrotizing arteritis of small and medium sized vessels. Kussmaul and Meier described the first case of systemic PAN in 1866 1. Early reports 8,9 confirm that cPAN is a separate entity to systemic PAN. We have limited our definition of cPAN to disease affecting the skin, muscle, joints, and peripheral nervous system, with corresponding biopsy confirmation. Any evidence of visceral involvement, either clinically (central nervous system, pulmonary, cardiac, gastrointestinal, or renal), radiographically (abnormal angiography), or by histology (visceral biopsy) were classified as systemic PAN. Nakamura et al 10 proposed further restriction of the definition of cutaneous PAN in that any extracutaneous involvement such as peripheral neuropathy and myalgias must be limited to the same area as skin lesions. Systemic PAN and cPAN appear to be fairly distinct entities on a clinical continuum. There are only 5 reported cases of cPAN evolving into systemic PAN 11,12.

On review of treatment regimens reported in the literature, most children respond to corticosteroids. Penicillin should be considered in children with increased ASO titres 13,14. Recent case series report success with low-dose methotrexate, cyclophosphamide, intravenous immunoglobulin, and biologic therapies 15,16.

In summary, cPAN can be challenging to diagnose and manage. A diagnosis of cPAN should be considered in a child with fever, tender subcutaneous nodules, livido reticularis, and arthralgias/arthritis. Most children respond to corticosteroids and have a benign course, but some children may be corticosteroid dependent or corticosteroid resistant, necessitating other immunosuppressive agents including DMARDs and biologic therapy. Multicentre pediatric vasculitis disease registries are necessary to inform development and standardization of best clinical practice for childhood cPAN.

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
Department Of Pediatrics and Medical Records Department, Kempegowda Institute Of Medical Science, Bangalore, India.
Competing Interests: 
None declared
Details of Authors: 
HARISH J, MD, Assistant Professor, Department of Pediatrics, Kempegowda Institute of Medical Science, Bangalore, India. MANJUNATH M N, Junior Resident, Department of Pediatrics, Kempegowda Institute of Medical Science, Bangalore, India. CHAITHANYA NAIR , Junior Resident, Department of Pediatrics, Kempegowda Institute of Medical Science, Bangalore, India.
Corresponding Author Details: 
DR MANJUNATH M N, Junior Resident, Department Of Pediatrics, Kempegowda Institute Of Medical Science, K R Road, VV Puram, Bangalore 560004, India.
Corresponding Author Email: 
drmanju.drmanju@gmail.com
References
References: 
  1. Kussmaul A, Maier R. Über eine bisher nicht beschriebene Arterienerkrankung (Periarteritis nodosa), die mit Morbus Brightii und mit rapid fortschreitender allgemeiner Muskellähmung einhergeht. Deutsches Archiv für Klinische Medizin. 1866;1:484–518.
  2. Ozen S, Pistorio A, Iusan SM, et al. EULAR/PRINTO/PRES criteria for Henoch-Schönlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: final classification criteria. Annals of the Rheumatic Diseases. 2010;69(5):798–806.
  3. 3.Daoud MS, Hutton KP, Gibson LE. Cutaneous periarteritis nodosa: a clinicopathological study of 79 cases. Br J Dermatol. 1997;136:706–713.
  4. Misago N, Mochizuki Y, Sekiyama-Kodera H, Shirotani M, Suzuki K, Inokuchi A, Narisawa Y. Cutaneous polyarteritis nodosa: therapy and clinical course in four cases. J Dermatol. 2001;28:719–727.
  5. Dohmen K, Miyamoto Y, Irie K, Takeshita T, Ishibashi H. Manifestation of cutaneous polyarteritis nodosa during interferon therapy for chronic hepatitis C associated with primary biliary cirrhosis. J Gastroenterol. 2000;35:789–793.
  6. Till SH, Amos RS. Long-term follow-up of juvenile-onset cutaneous polyarteritis nodosa associated with streptococcal infection. Br J Rheumatol. 1997;36:909–911
  7. Albornoz MA, Benedetto AV, Korman M, McFall S, Tourtellotte CD, Myers AR. Relapsing cutaneous polyarteritis nodosa associated with streptococcal infections. Int J Dermatol. 1998;37:664–666.
  8. Diaz-Perez JL, Winkelmann RK. Cutaneous periarteritis nodosa. Archives of Dermatology. 1974;110(3):407–414.
  9. Borrie P. Cutaneous polyarteritis nodosa. British Journal of Dermatology. 1972;87(2):87–95.
  10. Nakamura T, Kanazawa N, Ikeda T, et al. Cutaneous polyarteritis nodosa: revisiting its definition and diagnostic criteria. Archives of Dermatological Research. 2009;301(1):117–121.
  11. Magilavy DB, Petty RE, Cassidy JT, Sullivan DB. A syndrome of childhood polyarteritis. Journal of Pediatrics. 1977;91(1):25–30.
  12. David J, Ansell BM, Woo P. Polyarteritis nodosa associated with streptococcus. Archives of Disease in Childhood. 1993;69(6):685–688
  13. Kumar L, Thapa BR, Sarkar B, Walia BNS. Benign cutaneous polyarteritis nodosa in children below 10 years of age—a clinical experience. Annals of the Rheumatic Diseases. 1995;54(2):134–136. 
  14. Fink CW. The role of the streptococcus in poststreptococcal reactive arthritis and childhood polyarteritis nodosa. Journal of Rheumatology. 1991;18(29):14–20
  15. 15.Eleftheriou D, Melo M, Marks SD, et al. Biologic therapy in primary systemic vasculitis of the young. Rheumatology. 2009;48(8):978–986.
  16. Ozen S, Anton J, Arisoy N, et al. Juvenile polyarteritis: results of a multicenter survey of 110 children. Journal of Pediatrics. 2004;145(4):517–522.

A Rapid Need Assessment Survey of Anaesthesia and Surgical Services in District Public Hospitals in Cross River State, Nigeria

Authors
Queeneth N. Kalu, Atim I. Eshiet, Essien I. Ukpabio, Anietimfon U. Etiuma and Emmanuel Monjok.
Article Citation and PDF Link
BJMP 2014;7(4):a733
Abstract / Summary
Abstract: 

Background: The district hospitals in Cross River State of Nigeria serve majority of the population residing in the rural areas and little is known about their capacity to provide anaesthetic and surgical care. The present study is an initial needs assessment of anaesthesia and surgical services in public hospitals in Cross River State as a stepping stone for strengthening anaesthesia and surgical services.
Methods: A standardized Lifebox Hospital Initial Needs assessment questionnaire and another structured questionnaire were used to assess the anaesthesia and surgical services in 16 general hospitals (district hospitals). The survey did not involve face-to-face interviews.
Results: There was no practicing physician-anaesthetist in the 16 district hospitals in Cross River State. There were only 13 trained nurse-anaesthetists distributed unevenly in the 16 surveyed district hospitals. One visiting consultant anaesthetist and five visiting consultant surgeons from the University Teaching Hospital worked at the general hospital in the capital city leaving all others in rural locations without any specialist provision. Apart from the nurse-anaesthetists in the general hospital in Calabar and at Dr Lawrence Henshaw Memorial Hospital, also in Calabar both in the capital city, the others working in the rural hospitals have had no refresher or In-service training in the past 2 years. Many of the district hospitals lack basic anaesthetic equipment. An average of 3-53 surgeries are performed at the district hospitals with intravenous Ketamine as the commonest technique of anaesthesia.
Conclusion:  The district hospitals’ anaesthetic and surgical capacity is grossly inadequate in relation to the population being served. It is recommended that shorter training programs for physicians at the primary and secondary levels of care and regular revision courses for nurse anaesthetists in Nigeria will strengthen the district surgical and anaesthetic capacity and services with urban-rural shift in manpower especially with government incentive for rural health workforce.

INTRODUCTION

Surgery and anaesthesia have traditionally been viewed as expensive, resource-intensive and requiring highly specialized training.1 This misconception has led to surgery and anaesthesia taking a back seat to public health, maternal and child health, and infectious diseases in global health.2 Surgery has also been termed the “neglected stepchild of global health.3These concepts have changed rapidly since it has been found that surgical diseases contribute about 11% to Disability Adjusted Life Years4 and therefore would benefit from preventive and public health strategies necessary to achieve the Millennium Development Goals. The realization of the huge public health burden of surgical diseases in low and medium income countries (LMICs), and the fact that surgical services and treatment could be made cost effective, led World Health Organization (WHO) to launch the Global Initiative for Emergency and Essential Surgical Care (GIEESC) in 2005.5

The GIEESC is a global forum whose goal is to promote collaboration among diverse groups of stakeholders to strengthen the delivery of surgical services at the primary referral level in LMICs.5 Improvements in surgical services at the primary referral level in LMICs will equally require the provision of safe and effective anaesthesia. The provision of safe and effective anaesthesia will need adequately trained human resources and essential health technologies. The surgical and anaesthesia service capacity have generally been very low in sub-Saharan Africa (SSA) as evidenced through surveys conducted in Ethiopia,6 Gambia,7,8 Ghana,9,10 Liberia,8,11 Malawi,12 Nigeria,13 Sierra Leone,8,14 Rwanda,15,16 Tanzania,8,17 and Uganda.18 The survey from Nigeria was conducted among rural private hospitals and was administered to attending members in a conference of the Association of Rural Surgical Practitioners of Nigeria.13 This was done using the Personnel, Procedures, Equipment and Supplies (PIPES) survey tool developed by the non-governmental organization Surgeons Overseas (SOS).13 This is a tool developed to assess surgical capacity through the workforce, infrastructure, skill, equipment, and supplies of health facilities in LMICs.13 The other indicated surveys done in SSA used a comprehensive survey tool designed by the Harvard Humanitarian Initiative. This tool was adapted from the WHO Tool for Situational Analysis to Assess Emergency and Essential Surgical Care as part of an international initiative to assess surgical and anaesthesia capacity in LMICs.

The present survey used a rapid assessment tool known as the Lifebox Hospital Initial Needs Assessment questionnaire with another structured questionnaire to assess anaesthesia services in public hospitals in the Cross River State (CRS) of Nigeria. Lifebox (www.lifebox.org) is a non-profit organization saving lives by improving the safety and quality of surgical care in low-resource countries.19 Since 2001, Lifebox has trained more than 2000 anaesthesia providers, and more than 4200 pulse oximeters have been supplied to more than 70 low-resource countries thereby closing the operating room pulse oximetry gap in about 15 countries.19 This organization is supported by the World Federation of Societies of Anaesthesiologists (WFSA), Association of Anaesthetists of Great Britain and Ireland, Harvard School of Public Health and the Brigham and Women’s Hospital in Boston, United States of America.19 This survey was primarily aimed at the secondary health care facilities which are owned and managed by the CRS Ministry of Health (MOH). This survey audit will identify the anaesthesia providers in CRS, their level of training and retraining as well as equipment available for providing safe anaesthesia and monitoring patients in the peri-operative period. The data will also identify baseline information and gaps in anaesthesia and surgical capacity as a first step for the CRS MOH initiative to improve surgical and anaesthesia services. This information is a stepping-stone for national and international assistance since CRS is a relatively poor state in the Nigerian Federation.

Country and State overview

Nigeria is the most populous African country, located in the West African sub-region with a population of more than 160 million people.20 It is a Federal Republic with 36 states and a Federal Capital Territory. It is politically sub-divided into six geo-political zones: North-Central, North-Eastern, North-Western, South-Eastern, South-South and South-Western. There are 774 Local Government Areas (LGAs) where more than 60% of the population reside. The health care system is divided into three levels: primary, secondary and tertiary. There are public and private health facilities operating at all levels. The primary healthcare facilities (health centres) are managed by the Local Government, the secondary healthcare facilities (general hospitals) are managed by the State Government, while the tertiary facilities (University Teaching Hospitals and Federal Medical Centres) are managed by the Federal Government. Health indicators for Nigeria are among the worst in the world despite the fact that Nigeria is the sixth largest exporter of crude oil. The United Nations Human Development Index ranked Nigeria 156 out of 187 countries.21 In particular, Nigeria is one of the five countries contributing more than 50% to the global maternal mortality ratio22 and one of the countries with the highest physician’s and nurse’s emigration to developed countries.23 Physicians and nurses who remain in Nigeria predominantly practice in urban cities leaving the LGAs, most of them rural with severe shortages in health manpower.

CRS, with approximately 3.2 million population and 20156 square kilometres, is located in the South-South geo-political zone.24 The state has boundaries with the Republic of Cameroon in the East, Benue State in the North, Ebonyi State in the North West and Akwa-Ibom State in the South.24 It is divided into 18 LGAs with 18 general hospitals and 613 primary health centres. There is only one tertiary health facility, the University of Calabar Teaching Hospital (UCTH) located in Calabar, the capital city, which provides specialist care to the entire population. Being a tourism state, the importance of safe anaesthesia as a component of safe surgery cannot be overemphasized.

Physician-anaesthetist, nurse-anaesthetist and surgery training programs in Nigeria

Physicians are trained to be specialist anaesthetists or surgeons in a four-year training program leading to the Fellowship in Anaesthesia (FMCA) or Surgery (FMCS) of the National Postgraduate Medical College of Nigeria (NPMCN) or the Fellowship in Anaesthesia or Surgery (FWACS) of the West African College of Surgeons (WACS). This is after a six-year medical education program in the university leading to the Bachelor of Medicine and Bachelor of Surgery degree, one-year rotatory internship, and one-year of compulsory National Youth Service. Most Fellows, after completion (average time of completion is 7-8 years), work in University Teaching Hospitals and Federal Medical Centres, all located in urban cities. Another training program for doctors designed for primary and secondary healthcare is the Diploma in Anaesthesia (D.A) of the Universities or WACS, which is a 12-month training program. There is no short training program in Surgery.

Nurses are trained as nurse-anaesthetists after 18 months of training in a post-basic nursing program. The basic nursing training program is three-years of training in general nursing, after completing six years of secondary school education. There are now few university degree programs leading to the Bachelor’s degree in Nursing Science (BSN) from the universities. All these nursing training programs lead to certification by the Nursing and Midwifery Council of Nigeria.

Rural-urban practice

Physician-anaesthetists (Fellows and Diplomates), nurse-anaesthetists and consultant surgeons are all concentrated in urban hospitals leaving the rural areas and urban slums with a critical shortage of anaesthetic and surgical workforce. Therefore the majority of the surgical and anaesthetic procedures in rural areas in Nigeria are carried out by government-employed medical officers with almost all anaesthesia being provided by nurse-anaesthetists. In some very remote districts, Community Health Extension Workers (CHEWs) and Community Health Aids with little or no formal training in providing surgical care, are the only health workers available to provide some form of surgical care. The Association of Rural Surgical Practitioners of Nigeria (ARSPON) has been making some effort to address this workforce gap in rural areas by providing short on-the job training for medical officers to enable them to provide safe and affordable surgery to the rural population.13 The concept of surgical task-shifting to “non-physician clinicians” to address this rural-urban surgical workforce disparity, as is being officially done in other LMICs of SSA25 is not acceptable in Nigeria.

METHODOLOGY

A standardized questionnaire, the Lifebox Hospital Initial Needs Assessment Survey (Appendix 1) and another structured questionnaire (Appendix 2) was distributed to all 18 general hospitals (secondary health facilities) in CRS. All the general hospitals, which are the first referral hospitals in the districts, perform surgery. The site visit was conducted in April/May 2014. Permission to conduct the site visit was given by the CRS Honorable Commissioner for Health. The hospital surveys did not involve face-to-face interviews with the medical superintendents, hospital matrons or anaesthesia providers. The questionnaires were to be completed by the anaesthesia providers and medical superintendents in each of the hospitals visited. Each completed questionnaire was to be sent to the office of the Honorable Commissioner for Health at the MOH headquarters in Calabar, the capital city. The results are presented in frequency tables and charts.

RESULTS

A total of 16 well-completed questionnaires were received from 18 general hospitals/secondary healthcare facilities visited (88.9 % response rate). Averages of 3 - 53 surgeries are performed monthly in each of the hospitals (Table 1). The common procedures performed include: herniorrhaphy, appendicectomy, caesarean section, myomectomy, prostatectomy and exploratory laparotomy (Table 1). There are no practicing physician anaesthesiologists or surgeons employed by the State MOH except for one visiting consultant anaesthesiologist and five visiting consultant surgeons from the University of Calabar Teaching Hospital (UCTH), at the General Hospital, Calabar, which is located in the capital city of the State (Table 1). There are 13 nurse-anaesthetists distributed unevenly in the 16 hospitals (Table 1). There are no clinical officers cadres in the Nigerian healthcare system. Apart from the nurse-anaesthetists at the General Hospital in Calabar and Dr Lawrence Henshaw Memorial Hospital, also in Calabar, the other nurse-anaesthetists have had no refresher course or in-service training in the past two years. In the 16 general hospitals, the commonest anaesthetic technique used is Total Intravenous Anaesthesia (TIVA) with Ketamine (Table 1).

Table 1 : Summary of audit of anaesthesia services in the 16 district hospitals in Cross River State, April/May2014

Hospital

Number of anaesthetists

Type of anaesthesia administered Scope of surgery Average number of surgeries Refresher course within last two years
  Nurse-anaesthetist Physician-anaesthetist        
General Hospital, Obubra 0 0 Ketamine Herniorrhaphy, Laparotomy, C/S, Appendicectomy, 10 No
General Hospital, Ogoja 4 0 GA(ETT), Spinal, Local, Ketamine Herniorrhaphy, Laparotomy, C/S, Appendicectomy, Myomectomy & Others 15 No
General Hospital, Sankwala 1 0 Local Others 11 No
General Hospital, Okpoma 0 0 Local, Ketamine Herniorrhaphy, Appendicectomy & Others 3 No
General Hospital, Calabar 1 1 (Visiting) GA (ETT), Face Mask, Spinal, Epidural, CSE, Local, GA(Ketamine) Herniorrhaphy, Laparotomy, C/S, Appendicectomy, Myomectomy & Others 53 Yes
General Hospital, Ugep 1 0   Herniorrhaphy, Laparotomy, C/S, Appendicectomy, Myomectomy & Others 18 No
Cottage Hospital, Oban 0 0 Ketamine Herniorrhaphy, C/S, Appendicectomy, Myomectomy 4 No
Cottage Hospital, Akpet 0 0 Local, Ketamine Herniorrhaphy, Laparotomy, C/S, Appendicectomy. 10 No
Lutheran Hospital, Yahe 1 0 Local, Ketamine Herniorrhaphy, Laparotomy, C/S, Appendicectomy, Myomectomy & Others 5  
Eja Memorial Joint Hospital, Itigidi 1 0 Local, Ketamine Herniorrhaphy, Laparotomy, C/S, Appendicectomy, Myomectomy 15 No
St. Joseph Hospital, Akpabuyo 1 0 Local, Spinal, Ketamine Herniorrhaphy, C/S, Appendicectomy, Myomectomy 5 No
Dr. Lawrence Henshaw Memorial Hospital, Calabar South 1 0 GA (ETT), Face Mask, Local, Ketamine Herniorrhaphy, Laparotomy, Appendicectomy, Myomectomy & Others 10 Yes
General Hospital, Ukem, Odukpani 0 0 Ketamine Herniorrhaphy, Appendicectomy 3 No
Ranch Medical Center, Obudu 1 0 Ketamine Herniorrhaphy, Laparotomy, C/S, Appendicectomy, Myomectomy 5 No
General Hospital, Akamkpa 1 0 Local, Ketamine Herniorrhaphy, Laparotomy, C/S, Appendicectomy, Myomectomy 20 No
Government House Clinic, Calabar 0 0 Local, Ketamine Herniorrhaphy, Laparotomy, Appendicectomy 3 No
TOTAL 13 1 (Visiting)     190  

GA: General Anaesthesia. ETT: Endotracheal Intubation. C/S: Caesarean Section. CSE: Combined Spinal and Epidural anaesthesia.

Basic anaesthetic equipment such as anaesthetic machines, oxygen cylinders, suction machines, and pulse oximeters were lacking in most of the hospitals visited (Box 1).

Box 1. Summary of Equipment in the 16 General Hospitals, Cross River State, Nigeria: April-May 2014
· 10% of the hospitals had pulse oximeter
· 20% of the hospitals had oxygen cylinders
· 20% of the hospitals had suction machines
· 30% of the hospitals had anaesthetic machines
· 80% of the hospitals had recovery beds
· 100% of the hospitals perform surgery

The WHO Surgical Safety Checklist Information was administered to the hospitals management team at the Districts Hospital (Box 2). This shows that all the surgical teams had never used the WHO checklist, never received training, and the checklist was not available in the operating rooms, although all surgical personnel would like to receive training on the WHO checklist and pulse oximetry

Box 2. World Health Organization (WHO) Surgical Safety Checklist Information
· How often do the surgical teams at your hospital use the WHO Surgical Safety Checklist? NEVER
· Has your hospital received training in the WHO Surgical Safety Checklist? NO
· Is the WHO Surgical Safety Checklist available in your operating rooms? NO
· Would you like to receive training in pulse oximetry and the WHO checklist? YES

DISCUSSION

This survey aimed to provide a quick assessment of anaesthesia and surgical services in public hospitals in CRS of Nigeria. The data shows gross and significant shortages in anaesthesia and surgical providers in all 16 general hospitals. There were no consultant anaesthetists, diplomate anaesthetists or consultant surgeons employed in the CRS MOH. There were only 13 nurse-anaesthetists working in the 16 general hospitals, and one visiting consultant anaesthetist and five visiting consultant surgeons at the General Hospital, Calabar, the capital city. In six of the hospitals, there were no nurse-anaesthetists providing care for the surgical procedures being conducted. As it has been reported from the many surveys in SSA.6, 18, 26 most of the procedures in all the hospitals are being done by generalist medical doctors and general nurses, many without any postgraduate training in surgery and anaesthesia.

The gross inadequacy of the anaesthetic workforce in this survey represents what is found in many of the 778 LGAs (Districts) in the Federal Republic of Nigeria. This is because many of the LGAs are rural and studies have indicated the general difficulties of most health workers seeking jobs in rural hospitals. The lack of specialist anaesthetists in peripheral hospitals in most of Nigerian Districts therefore requires a re-direction of the training programs for doctors in Nigeria with greater emphasis on the shorter training program design for primary and secondary healthcare levels. Inaddition, annual refresher courses should be made mandatory for nurse-anaesthetists especially for those practicing in rural areas.

A recent review of the met and unmet needs of surgical disease in rural SSA, where district and rural hospitals are the main providers of care, shows a very huge burden.27 An important finding is the discrepancy between surgical care needs and provision.27 Since the majority of the population in SSA reside in rural areas, there is the need to strengthen the surgical services at this level. This is the first of the four recommendations of the Bellagio Essential Surgery Group.28 Many of the surveys using the WHO Situational Analysis Tool have described the lack of capacity in many district hospitals to meet the local surgical and anaesthesia needs.6-18 One study, using pulse oximeter availability as a measure of operating room resources, showed that between 58.4% and 78.4% of operating rooms in West Africa, East Africa and Central SSA do not have pulse oximeters.29 This finding was also clearly shown by our own rapid survey and assessment. Three important factors have been responsible for these findings. These are lack of resources, lack of manpower and the need for training.27 The need for training to improve the quality of the surgical and anaesthesia providers at the district hospitals is the third recommendation of the Bellagio Essential Surgery Group.28

Training programs and improvement of the facilities at the District Hospital has been shown to increase the number of operations performed.27Also, the presence of a visiting consultant anaesthetist in the District Hospital has been shown to increase the scope of anaesthesia services during the visiting period.30 The visit left more knowledgeable local staff in the care of their patients especially in peri-operative care.30 The need for developing countries in SSA, particularly in Nigeria, to concentrate more on shorter training programs in surgery and anaesthesia at their current level of development has been advocated.31,32 This has been shown by Sani et al where a 12-month training program for General Practitioners in district hospitals in Niger significantly reduced the number of referrals to the regional and specialist hospital.33 In many other SSA countries, where gross shortages of medical manpower exist, surgical task shifting has been championed and research has shown that these are cost effective interventions.25, 34 This is, however, not acceptable in Nigeria which is Africa’s most populous country with very poor health indicators.

There are some limitations to this study. Firstly, it was a snapshot of anaesthesia and surgical services which did not highlight in detail the eight key areas of surgical and anaesthesia care, as in other surveys. These key areas include: access and availability of hospital services, human resources, physical infrastructures (including availability of water and electricity), surgical and anaesthetic procedures, surgical and anaesthesia outcome, essential equipment availability, NGO and international organizations providing care, and access to essential pharmaceuticals. Secondly, this assessment did not include the only public tertiary hospital in the State and private hospitals. Lastly, this was an initial assessment in preparation for a more detailed survey based on the WHO guidelines when research funds are received.

CONCLUSION AND RECOMMENDATIONS

Therehas been a paradigm shift in global public health and the concept of primary healthcare which has resulted in increased awareness of the importance and contributions of surgical disease to the overall burden of disease especially in LMICs. This rapid survey of anaesthesia services in CRS, one of the 36 states in Nigeria, will serve as a window to inform other Nigerian State governments of the need to increase surgical and anaesthesia capacity and funding in their development agenda. It is therefore recommended that visiting consultant’s services to all the general hospitals in an organized and planned fashion should be highly encouraged. All the anaesthesia caregivers should attend refresher courses at least once every two years. These courses can be arranged locally, or sponsorship provided for attendance of relevant courses by Anaesthesia Trainers within and outside the State. Basic anaesthesia equipment and guidelines as recommended by the Nigerian Society of Anaesthetists (Box 3) must be available and followed to enhance patient safety. It is also recommended that the government should give incentives to medical and nursing staff working in rural areas so that there will be a reversal of the rural- urban shift. The Lifebox global oximetry project is interested in making high quality, low-cost pulse oximeters available in every operating room. Therefore, every secondary care facility in the country should take advantage of this laudable program.

Box 3. Nigerian Society of Anaesthetists Standard Guidelines for the Practice of Anaesthesia
Anaesthetic Personnel
· Certified physician anaesthetist
· Trained nurse-anaesthetist under supervision by physician-anaesthetists
· Maximum number of nurses to physicians should be 4:1
· Where there is no physician-anaesthetist, nurses should adhere strictly to the guidelines and conditions of their certification
· The surgeon should provide coverage especially in the area of patient resuscitation and fitness for surgery and take full responsibility for any decisions made against the guidelines.

Anaesthetic equipment for each theatre
Standard Continuous Flow (Boyles) Anaesthetic Machine with:
- Closed breathing system
- Adult semi-closed breathing system
- Paediatric breathing system
Suction Machine
- Electric
- Manual
Suction Catheters – disposable, various sizes
Laryngoscope set with batteries and:-
- 2 standard and 1 long curved blades
- 2 standard and 1 long straight blades
- Neonatal laryngoscope with 2 straight blades.
Intubating Forceps (Magill)
- Adult
- Paediatric
- Neonatal
Self-inflating Resuscitation Bag
- Adult
- Paediatric
- Infant
Anaesthetic Face Masks : Size 0, 1, 2, 3, 4
Paediatric (Rendell-Baker) – Size 00,0,1
Naso-gastric tubes
Head – Harness
Oropharyngeal Airways 00 – 5
Endotracheal tubes (cuffed, noon-cuffed 2.5. – 9.0. mm)
- Red rubber, latex reinforced, portex
Plastic laryngeal Mask Airway (Sizes 1–5)
Endobronchial tubes
Bougies
Fluid Warmer
Warming Mattress (for paediatrics)
Pressure Infusor
Syringe Infusion Pump with lines

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
The authors are grateful to the CRS Honorable Commissioner for Health for giving us the permission to carry out this survey. We are also thankful to the medical and nursing staff of all the sixteen secondary health care facilities for making this survey a reality. Special acknowledgement goes to LIFEBOX for the donation of thirty (30) free pulse oximeters to improve anaesthetic practice as a result of this survey. This study was carried out in collaboration between all authors. QNK and AIE conceived and designed the study, and QNK visited the hospitals and distributed the questionnaires. EIU, AUE and EM managed the literature searches and reviews, and wrote the first draft. All authors read and approved the final manuscript.
Competing Interests: 
None declared
Details of Authors: 
QUEENETH NDUKWE KALU, MB, BCH, DA, FWACS, DA (WFSA), Consultant Anaesthesiologist, UCTH, Calabar, Cross River State, Nigeria. ATIM IMEH ESHIET, MB, BCH, DA, FMCA, FICS, FWACS. Consultant Anaesthesiologist/Professor - UCTH, Calabar, Cross River State, Nigeria. ESSIEN ITA UKPABIO, MB, BCH, DA. Senior Registrar in Anaesthesiology - UCTH, Calabar, Cross River State, Nigeria. ANIETIMFON UMOH ETIUMA, MB, BCH, FMCS, FWACS. Consultant Surgeon/Professor - UCTH, Calabar, Cross River State, Nigeria. EMMANUEL MONJOK, MD, MPH. Visiting Consultant, Family Medicine/Public Health - UCTH, Calabar, Cross River State, Nigeria.
Corresponding Author Details: 
Dr Queeneth N. Kalu. Department of Anaesthesiology, University of Calabar Teaching Hospital, Calabar, Nigeria.
Corresponding Author Email: 
queen_kalu@yahoo.com
References
References: 
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  10. Choo S, Perry H, Hesse AA, Abantanga F, Sory E, Osen H, Fleischer-Djoleto C, Moresky R, McCord CW, Cherian M, Abdullah F. Assessment of capacity for surgery, obstetrics and anesthesia in 17 Ghanaian hospitals using the WHO assessment tool. Trop Med Int Health 2010; 15: 1109-1115.
  11. Sherman L, Clement PT, Cherian MN, Ndayimirije N, Noel L, Dahn B, Gwenigale WT, Kushner AL. Implementing Liberia’s poverty reduction strategy: an assessment of emergency and essential surgical care. Arch Surg 2011; 146(1): 35-39.
  12. Lavy C, Tindall A, Steinlechner C, Mkandawire N, Chimangeni S. Surgery in Malawi- a national survey of activity in rural and urban hospitals. Ann R Coll Surg Engl 2007; 89(7): 722-724.
  13. Henry JA, Windapo O, Kushner AL, Groen RS, Nwomeh BC. A Survey of Surgical Capacity in Rural Southern Nigeria: Opportunities for Change. World J Surg 2012; 36: 2811-2818.
  14. Kingham TP, KamaraTB, Cherian MN, Gosselin RA, Simkins M, Meissner C, Foray-Rahall L, Daoh KS, Kabia SA, Kushner AL. Quantifying surgical capacity in Sierra Leone: a guide for improving surgical care. Arch Surg 2009; 144(2): 122-128.
  15. Notrica MR, Evans FM, Knowlton LM, Kelly-McQueen KA. Rwanda surgical and anesthetic infrastructure: a survey of district hospitals. World J Surg 2011; 35: 1770-1780.
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  17. Penoyar T, Cohen H, Kibatala P, Magoda A, Saguti G, Noel L, Groth S, Mwakyusa DH, Cherian M. Emergency and surgical services of primary hospitals in the United Republic of Tanzania. BMJ 2012; Open 2(1): e000369.
  18. Linden AF, Sekidde PS, Galakande M, Knowlton LM, Chackungal S, McQueen KA. Challenges of surgery in developing countries: a survey of surgical and anesthesia capacity in Uganda’s public hospitals. World J. Surg 2012; 36: 1056.
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Prevalence and implications of genital tattoos: A site not forgotten

Authors
Thomas Neluis, Myrna L. Armstrong, Cathy Young, Alden E. Roberts, LaMicha Hogan, and Katherine Rinard
Article Citation and PDF Link
BJMP 2014;7(4):a732
Abstract / Summary
Abstract: 

Purpose:  To provide information on men who have tattooed one anatomical site, the genital region (pubic and/or glans penis), that is uncommonly noted.
Methods: Two methods were used.  First, the limited cultural and medical literature was reviewed. Secondly, a subsample of 14 men were analyzed, taken from a primary study examining male genital piercings (N = 445), who responded affirmatively to one survey question about penile tattoos.
Findings:  The literature (n = 25) was limited.  Cultural literature revealed a long, rich history of genital markings for esthetics, sexual enhancement, and tribal status, whereas the medical literature reflected limited observational type information, some actual case histories, and few studies.  From the small subsample, qualitative and quantitative data were provided.  Similarities to those who wore general body tattoos were validated such as being single, heterosexual, having some college/vocational education, monthly binge drinking, no skin complications, and a strong propensity for a Need for Uniqueness.  Reportedly, they were major body art wearers and continue to enjoy them.  First age occurrence of sexual intercourse was similar to the national average of 17 years. Challenged assumptions included (a) no consensus regarding being risk takers, (b) significant reported forced sexual activity, and no (c) physical, sexual or mental abuse.
Conclusions:  From our experience, those with genital tattoos are seen primarily for a normal range of developmental and physiological urologic issues, not their decorative markings; these genital tattoos are an integral part of their cultural and personal expression and most likely will increase. Yet, the markings are only skin deep so clinicians should adopt a nonjudgmental approach and employ methods of proactive patient health education.

Keywords: 
Key Words: Penis, tattoos, males, genital tattoos, Need For Uniqueness

INTRODUCTION

Maintaining its longstanding presence as one of the oldest forms of art, body tattooing has increased exponentially within mainstream society, as well as in social acceptance. Generally worn to display individuality and creativity, these distinctive forms of indelible markings are present in every culture, whether on tribal men, or people of status. Procedurally when inserting the decorative markings, the approach in studio tattooing has not changed significantly as artists are still using “an electrically powered, vertically vibrating instrument to inject tattoo pigment 50 to 3,000 times per minute up to or into the dermis at a depth of 1/64th to 1/16th of an inch”1

While no national registry provides prevalence, a 2012 Harris Poll cited one in five United States (U.S.) adults have at least one tattoo (21%), an increase of 16% and 14% from previous surveys taken in 2003 and 2008 respectively.2 Tattoo numbers were even higher in some variables including age between 30-39 years (38%), Hispanics (30%), females (23%), and those living in the Western part of the U.S. (26%). No questions were identified in the 2012 poll that queried tattooed body site locations. Other studies cite almost a 25% presence of tattoos.1,3-7 The amount of tattoo studios also echoes the growing body art phenomenon.

Given the societal blaze of tattooing, the medical literature on body art has also increased. Yet, most of the information still remains focused on small case reports6 about traditional locations (arms, legs, chest, back), their decision-making, various risk-taking behaviors,8 and the small amount of complications.7 Those with various adverse skin reactions or major complications seem to have had tattoos with colored pigment.6

While body art can be found virtually everywhere on the human anatomy, several articles have surfaced concerning genital body piecing.4-5, 9-11 Current studies validate the increasing rate of all types of tattooed 4,8 people, from a variety of occupations and social classes, with markings on visible and non-visible locations.7 This article reports on the limited medical literature found about men with genital tattoos (pubic and/or the glans penis). Also presented is a subsample data analysis of 14 men from a primary study examining male genital piercings,11-12 who responded affirmatively to one survey question about penile tattoos. This synopsis and subsample data analysis are provided for clinicians to have further, recent evidence about men with genital tattoos for decision making during patient encounters in health care settings. The terminology of penile and genital tattoos will be used interchangeably in this article.

METHODS

Literature Synopsis

Historically, the cross-cultural literature is rich in visual genital tattoo descriptions. In South America, the Moche on the North Coast of Peru (A.D. 150-800) produced ceramics illustrating vivid sexual imagery and highly decorated male genitals.13 Phallus decorations with dots, concentric lines, and other tattoo markings on the penile skin and mucosa during the Upper Paleolithic era in Europe 12,700 to 11,000 years ago have been reported.14-15 Likewise, the Samoan Island culture, where the word ”tattoo” is believed to have originated from “tatau,”, has maintained ritualistic16 traditions for over two thousand years; they are initiated at the time of puberty for future leadership roles. These 10+ days of ceremonies include very painful, repeated tattooing of the scrotum (tafumiti) and the penis (tafito). Other nearby primitive Polynesian tribes have believed this tattooing as highly erotic,16 whereas the indigenous Maori (New Zealand) trust that the pigment for these tattoos can trap cosmic energy.14 Circumcision and tattooing were thought to produce the same effect of magic protection and healing powers after scar healing.14 In the Japanese culture, an examination of Yakuza (racketeers or gangsters) also describes the genitalia as a site that is tattooed,17 fulfilling their principles of tattoos always being covered.

Searching for information about genital tattoos was more challenging within the medical literature. A comprehensive longitudinal 40 year search of the national and international electronic medical literature (1973-2013) published in English and their associated reference lists was conducted with MEDLINE, EMBASE, CINAHL, SCOPUS, and OVID. Only 20 articles were located that mentioned genital tattoos. Articles were from international authors (n = 11) and the U.S. (n = 9); they all produced interesting reading. One reference cited women with genital tattoos.7

Genital tattoos in the early literature were labeled as criminal, or personality disorders tattoos;18 one recent article discussed them under the header of genital self-mutilation.16 Others described them as a valuable clue for forensic pathology identification.19-20 World War II articles cited descriptive stories of soldiers with penile tattoos,21-22 with one reporting up to 10 sailors being seen.23 Besides reporting on how the fate of Bulgaria was determined by three tattooed men (Churchill with an anchor on his left arm, Roosevelt with a family coat of arms tattoo, and Stalin with a death’s head on his chest),24 Kazandjieva25 then provides vivid examples of auto-aggression markings that his countrymen self-inflicted after the Communist takeover. This included glans penis tattoos which are described as producing great pain.15,25 One political candidate, while campaigning, is reported as suggesting punitive action for those HIV+ by “putting indelible, glow-in-the-dark tattoos on [their] genitals.”26 Traumatic tattoos associated with gunpowder explosions and blast burns are also mentioned on the glans penis.27

Two studies also described inmates with genital tattoos and discussed how these markings demonstrated aggressive behavior within this type of environment. Here large, colorful tattoo designs and wording on the glans penis tattoos were described28-29 which seemed to satisfy the inmate’s flaunt of personal pain endurance. Additionally, Cuban refugees (Marielitos) fleeing to the U.S. were reported as having genital tattoos; they also were from prison subcultures and their markings had various sexual overtones.29

Four other reports described those with penile tattoos also routinely inserting foreign bodies12,30 and paraffinoma12,31,32 into the penis. In Pehlianov’s study (also in Bulgaria) they included a control group of another 25 men with genital tattoos. Recently, a unique case of non-ischemic priapism for 3 months was reported33 following prolonged bleeding from a manual penile tattoo procedure in Iran. The authors suggested the hand-held tattoo needle had penetrated too deeply producing an arteriovenous fistula and the subsequent persistent half-rigid priapism. The authors also noted that the 21 year old patient expressed no regret, depression, or other complications related to the genital tattoo.

Original Study

The initial study queried males with genital piercings using available internet survey software,12 as it was considered a hidden variable. Anonymity and access to people nationally and internationally were major advantages for using this nontraditional approach. The university institutional review board deemed the study status as Exempt. To obtain quantitative and qualitative data about those men with genital piercings, an 83 item web-based survey was used; overall results, and another subsample of this data, are published elsewhere.11-12

Subsample of those with Penile Tattoos

From the original 445 male genital pierced individuals that responded to the question regarding having tattoos on their penis, 14 replied affirmatively. This subsample had previously been determined not be an outlier of the larger group of genital pierced men.12 While a short general description (age span at the time of tattoo procurement, urethral “play,” design types, motives, and tattooists) about the 14 member genital tattoo subsample was published in 2010,12 further investigation leading to quantitative and qualitative (Figure 1) data is presented here.

Figure 1: Subsample Respondent Qualitative Quotes
*Black tribal flames on the top of the shaft, done at [age] 38
* For erotic reasons, self done with no complications, done at [age] 54
*I got it because I wanted it. After it was finished I realized I needed it, done at [age] 30
* I self tattoo’d my penis on the glans and around the corona ridge in order to make up for its’ lack of size and to enhance its appearance. I used a sailmaker’s needle and Indian ink and there were no complications, done at [age] 43.
*one small cross pigment tattoo!
*I’m a little more than average in size, but I still have issues with my genitals. The way they look and their size. Piercings and tattoos have helped me quite a lot.
*I sketched a rose one day, like[d] the design, decided to get it tattooed on my penis. The stem is green with some yellow highlights, the bud is red, all black outline. The tattoo was applied with a standard machine . . .healing was actually quicker and easier than any of my other tattoos.
*It’s a little heart just next to ‘captain hemingway’ which I hand poked and used india ink for it when I was 17. . . thought our penis deserved a reminder of our affection . . .no complications experienced but since it was hand done with a [sterile] needle it’s kind of blurry

This subsample had significantly more foreskin genital piercings (chi-square = 11.5) = 1; P = .001), whereas the most common genital piercing of the larger group of those without genital tattoos11 had Prince Albert piercings (inserted through external urethra). No question inquired which came first, the genital piercing or genital tattoos.

Data Analysis

For this subsample analysis, (and original study11-12), IBM SPSS 21was used to obtain frequencies and chi-square analysis. Cross tabulations for the subsample were obtained by comparing those with and without penile tattoos.

RESULTS

Demographics

Almost all of the subsample respondents with penile tattoos were reportedly Caucasian (92%) and their ages ranged from 18 to 67 years (average 42.3). Of those that replied, six lived in the U.S. and five cited various international locations. Over half had vocational or college education (64%) and significantly more were likely to be single (25%) or divorced (25%), (chi-square 12.6) = 5; P = .027). Data regarding religious faith was weak to non-existent (75%). Respondents self-reported a good state of health (92%) (chi-square = 8.7) = 3; P = .034), yet 50% cited no annual health check-ups.

Risk Behaviors

Within this subsample, there was no consensus about being a “risk taker”. Recreational drugs were reportedly not used (91%), over half were non-smokers (55%), but monthly alcohol use with binge drinking (5+ or more drinks) was cited (78%). Their “motives for genital tattoos were for esthetics, sexual, and personal pleasure”12; a variety of penile tattoo designs were described (Figure 1), created either “by studio artists (n = 11) or self-inflicted (n = 3)”.12 All of them described having other body art, such as piercings and other general body tattoos. Some reported an average of 4 piercings (81%) and a significant amount of general body tattoos (average 3.5) (chi-square = 11.1) = 5; P = .049), that still interest them (85%) (chi-square = 8.9) = 3) P = .031).

Sexual Activity

This subsample’s average age of first intercourse was 17 years, with most citing women as their sexual partners (92%), most preferred penile/vaginal intercourse (79%), and only one respondent reported a sexually transmitted infection (gonorrhea). When asked about any forced sexual activity (rape), this subsample had a significant amount of those who answered affirmatively (23%) (chi-square = 7.7) = 1; P = .005). Virtually no sexual, physical, or mental abuse was reported.

Need for Uniqueness

A four-item scale called the Self-Attributed Need for Uniqueness (SANU)34 was present in the survey to determine the respondent’s self-view (Cronbach alpha = .86). Using a Likert scale, the subsample’s moderate, strong and very strong perspectives were collectively summarized. These respondents with penile tattoos preferred to be different (79%), distinctive (86%), intended to do things to make themselves different than those around them (72%), and reported a Need For Uniqueness (93%) (Cronbach alpha = .77). To validate this finding, when all 5 responses of SANU were totaled,12 the mean was 12.43 documenting a more positive perspective for intentionally wanting to be different, distinctive, and unique.

DISCUSSION

This article reviewed both the cross cultural and medical literature about those with genital tattoos, as well as included both a quantitative and qualitative subsample data analysis of a small group of men who specifically reported penile tattoos. Yet, with certainty this small sample size produced limitations and reporting/survey bias. Additionally, any generalizability with the findings of this subsample should be noted as the respondents could have self-selected their participation and used their personal judgment to interpret the survey questions in this non-experimental cross-sectional study using internet survey methodology.12

From this review and to our knowledge, few have studied groups of men with genital tattoos, a difficult group of subjects to find with this hidden variable.12,31 Cultural descriptions documented a long, rich history 12, 14-17, 29,31 of genital markings for esthetics, sexual enhancement, and tribal status, whereas the medical literature reflected limited observational type information, and few actual case histories or scientific studies. Although there were no mental health evaluations12 cited in this medical literature, more psychopathic, deviant behavior discussions were made about the individuals with genital tattoos.16-18,26,32,35 In contrast, two authors30,33 comment on the “normalcy” of their patients that presented with genital tattoos.

Genital tattoos may be more common than this very small subsample size suggested as great emphasis has been placed on male penile size in many cultures, for a long time.31,36 The augmentation of these genital markings and decorative designs seemed to have motivated their sexual health, self-enhancement9-10 and well-being.31 Thus, when further studies are considered for this population with a hidden variable, these findings should assist with further ideas of investigation.

Current society has a strong 25 year renaissance of procuring tattoos with at least one in five, and perhaps even four, individuals possessing a tattoo, on virtually every part of their body, without major complications. This small subsample of those who have genital tattoos validates some similarities to those who wear general body tattoos such as a single heterosexual orientation, possessing some college/vocational education, monthly binge drinking,1,3-5,10 and a strong propensity for a Need for Uniqueness.4-5,37 They were major body art wearers and continue to enjoy them, as others have also reported.4-5,10-12

Yet other demographic assumptions were challenged for this subsample of men with genital tattoos. These international respondents tended to be older Caucasians and not as ethnically diverse; there also was not a consensus as to them being risk takers, as has been repeatedly reported by many other body art respondents.1,3-5,11-12

Subsample respondents reported their average first occurance of sexual intercourse at age 17, similar to the national figures.38 Significant experiences of rape were also reported in this subsample, as in women with genital piercings.4-5,9-10 The national rate for forced sexual activity is 10.5%38 and those with genital tattoos reported over twice that amount (23%). No sexual abuse was reported in contrast to a recent German study39 examining general body tattooing.

As with any type of invasive procedure, there can be complications with certain types of body art. When these complications occur, body art wearers typically first seek the internet and/or their studio artist for health advice before presenting to clinicians.1,8,10-12 Yet, overall for the amount of general tattooing done, this type of body art produced limited documented complications and more potential concerns.7-8,11, 30,33 More complications were reported when the tattoos contained colored pigments.6

These tattoos are an integral part of their cultural and personal expression.12,31,33 From our experience many of these male patients with genital tattoos are not seen primarily because of their decorative markings,31 but during clinical evaluations for other issues presented with the normal range of urologic issues involving overall genitourinary and sexual function. Genital tattoos can be an ambivalent findings for many clinicians, but these indelible skin markings (tattoos) are only skin deep,40 and provide valuable cues such as a history of sexual trauma.39 Currently more genital tattoos are seen among our freedom-impaired patients, where the prevalence of general body tattoos among the inmates can be as high as 67%.41

Anecdotally, when healthcare staff discover a patient with genital body art, this discovery can be met with judgmental attitudes and behaviors which could impact care. To adequately assess, evaluate and treat the individuals that have chosen to have genital tattooing, clinicians should strive to provide a thoughtful, nonjudgmental patient-centered approach, along with a generous application of health education, for their present, or even future body art.11

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
The authors acknowledge the grateful assistance of Margaret Vugrin, MSLS, AHIP, Reference Librarian, Texas Tech University Health Sciences Library, Lubbock, TX The authors disclose no conflict of interest or research support for the development of this manuscript. Author Contributions: TN/MLA/AR-research design & analysis; Draft manuscript-TN/MLA/CY/LH/KR/AR
Competing Interests: 
None declared
Details of Authors: 
THOMAS NELIUS MD, Ph.D. Assistant Professor, Texas Tech University Health Sciences Center Department of Urology, School of Medicine, Lubbock, TX 79430 USA. MYRNA L. ARMSTRONG Ed.D., RN, FAAN, Professor Emerita, Texas Tech University Health Sciences Center School of Nursing, TX 78654 USA. CATHY YOUNG, DNSc, FNP-BC, FAANP, FAAN, Associate Professor, Tarleton State University, Texas 76028 USA. ALDEN E. ROBERTS, Ph.D. Professor, Department of Sociology, Anthropology and Social Work, Texas Tech University, Lubbock, TX 79409, USA. LA MICHA HOGAN, MSN, RN, FNP-BC, Clinical Instructor, Texas Tech University Health Sciences Center School of Nursing, Lubbock, TX, USA 79430. KATHERINE RINARD, MD, Tx 79601, USA.
Corresponding Author Details: 
MYRNA L. ARMSTRONG Ed.D., RN, FAAN, Professor Emerita, Texas Tech University Health Sciences Center School of Nursing, 39 Augusta Dr, Marble Falls, TX 78654 USA.
Corresponding Author Email: 
myrna.armstrong@ttuhsc.edu
References
References: 
  1. Armstrong ML, Pace-Murphy K.  Tattooing: Another risk-behavior in adolescents warranting national health teaching.  Applied Nurs Res.  1997;10(4): 181-189.
  2. Braverman S.  The Harris Poll:  One in five US adults now has a tattoo.  Retreived 5/16/13 from www.harrisinteractive.com/NewsRoom/HarrisPolls/tabid/.../Default.aspx
  3. Armstrong ML, Roberts AE, Owen DC, et al.  Toward building a composite of college student influences with body art.  Issues Comprehensive Ped Nurs. 2004;27:277-295. 
  4. Koch JR, Roberts AE, Armstrong ML, et al.  Body art, deviance, and American college students.  Soc Science J.  2010;47(1):151-161.
  5. Owen DC, Armstrong ML, Koch JR, et al.  College students with body art: Well being or high risk behavior.  J Psych Soc & Mental Health Services.  2013;51(10): 20-28.
  6. Wenzel SM, Rittmann I, Landthaler M, et al.  Adverse reactions after tattooing: Review of the literature and comparison to results of a survey.  Dermat 2013;226(2):138-147.  DOI:10.1159/000346943
  7. Mayers L, Chiffriller SH.  Body art (body piercing and tattooing) among undergraduate university students:  Then and now  J Adol Health.  2008;42:201-203. 
  8. O‘Malley PA.  Pharmacology Consult:  Tattoos and piercings: Reasons, risks, and reporting.  Cl Nurs Spec.  2013;27(1):14-16  DOI: 10.1097/NURS.Ob013e31827c28a5.
  9. Hogan L, Rinard K, Young C, et al.   A cross-sectional study of men with genital piercings.  Br J Med Pract.  2010;3(2):315-322.  
  10. Young C, Armstrong ML, Mello I, et al.  A triad of evidence for care of women with genital piercings.  J Am Acad NP.  2010;22:70-80.
  11. Nelius T, Armstrong ML, Rinard K, et al. Genital piercings: Diagnostic and therapeutic implications for Urologists. J Urology.  2011;78;998-1008.
  12. Rinard K, Nelius T, Hogan L, Young C, et al. Cross-sectional study examining four types of male penile and urethral "play". Urology.  2010;76(6):1326-1333.
  13. Weismantel M.  Moche sex pots: Reproduction and temporality in Ancient South America.  Am Anthropologist.  2004;106(3):495-505. 
  14. Angulo JC, Garcia-Diez M, Martinez M.  Phallic decoration in paleolithic art:  Genital scarification, piercing and tattoos.  J Urology.  2011;186:2498-2503. 
  15. Rowanchilde T. Male genital modification: A sexual selection interpretation.  Human Nature.  1996;7(2):189-215.
  16. Van Der Horst C, Martinez P, Seif C, et al.  Male genital injury:  Diagnostics and treatment.  BJU Int.  2002;93:927-930.
  17. Tsunenari S, Yonemitsu K, Kanbe T, et al.  How to identify the Yakuza, Japanese racketeers—their sociology, criminology and physical characteristics.  Ann Acad Med. 1984;13(1);25-31. 
  18. Post RS.  The relationship of tattoos to personality disorders.  J Criminal Law, Criminology and Police Science.  1968;59(4): 516-520.
  19. Fatteh A.  Handbook of Forensic Pathology.  1973  Philadelphia:  J.B. Lippincott.
  20. Burton JL.  The external examination:  An often-neglected autopsy component.  Curr Diag Path. 2007;13:357-365.
  21. Barry MJ.  Tattoos and identity (Letters to the journal).  Canad Med Ass J. 1963;89:1044.
  22. Grumet GW.  Psychodynamic implications of tattoos.  Amer. J. Orthopsychiat.  1983;53(3):482-492. 
  23. Burg BR.  Tattoo designs and locations in the Old U.S. Navy.  J Am Culture. 1995;18(1):69-75.
  24. Adatto M.  Living Skin, 1993: Basle: Editiones, Roche.
  25. Kandijeva J, Kamarashev J, Kadurina M, et al.  Unprofessional tattoos in Bulgaria – psychological aspects.  JEADV. 1995;4;254-259. 
  26. David Duke, running for governor proposes tattooing people with HIV.  AIDS policy & law. 1995(May 19); 53:7.  
  27. Baruchin AM, Schaf S.  Care of traumatic tattoos associated with gunpowder explosions and blast burns (Section V:  Chapter 54).  In M. Masellis & SWA Gunn.  The Management of Mass Burn Casualties and Fire Disasters. 1992  Netherlands:  Springer Kluwer Academic Publishers  292-295.  
  28. McCarron K.  Skin and self-indictment:  Prison tattoos, race, and heroin addiction.  ESC. 2008;34(1):85-102.
  29. Martinez RMA, Wetli CV.  Tattoos of the Marielitos.  Am J For Med & Path.  1989;10(4):315-325.
  30. Matsuzaka J, Aoki H, Banya Y, et al.  A foreign body of the corpus cavernosum in a patient with cleft glans penis: A case report.  Acta Urol. Jpn. 1994;545-547.
  31. Pehlivanov G, Kavaklieva S, Kazandjieve J, et al  Foreign-body granuloma of the penis in sexually active individuals (penile paraffinoma).  JEADV. 2008;22:845-851.
  32. Scholten E, Nanhekhan LV, Oudit DM, et al.  Scrotal and penile reconstruction after massive self-injection of liquid paraffin and petroleum jelly.  Plas & Recont. Surg.  2005;115(7):2168-2169. 
  33. Zargooshi J, Rahmanian E, Motaee H, et al.  Nonischemic priapism following penile tattooing.  J Sex Med. 2012; 9:844-848. 
  34. Lynn M, Synder CR. Uniqueness seeking.  In C.R. Snyder & S.J. Lopez (Eds).  Handbook of Positive Psychology.  New York:  Oxford University Press 2002;395-410.
  35. Taylor AJW.  Criminal tattoos.  Int.Rev. App Psychol.  1974; 29(2); 121-129.
  36. Wylie K.  The way forwards with the obession with the penis.  Sexologies.  2008; 17:S46.
  37. Tiggemann M, Golder F.  Tattooing: An appearance-based expression of uniqueness.  Body Image: Int J Research.  2006;3:309-315. 
  38. Guttmacher Institute.     Facts on American Teens‘ Sexual and Reproductive Health.  .  Retrieved 5/26/13 from www.guttmacher.org/pubs/FB-ATSRH.html
  39. Stirn A, Oddo S, Peregrinova L, et al.  Motivations for body piercings and tattooss—The role of sexual abuse and the frequency of body modifications.  Psych Res.  2011;190(2-3):359-363. 
  40. Susman J. Perspicacity, profiling, and prejudice. J Fam Prac. 2007;56(2):83.
  41. Titilayo CA, Balogun JA, Adefuye AS, et al.  Body art practices among inmates:  Implications for transmission of bloodborne infections.  Am J Inf Control. 2010;38(2):121-129. 

Global Health and the 10/90 gap

Authors
Marco Luchetti
Article Citation and PDF Link
BJMP 2014;7(4):a731

Global Health can be defined as “an area for study, research, and practice that places a priority on improving health and achieving health equity for all people worldwide”. 1 Article 25 of the 1948 Universal Declaration of Human Rights declares that, “everyone has the right to a standard of living adequate for the health of himself and of his family”. 2 Unfortunately, the health disparity between high-income and low-income countries, as well as between individuals within a country, often makes this impossible, leaving many people living in unhealthy settings without sufficient access to care.  

The field of global health is concerned with the health of populations worldwide, focusing on issues that typically have global, political, and economic significance. These health issues usually transcend national boundaries and are best solved through international collaboration. 3 Global health initiatives aim to improve the health and wellbeing of impoverished, vulnerable, and underserved people worldwide. 1 These initiatives include poverty reduction strategies, disease prevention measures (for HIV/AIDS, malaria, and tuberculosis, for instance), efforts to improve nutrition and food security, policy to raise environmental standards and living conditions, and the promotion of gender equality.  

In 2001, the Commission of the World Health Organization (WHO) recommended to fund global health with 0.1% of GDP. 4

The average expenditure per capita for health in low-income countries is estimated at $ 20 per year while that of Western countries is estimated at $ 947. The target to be reached to help out the most disadvantaged countries is $ 44-60 per capita, which would ensure the populations of the poorest countries with the access to essential health services. Directing the 0.1% of the GDP of developed Western countries to the aids for global health would mean closing the gap to reach the target base of $ 44-60 that would allow the saving of 8 million lives a year. 4

Despite the good intentions, there is still a marked disparity between the current spending levels and the commitments made by developed countries in a context in which, among other things, the percentage of aid for global health has been in decline for almost all donor countries.

Activists claim that only 10 per cent of global health research is devoted to conditions that account for 90 per cent of the global disease burden – the so-called ‘10/90 Gap’. 5 They argue that virtually all diseases prevalent in low income countries are ‘neglected’ and that the pharmaceutical industry has invested almost nothing in research and development for these diseases.

In fact, the WHO acknowledges that there are only three diseases that are genuinely ‘neglected’: African trypanosomiasis, leishmaniosis and Chagas disease. 6

A large proportion of illnesses in low-income countries are entirely avoidable or treatable with existing medicines or interventions. Most of the disease burden in low-income countries finds its roots in the consequences of poverty, such as poor nutrition, indoor air pollution and lack of access to proper sanitation and health education. The WHO estimates that diseases associated with poverty account for 45 per cent of the disease burden in the poorest countries. 7 However, nearly all of these deaths are either treatable with existing medicines or preventable in the first place.

If treatments exist for the majority of poor countries’ health problems, why then do mortality rates remain so high? Any discussion of this question must address the problem of access to essential medicines, which remains an intractable political and economic problem. According to the WHO, an estimated 30 per cent of the world population lacks regular access to existing drugs, with this figure rising to over 50 per cent in the poorest parts of Africa and Asia. 8 And even if drugs are available, weak drug regulation may mean that they are substandard or counterfeit.

Within these populations, it is the poorest socioeconomic groups that disproportionately suffer from a lack of access to existing medicines. 9 The implications of this failure of public health policy on global mortality are profound – according to one study, over 10 million children die unnecessarily each year, almost all in low-income or poor areas of middle income countries, mostly from a short list of preventable diseases such as diarrhoea, measles, malaria and causes related to malnutrition. 10

Many governments fail their populations in this respect by imposing punitive tariffs and taxes on medicines, and by skewing their spending priorities in favour of defence over health. The governments of poor countries hinder the creation of wealth, imposing obstacles in the way of owning and transferring property, imposing unnecessary regulatory barriers on entrepreneurs and businesses, and restricting trade through extortionate tariffs. It is these and other political failures that have left poor populations without the necessary resources to access the medicines that could so easily transform their quality of life.

In conclusion, it appears more and more urgent and necessary to decide where to direct our efforts and investment in research, without prejudice, analyzing all the possible strategies for tackling global health issues, including those standing beyond the current economic paradigm based on the market.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
MARCO LUCHETTI, MD, MSc, Senior Consultant, Dept. of Anaesthesia & Intensive Care, A. Manzoni General Hospital, Via dell'Eremo 9/11, 23900 Lecco, Italy.
Corresponding Author Details: 
Dr. Marco Luchetti, Dept. of Anaesthesia & Intensive Care, A. Manzoni General Hospital, Via dell'Eremo 9/11, 23900 Lecco, Italy.
Corresponding Author Email: 
m.luchetti@fastwebnet.it
References
References: 
  1. Koplan JP, Bond TC, Merson MH, et al. Towards a common definition of global health. The Lancet 2009; 373: 1993-1995.
  2. The United Nations. The Universal Declaration of Human Rights. Retrieved 10 April 2013. <http://www.un.org/en/documents/udhr/>.
  3. Brown TM, Cuento M, Fee E. The World Health Organization and the transition from ‘international’ to ‘global’ public health. American Journal of Public Health 2006; 96(1): 62-72.
  4. World Health Organization (WHO). Macroeconomics and health: investing in health for economic development, Report of the Commission on Macroeconomics and Health, Geneva, World Health Organization, 2001b.
  5. Drugs for Neglected Diseases Working Group, Fatal Imbalance: The Crisis in Research and Development for Drugs for Neglected Diseases, MSF, September 2001.
  6. WHO-IFPMA Round Table, Working paper on priority infectious diseases requiring additional R&D, July 2001.
  7. World Health Organization (WHO), World Health Report, 2002.
  8. World Health Organization (WHO), Medicines Strategy Report, 2002–2003.
  9. Victora CG, Wagstaff A, Schellenberg JA, et al. Applying an equity lens to child health and mortality: more of the same is not enough. Lancet 2003; 362: 233–41.
  10. Black RE. (2003). Where and why are 10 million children dying every year? The Lancet; 361: 2226–34.

Case report: DiGeorge syndrome presenting with hypoparathyrodism and Learning Difficulties in adulthood.

Authors
Nawras Al-taie ,Sandra Scheuter-Mlaker , Michael Schlesinger , Heidemarie Abrahamian
Article Citation and PDF Link
BJMP 2014;7(4):a730
Abstract / Summary
Abstract: 

We report a 40 year old female with mild dysmorphic facial features, learning difficulties, epilepsy and chronic dermatitis, presenting with symptomatic hypocalcaemia. The laboratory investigations confirmed the diagnosis of hypoparathyroidism. The hint to DiGeorge syndrome was the hypoparathyroidism in association with learning difficulties and dysmorphic features. Chromosomal analysis using fluorescence in situ hybridization (FISH) analysis showed a deletion of chromosome 22q11.2 and confirmed the diagnosis of DiGeorge syndrome. This case report demonstrates that DiGeorge syndrome should be considered while investigating hypocalcaemia and Hypoparathyroidism in adulthood as this syndrome has very important implications for health and future family planning for patients and their families.

Case Report

Our patient is a 40-year-old lady who presented to our department feeling unwell with fever and numbness in both hands. Past medical history showed recurrent urinary tract infections, rheumatoid arthritis, chronic eczema and epilepsy .She was taking Levetiracetam 500mg twice daily and Clobazam 5 mg twice daily for the epilepsy. She is also known to have learning difficulties. Mild hypocalcaemia was documented few years back in a previous admission in other hospitals, but the cause was unclear. On admission, she was hemodynamically stable with mild facial dysmorphism, and positive Trousseau's and Chvostek's signs.

Blood tests showed a low corrected calcium 1.5 mmol/L (NR 2.25-2.5 mmol/L), high C-reactive protein, Leukocytosis, and 3.0 mmol/L serum potassium level (NR 3.5-5.0 mmol/L). Other routine blood tests were normal. Further investigations showed low Serum parathyroid hormone levels, normal magnesium levels and normal TSH level. A CT scan of the brain was unremarkable. Electrocardiogram showed QT prolongation (with QTc of 520 ms). The diagnosis of hypoparathyroidism and urinary tract infection was established and the patient was treated with antibiotics to cover urinary tract infection and calcium supplements for hypocalcaemia. The patient symptoms improved significantly and was discharged on calcium supplements and Calcitriol (Rocaltrol 0.25 mcg) with a calcium level of 2.1 mmol/L. The presence of hypoparathyroidism in association with learning difficulties, eczema and epilepsy prompted chromosomal analysis for DiGeorge syndrome. The microdeletion of chromosome 22q11.2 was confirmed by FISH (fluorescent in situ hybridization) analysis. Cardiac echo examination demonstrated no abnormalities and abdominal ultrasound examination showed no renal abnormalities. The patient was offered Genetic counselling together with her family.

Discussion:

DiGeorge syndrome is a well-known genetic disorder with a prevalence of 1:4000 live births1.  It was initially described by Angelo DiGeorge a physician and paediatric endocrinologist in 1968 2. DiGeorge is a developmental defect caused by a microdeletion of chromosome 22q11.2; it is also known as velocardiofacial syndrome or CATCH 22 syndrome to describe the classical features of this syndrome (C-Congenital heart disease, A-Abnormal facies, T-Thymus hypoplasia, C-Cleft Palate and H- Hypocalcaemia due to Hypoparathyroidism. Autoimmune disorders, skeletal defects, renal abnormalities, psychiatric and behavioural disorders are also associated with this syndrome.

DiGeorge is an autosomal dominant syndrome but the majority of patients have de novo mutations caused mainly by the microdeletion of chromosome 22q11.2 which leads to developmental disorders such as the failure of development of pharyngeal pouch system 3, 4. These developmental disorders are the main cause of the classic features and presentation of DiGeorge syndrome such as congenital heart diseases, hypoplasia of the parathyroid glands and thymus, congenital immune deficiency and renal abnormalities5  .

Congenital Conotruncal cardiac defects that involve truncoaortic sac can present in 70% patients with DiGeorge Syndrome. The most common cardiac anomalies are interrupted aortic arch, Tetralogy of Fallot, Atrial septal defect and ventricular septal defects 4, 5, 6  .

Hypocalcaemia is due to hypoparathyroidism and is present in about 60 % of patients 5, 7  . Hypocalcaemia is a strong predictor of DiGeorge syndrome if it is associated with other clinical features such as cardiac defect and immunodeficiency. Hypocalcaemia commonly presents as muscle cramps, numbness, tetany, focal or generalized seizures, prolong QT and hypotension.

Immunodeficiency is rare in adults and but it may present in up to 70-80% of the children with DiGeorge syndrome.  Immunodeficiency occurs because of the low T cell count due to thymus hypoplasia. The function of T cells is however, usually preserved. Patients with immunodeficiency may have recurrent viral chest infection, systemic fungal infections frequent bacterial infections 8 .

The characteristic facies of DiGeorge include long face, narrow palpebral fissures, broad nasal bridge, micrognathia and asymmetrical crying face.

Psychiatric disorders have been reported with 22q11.2 deletion syndromes such as schizophrenia, bipolar disorder, anxiety and affective disorders.

Other conditions that may be associated with DiGeorge are atopic disorders (asthma and eczema) rheumatoid arthritis, autoimmune thyroiditis, renal abnormalities (such as multicystic kidneys andVesicoureteral reflux).

Conclusion:

Due to the variety of symptoms and the de novo mutations, DiGeorge Syndrome should be considered in adults presenting with hypocalcaemia due to hypoparathyroidism even in the absence of the classical features. The syndrome has significant health implications, and confirming the diagnosis is important for future family planning.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
NAWRAS ALTAIE, Department of Internal Medicine, Otto-agner Hospital, Baumgartner Höhe 1, Vienna, Austria.
Corresponding Author Details: 
DR NAWRAS ALTAIE, Department of Internal Medicine, Otto-agner Hospital, 1140 Wien, Baumgartner Höhe 1,Pav.13/2, Vienna, Austria.
Corresponding Author Email: 
nawrasih@yahoo.com
References
References: 
  1. K. Devriendt, J. P. Fryns, G. Mortier, M. N. Van Thienen, and K. Keymolen, “The annual incidence of DiGeorge/velocardiofacial syndrome,” Journal of Medical Genetics, vol. 35, no. 9, pp. 789–790, 1998.
  2. DiGeorge AM. Discussion of paper by Cooper MD, Peterson RDA and Good RA: a new concept of the cellular base of immunology. J Pediatr 1965;67:907.
  3. H. B. Robinson, “DiGeorge's or the III-IV pharyngeal pouch syndrome: pathology and a theory of pathogenesis,” Perspectives in Pediatric Pathology, vol. 2, pp. 173–206, 1975
  4. Kirsten Mølsted, Maria Boers and Inger Kjær , “The morphology of the sella turcica in velocardiofacial syndrome suggests involvement of a neural crest developmental field,” American Journal of Medical Genetics A, vol. 152, no. 6, pp. 1450–1457, 2010.
  5. Ryan AK, Goodship JA, Wilson DI. Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study. J Med Genet 1997;34:798–804.
  6. Marino B, Digilio MC, Toscano A, Anaclerio S, Giannotti A, Feltri C, de Ioris MA, Angioni A, Dallapiccola B. Anatomic patterns of conotruncal defects associated with deletion 22q11. Genet Med. 2001;3:45–48
  7. Choi JH, Shin YL, Kim GH, Seo EJ, Kim Y, Park IS, et al. Endocrine manifestations of chromosome 22q11.2 microdeletion syndrome. Horm Res. 2005;63(6):294-9
  8. L. M. Piliero, A. N. Sanford, D. M. McDonald-McGinn, E. H. Zackai, and K. E. Sullivan, “T-cell homeostasis in humans with thymic hypoplasia due to chromosome 22q11.2 deletion syndrome,” Blood, vol. 103, no. 3, pp. 1020–1025, 2004

Association between plasma adiponectin and risk of myocardial infarction in Asian Indian patient with diabetes

Authors
Arun Narayan, Sanjay Kulkarni, Rahul Kothari, Telugu Seetharam Deepak, Punith Kempegowda
Article Citation and PDF Link
BJMP 2014;7(4):a729
Abstract / Summary
Abstract: 

Context: Recent epidemiological studies have established association of adiponectin with insulin resistance and cardiovascular risk factors. However, newer reports state an ethnic difference in this association.

Objectives: The present study was done to assess the association between plasma adiponectin levels and coronary event in Asian Indian patients with diabetes. The relation between plasma adiponectin and various cardiovascular risk factors in an acute coronary event was also studied.

Methodology: The prospective study was conducted at a tertiary care center in Bangalore, India. Three groups of 30 patients-Patients with diabetes with Myocardial Infarction (MI), Patients with diabetes without MI and controls (age and sex matched non-patients with diabetes)- were included in the study. The association between plasma adiponectin level and MI in patients with diabetes was studied in comparison to patients with diabetes without MI.

Statistical analysis used: Analysis of Variance, Spearman Correlation

Results: Patients with diabetes with MI had significantly lower plasma adiponectin when compared to patients with diabetes without MI which in turn was lower than in normal subjects (P<.001). Plasma adiponectin was significantly correlated with abdominal obesity (r=-.31), fasting glucose level (r=-.61), glycated haemoglobin (r=-.63) and triglycerides (r=-.54) (all P <.001). There was no significant correlation between plasma adiponectin levels and High Density Lipoprotein-Cholesterol in the present study.

Conclusions: The present study and the recent evidence suggest that cross-talk between inflammatory signalling pathways and insulin signalling pathways may result in insulin resistance and endothelial dysfunction that synergize to predispose to cardiovascular disorders.

Key Messages: Adiponectin is a potential target in future research for reducing morbidity and mortality associated with atherosclerotic disease.

Keywords: 
Adiponectin, Diabetes, Myocardial infarction, HDL cholesterol.

Introduction

Adiponectin, first reported in 1995 by Scherer et al, is a novel and important member of the adipokine family.1 It is a collagen-like protein that is exclusively synthesised in white adipose tissue and is the gene product of adipose most abundant gene transcript 1 (apM1).

Adiponectin has been postulated to play an important role in the modulation of glucose and lipid metabolism in insulin-sensitive tissues in both humans and animals. Various studies have reported a protective effect of plasma adiponectinagainst type 2 Diabetes Mellitus (T2DM) 2-6. Adiponectin is also inversely associated with traditional cardiovascular risk factors, such as total and low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and is positively related to high-density lipoprotein cholesterol (HDL-C).7 Recent studies suggest that it may have anti-atherogenic and anti-inflammatory properties .8-10 A few researchers who studied the combined effects of these findings reported inverse correlation between plasma adiponectin and risk of coronary heart disease.11-15

Recent epidemiological studies have shown that association of adiponectin with insulin resistance and cardiovascular risk factors vary with ethnicity. Mente et al studied the ethnic variations in adiponectin concentrations and insulin resistance and found that South Asians and aboriginal people display a greater increase in insulin resistance with decreasing levels of adiponectin compared to Chinese and Europeans .16 However, a similar study involving Asian Indian teenagers showed that adiponectin did not correlate directly with measures of insulin sensitivity, overweight, and other cardio-metabolic variables .17 Similar studies in adults are not available.

The present study was done to assess the association between plasma adiponectin levels and coronary event in patients with diabetes. Also the relation between plasma adiponectin level and various cardiovascular risk factors were studied in patients with diabetes with and without acute coronary event.

Subjects and Methods:

The prospective study was conducted at a tertiary care centre in Bangalore, India from January 2008 to December 2009. The study was approved by the institution ethics committee. Three groups of patients, age and sex matched, were included in the study. The first group included 30consecutive T2DM patients admitted with a diagnosis of myocardial infarction (MI) at the study centre. While the second consisted of patients with T2DM without MI, the third group were patients without diabetes without any history of acute coronary event. MI was diagnosed as per World Health Organization’s criteria.18 Patients aged less than 18 years were not included in the study. Patients with diabetes with chronic kidney disease or receiving Thiazolidinediones were also excluded from the study as it would alter plasma adiponectin levels.

Fasting Blood Glucose (FBG), Post-Prandial Blood Glucose (PPBG), Glycated Hemoglobin (HbA1C), Fasting Lipid Profile, Baseline Electrocardiogram and Plasma Adiponectin were done for all the study subjects. In addition, Coronary Angiogram was done for patients with diabetes with MI to confirm Coronary Artery Disease (CAD) and treadmill tests were done for patients with diabetes without MI to exclude underlying CAD.

FBG and PPBG, serum total cholesterol and serum triglycerides were estimated using enzymatic kit method (Vital Diagnostics, Mumbai, India); and serum HDL-C (Bayer Diagnostics, Baroda, India) using a semi-auto-analyser.

Plasma Adiponectin levels was estimated using Human Total Adiponectin/Acrp30 Quantikine ELISA Kit (R&D Systems Inc., India). This assay employs the quantitative sandwich enzyme immunoassay technique. A monoclonal antibody specific for the Adiponectin globular domain has been pre-coated onto a microplate. Standards and samples are pipetted into the wells and any Adiponectin present is bound by the immobilised antibody. After washing away any unbound substances, an enzyme-linked monoclonal antibody specific for the Adiponectin globular domain is added to the wells. Following a wash to remove any unbound antibody-enzyme reagent, a substrate solution is added to the wells and colour develops in proportion to the amount of Adiponectin bound in the initial step. The colour development is stopped and the intensity of the colour is measured.

Statistical Analysis

Statistical analyses were performed using Statistical Package for Social Sciences (SPSS) for Windows 16.0 (SPSS Inc., Chicago, USA). The results for each parameter (numbers and percentages) for discrete data and average (mean + standard deviation) for continuous data are presented in tables and figures using Microsoft office 2007 software package.

Two-way Analysis of Variance (ANOVA) was performed for plasma adiponectin in patients with diabetes with MI, patients with diabetes without MI and controls as the grouping factor. Two tailed ‘P’ values less than 0.05 were considered significant. Spearman correlation was performed to analyse the association between plasma adiponectin, BMI, FBG, PPBG, HbA1C, serum triglycerides, HDL-C and LDL-C.

Results

The following results are expressed as mean± standard deviation. The mean age of the study subjects in the three groups-patients with diabetes with MI, patients with diabetes without MI and Controls- was 58.00±8.77 years, 57.17±9.34 years and 54.20±7.28 years respectively. The descriptive statistics of the various parameters under study is given in table 1.

Patients with diabetes with MI had significantly lower plasma adiponectin levels (6.11±1.82) when compared to patients with diabetes without MI (9.47±1.55) which in turn was lower than normal subjects (17.82±1.30) (P<.001) . Plasma adiponectin was significantly correlated with BMI (r=-.31), FBG (r=-.61), HbA1C (r=-.63) and triglycerides (r=-.54) (all P<.001). We did not find any significant correlation between plasma adiponectin levels and HDL-C (Table 2).

Table 1: Descriptive statistics of various parameters under study

Variable Controls Mean (±Std. Dev) Patients with diabetes without MI Mean(±Std. Dev) Patients with diabetes with MI Mean(±Std. Dev)
Plasma Adiponectin 6.11(±1.82) 9.47(±1.55) 17.82(±1.30)
Fasting Blood Glucose 123.50(±17.85) 133.23(±16.14) 88.80(±6.27)
Post-Prandial Blood Glucose 190.53(±19.27) 209.33(±28.72) 125.30(±6.200
Glycated Haemoglobin 7.81(±0.92) 8.04(±1.24) 4.06(±0.62)
Total Cholesterol 205.77(±19.92) 214.43(±21.54) 138.07(±10.38)
Serum Triglycerides 148.80(±11.32) 160.53(±14.61) 127.23(±6.11)
Serum HDL 45.13(±8.57) 37.43(±9.73) 44.87(±7.78)
Serum LDL 129.30(±22.55) 137.27(±18.83) 120.03(±8.27)
Body Mass Index 27.82(±2.39) 27.08(±2.20) 25.40(±2.63)

Table 1: Patients with diabetes with MI had significantly lower plasma adiponectin when compared to patients with diabetes without MI which in turn was lower than in normal subjects

Table 2: Spearman correlation between adiponectin and body mass index, blood lipids, HbA1C, fasting and post-prandial glucose levels

  Adiponectin BMI FBG HBA1C TG HDL LDL
Adiponectin 1.00 -0.31** -0.61** -0.63** -0.54** 0.02 -0.16
BMI   1.00 0.37** 0.29** 0.25* -0.14 0.10
FBG     1.00 0.62** 0.61** -0.17 0.21*
HBA1C       1.00 0.83** -0.45** 0.35**
TG         1.00 -0.53** 0.33**
HDL           1.00 -0.07
LDL             1.00

** Correlation is significant at the 0.01 level (2-tailed); * Correlation is significant at the 0.05 level (2-tailed); (BMI- Body Mass Index, FBG- Fasting Blood Glucose, HDL- High Density Lipoprotein, LDL-Low Density Lipoprotein, HBA1C- Glycated Haemoglobin, TG- Serum Triglycerides); Plasma adiponectin was significantly correlated with BMI, FBG, HbA1C and triglycerides (all P<.001). The correlation between plasma adiponectin levels and HDL-C was not statistically significant.

Discussion

In the present study, we found decreased plasma adiponectin concentrationsin the patients with diabetes which was further lower in patients with an acute coronary event indicating that it may be a predictor of macroangiopathy. Hotta et al found similar results in their study and proposed that accumulation of adiponectinin atherosclerotic vascular walls may accelerate its half-lifein plasma, resulting in the reduction of the plasma concentrationof adiponectin in subjects with CAD .19 Ouchi et al studied the molecular basis of link between adiponectin and vascular disease and found that adiponectinmodulates endothelial inflammatory response and that the measurementof plasma adiponectin levels may be helpful in assessment ofCAD risk. 20 Large scale prospective experimental research is needed to clarify these theories.

The relation between plasma adiponectin and the various known metabolic risk factors were on par with the world literature, except for HDL-C. Koenig et al reported an additive effect of HDL-C and adiponectin on CAD risk prediction. 21 In their joint analyses, the highest risk for T2DM as well as acute coronary events was observed in men with low adiponectin in combination with low HDL-C levels. In the present study, the mean HDL-C levels were lower in patients with diabetes with MI compared to patients with diabetes without MI. However, we did not find any significant correlation between plasma adiponectin levels and HDL-C in the present study. Similar findings were obtained by Schulze et al indicating that although plasma adiponectin has been established to be correlated with insulin resistance, CAD and metabolic disease, the interrelation between these is far more complex.

The molecular mechanisms by which adiponectin exerts its multiple functions and whether its actions are receptor mediated still remain a mystery. Is the primary activity of adiponectin antiatherosclerotic, or is it principally a modulator of lipid metabolism and regulator of insulin sensitivity, or is it all of the above? The answers to these and other intriguing questions will undoubtedly provide additional insight into the metabolic roles of this new adipocyte hormone.

Conclusion

The present study and the recent evidence suggest that cross-talk between inflammatory signalling pathways and insulin signalling pathways may result in insulin resistance and endothelial dysfunction that synergise to predispose to cardiovascular disorders. Large scale prospective studies are needed to examine the ability of increase in adiponectin levels and insulin sensitivity to improve primary end points including incidence of diabetes and outcomes of cardiovascular events.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
ARUN NARAYAN, M.D, D.T.M & H(U.K), Senior Professor and Head, Department of Medicine, M S Ramaiah Medical College, Bangalore-560054, India . SANJAY KULKARNI, MD, Professor, Department of Medicine, M S Ramaiah Medical College, Bangalore-560054, India. RAHUL KOTHARI, MD, Post-graduate resident, Department of Medicine, M S Ramaiah Medical College, Bangalore-560054, India. TELUGU SEETHARAM DEEPAK, M.D, Department of Critical Care, M S Ramaiah Medical College, Bangalore-560054, India. PUNITH KEMPEGOWDA, MBBS, MSc, Academic Clinical Fellow in Diabetes and Endocrinology, University Hospitals Birmingham NHS Trust, United Kingdom.
Corresponding Author Details: 
PUNITH KEMPEGOWDA, Academic Clinical Fellow, University Hospitals Birmingham NHS Trust, UK.
Corresponding Author Email: 
drpunith@gmail.com
References
References: 
  1. Scherer PE, Williams S, Fogliano M, et al. A novel serum protein similar to C1q, produced exclusively in adipocytes. Journal of Biological chemistry. 1995;270:26746-9.
  2. Lindsay RS, Funahashi T, Hanson RL, et al. Adiponectin and development of type 2 diabetes in the Pima Indian population. The Lancet. 2002;360:57-8.
  3. Daimon M, Oizumi T, Saitoh T, et al. Decreased serum levels of adiponectin are a risk factor for the progression to type 2 diabetes in the Japanese Population The Funagata study. Diabetes care. 2003;26:2015-20.
  4. Spranger J, Kroke A, Möhlig M, et al. Adiponectin and protection against type 2 diabetes mellitus. The Lancet. 2003;361:226-8.
  5. Snehalatha C, Mukesh B, Simon M, et al. Plasma adiponectin is an independent predictor of type 2 diabetes in Asian Indians. Diabetes care. 2003;26:3226-9.
  6. Duncan BB, Schmidt MI, Pankow JS, et al. Adiponectin and the development of type 2 diabetes the atherosclerosis risk in communities study. Diabetes. 2004;53:2473-8.
  7. Kazumi T, Kawaguchi A, Hirano T, et al. Serum adiponectin is associated with high-density lipoprotein cholesterol, triglycerides, and low-density lipoprotein particle size in young healthy men. Metabolism. 2004;53:589-93.
  8. Kobayashi K, Inoguchi T. Molecular Mechanisms of the Antiatherogenic Action of Adiponectin. Vascular Disease Prevention. 2007;4:7-9.
  9. Folco EJ, Rocha VZ, López-Ilasaca M, et al. Adiponectin inhibits pro-inflammatory signaling in human macrophages independent of interleukin-10. Journal of Biological chemistry. 2009;284:25569-75.
  10. Ouchi N, Walsh K. Adiponectin as an anti-inflammatory factor. Clinica chimica acta. 2007;380:24-30.
  11. Pischon T, Girman CJ, Hotamisligil GS, et al. Plasma adiponectin levels and risk of myocardial infarction in men. JAMA: the journal of the American Medical Association. 2004;291:1730-7.
  12. Lim H, Tayebjee M, Tan K, et al. Serum adiponectin in coronary heart disease: ethnic differences and relation to coronary artery disease severity. Heart. 2005;91:1605-6.
  13. Shojaie M, Sotoodah A, Shafaie G. Is adiponectin associated with acute myocardial infarction in Iranian non obese patients. Lipids Health Dis. 2009;8:17.
  14. Zhang MH, Spies C, Ali S, et al. Adiponectin and inducible ischemia in patients with stable coronary heart disease: data from the Heart and Soul study. Atherosclerosis. 2009;205:233-8.
  15. Laughlin GA, Barrett-Connor E, May S, et al. Association of adiponectin with coronary heart disease and mortality the rancho bernardo study. American journal of epidemiology. 2007;165:164-74.
  16. Mente A, Razak F, Blankenberg S, et al. Ethnic variation in adiponectin and leptin levels and their association with adiposity and insulin resistance. Diabetes care. 2010;33:1629-34.
  17. Snehalatha C, Yamuna A, Ramachandran A. Plasma adiponectin does not correlate with insulin resistance and cardiometabolic variables in nondiabetic Asian Indian teenagers. Diabetes care. 2008;31:2374-9.
  18. Rose GA, Blackburn H. Cardiovascular survey methods. Cardiovascular survey methods. 1968.
  19. Hotta K, Funahashi T, Arita Y, et al. Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arteriosclerosis, thrombosis, and vascular biology. 2000;20:1595-9.
  20. Ouchi N, Kihara S, Arita Y, et al. Novel modulator for endothelial adhesion molecules adipocyte-derived plasma protein adiponectin. Circulation. 1999;100:2473-6.
  21. Koenig W, Khuseyinova N, Baumert J, et al. Serum Concentrations of Adiponectin and Risk of Type 2 Diabetes Mellitus and Coronary Heart Disease in Apparently Healthy Middle-Aged MenResults From the 18-Year Follow-Up of a Large Cohort From Southern Germany. Journal of the American College of Cardiology. 2006;48:1369-77.

BJMP September 2014 Volume 7 Number 3

BJMP September 2014 Volume 7 Number 3

Full Issue Booklet   PDF

Editorial

Research Articles

Review Articles

Cognitive Behavioural Therapy for anxiety in children and adolescents with Autism Spectrum Disorder
Dr Hadi Shaker-Naeeni, Dr Trinisha Govender and Professor Uttom Chowdhury
Full Text  PDF

Case Reports/Series

Cyclophosphamide and Doxorubicin-induced Acute Pancreatitis in a Patient with Breast Cancer
Vincent Bryan Salvador, Manpreet Singh, Philip Witek and Gay Peress
Full Text  PDF
Prevalence of Psychiatric Disorders Following Brain Injury
Nismen Lathif, Emily Phipps, Philip Alton, Devena Tyagi Sharma
Full Text  PDF
Cholestatic hepatitis: An unusual presentation of lisinopril induced hepatotoxicity
Gurpinder Singh, Amit Kachalia, Jaspreet Kaur, Kinjal Kachalia, Shaojun Liu and Vincent Rizzo
Full Text  PDF

Clinical Practice

Content and Timing of Inpatient Discharge Summaries at the Mount
Abhishek Shastri, Santosh Bangar, Shoshanah Waldman, Elham Esfahani and Nick Brindle
Full Text  PDF

Stem Cell Therapy: Future of Pain Medicine, Editorial for BJMP

Authors
YiLi Zhou, Bohdan Warycha, and Hoang Vu
Article Citation and PDF Link
BJMP 2014;7(3):a728

Nearly 30% of seniors have chronic musculoskeletal pain. The most common cause of pain in seniors is related to the degenerative changes of the spine and joints9. Conventional treatments are often restricted to the management of symptoms. Use of chronic anti-inflammatory medications in seniors may bear serious risks in gastrointestinal and renal systems. Physical therapy has limited value. Epidural steroid injection(s) may provide up to three months of pain relief. However, there are some risks involved. Spine surgery for degenerative spine diseases has a limited success rate. Up to 30% or 40% of patients may continue to have pain after back surgery. Surgical repair of a knee injury and knee replacement surgeries are popular. However, the costs are relatively high. Many senior patients may not be ideal candidates for surgery due to cardiovascular conditions. Furthermore, all these treatments do not address the key cause of spine and joint pain due to degeneration of cells and subsequent tissue damage9. Recent development in stem cells therapy (SCT) has provided a new hope for seniors.

Back Pain

The major cause of back pain is the degeneration of the cells in the intervertebral discs. Over the last few years molecular, cell-based therapies and tissue-engineering strategies with SCT for disc regeneration have significantly increased. A recent report showed that injection of mesenchymal stem cells (MSC) into bovine intervertebral discs can increase the expression of extracellular type II collagen and maximize extracellular matrix production7. Chun et al 1injected human adipose-derived stem cells (ADSCs) into 20 mature male New Zealand white rabbits. The proliferation of ADSCs at the L4-5 disc was found at 10 weeks after cell injection. Histologically, the ADSC-injected discs exhibited elevated extracellular matrix secretion and little ossification of damaged cartilage in the nucleus pulposus compared with degenerative control discs.

In addition to the promising results from animal research, preliminary human studies showed mixed results. In 2006, Haufe et al3 reported 10 patients who underwent intradiscal injection of hematopoietic precursor stem cells (HSCs) obtained from their pelvic bone marrow. Of the 10 patients, none achieved any improvement of their discogenic low back pain after one year follow-up. More recently Orozco et al 8 reported a study of ten patients with chronic back pain treated with intradiscal injection of autologous expanded bone marrow MSC. Patients were followed for 1 year. Rapid improvements of pain and disability were reported (85% of maximum in 3 months). Although disc height was not recovered, water content was significantly elevated at 12 months. Advantages of intradiscal MSC therapy include simpler and preservation of normal biomechanics without surgery. However, long term survival of the transplanted MSCs in the harsh environment of the discs is still a major challenge. To the date, no double-blind, controlled studies have been published to confirm the clinical efficacy of SCT for the pain due to degenerative disc diseases.

Knee Pain

It is estimated there will be seven-fold increase in knee replacements in the United States between 2005 and 2030. However, SCT may reduce the future need for knee replacement5. Autologous MSC and ex vivo expanded skeletal SC all have shown promising results in the treatment of knee pain caused by osteoarthritis (OA).

In an experimental animal meniscus injury model, it has been reported 10 that transplantation of human meniscus stem/progenitor cells (hMeSPCs) effectively protected articular cartilage, promoted neo-tissue formation with better-defined shape and more matured extracellular matrix and smother surface cartilage, and maintained joint space at 12 weeks postsurgery11. MSC therapy may also reduce animal pain behavior14.

In human studies, Turajane et al13 conducted a case-series study with five patients that failed conservative treatment. It was reported that the combination of intra-articular autologous activated peripheral blood stem cells with growth factor addition/preservation along with hyaluronic acid in conjunction with arthroscopic microdrilling MCS resulted in Quality of Life improvements and succeeded in regenerating articular cartilage in early osteoarthritic knee disease. Skowronski12 reported 52 patients treated with autologous blood MSC for knee pain due to cartilage lesions. Scores improved across all scales with an average improvement of 23 points in the Knee Injury and Osteoarthritis Outcome Score scale and 35 points in the Lysholm knee scale at one year.

Koh et al4 treated eighteen patients with injection of autologous fat pad-derived MSC for knee pain due to OA. Patients were followed for 24 to 26 months after therapy. Western Ontario and McMaster Universities Osteoarthritis Index, Lyholm scores as well as VAS scores all significantly improved. Radiographic study showed the whole-organ MRI score had significantly improved from 60.0 points to 48.3 points at the final follow-up point. Particularly notable was the change in cartilage whole-organ MRI score, which improved from 28.3 points to 21.7 points. More recently, Vangsness et al reported15a randomized, double-blind, controlled study on adult human MSC delivered via intra-articular injection to the knee following partial medial meniscectomy. A single superolateral knee injection was given to 55 patients within seven to ten days after the meniscectomy. It was found that there was significantly increased meniscal volume determined by quantitative MRI in groups that received SCT. No patients in the control group had significant increase in meniscal volume. Patients with osteoarthritic changes who received MSC experienced a significant reduction in pain compared with those who received the control. This randomized, double-blind, controlled study confirmed that MSC could be a promising treatment for knee pain due to osteoarthritis and meniscus tear.

Challenges for SCT

The advantage of SCT is that stem cells can regenerate healthy and functionally specialized cells and tissues to replace the destroyed or degenerative tissues. Though it is promising, it is still facing a variety of challenges. Firstly, there are many studies reporting the clinical efficacy, most studies are open label. Only few, if any, double-blind, controlled studies have supported the efficacy of SCT for knee pain due to osteoarthritis. To the date, there are no controlled studies confirming the clinical efficacy of SCT for degenerative spine diseases. Thus more clinical studies are needed. Secondly, biological techniques for stem cell transplantation are waiting to be enhanced. For example, the stem cells transplanted into degenerated intervertebral discs will face a harsh environment, which has very high pressure, low nutrition and low oxygen. To enhance the cell survival rate and ensure the transplanted cells differentiating toward chondrocyte-like cells, which can produce proteoglycans and type II collagen, more basic science studies are needed2. The third challenge for SCT is iatrogenic cancerogenesis. Embryonic stem cells, including totipotent stem cells (produced from fusion of egg and sperm), and pluripotent stem cells (5-14 day old blastocytes) have a strong potency of cell reproducing and potentially highly teratogenic. Novel strategies such as using transgenic expression of the genetically engineered human recombinant DNases in proliferating and directed differentiation resisting stem cells are being developed to inhibit or prevent the iatrogenic cancerogenesis6. Adult SCs (Adipose, peripheral and bone marrow derived SCs) have the ability to differentiate and form a variety of tissues. These adult SCs have been used in researches to treat variety of human diseases. So far no iatrogenic carcinomas have been reported as the results of the treatment. The fourth major issue related to SCT is the legal challenge. Worldwide, different countries have different laws on SC research and use. Even President Barack Obama signed an executive order on March 9, 2009 to lift the restrictions on federally funded human embryonic stem cells (hESC) research, currently only adult stem cells (adipose, peripheral and bone marrow derived stem cells) are allowed to be used in most clinical settings. These cells should be minimally manipulated. Use of hESC from fetus, umbilical cord and amniotic fluid are all limited for research purposes. Researchers and clinicians must be familiar with the laws of their respective countries and states before becoming involved in SC therapy or research.

Conclusion

The treatment of chronic pain conditions is constantly evolving. Recent advancements in SCT for pain due to degenerative diseases in the spine and joints are promising and indicative that SCT will undoubtedly play a major role in the future. However, more studies are needed to enhance the biological techniques, confirm the clinical efficacy, reduce the risk of iatrogenic carcinoma and address the legal issues related to this exciting treatment. It is likely that SCT will be utilized more extensively in the future for replacing diseased tissues as an alternative to open back surgery or joint replacement.

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
None
Competing Interests: 
None
Details of Authors: 
YILI ZHOU, MD, PhD,Florida Pain and Rehabilitation Center, USA. BOHDAN WARYCHA, MD, Florida Pain and Rehabilitation Center, USA. HOANG VU, DO, Florida Pain and Rehabilitation Center, USA.
Corresponding Author Details: 
YiLi Zhou, MD, PhD. 1910 SW 18th Court, Ocala, FL 34471 USA
Corresponding Author Email: 
yilizhoumd@yahoo.com
References
References: 
  1. Chun HJ, Kim YS, Kim BK et al. Transplantation of human adipose-derived stem cells in a rabbit model of traumatic degeneration of lumbar discs. World Neurosurg. 2012;78:364-71.
  2. Gou S, Oxentenko SC, Eldrige JS et al. Stem Cell Therapy for Intervertebral Disk Regeneration. Am.J.Phys.Med.Rehabil. 2014.
  3. Haufe SM, Mork AR. Intradiscal injection of hematopoietic stem cells in an attempt to rejuvenate the intervertebral discs. Stem Cells Dev. 2006;15:136-7.
  4. Koh YG, Jo SB, Kwon OR et al. Mesenchymal stem cell injections improve symptoms of knee osteoarthritis. Arthroscopy 2013;29:748-55.
  5. Maclaine SE, McNamara LE, Bennett AJ et al. Developments in stem cells: implications for future joint replacements. Proc.Inst.Mech.Eng H. 2013;227:275-83.
  6. Malecki M, LaVanne C, Alhambra D et al. Safeguarding Stem Cell-Based Regenerative Therapy against Iatrogenic Cancerogenesis: Transgenic Expression Controlled By Promoter in Proliferating and Directed Differentiation Resisting Human Autologous Pluripotent Induced Stem Cells Leads to their Death. J.Stem Cell Res.Ther. 2013;Suppl 9.
  7. Mwale F, Wang HT, Roughly P et al. Link N and MSCs can induce regeneration of the early degenerate intervertebral disc. Tissue Eng Part A 2014.
  8. Orozco L, Soler R, Morera C et al. Intervertebral disc repair by autologous mesenchymal bone marrow cells: a pilot study. Transplantation 2011;92:822-8.
  9. Rodrigues-Pinto R, Richardson SM, Hoyland JA. An understanding of intervertebral disc development, maturation and cell phenotype provides clues to direct cell-based tissue regeneration therapies for disc degeneration. Eur.Spine J. 2014.
  10. Shen W, Chen J, Zhu T et al. Intra-articular injection of human meniscus stem/progenitor cells promotes meniscus regeneration and ameliorates osteoarthritis through stromal cell-derived factor-1/CXCR4-mediated homing. Stem Cells Transl.Med. 2014;3:387-94.
  11. Shen W, Chen J, Zhu T et al. Osteoarthritis prevention through meniscal regeneration induced by intra-articular injection of meniscus stem cells. Stem Cells Dev. 2013;22:2071-82.
  12. Skowronski J, Skowronski R, Rutka M. Cartilage lesions of the knee treated with blood mesenchymal stem cells - results. Ortop.Traumatol.Rehabil. 2012;14:569-77.
  13. Turajane T, Chaweewannakorn U, Larbpaiboonpong V et al. Combination of intra-articular autologous activated peripheral blood stem cells with growth factor addition/ preservation and hyaluronic acid in conjunction with arthroscopic microdrilling mesenchymal cell stimulation Improves quality of life and regenerates articular cartilage in early osteoarthritic knee disease. J.Med.Assoc.Thai. 2013;96:580-8.
  14. van Buul GM, Siebelt M, Leijs MJ et al. Mesenchymal stem cells reduce pain but not degenerative changes in a mono-iodoacetate rat model of osteoarthritis. J.Orthop.Res. 2014.
  15. Vangsness CT, Jr., Farr J, Boyd J et al. Adult human mesenchymal stem cells delivered via intra-articular injection to the knee following partial medial meniscectomy: a randomized, double-blind, controlled study. J.Bone Joint Surg.Am. 2014;96:90-8.

Cyclophosphamide and Doxorubicin-induced Acute Pancreatitis in a Patient with Breast Cancer

Authors
Vincent Bryan Salvador, Manpreet Singh, Philip Witek and Gay Peress
Article Citation and PDF Link
BJMP 2014;7(3):a727
Abstract / Summary
Abstract: 

Predominantly occurring as a consequence of alcohol use or biliary stones, acute pancreatitis is rarely caused by chemotherapy. Lately, there have been increasing published reports and reviews of drug-induced pancreatitis from a wide array of antineoplastic drugs. We present a case of a patient recently diagnosed with Stage 3 breast cancer who was initially treated with cyclophosphamide and doxorubicin and subsequently developed acute pancreatitis, which recurred twice after a re-challenge with cyclophosphamide and epirubicin, a derivative of doxorubicin, given individually on two separate occasions. Acute pancreatitis reported in this case is defined by its clinical manifestations, biochemical evidence and imaging studies. To our knowledge, this is the first case of acute pancreatitis occurring in a patient with breast cancer associated with these chemotherapeutic agents.

Abbreviations: 
CBC-complete blood count, FDA-Federal Drug Administration, NPO-nothing per os
Keywords: 
acute pancreatitis, chemotherapy, cyclophosphamide, doxorubicin, drug-induced pancreatitis

INTRODUCTION

Although it is well appreciated that pancreatitis is frequently secondary to biliary tract disease and alcohol abuse, it can also be caused by drugs, trauma and viral infections, or even be associated with metabolic and connective tissue disorders.1 Knowledge of the true incidence of drug-induced acute pancreatitis is dependent on the clinician’s ability to exclude other possible causes, and by promptly reporting the occurrence. Based on individual case reports and case control studies of drug-induced acute pancreatitis, the estimated overall incidence ranges from between 0.1 and 2% of pancreatitis cases.2,3 In particular, drug-induced acute pancreatitis is of mild severity and usually resolves without significant complications.4

Attempts have been made to categorize the risk of drugs causing acute pancreatitis. A previous classification system described by Mallory and Kern Jr. categorized drugs associated with acute pancreatitis as definite, probable, or possible.5 Trivedi et al. proposed a newer classification system for commonly used medications associated with drug-induced pancreatitis. Class I drugs are those medications with at least 20 reported cases of acute pancreatitis and at least one case with a positive rechallenge. Drugs with fewer than 20 but more than 10 reported cases of acute pancreatitis, with or without a positive rechallenge, are designated into Class II. While those medications with 10 or less reported cases, or unpublished reports in pharmaceutical or FDA files, are grouped into Class III.6

Acute pancreatitis as a result of either doxorubicin or cyclophosphamide, or a combination of both, or fluorouracil or epirubicin is a rare occurrence and has seldom been reported in the literature. Even the drug package labels registered with the FDA do not indicate the possible occurrence of pancreatitis. In this case report, we present a rare occurrence of drug-induced acute pancreatitis after the completion of the first cycle of the chemotherapy protocol involving cyclophosphamide and doxorubicin in a patient with stage 3 breast cancer, with recurrences of acute pancreatitis after re-challenging with cyclophosphamide and a derivative of doxorubicin, given individually on two separate occasions.

CASE PRESENTATION

A 58 year-old female presented to the emergency room with a one day history of severe, diffuse, deep-seated abdominal pain that radiated to her back, associated with nausea and vomiting, and was unrelieved despite the intake of NSAIDs. There was no reported fever, chills, diarrhea, dysuria, or antecedent trauma. Her medical history is notable for well-controlled hypertension, hyperlipidemia and hypothyroidism for which she takes amlodipine, atorvastatin and levothyroxine. She was recently diagnosed with left-sided breast cancer, Stage III, two months prior to admission and underwent a left modified radical mastectomy. Three days prior to the hospital visit, she was given her first cycle of chemotherapy with Doxorubicin 60 mg/m2 and Cyclophosphamide 600 mg/m2 along with Pegfilgrastim 6 mg and Fosaprepitant 150 mg. She is a former cigarette smoker, drinks alcohol infrequently, and denies illicit drug use. Her family history is unremarkable.

Physical examination revealed stable vital signs without a fever (36.6C). She had non-icteric sclerae and a dry oral mucosa. Chest exam revealed a well-healed left mastectomy scar and an infusaport located on the right anterior chest wall. Her breath sounds were clear bilaterally. Her heart sounds were normal. Her abdominal exam was significant for mild tenderness to palpation in the epigastric area without palpable masses, organomegaly or ascites. There was no evident ecchymosis observed. The extremities were warm to touch with intact and symmetrical pulses, and without bipedal edema.

Initial work-up revealed an elevated leukocyte count of 42,000 with 80% neutrophils and 17% band forms. Basic metabolic panel was normal except for mild hyponatremia of 129 mEq/L. Serum amylase and lipase were markedly elevated at 2802 units/L and >2000 units/L, respectively. Liver function panel was normal (Alk phos 63 U/L [ref range 30-115 U/L], GGT 21 U/L [ref range 3-40 U/L], total bilirubin 0.90 mg/dL [ref range 0-1.5 mg/dL]). The coagulation profile was within normal range. Imaging of the abdomen with a CAT scan with intravenous and oral contrast showed haziness in the pancreatic fat plane suggestive of pancreatic inflammation, with no gallstones, focal abscesses, hepatic masses, or biliary ductal dilatation (Figure 1). Right upper quadrant ultrasound was essentially normal (Figure 2).

Figure 1. Coronal view of CT scan of abdomen and pelvis with IV and oral contrast showing haziness in the peripancreatic fat plane.

Figure 2. Sonogram of the right upper quadrant of the abdomen showing gallbladder devoid of gallstones and non-dilated common bile duct.

She was admitted to the medicine unit with the assessment of acute pancreatitis likely secondary to doxorubicin and cyclophosphamide. Intravenous fluid hydration with normal saline was initiated. She was kept NPO (nothing per os) and was started on empiric Imipenem and IV Esomeprazole. Her abdominal pain was controlled with intravenous morphine and her nausea with Ondansetron as needed. The serial basic chemistry panel was monitored and electrolyte deficits were replaced accordingly. Further work-up was performed to identify other possible etiologies of pancreatitis. The lipid panel was within normal limits (cholesterol 169 mg/dL [0-200 mg/dL], HDL 74 mg/dL, LDL 71 mg/dL and triglycerides 54 mg/dL [0-150 mg/dL]). The serum calcium levels remained within the normal range throughout her hospital stay. An abdominal sonogram demonstrated absence of gallstones or dilatation of the common bile duct, with a normal appearing liver parenchyma and pancreas. During her stay in the medicine unit, the patient’s abdominal pain improved and she was gradually started on an oral diet, which she tolerated well. Her serum electrolytes remained stable, while her serial CBC revealed progressively decreasing trends in leukocytes, hemoglobin, hematocrit, and platelet count, findings which were attributed to her prior chemotherapy. Repeat serum amylase and lipase both trended downward. The patient was discharged with follow up in the Oncology clinic. A month later, she was started on another chemotherapy regimen that consisted of weekly administration of Paclitaxel 80 mg/m2 which, over the next two months, the patient completed without any complications. Then, after explaining the risks of recurrent pancreatitis, the patient consented to have a trial of cyclophosphamide 500 mg/m2 along with fluorouracil 500 mg/m2. Five days after receiving the chemotherapy, the patient developed acute pancreatitis which was attributed to cyclophosphamide. She again made a full recovery at that time. Three weeks later, her chemotherapy regimen was again changed, to epirubicin 90 mg/m2 and fluorouracil. Four days after receiving this regimen, she again, for the third time, had a recurrence of acute pancreatitis. At this time, a repeat abdominal sonogram revealed a 4mm echogenic focus adherent to the anterior gallbladder wall with a comet tail sign, suggestive of cholesterol crystals lodged within Rokitansky-Aschoff sinuses of the gallbladder wall. There were no visible gallstones. A subsequent MRI of the abdomen with contrast revealed a small rounded hypointensity in the dependent portion of the gallbladder wall that was suggestive of a gallstone, however, there was no biliary obstruction, choledocholithiasis or an obstructing pancreatic mass. At this point, chemotherapy was stopped and anastrozole along with radiation therapy was initiated. The patient continues to be followed regularly and has had no recurrence of pancreatitis since her last episode.

DISCUSSION

The case presented described the development of acute pancreatitis in a patient with breast cancer three days after receiving the chemotherapy regimen consisting of cyclophosphamide and doxorubicin. After re-challenging the patient with cyclophosphamide, and again a few weeks later with a derivative of doxorubicin, epirubicin, acute pancreatitis recurred on each occasion. Despite the presence of cholelithiasis detected on the abdominal MRI, the temporal presentation of acute pancreatitis after chemotherapy exposure is highly suggestive of the role these chemotherapeutic agents played in triggering these three acute attacks. Acute pancreatitis was diagnosed based on the clinical suspicion and symptoms suggestive of the acute pancreatitis and was supported by the marked elevation in serum amylase and lipase, as well as, the radiologic evidence of pancreatic inflammation, both of which are markers of acute pancreatitis.

Chemotherapy-induced acute pancreatitis involving cyclophosphamide and doxorubicin either alone or in combination, is quite rare that even the drug labels registered with the FDA do not indicate acute pancreatitis as one of the possible complications. This scenario highlights the importance of drug surveillance and prompt reporting in order to maintain a credible drug safety database.

Though the drug latency, which is the interval between the initial exposure to the drug and the development of acute pancreatitis, differs variably, the present case is considered to have an intermediate latency (1-30 days). Other drugs may have short (< 24 hours) or long (>30 days) latency periods. Examples of drugs with short latency are acetaminophen, codeine, erythromycin and propofol. Intermediate latency drugs include L-asparaginase, pentamidine and stibugluconate. Drugs with long latency are estrogen, tamoxifen, valproate and dideoxyinosine.7

Based on the revised classification of Badalov et al, the combination of cyclophosphamide and doxorubicin is classified as Class IV drugs, which have the weakest association with acute pancreatitis due to limited information and the lack of adequate detailed case reports. Fluorouracil, which has been known to cause a gastrointestinal ulcer, is also categorized as a Class IV drug, while epirubicin, which is derived from doxorubicin, has not been classified, as it has not been reported before to cause acute pancreatitis. In implicating drugs in the etiology of acute pancreatitis, two conditions must be considered to weigh the strength of the association between the causality and the disease process, namely: a positive rechallenge test resulting in the recurrence of pancreatitis and a similar latency period between the drug exposure and development of the disease.7

The combination of drugs rather than a single agent was implicated for drug-induced pancreatitis in a previous case report that described the development of acute pancreatitis shortly after the second cycle of the chemotherapy regimen composed of cyclophosphamide, doxorubicin, and vincristine in a patient with mediastinal immunoblastic lymphoma. The pancreatitis episode resolved over 48 hours without complications.8

Another case was described in a patient with breast cancer developing acute pancreatitis four days after the third cycle of chemotherapy, which involved docetaxel and carboplatin.9

Toprak et al. reported the occurrence of acute pancreatitis in a patient with multiple myeloma after the initial treatment with the triple regimen chemotherapy protocol consisting of vincristine, doxorubicin, and dexamethasone. In this case report, symptoms suggestive of acute pancreatitis started to manifest on the first day of the treatment, with resolution following discontinuation of the drugs.10

Other antineoplastic agents for breast cancer associated with drug-induced pancreatitis are alemtuzumab, trastuzumab and tamoxifen. Extended use of these medications may cause chronic pancreatitis as a result of their causing repeated clinical or subclinical episodes of acute pancreatitis.6 Most cases of drug-induced pancreatitis follow a mild clinical course.7

In a retrospective study involving 1613 patients diagnosed with acute pancreatitis in a gastroenterology center, the incidence of drug-induced pancreatitis had been reported in 1.4% of patients treated for acute pancreatitis. It has been observed that a higher incidence of drug-induced acute pancreatitis occurs in elderly or pediatric patients, and in those patients with inflammatory bowel disease or AIDS.11

The pathophysiology behind drug-induced pancreatic injury remains unclear. Potential mechanisms underlying such pancreatic injury might be related to drug hepatotoxicity which can be secondary to intrinsic toxicity of the drugs affecting the tissue, or due to an idiosyncratic reaction. In the vast majority of the cases, an idiosyncratic reaction could be the main pathway for tissue injury through a hypersensitivity reaction or production of toxic intermediate metabolites. Idiosyncratic reactions have a longer latency period of months to years before the onset of pancreatitis while the onset of hypersensitivity reactions is earlier (i.e. 1-6 weeks).7

CONCLUSION

Due to a variable latent period between the initial drug exposure and the onset of clinical symptoms, drug-induced pancreatitis must remain as a differential diagnosis in patients receiving chemotherapy regimens and presenting with the constellation of symptoms typical of acute pancreatitis. Due to the unclear pathogenesis of chemotherapy-induced pancreatitis, post-marketing surveillance and adverse drug reporting are paramount in elucidating the effect these drugs have on the pancreas.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
VINCENT BRYAN SALVADOR, M.D. Department of Medicine, Icahn School of Medicine at Mt. Sinai/Queens Hospital Center, 82-68 164th Street, Jamaica, New York, USA 11432. MANPREET SINGH, M.D. Department of Medicine, Icahn School of Medicine at Mt. Sinai/Queens Hospital Center, 82-68 164th Street, Jamaica, New York, USA 11432. PHILIP WITEK, M.D. Department of Medicine, Icahn School of Medicine at Mt. Sinai/Queens Hospital Center, 82-68 164th Street, Jamaica, New York, USA 11432. GAY PERESS, M.D. Department of Medicine, Icahn School of Medicine at Mt. Sinai/Queens Hospital Center, 82-68 164th Street, Jamaica, New York, USA 11432.
Corresponding Author Details: 
VINCENT BRYAN SALVADOR, M.D. Department of Medicine, Icahn School of Medicine at Mt. Sinai/Queens Hospital Center. 82-68 164th Street, Jamaica, New York, USA 11432.
Corresponding Author Email: 
docvincesalvador@aol.com
References
References: 
  1. Sakorafas GH & Tsiotou AG. Etiology and pathogenesis of acute pancreatitis: current concepts. J Clin Gastroenterol. 2000;30:343-356.
  2. Nitsche CJ, Jamieson N, Lerch MM et al. Drug induced pancreatitis. Best Pract Res Clin Gastroenterol.2010;24(2):143-145.
  3. Wilmink T & Frick TW. Drug induced pancreatitis. Drug Safety. 1996;14:406-423.
  4. Tonsi AF, Bacchion M, Crippa S, Malleo G & Bassi C. Acute pancreatitis at the beginning of the 21st century: The state of the art. World J Gastroenterol 2009; 15(24):2945-2959.
  5. Mallory A & Kern F Jr. Drug-induced Pancreatitis: A Critical Review. Gastroenterol. 1980;78:813-820.
  6. Trivedi CD & Pitchumoni CS. Drug-Induced Pancreatitis: An Update. J Clin Gastroenterol. 2005;39:709-716.
  7. Badalov N, Baradarian R, Iswara K et al. Drug-Induced Acute Pancreatitis: An Evidence-Based Review. Clin Gastroenterol Hepatol. 2007;5:648-661.
  8. Puckett JB, William B & McFarland JA. Pancreatitis and Cancer Chemotherapy. Ann Intern Med. 1982;97(3):453.
  9. Singh V, Devata S & Cheng YC. Carboplatin and docetaxel-induced acute pancreatitis: brief report. Int J Clin Oncol. 2010;15:642-644.
  10. Toprak SK, Ocal S, Erismis B et al. Acute Pancreatitis Following VAD Chemotherapy Combination Consisting of Vincristine, Doxorubicin, and Dexamethasone in a Newly Diagnosed Multiple Myeloma Patient: A Case Report. The Internet Journal of Oncology. 2012; 8(2). Accessed at: http://archive.ispub.com/journal/the-internet-journal-of-oncology/volume-8-issue-2/acute-pancreatitis-following-vad-chemotherapy-combination-consisting-of-vincristine-doxorubicin-and-dexamethasone-in-a-newly-diagnosed-multiple-myeloma-patient-a-case-report.html#sthash.BFCHZGAr.mjxZj1fi.dpuf. Accessed on: 18 October 2013.
  11. Lankisch PG, Droge M & Gottesleben F. Drug induced Acute Pancreatitis: Incidence and Severity. Gut. 1995;37:565-567.

Content and Timing of Inpatient Discharge Summaries at the Mount

Authors
Abhishek Shastri, Santosh Bangar, Shoshanah Waldman, Elham Esfahani and Nick Brindle
Article Citation and PDF Link
BJMP 2014;7(3):a726
Abstract / Summary
Abstract: 

Aim: The discharge summary is a vital component of patient care. It is a means by which information is conveyed to clinicians and community mental health team who will be involved in follow-up patient care. This calls for accuracy as well as completeness of information as these are vital components that can directly impact patient care. Timing of discharge letter/summary reaching the follow-up physician, general practitioner or community mental health team, from point of discharge can also play a key role in patient management. This audit looks at the content and timing of discharge summaries from The Mount, Old Age Psychiatry hospital as to whether it adheres to the local Trust guidelines.

Methods: Discharge summaries from electronic database were reviewed. In cycle 1 of the audit, adherence to local Trust guidelines in relation to the content, accuracy and timing of discharge summaries were studied. In the follow-up audit cycle, changes in clinical practice brought about following recommendations were studied. 

Results: Recommendations and feedback were found to be effective in significantly improving adherence to inclusion of family history (p<0.001), social history (p<0.001), premorbid history (p=0.036), progress and treatment during hospital stay (p=0.049) in the discharge summary. Significant decrease was observed in inclusion of follow-up arrangements (p=0.007). Other significant improvements included lesser spelling errors (p<0.001), dictation (p<0.001) and typing (p<0.001) of discharge letter within 5 working days of discharge of patient.

Conclusions: This study adds to importance of accuracy and timing of discharge summaries to ensure good medical practice and continuity of care. It also establishes scope for improvement and recommendations that can further improve clinical practice. Furthermore, key decisions on patient care can be made by follow-up health professionals, at the earliest and with the help of appropriate information.

Introduction

The discharge summary is an integral part of continuing patient care. Apart from containing vital information regarding current admission, it also conveys key findings and plans to clinicians who will be taking over the care of the patient. This would mean communicating important information about patients to ensure appropriate and safe follow-up management. Studies involving discharge summaries have looked into role of communication from secondary to primary care and have highlighted the importance of accuracy and quality of information,1 errors2 and general practitioner (GP) preference.3 Systematic reviews have found low availability (12-34%) of discharge summary during first visit post-discharge as well as wide variations in content of discharge summaries thereby directly affecting patient management.4,5 The timing of discharge summary completion and reaching the follow-up physician is therefore of prime importance wherein this has been also found to influence and reduce the risk of rehospitalisation.6 The content necessary for a ‘good’ or ‘high-quality’ discharge summary has been studied via surveys. The inclusion of important data such as diagnosis, discharge drugs, complications, laboratory results and follow-up plans have been considered to be important clinical information by hospital physicians and GPs.7

Hospital discharge summaries can be hand-written, dictated or in electronic format. These formats have their benefits and downfalls. Hand-written summaries have been found to be well-accepted by primary care physicians although involve the factor of legibility.8 A randomised-controlled trial found no difference between electronic and dictated discharge summaries for primary care physician satisfaction.9 Although the use of electronic discharge summaries has significantly improved both the content and timing of discharge summaries reaching follow-up physician or healthcare staff,10 they have been found to contain higher number of errors in patient progress, additional diagnosis and free-text components.11

This audit examined the timing and content of discharge summaries at The Mount and whether they met local Trust standards. A follow-on audit was conducted to study the impact of recommendations that had been put forward at the end of Cycle 1 of the audit.

Aim and Objectives

Aim

Cycle 1: To study the content, accuracy and timing of discharge summaries at The Mount, Old Age Psychiatry hospital.

Cycle 2: To examine changes in clinical practice following recommendations from Cycle 1 of audit involving content and timing of discharge summaries from The Mount.

Objectives

Cycle 1: To ascertain whether Trust guidelines regarding content of discharge summaries are met and also whether the timeline guidance is being maintained.

Cycle 2: To examine adherence to the Trust guidelines as well as to study the changes brought about by recommendations at the end of Cycle 1.

Criteria/ Standards

Trust guidelines state:

  • Discharge summaries must be typed and sent in 5 working days post-discharge from hospital.
  • They must include the following information (Box 1):
Box 1 Trust guidelines for inclusion of information in discharge summaries
  • Patient ID
  • Date dictated
  • Patient Name
  • Date of Birth
  • Name of consultant
  • Admission address
  • Discharge address
  • Admission date
  • Discharge date
  • Reasons for admission
  • History of present illness
  • Past medical history
  • Past psychiatric history
  • Family history
  • Social history
  • Occupational history
  • Premorbid history
  • Mental health examination
  • Physical examination
  • Results of investigations
  • Progress & treatment during admission
  • Final diagnosis
  • Discharge medications
  • Follow-up arrangements
  • Name of key worker
  • Number of pages

Method

Audit Sample

Patients admitted and discharged from Ward 3 & 4 of The Mount, between 01.04.2011 to 31.10.2011. A total of 103 patient discharge summaries were therefore analysed in Cycle 1 of the study. For cycle 2, the audit sample comprised of patients admitted and discharged from Ward 3 & 4 of The Mount, between 01.04.2012 to 31.10.2012. A total of 97 patient discharge summaries were therefore analysed in this part of the study.

Data Collection

Data was collected using an anonymous data collection tool (Appendix 1) which was designed according to Trust guidelines. Administrative staff provided the clinical audit leads with list of patients discharged during the study dates. The electronic patient record system of the Trust (PARIS: Patient Record Information System) was used to study the discharge summary letters. Data collection was performed under the supervision of consultant responsible for the audit, between November 2011 and January 2012 for cycle 1 and for cycle 2 data collection was performed between October 2013 and November 2013. Patient confidentiality and anonymity was maintained.

Data Analysis

Qualitative data was gathered, coded and collated on to a Microsoft Excel spread sheet. The data collected was reviewed by the authors to ensure each aspect of data collection tool was filled. The data was analysed by the Clinical Audits Facilitator at the Trust Clinical Audit Support Team and placed into a report format for dissemination.

Results

The number of discharge summaries analysed in Cycle 1 and 2 of this study was 103 and 97 respectively.

Data were collected using the data collection tool (appendix 1). Dates of discharge, dictation and typing were recorded. Date of typing was used as a proxy of date sent to GP since there was no record of this. Seven days were permitted for discharges to be sent (equivalent to 5 working days). Discharge summaries were read and it was recorded if each stipulated heading from the Trust guidelines was present. No comment was made on quality of information; only consideration was whether information was present or absent.

Compliance with each point from the above categories is shown in the following series of tables and comparison is made between the studies in Cycles 1 and 2 (Table 1-4). The statistical significance of the differences found in the two audit cycles was evaluated using chi-square tests.

Table 1 Presence of information on discharge summary according to Trust guidelines
Criteria Adherence % 2011 (n=103) Adherence % 2013 (n=97) Statistical significance
Patient code 100% (n=103) 97% (n=94) p=0.721
Date dictated 72% (n=74) 98% (n=95) p<0.001
Patient Name 100% (n=103) 100% (n=97) No change
Date of birth 97% (n=100) 100% (n=97) p=0.090
Name of consultant 98% (n=101) 99% (n=96) p=0.596
Name of current GP 98% (n=101) 98% (n=95) No change
Admission address 98% (n=101) 100% (n=97) p=0.167
Discharge address 98% (n=101) 100% (n=97) p=0.167
Admission date 97% (n=100) 100% (n=97) p=0.090
Discharge date 97% (n=100) 99% (n=96) p=0.342
Legal status 99% (n=102) 98% (n=95) p=0.525
Reasons for admission 98% (n=101) 98% (n=95) No change
History of present illness 100% (n=103) 99% (n=96) p=0.301
Past medical history 89% (n=92) 95% (n=92) p=0.150
Past psychiatric history 95% (n=98) 98% (n=95) p=0.282
Family history 19% (n=20) 86% (n=83) p<0.001
Social history 56% (n=58) 89% (n=86) p<0.001
Occupational history 67% (n=69) 68% (n=66) p=0.873
Premorbid history 37% (n=38) 52% (n=50) p=0.036
Mental health examination 95% (n=98) 93% (n=90) p=0.482
Physical examination 86% (n=89) 92% (n=89) p=0.227
Results of investigations 84% (n=87) 78% (n=76) p=0.265
Progress & treatment during admission 96% (n=99) 100% (n=97) p=0.049
Final diagnosis 92% (n=95) 97% (n=94) p=0.147
Discharge medications 98% (n=101) 97% (n=94) p=0.602
Follow-up arrangements 86% (n=89) 79% (n=77) p=0.007
Name of key worker 64% (n=66) 56% (n=54) p=0.225
Number of pages 0% (n=0) 0% (n=0) No change
Are there any spelling/typing errors in the list of medications? 90% (n=8) 98% (n=2) p=0.064
Are there any spelling/typing errors in the diagnosis and medical terminology? 78% (n=21) 99% (n=1) p<0.001

Table 1: The presence of information mentioned in the Trust guidelines is analysed. The percentage adherence in cycle 1 is compared with findings from cycle 2. Significant increase in inclusion of family history, social history, follow-up arrangements and date of dictation is observed. A healthy increase is also observed in inclusion of premorbid history and progression and treatment during admission. A significant reduction in spelling/typing errors is also seen. The decrease in inclusion of name of key worker, discharge medications, mental health examination and results of investigation amongst others is also noted. GP, general practitioner.

The comparison of findings from Cycle 1 and 2 establish a significant increase in adherence to family history (p<0.001), social history (p<0.001), premorbid history (p=0.036) as well as progress and treatment during hospital stay (p=0.049) components of the discharge summary. There was also a significant increase in inclusion of date of dictation of discharge summaries (p<0.001). Increase in adherence to most of the components of discharge summaries was observed. However, there was significant decrease in inclusion of follow-up arrangements (p=0.007) as well as a decrease in inclusion of name of key-worker assigned to patient (from 64% in cycle 1 to 56% in cycle 2; p=0.0225). A significant decrease in spelling/typing errors in diagnosis or medical jargon was observed (p<0.001).

Timing of Discharge Summaries

Table 2 Time taken between discharge of patient and dictation of letter
Days Adherence % 2011 (n=74) Adherence % 2013 (n=94) Statistical significance
0-7 30% (n=22) 73% (n=69) p<0.001
8-15 24% (n=18) 22% (n=21) p=0.762
16-22 18% (n=13) 4% (n=4) p=0.004
23+ 29% (n=21) 0% (n=0) p<0.001

Table 2: The time taken between discharge of patient and dictation of letter is analysed. A significant increase is observed in the dictation of letter as per Trust guidelines (within 5 working days).

Table 3 Time taken between dictation and typing of discharge letter
Days Adherence % 2011(n=75) Adherence % 2013 (n=94) Statistical significance
0-5 84% (n=63) 73% (n=69) p<0.001
6-11 7% (n=5) 24% (n=23) p=0.192
12+ 9% (n=7) 2% (n=2) p<0.001

Table 3: The time taken between dictation of letter and typing of discharge letter is analysed. A significant decrease is observed in the time taken for typing of letter within 5 days of dictation of letter.

Table 4 Time take between discharge and typing of discharge letter
Days Adherence % 2011 (n=100) Adherence % 2013 (n=96) Statistical significance
0-7 18% (n=18) 52% (n=50) p<0.001
8-15 32% (n=32) 34% (n=33) p=0.724
16+ 60% (n=60) 14% (n=13) p<0.001

Table 4: The time taken between discharge of patient and typing of discharge letter is analysed. A significant increase is observed in the early typing of discharge letter from the date of discharge of patient.

The number of discharge summaries being dictated and typed within 7 days of discharge was significantly increased (p<0.001) and a significant decrease in discharge letters being dictated more than 2 weeks (p=0.004) or 3 weeks (p<0.001) of patient being discharged was observed. The time taken between dictation of letter and it being typed up was also found to have dropped, with 73% being done within 7 days, significant decrease (p<0.001) being observed since the first cycle. Furthermore, a significant increase is observed in early (less than 7 days) typing of discharge letter since patient being discharged (p<0.001).

Discussion:

The discharge summary is a very important means to communicate medical (both physical and psychiatric) and nursing interventions to the GP or community mental health team. This in turn helps in making invaluable decisions to patient care in the community. Hence, it is worth spending time on doing a good discharge letter which includes relevant information. A timely discharge letter can also be very useful in this regard.

At the end of Cycle 1 of the audit, recommendations that were made included (Appendix 2):

  • Disseminating information amongst all junior doctors, consultants and administrative staff on each ward to include the above mentioned headings in accordance with Trust guidelines.
  • Information was also provided regarding finding out Name of Keyworker in PARIS system.
  • A specific note was also placed regarding to spell out medical terminologies that would assist in the typing of discharge summaries by administrative staff.

From the results, it is evident that the content of the discharge summary has largely been maintained. In other words, good practice was maintained and recommendations from previous audit were implemented in most spheres of discharge letters. However, despite the recommendation of finding out name of key-worker from PARIS system, there was a decrease (from 64% in first cycle to 56% in second cycle) in its inclusion (p=0.225). Thus, training in usage of information technology system is essential. Providing appropriate instruction and training to junior doctors has been found to be useful in improving the quality of discharge summaries.12 Therefore, it might be beneficial to include instructions or guidelines for appropriate discharge summaries at local Trust or departmental inductions. This will help junior doctors in ensuring completion of accurate and succinct discharge summaries that will aid in patient management.

There was a reduction in documentation of discharge medication, follow up arrangement, mental state examination and physical health investigation carried out as an in-patient. This certainly needs improving as these are the relevant areas to facilitate smooth transition of care in the community and follow-up arrangement. With regard to the timing of the discharge summary, this was found to have significantly improved from the previous audit cycle. For example, the timing between discharge and dictation (within 7 days) has increased from 30% to 73% and almost all discharge summaries are dictated no later than 3 weeks. The possible reasons for delays in dictation could be ongoing workload, availability of medical staff and of the medical notes, as these are sometimes requested by the Intermediate Community Service (ICS) team. There was a slight drop in the time between dictation and typing (from 84% to 73%), which could possibly due to availability of administrative staff, dictation tapes or medical notes and proof reading by medical staff. Significant increase was observed in inclusion of date of dictation of discharge summaries which will be a useful component for future audits. A significant decrease in spelling/typing errors in diagnosis or medical terminologies was observed. Furthermore, there was significant increase in inclusion of family history, social history, premorbid history as well as information on progress and treatment during hospital in the discharge summary. Therefore, timely audit and feedback can be very useful in improvement of discharge summaries and patient care.

Recommendations & Actions:

  1. Raise awareness amongst senior house officers (SHO’s) and other doctors in the Trust regarding recording of pre-morbid history, occupational history, name of keyworker as this was only done in 52%, 62%, 56% cases respectively. This could be done by disseminating findings from this audit amongst SHO’s and other doctors of Trust through hand-outs to wards as well as through local teaching session.
  2. Remove number of pages from the list of sub-headings needed in discharge summary as this is dependent on typing and not necessarily possible to estimate while dictating discharge summary. However, it is an important part of discharge summary. Therefore, send information with audit findings to medical secretaries informing the need to keep number of pages in the discharge summary.
  3. Consider adding a section on documentation of risk assessment should be included in the discharge summary as well as ‘early relapse signature’ which would enable early intervention in the community to avoid inpatient admission. This could be included in the discharge summary. This would involve liaising with consultants and the responsible person for making/printing discharge summaries for Trust.

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
Dr Zoe Clough and Dr Alex Nalson for their help in data collection for Cycle 1 of this study. Dominik Klinikowski, Clinical Audit Facilitator at Leeds & York Partnership NHS Foundation Trust.
Competing Interests: 
None declared
Details of Authors: 
ABHISHEK SHASTRI, MBBS, PGDIP PSYCHIATRY, MPHIL, Foundation House Officer 2, The Mount, Leeds & York Partnership NHS Foundation Trust, Leeds, UK. SANTOSH BANGAR, MBBS, DPM, MD(Psychiatry), PGDip Clin Psy, MRCPsych (UK), ST 5 in Old Age Psychiatry, The Mount, Leeds & York Partnership NHS Foundation Trust, Leeds, UK. SHOSHANAH WALDMAN MBChB, BA, Core Trainee in Psychiatry, The Mount, Leeds & York Partnership NHS Foundation Trust, Leeds, UK. ELHAM ESFAHANI, MBBS, Core Trainee in Psychiatry, The Mount, Leeds & York Partnership NHS Foundation Trust, Leeds, UK. NICK BRINDLE, BSc (Hons), MB, ChB, MRCP (UK), MRCPsych (UK), Consultant Old Age Psychiatrist, The Mount, Leeds & York Partnership NHS Foundation Trust, Leeds, UK.
Corresponding Author Details: 
Dr Santosh Bangar, ST 5, Old Age Psychiatry, The Mount, 44 Hyde Terrace, Leeds LS2 9LN, United Kingdom.
Corresponding Author Email: 
santosh.bangar@nhs.net
References
References: 
  1. Kazmi SMB. Quality of Electronic Discharge Summaries at Newham University Hospital: An Audit. Br J Med Pract 2008; 1:30-32.
  2. Crossan I Curtis D, Ong YL. Audit of psychiatric discharge summaries: completing the cycle. Psychiat Bull 2004; 28:329–331.
  3. Serfontein J, Dodwell D, Patel P. Psychiatric discharge summaries: what do general practitioners want? Mental Health in Fam Med 2011; 8:167-171.
  4. Kripalani S, LeFevre F, Phillips CO, et al. Deficits in communication and information transfer between hospital-based and primary care physicians: implications for patient safety and continuity of care. JAMA. 2007; 297:831-841.
  5. Knai C, Doering N, Panteli D, et al. A systematic review of research on discharge summaries in Europe. Eur J Pub Health. 2013; 23: doi:10.1093/eurpub/ckt126.042.
  6. van Walraven C, Seth R, Austin PC, et al. Effect of discharge summary availability during post-discharge visits on hospital readmission. J Gen Int Med 2002; 17:186-192.
  1. van Walraven C, Rokosh E. What is necessary for high-quality discharge summaries? Am J Med Quality 1999; 14:160-169.
  2. Paterson JM, Allega RL. Improving communication between hospital and community physicians. Feasibility study of a handwritten, faxed hospital discharge summary. Discharge Summary Study Group. Can Fam Phy 1999; 45:2893-2899.
  3. Maslove DM, Leiter RE, Griesman J, et al. Electronic versus dictated hospital discharge summaries: a randomized controlled trial. J Gen Int Med 2009; 24:995-1001.
  4. O’Leary KJ, Liebovitz DM, Feinglass J, et al. Creating a better discharge summary: improvement in quality and timeliness using an electronic discharge summary. J Hosp Med 2009; 4:219-225.
  5. Callen JL, Alderton M, McIntosh J. Evaluation of electronic discharge summaries: a comparison of documentation in electronic and handwritten discharge summaries. Int J Med Informatics 2008; 77:613-620.
  6. Myers JS, Jaipaul CK, Kogan JR, et al. Are discharge summaries teachable? The effects of a discharge summary curriculum on the quality of discharge summaries in an internal medicine residency program. Acad Med 2006; 81 (suppl 10): s5-S8.

A case report of sertraline-induced hyperpigmentation

Authors
Fayyaz Khan and Carl Littlejohns
Article Citation and PDF Link
BJMP 2014;7(3):a725
Abstract / Summary
Abstract: 

This is a case report of a 27 years old Caucasian lady with Bipolar Affective Disorder that developed hyperpigmentation, after starting sertraline for low mood. Her current medications also included semi sodium valproate 1000 mg orally daily, quetiapine modified release 400 mg orally daily, tramadol 50mg orally twice a day and co-codomol orally on an as required basis for back pain. She denied any illicit drug intake and there is no significant past medical or family history. Sertraline was stopped and replaced by duloxetine, but unfortunately the hyperpigmentation persisted. Only one previous case of sertraline-induced hyperpigmentation was found.

Abbreviations: 
ICD- International Classification of Diseases
Keywords: 
Sertraline, anti depressant, SSRI, hyperpigmentation

Introduction:

Sertraline is selective serotonin reuptake inhibitor (SSRI). It is a commonly prescribed antidepressant. The common side effects of SSRI’s are nausea, vomiting, diarrhoea, dyspepsia, anorexia and weight loss.

To our knowledge this is the only second reported case of sertraline-induced hyperpigmentation. It is interesting to note that in some cases sertraline has been used as replacement medication following antidepressant induced hyperpigmentation. So it is important that both clinicians and patients are aware of this potential rare side effect of sertraline.

Case Report:

In this case report we present a 27 years old Caucasian lady that developed hyper pigmentation, after starting sertraline.

The patient, a 27 years old lady was diagnosed with Bipolar Affective Disorder (ICD-10)2 years ago. She was prescribed sertraline 50mg for low mood. Her current medications also include semi sodium valproate 1000 mg orally daily, quetiapine modified release 400 mg orally daily, tramadol 50mg orally twice a day and co-codomol orally on an as required basis for back pain. She was not prescribed any depot medications. To our knowledge she was compliant with her medication.

She responded well but reported that she had developed hyperpigmentation after four weeks. This persisted after suffering a recurrence of low mood and being seen in clinic 5 months later.

There is no significant past medical or family history. She has been on various psychotropic medications in the past including fluoxetine, venlafaxine, olanzapine and procyclidine.

Physical examination revealed focal hyperpigmentation limited to the upper lip. It was dark brown in color with sharply defined outline and was not associated with itching, redness, rash or excoriation. It was gradually getting darker in color and she had to wear a lot of make up to conceal it. The patient was referred to a consultant dermatologist for an opinion but unfortunately she did not attend her appointment. This has been acknowledged as a limitation of our case report. Routine blood tests were within the normal range. She also reported some weight gain with sertraline.

She did not report any previous history of dermatological disorders or any endocrine conditions and Addison's disease was excluded. She did not begin any new medication or vaccines prior to onset of the hyperpigmentation and denied ever having chlorpromazine, tricyclics, tetracyclines, amiodarone, hormone replacement therapy, aspirin, chemotherapy or minocycline. However three years ago, she had taken anti malarial medication before going to the Dominican Republic. She also denied any intake of herbal medication, non-prescribed medication or illicit drugs.

She also denied excessive exposure to sunlight during the time of development of hyperpigmentation and she was not pregnant. There is no history of heavy metal exposure.

The probability of adverse drug reaction assessed by using Naranjo Scale indicated a probable association between the use of sertraline and hyperpigmentation. Subsequently her sertraline was stopped and replaced by duloxetine 30mg daily. Unfortunately the hyperpigmentation persisted after three off sertraline but is no longer worsening.

Discussion:

Bipolar Affective Disorder also known as bipolar disorder, manic-depressive disorder, or manic depression is characterised by two or more episodes in which patients mood and functionality is significantly disturbed, this disturbance on some occasions includes episodes of mania or hypomania with elevated mood and increased energy levels and on others episodes of depression with low mood, tiredness and diminished pleasure in activities. Recovery is usually complete between these episodes. 1

The pharmacological treatment of bipolar affective disorder depends on nature and degree of presenting episode and includes mood stabilisers like lithium, valproate, carbamazepine and lamotrigine, anti psychotics like olanzapine, quetiapine, aripiprazole and risperidone and antidepressants like sertraline, citalopram and venlafaxine.

Sertraline, citalopram, escitalopram, fluoxetine, fluvoxamine and paroxetine selectively inhibits reuptake of serotonin, hence named selective serotonin reuptake inhibitor (SSRI).

In our case the patient was on semi sodium valproate and modified release quetiapine and was later prescribed sertraline to help with low mood.

A literature review of English language using PubMed database was done on 15th June 2013. The terms searched were “sertraline”, “serotonin reuptake inhibitor”, “SSRI”, “anti depressants”, “hyperpigmentation”, “pigmentation”, and it found case reports of antidepressant associated hyperpigmentation with citalopram2, mirtazapine3 and imipramine.4, 5,6,7 It is interesting to note that in some of the case reports the antidepressants were replaced by sertraline after development of hyperpigmentation, but there was no record as to whether the lesion resolved.2, 3,4

Only one previous case of sertraline-induced hyperpigmentation was found8,which also unfortunately persisted after discontinuation of the antidepressant.

As hyperpigmentation has also been reported with other SSRIs, clinicians should be more aware that hyperpigmentation might be related to the class effect, rather than the individual drugs.

Though the exact biological mechanism for the development of hyperpigmentation is not clear and further research is needed, the secretion of melanocyte stimulating hormone (a-MSH) is closely associated with skin pigmentation, and serotonin and dopamine transmitters appear to be involved which may point to a possible mechanism for the hyperpigmentation.

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
Nil
Competing Interests: 
None declared
Details of Authors: 
FAYYAZ KHAN, MBBS, MRCPsych, MSc in Psychiatric Practice, ST5 General Adult Psychiatry, Cheshire and Wirral Partnership NHS Trust, UK. CARL LITTLEJOHNS, MBChB, FRCPsych, Consultant Psychiatrist, Cheshire and Wirral Partnership NHS Trust, UK.
Corresponding Author Details: 
FAYYAZ KHAN, ST5 General Adult Psychiatry, Cheshire and Wirral Partnership NHS Trust, UK.
Corresponding Author Email: 
doctorfayyaz@hotmail.com
References
References: 
  1. WHO International Classification of Diseases (ICD-10).
  2. Inaloz HS, Kirtak N, Herken H, et al. Citalopram-induced Photopigmentation. The Journal of Dermatology 2001; 28:742-745.
  3. Mendhekar D, Inamdar A. Mirtazapine and hyperpigmentation. The World Journal of Biological Psychiatry 2009; 10(4): 688-689.
  4. Metelitsa AI, Nguyen GK, Lin AN. Imipramine-Induced Facial Pigmentation: Case Report and Literature Review. J Cutan Med Surg 2005; 341-345.
  5. D’Agostino ML, Risser J, Robinson-Boston. Imipramine-induced hyperpifmentation: a case report and review of the literature. J Cutan Pathol 2009; 36:799-803
  6. Mehr N, WuJJ, Dyson SW, Woseth DM. Imipramine-induced hyperpigmentation of the skin. Dermatol Online J 2007; 13:8
  7. Mendhekar DN. Imipramine monotherapy-induced hyperpigmentation in an adolescent girl. Indian J Med Sci 2005; 45 (9); 405-406
  8. Ghanizadeh A. Sertraline and Hyperpigmentation: A Case Report. CNS Spectrum 2007; 2(6) 418.

Effectiveness of cognitive behavioural psychotherapy alone and combined with pharmacotherapy in binge eating disorder: a differential research.

Authors
Lanzarone Cristina, Cuzzocrea Francesca, Larcan Rosalba, Bongiorno Antonio and Minì Valentina
Article Citation and PDF Link
BJMP 2014;7(3):a724
Abstract / Summary
Abstract: 

Objective: This research aimed to verify the differences between patients with Binge Eating Disorder (BED) treated with Cognitive Behavioural Therapy (CBT) alone and those treated with CBT in combination with medication.

Method: A selection of 30 subjects affected by BED was carried out on the basis of experimental outcomes that evidenced the efficacy of Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin-Noradrenaline Reuptake Inhibitors (SNRIs) in the treatment of obesity associated with BED. Some participants underwent CBT alone while the others, in addition to CBT, were treated with bio-equivalent doses of either Paroxetine or Venlafaxine. Binge eating behaviour, impulse regulation, different features of eating behaviour (restrained eating, uncontrolled eating and emotional eating) and different psychotic conditions (Psychopathic Deviate, Depression and Hypomania) were studied during pre- and post-treatment phases. Both the psychological (CBT) and the pharmacological (CBT + SSRIs/SNRIs) therapies were assessed in keeping with the parameters examined.

Results: The data showed that CBT alone seems to favour a greater reduction in depression and hypomania as well as the subject’s ability to control eating behaviour; whereas pharmacological treatment appears to control primarily the impulsiveness of food intake. 

Keywords: 
Eating Behaviours, Bing Eating Disorder, Personality, Cognitive-Behavioural Therapy, Pharmacotherapy

Introduction

Binge Eating Disorder (BED) was first defined by Stunkard in 19591; he identified peculiar food intake features characterized by a loss of control in a subgroup of obese patients. Various efforts have been made, ever since, to provide a non-sociological approach to individuals with such a behaviour disorder, which has long been considered a variant of Bulimia Nervosa.

Unlike patients affected by Bulimia Nervosa, patients with BED appear to be overweight and mainly obese. Thus, the treatment aims not only at reducing BED and its related psychopathology, but also at assessing the weight gain experienced by these patients to prevent a further worsening of physical health.

Walsh & Devlin2 evaluated the use of medication in the treatment of Bulimia Nervosa and BED, underlining the efficacy of antidepressant medication in the treatment of Bulimia Nervosa. The antidepressant efficacy led to consider its use in BED more accurately.

Williamson, Martin & Stewart3 stated that pharmacotherapy was not an effective treatment for Anorexia Nervosa. However, it did prove to be successful in Bulimia Nervosa and BED, although subjects affected with eating disorders apparently respond better to psychotherapy approaches.

Systematic investigations have been conducted on the aetiology of BED. Biological and genetic factors, neurotransmitters and hormones have been involved in the onset of binge eating and play an important role in the regulation of hunger and mood.4, 5 However, a definitive aetiological theory has not been developed and tested.3

BED is characterized by a relevant psychological component that in many cases is under-evaluated. Patients with BED have difficulty in interpreting the visceral sensations of hunger and satiety; they take large amounts of food even during regular meals and, moreover, their food contains more fat than protein.6, 7

In fact, Axis I and II disorders (DSM IV-TR) share common features with binge eating.8 Axis I psychiatric disorders (including depression, anxiety, body dysmorphic disorder, or chemical addiction) characterize many BED patients, and research has evidenced the presence of panic, loss of control, impulsivity, compulsive behavior, obsessive thoughts about food and social phobia.9 Axis II personality disorders (especially borderline personality disorder) are frequently related to patients suffering from eating disorder and comorbidity with Avoidant Personality Disorder and Obsessive-Compulsive Disorder was observed.10

BED is not associated with a restrained eating control, but probably with an increase of uncontrolled eating and emotional eating.11, 12

Pharmacological agents, compared to placebo, have been used in the treatment of BED. Appolinario, Bacaltuchuk, Sichieri et al13 evaluated the efficacy of Sibutramine to reduce the frequency of binge eating, while McElroy, Arnold, Shapira et al14 focused on Topiramate and evidenced a greater reduction in binge eating frequency but with side effects such as paraesthesia.

Other studies showed the efficacy of Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin-Noradrenaline Reuptake Inhibitors (SNRIs) in the treatment of obesity associated with BED15, 16, 17, 18 showing that SSRIs and Tricyclic Antidepressants (TCAs) reduced the frequency of BED compared to placebo.19 To determine which patients are most likely to benefit from medications, and how to sequence the various therapeutic interventions available better, are questions still open to debate.

Moreover, results in many cases appear to be divergent. Ciao, Latner and Durso20 underlined the influences of other factors that may influence treatment efficacy. They observed that many obese individuals who might benefit from weight loss treatment nevertheless do not plan or desire to seek treatment and perceive multiple barriers to treatments.

Pharmacotherapy may enhance weight loss,19 although other results suggest that pharmacotherapy may be associated with a reduction in binge frequency in obese patients with BED, but it does not lead necessarily to weight reduction.21 These medical treatments seem to be effective in reducing binge frequency over the short-term, and the subsequent discontinuation of the medication seems to be associated with a relapse of binge eating. Thus further studies of the role of pharmacotherapy in the treatment of BED need to be carried on.22

According to Williamson, Martin and Stewart3 the additive effects of psychotherapy, e.g. Cognitive Behavioural Therapy (CBT), and pharmacotherapy have to be investigated. At present it seems that adding pharmacotherapy to psychotherapy does not help to reduce binge frequency compared to psychotherapy alone.

The efficacy of CBT has been substantiated by scientific literature23, 24, 25, 26 and Vaidya27 stating that CBT helps patients reduce eating disorder habits by making them aware of the cause of their self-sabotage, while affecting weight indirectly.

Psychotherapy treatment over a one-year period deals with binge symptoms and aims at reducing the possibility of relapse by gathering different techniques for the maintenance of long-term results through the use of specific individual intervention protocols. The main target of the intervention is to facilitate the management of no-control food intake episodes and of impulsivity through the alteration of behaviour, and of cognitive and emotional factors related to eating disorders.

Thus, the main objective of this research was to verify the possible differences between those subjects with BED who underwent psychotherapy combined with pharmacotherapy and those who underwent psychotherapy only. In particular, it aimed at verifying possible differences between the various therapeutic strategies on eating behaviour (restrained eating, uncontrolled eating and emotional eating) and the behavioural and psychopathological features (psychopathic deviate, depression and hypomania).

The main hypothesis was to determine if patients who underwent CBT and pharmacotherapy with bio-equivalent doses of the SSRI Paroxetine or SNRI Venlafaxine obtained a considerable benefit from the pharmacotherapy on impulse regulation, on eating behavior and on personality features compared to those who underwent CBT alone.

The second hypothesis was to verify if Paroxetine and Venlafaxine treatments were equally effective on impulse regulation, eating behavior and on personality characteristics.

Methodology

Participants

A group of 30 subjects with BED were selected. All these subjects applied for support to the Inter-Service-Psychology Clinic for Eating Disorders and they were assisted by a Cognitive Behavioural Therapist. They were all of Italian nationality, aged 22 to 52, with a Body Mass Index (BMI) range of 26 to 35. All participants belonged to a middle class socio-cultural level. They were informed of the objectives of the research and signed a consent form. Those subjects who were diagnosed with binge eating less than two years ago, those aged over 65, or those who were suffering from other debilitating or chronic diseases were preliminarily excluded from this research.

Measures and procedure

Participants were recruited according to the nature of the assessments. More specifically, assessments had to address the effect of psychotherapy and pharmacotherapy in subjects with BED on their impulse regulation, their eating behavior (restrained eating, uncontrolled eating and emotional eating), and their personality features (Psychopathic Deviate, Depression and Hypomania). The 30 subjects selected were randomly assigned to three different treatments. Ten subjects had only CBT, ten subjects underwent psychotherapy with Paroxetine, and ten subjects underwent psychotherapy with Venlafaxine.

Each participant answered questionnaires during the assessment phase and in the post-training phase (after one year of psychotherapy). More specifically:

Binge Eating Scale (BES)28 is a 16-item questionnaire which assesses the presence of binge eating behaviour indicative of an eating disorder. The score ranges from 0 to 46 (non-binging <17; moderate binging = 18-26; severe binging = 27 and higher), which in this research had an adequate internal consistency (a = 0.84).

Eating Disorder Inventory-2 (EDI-2)29 aims at quantifying some psychological and behavioural features. It consists of 64 questions grouped into 11 scales. For each item, the participants are asked to answer by using the following frequency adverbs: "always", "usually", "often", "sometimes", "rarely", and "never". The rating is measured with a score between 0 and 3: the maximum score of 3 corresponds to the intensity of the symptom ("always" or "never" depending on whether the direction of the item is positive or negative), score 2 corresponds to a degree intensity immediately below ("usually" or "rarely"), score 1 to an even lower level of intensity ("often" or "sometimes"), while a score of 0 is assigned to the three "asymptomatic" answers. So, those items with a positive direction are assigned the following scores: always = 3, usually = 2, often = 1, sometimes = 0, rarely = 0, never = 0; items with a negative direction are evaluated in the opposite way: never = 3, rarely = 2, occasionally = 1, and often, usually, always = 0. The sub-scale scores are calculated by simply adding all the scores of items of each specific sub-scale.

This research availed the Impulse Regulation Scale with an adequate internal consistency (a = 0.82). This scale shows the ability to regulate impulsive behaviour, especially binge behaviour.

Three Factor Eating Questionnaire (TFEQ)30 is a self-report questionnaire consisting of 51 items.The questionnaire refers to daily dietary practice and measures three different aspects of eating behaviour: (1) restrained eating (conscious restriction of food intake in order to control body weight or to promote weight loss – cut-off: ≤11; a = 0.79); (2) uncontrolled eating (tendency to eat more than usual due to a loss of control over intake accompanied by subjective feelings of hunger – cut-off: ≤8; a = 0.81): (3) emotional eating (inability to resist emotional cues – cut-off: ≤7; a = 0.83).

Minnesota Multiphasic Personality Inventory-2 (MMPI-2)31 consisting of 567 items with dichotomy answers (true/false) is most commonly used by mental health professionals to assess and diagnose mental illness. The MMPI is based on ten clinical scales that are used to indicate different psychotic conditions. In this research the scoring of the three following scales were taken into consideration: (1) Psychopathic Deviate Scale (Pd) (50 items) which measures social deviation, lack of acceptance of authority and amorality. This scale can be thought of as a measure of disobedience. High scorers tend to be more rebellious, while low scorers are more likely to accept authority. An adequate internal consistency was obtained in this research (a = 0.83); (2) Depression Scale (D) (57 items). The highest scores may indicate depression, while moderate scores tend to reveal a general dissatisfaction with one’s own life. A sound internal consistency was obtained through this research (a = 0.81); (3) Hypomania Scale (H), with 46 items, identifies such characteristics of hypomania as elevated mood, accelerated speech, locomotive activity, irritability, flight of ideas, and short periods of depression. In this research the internal consistency was a = 0.79.

Results

The Statistical Package for Social Science (SPSS 10.1) was implemented to verify the hypothesis. The limited number of subjects enabled analysis of data through non-parametric statistics. In order to verify statistical differences between simple comparisons on paired data the Mann-Whitney (U) test32 was applied. In order to verify statistical differences within phases (pre- Vspost-training), Wilcoxon Signed Ranks Tests33 were calculated separately on paired data.

Table 1 synthesizes the means and standard deviations of eating behaviour and of impulse regulation obtained by the three groups: CBT alone; psychotherapy with Paroxetine (CBT+P); and psychotherapy with Venlafaxine (CBT+V) in pre- and post-treatments.


Groups

Phases

Binge Eating Disorder

Impulse Regulation Scale

MIN MAX M SD MIN MAX M SD

CBT (N=10)

Pre 28 35 31.43 2.41 74 94 85.93 6.84
Post 25 33 28.71 2.46 71 91 83.07 6.67

CBT+P (N=10)

Pre 26 35 30.90 3.54 77 94 86.80 5.29
Post 24 31 27.90 2.85 74 91 82.10 5.72

CBT+V (N=10)

Pre 27 35 30.80 2.78 83 94 87.80 3.91
Post 24 31 27.20 2.57 79 90 83.80 3.71

Table 1 – Minimum and maximum scores, Means and Standard Deviations of eating behaviour and of impulse regulation obtained by three differential groups.

By comparing the total scoring in BES during the pre-treatments phase, no statistical differences between groups were noticed. Subjects who only underwent CBT had the same result than those who had addition of Paroxetine (CBT+P) [U = 64; Z = 0.35; p = 0.75] and Venlafaxine (CBT+V) [U = 59; Z = 0.62; p = 0.55]. There were no initial statistical differences between the two groups that received pharmacotherapy [U = 50; Z = 0.1; p = 0.99].

In the post-treatment phases, the presence of binge eating behaviour appeared to be the same in all groups. Subjects belonging to the CBT group obtained the same results as those belonging to the CBT+P [U = 58; Z = 0.68; p = 0.5] and the CBT+V groups [U = 47; Z = 1.36; p = 0.19]. No statistical differences between medication use were noticed [U = 41; Z = 0.69; p = 0.53].

All groups in post-treatment phases seem to equally benefit from the treatment. Comparing scores obtained by participants in the pre- and post-treatments, statistically significant differences were found in subjects undergoing CBT [Z=3.38, p < 0.001] and those with the addition of Paroxetine [Z = 2.848; p < 0.004] and Venlafaxine [Z = 2.859, p < 0.004].

For this research, Impulse Regulation Scale scores were taken into consideration. In the pre-treatment phase relative to each group, all groups showed the same difficulties to regulate impulsive behaviour. The CBT group showed the same impulse regulation as those belonging to the CBT+P [U = 68; Z = 0.12; p = 0.93] and CBT+V group [U = 64; Z = 0.33; p = 0.75]. No initial statistical differences between pharmacotherapy groups were found [U = 45; Z = 0.39; p = 0.74].

In post-treatment, no statistical differences between groups were observed. The CBT group achieved the same results as the CBT+P [U = 60; Z = 0.56; p = 0.58] and CBT+V group [U = 64; Z = 0.32; p = 0.75]. No statistical differences between the use of Paroxetine and Venlafaxine were found either [U = 39; Z = 0.84; p = 0.44].

All groups seemed to benefit from the treatments. In fact, comparing the scores obtained by participants in the pre- and post-treatments, statistically significant differences were observed in subjects who underwent CBT [Z = 3.38, p < 0.001] as well as in subjects supported by Paroxetine [Z = 2.84; p < 0.005] and Venlafaxine [Z = 2.97, p < 0.003].

Table 2 synthesizes the means and standard deviations of different features of eating behavior (restrained eating,uncontrolled eating andemotional eating)showed by the three groups (CBT, CBT+P, and CBT+V) in pre- and post-treatment.

Groups

Scales

Pre-Treatment

Post-Treatment

MIN MAX M SD MIN MAX M SD

CBT

restrained eating 5 9 6.64 1.28 5 8 5.86 .95
uncontrolled eating 13 16 14.71 1.07 11 15 12.93 1.21
emotional eating 8 13 9.93 1.21 7 11 8.57 1.22

CBT+P

restrained eating 5 9 6.50 1.43 5 7 6.00 .82
uncontrolled eating 13 16 14.10 1.11 10 13 11.60 1.07
emotional eating 8 13 10.70 1.64 8 11 9.80 1.03

CBT+V

restrained eating 5 8 6.10 1.11 4 7 5.50 .85
uncontrolled eating 12 16 13.90 1.37 10 13 11.40 1.17
emotional eating 9 13 10.60 1.43 7 11 9.10 1.19

Table 2 – Minimum and maximum scores, Means and Standard Deviations of different aspects of eating behavior (restrained eating, uncontrolled eating and emotional eating) obtained by three differential groups

In eating behaviour as well, all groups in pre-treatment phases appeared to be equivalent. The CBT group had the same mean result in restrained eating than those subjects who also underwent pharmacotherapy [CBT+P: U = 65; Z = 0.33; p = 0.74; and CBT+ V: U = 53; Z = 1.03; p = 0.55]. In the pre-training no statistical differences between groups with pharmacotherapy were noticed [U = 42; Z = 0.59; p = 0.58].

By analyzing the groups in pre-treatment phases no statistical differences in uncontrolled eating behaviour and emotional eating behaviour were found. In pre-treatment phase, the CBT subjects had the same statistical mean in uncontrolled eating [U = 48; Z = 1.33; p = 0.21] and in emotional eating [U = 48; Z = 1.32; p = 0.21] as those who took Paroxetine. No statistical differences were found when comparing CBT subjects with those that were taking Venlafaxine [uncontrolled eating: U = 48; Z = 1.33; p = 0.21; emotional eating: U = 48; Z = 1.32; p = 0.21]. In the pre-training phase there were no statistical differences between groups with pharmacotherapy [uncontrolled eating: U = 46; Z = 1.44; p = 0.17; emotional eating: U = 51; Z = 1.12; p = 0.28] were found.

All groups showed indistinctively less difficulty on restrained eating habits. In fact, by comparing post-training scores, the participants of CBT obtained the same results as those treated with Paroxetine [U = 61; Z = 0.56; p = 0.62] and Venlafaxine [U = 58; Z = 0.75; p = 0.51]. Therefore CBT alone appeared to be less effective on reducing uncontrolled eating than those with the addition of Paroxetine [U = 30; Z = 2.4; p < 0.02] and Venlafaxine [U = 26; Z = 2.6; p < 0.009]. Participants who underwent only CBT presented with less difficulties on emotional eating control than those with Paroxetine [U = 31; Z = 2.31; p < 0.02], but they achieved the same post-treatment score as those supported by Venlafaxine [U = 52; Z = 1.08; p = 0.31].

Comparing post-treatment outcomes, the effectiveness of Paroxetine and Venlafaxine appeared to be the same on restrained eating behaviour [U = 34; Z = 1.2; p = 0.25], on a better controlled eating behaviour [U = 45; Z = 0.39; p = 0.69] and on a higher emotional eating control behavior [U = 33; Z = 1.29; p = 0.2].

Comparing pre- and post-treatment results helped to observe a significant improvement in all groups. Participants who followed only CBT showed less difficulty to restrained eating behaviour [Z = 2.6; p < 0.009] in post-treatment. The same results were observed in those supported by Venlafaxine [Z = 2.12; p < 0.03], while no statistical differences were detected in a post-treatment phase in those groups supported by Paroxetine [Z = 1.89; p = 0.06].

Moreover it was possible to observe a considerable decrease in uncontrolled eating behaviour in all groups [CBT: Z = 3.49; p < 0.0001; CBT+P: Z = 2.84; p < 0.005; CBT+V: Z = 2.88; p < 0.004]. The same results were observed in the way emotional eating was handled. All groups benefited from treatments [CBT: Z = 3.27; p < 0.001; CBT+P: Z = 2.46; p < 0.01; CBT+V: Z = 2.87; p < 0.004].

Table 3 synthesizes means and standard deviations of Psychopathic Deviate (Pd), Depression (D) and Hypomania scales (H) obtained by the three groups (CBT, CBT+P, and CBT+V) in pre- and post-treatments.

Groups

Scale

Pre-Treatment

Post- Treatment

MIN MAX M SD MIN MAX M SD

CBT

Psychopathic Deviate (Pd) 68 85 74.14 5.02 60 80 66 5.38
Depression (D) 63 81 72.50 5.58 61 78 69.86 5.39
Hypomania (H) 39 75 62 8.15 41 72 59.50 7.29

CBT+P

Psychopathic Deviate (Pd) 70 84 74.80 3.97 67 80 71.40 3.72
Depression (D) 66 76 70.80 3.91 64 74 67.80 3.58
Hypomania (H) 46 70 60.30 7.94 40 63 54.10 8.08

CBT+V

Psychopathic Deviate (Pd) 70 85 76.20 5.41 66 80 72.90 5.06
Depression (D) 65 80 70.80 4.76 61 75 66.60 4.69
Hypomania (H) 42 72 60.10 10.67 41 69 54 10.27

Table 3 – Minimum and maximum scores, Means and Standard Deviations of different aspects of Psychopathic Deviate obtained by three differential groups

As evidence of the homogeneity of the groups, the comparisons revealed no statistically significant differences in the pre-treatment phase. The CBT group subjects and those who received Paroxetine [Pd: U = 58; Z = 0.67; p = 0.51; D: U = 55; Z = 0.85; p = 0.39; H: U = 63; Z = 0.41; p = 0.71] showed similar scores. Likewise, the CBT group subjects and those treated with Venlafaxine [Pd: U = 53; Z = 0.99; p = 0.34; D: U = 58; Z = 0.71; p = 0.51; H: U = 65; Z = 0.26; p = 0.79] showed similar scores. The two groups treated subsequently with pharmacological support showed similar initial scores as well [Pd: U = 44; Z = 0.46; p = 0.68; D: U = 50; Z = 0.1; p = 0.99; H: U = 44; Z = 0.45; p = 0.68].

Comparing the results obtained in the post-treatment phase instead, those participants exposed to CBT alone showed a greater reduction of Pd compared to those who had taken Paroxetine [U = 23; Z = 2.76; p < 0.005] and Venlafaxine [U = 23; Z = 2.77; p < 0.005], whereas no differences were found comparing the scores obtained post-treatment in both groups of subjects with pharmacological treatments [U = 41; Z = 0.65; p = 0.53].

In post-treatment, the CBT group participants showed similar scores when compared to those taking Paroxetine [D: U = 54; Z = 0.91; p= 0.37; H: U = 41; Z = 1.67; p = 0.09] and Venlafaxine [D: U = 44; Z = 1.49; p = 0.14; H: U = 49; Z = 1.2; p = 0.23]. There have been no further significant differences in scores obtained post-treatment by the two pharmacotherapy groups [D: U = 39; Z= 0.84; p = 0.44; H: U = 0.47; Z = 0.23; p = 0.85].

All participants seem to have benefited from the proposed treatment. The CBT group had a significant reduction of Pd [Z = 3.3; p < 0.001], D [Z = 3.37; p < 0.001] and H [Z = 3.19; p < 0.001].

A similar result was found by comparing the pre- and post-treatment scores of the subjects supported by Paroxetine [Pd: Z = 2.7; p < 0.007; D: Z = 2.82; p < 0.005; H: Z = 2.82; p < 0.005].

Even in the group treated with Venlafaxine, a significant reduction of Pd [Z=2.87; p< 0.004], D [Z = 2.84; p < 0.004] and H [Z = 2.81; p < 0.005] was confirmed.

Discussion

The use of pharmacological therapy for overweight patients with BED has been less thoroughly studied. SSRIs (Citalopram, Sertraline, Fluoxetine, and Fluvoxamine) have mainly been used as the active compound in the pharmacological trials of patients with BED in order to improve mood symptoms and weight loss.34 Likewise, in many cases, promising results have been obtained with Venlafaxine in BED.35

Most of the research has focused on specific aspects of binge eating disorder, such as reduction in binge frequency and weight reduction. In general the results are associated with higher discontinuation rates.36

In this research, we did not only focus on the binge eating behaviour and impulse regulation in patients with BED. The main objective of this research was to analyze some aspects of eating behaviour (restrained eating, uncontrolled eating and emotional eating) and, more specifically, different psychotic conditions (psychopathic deviate, depression and hypomania).

The first hypothesis of this research was to verify differences between patients with binge eating disorder that followed CBT either with or without a pharmacotherapy support. The results confirmed that CBT and pharmacotherapy are equally effective in the treatment of BED and equally modified patients’ impulse regulation. Paroxetine and Venlafaxine medications did not enhance the control of binge eating or guarantee management of impulse regulation better than CBT alone.

This research also aimed at evaluating the efficacy of CBT with or without pharmacotherapy on some factors related to eating behaviour, such as the tendency to consciously monitor and reduce the caloric intake (restriction), the tendency to lose control on food intake (uncontrolled eating) and the conscious perception of the sensation of craving for food (emotional eating). The results suggest that CBT offers the same results regarding the reduction of caloric intake (restriction) as pharmacological treatment. It is less efficient in reducing the lack of control in food intake (uncontrolled eating), although it helps to reduce the sensation of craving for food (emotional eating) compared to pharmacotherapy.

In this research the effects of standardized treatments of CBT with or without the use of pharmacotherapy with bio-equivalent doses of Paroxetine and Venlafaxine were analyzed on psychopathic deviation, depression, and hypomania. The results confirmed that CBT showed a greater reduction of psychopathic deviation compared to those groups who underwent pharmacotherapy. Moreover, pharmacotherapy led to a higher reduction of depression and hypomania than CBT alone.

The second hypothesis was to verify if the SSRI Paroxetine and SNRI Venlafaxine were equally effective on impulse regulation, eating behaviour and personality features. The analysis showed that Paroxetine and Venlafaxine were equally effective on binge eating control and impulse regulation, but some differences in reducing dysfunctional eating behavior were found. Venlafaxine, compared to Paroxetine, seems to offer a greater improvement in emotional eating and restriction eating behavior. In fact CBT could be efficient to assess the tendency to reduce caloric intake (restriction) and to reduce the sensation of craving for food (emotional eating) more than Paroxetine alone. In order to reduce the tendency to lose control on food intake (uncontrolled eating) it could be helpful to administer Paroxetine or Venlafaxine.

Limitations

While the clinical groups were equivalent in all the parameters taken into consideration in the pre-treatment phase, the absence of a control group (no treatment) significantly reduced the possibility to accurately verify the conclusion. Due to ethical reasons we were not allowed to select a group of patients without any specific treatment. In order to correct this weakness in the research, it might be helpful to extend the sample and analyze the changes over a longer period of time.

It is relevant to analyze appropriately these aspects through controlled trials in order to test the efficacy and long-term outcome of psychotherapy, pharmacotherapy, and psychotherapy in combination with pharmacotherapy for treating BED.

Conclusion

In conclusion, patients with eating disorders usually suffer from other psychiatric disorders besides their eating disorder. Many results also confirm substantial comorbidity among obesity, BED, mood and anxiety disorders and metabolic syndrome in weight loss seeking populations.37

In such cases, it is important to understand the characteristics of the additional psychiatric disorders and the impact these ones have throughout the treatment.

As underlined by American Dietetic Association (ADA) Reports,38 understanding the complexities of eating disorders, such as influencing factors, comorbid illness, medical and psychological complications, is critical in the effectiveness of the treatment of eating disorders.

Eating disorders are complex medical illnesses since they have psychological, behavioural, and physiological components. Previous researchers underlined the importance to investigate gender differences in binge eating and associated behavioural correlates39 and, in order to prevent eating disorders, it is important to carry out individual treatment even on personality traits if the individual disorders have already occurred.40 Of course, a multidisciplinary approach involving a collaborative team of psychological, nutritional, and medical specialists as underlined in this research must be pursued in order to obtain important and at least short-term results.41

The results of this research confirm the need to analyze BED from an integrative perspective and to suggest treatments based on an interdisciplinary approach. The psychological (CBT) and pharmacological (Venlafaxine and Paroxetine) therapies were both efficient in different ways on the reduction of all the negative variables related to eating disorder. However any treatment could be inadequate in the absence of an accurate diagnosis that takes into consideration biological, genetic, psychological and nutritional components.

The assessment phase still plays an important role in determining which treatment is best for each patient. Accuracy in the medical examination when dealing with medical issues, as well as during the assessment examination and the psychological functioning evaluation is recommended.

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
Lanzarone C. assisted with concept, study design and generation of the initial draft of this manuscript. Cuzzocrea F. assisted with manuscript preparation, data analysis and interpretation and manuscript editing. Larcan R. and Bongiorno A. assisted with concept, manuscript preparation and editing and study supervision. Mimì V. assisted with scoring data. Buggè C. assisted with the editing in English. All authors take responsibility for the integrity of the data and the accuracy of the data analysis. All authors contributed to and have approved the final manuscript.
Competing Interests: 
None declared
Details of Authors: 
CRISTINA LANZARONE, PSYCHOTHERAPEUTIC, SISDCA, Via Narbone,48, Palermo, Italy. FRANCESCA CUZZOCREA, PHD PROFESSOR, Department of Human and Social Sciences,University of Messina, Via Tommaso Cannizzaro, 278 Messina, Italy. ROSALBA LARCAN, FULL PROFESSOR, Department of Human and Social Sciences,University of Messina, Via Tommaso Cannizzaro, 278 Messina, Italy. ANTONIO BUONGIORNO, FULL PROFESSOR, Department of Psychology, University of Palermo, Italy. VALENTINA MIMì,PSYCHOTHERAPEUTIC, SISDCA, Via Narbone,48, Palermo, Italy.
Corresponding Author Details: 
FRANCESCA CUZZOCREA, PHD PROFESSOR, Department of Human and Social Sciences,University of Messina, Via Tommaso Cannizzaro, 278 – Messina - Italy.
Corresponding Author Email: 
fcuzzocrea@unime.it
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Cognitive Behavioural Therapy for anxiety in children and adolescents with Autism Spectrum Disorder

Authors
Dr Hadi Shaker-Naeeni, Dr Trinisha Govender and Professor Uttom Chowdhury
Article Citation and PDF Link
BJMP 2014;7(3):a723
Abstract / Summary
Abstract: 

This article is a review of the use of Cognitive Behavioural Therapy for anxiety in children and adolescents with high functioning Autism Spectrum Disorders (ASD). It first briefly outlines some of the key features of ASD, comorbid anxiety, and the increasing necessity to identify effective intervention strategies for use in this group of individuals, before providing a critique of the literature available. It looks at the adaptations that are commonly suggested to tailor a CBT intervention to the specific needs of an ASD population, and at the studies done so far.

Autistic Spectrum Disorder is a term used to describe a condition in which the person has difficulties in social reciprocation, communication and ritualised or rigid behaviour. Most people on the Autistic Spectrum will have social skills difficulties but not necessarily meet criteria for other clinical problems. Look for associated co-morbid conditions such as Depression and Attention Deficit Disorder. A common associated presentation which can be debilitating but often overlooked is anxiety.

People on the Autistic Spectrum should have access to a range of treatments for anxiety as other clinical populations. Modified Cognitive Behavioural Therapy can be successfully used to manage anxiety disorders in people on the Autistic Spectrum.

Abbreviations: 
ASD;Autism Spectrum Disorder. CBT;Cognitive Behavioural Therapy.
Keywords: 
ASD, Anxiety, CBT, Group therapy, Autism, children, Adolescent

Description of the disorder

Autism Spectrum Disorders (ASD) is the umbrella term increasingly used to describe the set of pervasive developmental disorders that included the diagnosis of Autism, Asperger’s Syndrome, and Pervasive Developmental Disorder Not Otherwise Specified under DSM IV. These are a group of disorders characterised by pervasive difficulties in a combination of the key areas of social communication interaction, and restrictive repetitive behaviours or activities 1, 2. The Diagnostic and Statistical Manual of Mental Disorders (the DSM-5), released by the American Psychiatric Association, officially eliminated many familiar autism spectrum diagnoses and now incorporated them into the single diagnosis of autism spectrum disorder. In DSM-IV, Asperger Syndrome was diagnostically differentiated from Autism by the lack of a significant language delay and intellectual functioning within the normal range.

The epidemiology of ASD is approximately estimated 30 in 10,000, although with increasing awareness of the disorder, this has led to greater rates of diagnosis, more recent estimates suggest the rate may be as high as 60 in 10,000 3. ASD may be as common as 1 in every 68 children according to the United States Centre for Disease Control 4.

Difficulties with an understanding of prevalence possibly related to early studies relying on clinically identified cases rather than community-based surveys, which may have resulted in cases not in treatment were being missed, and possibly only the most severe cases being recorded. Previous estimates may also have been incorrect due to previous narrower case definitions. As sampling methods have improved and better diagnostic instruments are used more cases have been identified and there has been a better delineation of ASD from other psychotic disorders. As more children with ASD are identified, there will be a likely rise in the number of families and children seeking treatment.

Comorbidities

There are very high levels of co-morbid psychiatric difficulties amongst this population with estimates ranging from 7-15%. Anxiety related concerns are among the most common presenting problems for school age children and adolescents with ASD 5. Several studies have examined the prevalence of anxiety within the ASD population. A review by white et al 6 of 11 such studies reported a prevalence to range from 11-84%. This large range in the prevalence may be accounted for by difference in methods used to measure anxiety, differences in definitions and in diagnostic subtypes.

Studies have also looked at prevalence rates of anxiety within the ASD population to other populations. Compared to groups of typically developing children, those with autism had a higher occurrence of anxiety 7, 8. Comparison with other groups considered to be at risk
(children with conduct disorders and learning disabilities) children with ASD were more likely to be diagnosed with an anxiety disorder and/or have more intense anxiety symptoms 9,10.

A formal diagnosis of anxiety disorder in this group is hard for therapists due to overlap between comorbid anxiety and the core symptoms of ASD makes. Several anxiety disorders in DSM- IV and ICD 10 have autism as an exclusion criterion, implying that an anxious procession style is a feature of ASD.

The development of anxiety among children with ASD may relate to their cognitive impairment as they may lack the cognitive flexibility to generate strategies to adapt to varying circumstances and may experience distress over even trivial changes in the environment. The information processing style in children with ASD termed ‘weak central coherence’ is similar to non ASD anxious children whereby they selectively attend to threatening cues which results in the misinterpretation of ambiguous situations as threatening 11,12. As a consequence these cognitive deficits can result in a repertoire of social and communication difficulties resulting in children experiencing severe difficulties in social relationships which may in turn lead to the development of anxiety 13. If a child or adolescent has a co-occurring anxiety disorder, this could further negatively impact on the overall social impairment associated with ASD. This can impact on the child or adolescents ability to participate in activities at school, at home and within the community. Children with significant anxiety symptoms are at risk for serious educational difficulties, later unemployment, substance abuse and other psychiatric problems 14.

Some of the most frequently reported anxiety disorders and symptoms seen in children with Autistic Spectrum disorders are simple phobia, generalised anxiety disorder, separation anxiety disorder, obsessive-compulsive disorder and social phobia.

Treatment with Cognitive Behavioural Therapy

Pharmacological and psychosocial treatment have been the most common approaches to the treatment of anxiety in children with ASD but no single anxiety treatment has emerged to attain well established or probably efficacious empirically supported treatment status for children with an autistic spectrum disorder. Evidence for pharmacological intervention is limited. Also the effects of medication only appear to last as long as the medication is used, with relapse once regime is ceased.

The recommended treatment of choice by NICE guidelines for mood and anxiety disorders is cognitive behavioural therapy (CBT) and the primary psychosocial treatments have used CBT.

Despite the fact that CBT has been shown to be an effective empirically supported treatment for typical children, there continues to be differing views as to whether or not it can be used effectively with other populations. Some of the difficulties associated with treating children with ASD are due to suggestions from research that children with ASD have difficulty in identifying emotions and cognitions both in themselves and others. As CBT relies on the child’s ability to infer their own emotional states and thoughts in order to shift their cognitive style and in turn their anxious behaviour, standard CBT treatments need modification to address the difficulties associated with this.

Although there is recognition of the high comorbidity of anxiety with ASD, there have also been suggestions to the use of strict behavioural analysis 15 and an argument against using a cognitive component to treat this population. Lindsay 16 provides a different view, arguing children with ASD can benefit from the use of a cognitive component.

Various modifications have been proposed on the approach of CBT in this population. Some of the models have suggested adjustment of the developmental level to reflect the child’s ability, the use of coping model instead of curative model, the involvement of caretakers, and extending treatment both by the number of sessions and by overall session duration 17. Attwood 18 has recommended the use of role-plays and visuals, the involvement of special interests of the young person, the adjustment of material according to the developmental level and the incorporation of a social skills module due to the vast deficits associated with ASD. Anderson and Morris 19 recommend a more directive approach to treatment and the use of specifically in vivo practice to aid in the generalisation of skills. Each of these variations may contribute differently to the adaptation of CBT to meet the specific needs of the child being treated; however, the most appropriate pattern of practical and functional strategies is yet to be determined.

Chorpita and Daleiden 20 in their review of evidence based treatment for children and adolescents noted the most commonly used techniques to treat anxiety in typically developing children. These include exposure, relaxation, cognitive restructuring and modelling in that order. The most commonly used techniques to treat ASD include communication skills training, modelling, social skills training, goal setting and parent psycho-education.

CBT generally consists of six components which include assessment of the nature and degree of the disorder, affective education, cognitive restructuring, stress management, self-reflection and a schedule of activities to practice new cognitive skills. It is important to ensure that the young person has the same definition and interpretation of words, and affective education can help increase their vocabulary of emotional expression.

Attwood 21 has described several intervention components which can be added to CBT. Some of the suggestions include; a) Increasing the use of visual aids. b) Associating emotions with tangible objects. c) An emphasis on coping strategies that do not require the use of abstract language for instance the use of relaxation. d) Use of alternative communication modes. e) Embedding the use of preservative interests into CBT sessions. f) Increasing the focus on teaching social skills.

Attwood also developed the concept of an emotional toolbox and focused on working with the young person in identifying different tools to ‘fix’ problems that occur as a consequence of negative emotions including anger, anxiety and sadness. The ‘tools’ are further divided into those that constructively release or reduce energy and those that improve thinking. The therapist generally works together with the young person to draw a variety of tools and activities which encourage constructive emotions repair.

Cognitive restructuring aims to enable the young person to correct distorted conceptualisations and dysfunctional beliefs. It involves challenging the current thinking with logical evidence and ensuring rationalisation and cognitive control of their emotions. Young people with ASD can make false assumptions of their circumstances and intentions of others due to impaired or delayed theory of mind abilities. These young people also tend to make literal interpretations and are less able to seek alternative explanations or responses.

Summary of Case Reports, Case Series, and Randomised Control Trials

Method

Studies that used CBT with the aim of reducing anxiety symptoms in young people with an ASD diagnosis were looked at.

Search Procedures

A search was carried out in electronic bases: Psychinfo and Medline. The publication year was not restricted but the search was limited to English- language peer reviewed journals. Over the databases, the terms ‘Asperger’, ‘Autism’, or ‘developmental disability’, plus ‘anxiety’ or ‘CBT’ and the search was limited to children and adolescents.

Review of Case series and reports

There have been five case studies that used CBT in treatment of anxiety as well as one case report that used CBT in treatment of OCD in children with ASD.

The first case study by Reaven and Hepburn (2003)22 reported a 7 year old girl with Asperger syndrome who markedly responded to a 6 month modified CBT treatment which was primarily tailored for her OCD. Afterwards, Greig and MacKay (2005) 23, Sze and Wood (2007) 24 and (2008) 25, Reaven et al (2009) 26, and White et al (2009) 27 reported further successful outcomes of using modified CBT for treatment of Anxiety in children with ASD. See table 1 for a summary of published case reports and series of studies.

Table 1: A Summary of Published Case Reports and Series of studies using CBT for anxiety symptoms in young people with an ASD diagnosis

AUTHOR
(year)
Sample Anxiety Measure Characteristics of intervention Outcome
Reaven & Hepburn (2003)22 a 7 year old girl with Asperger syndrome   6 months modified CBT treatment based upon the work of March and Mulle Obsessive-compulsive symptoms improved markedly
Greig and MacKay (2005) 23 12 year old male with ASD and unspecified anxiety disorder TSCC, Teacher Report, SWQ 15 sessions Anxiety score on TSCC reduced from 19 to 5. Teacher report suggested improvements at school.
Sze and Wood (2007) 24 11year old female SAD, OCD, GAD, HFA ADIS 16 sessions 90 minutes each over 4 months family cognitive behavioural therapy (FCBT) No longer met criteria for SAD, GAD or OCD on the ADIS by child or parent report
Sze and Wood (2008) 25 10 year old male with ASD,GAD, SAD ADIS, CGI, MASC, CBCL, SSRS, VABS Enhancing CBT No longer met criteria for Social phobia or GAD, on the ADIS, improvement CGI , MASC
Reaven et al (2009) 26 7 male, 3 female mean age 11years, 12 weeks Active Treatment 10 parent-child dyads(n = 10) Wait List Control (n = 23)based on order of enrolment, not random assignment SCARED 12 weekly sessions of 1.5 hours

Large group time, separate parent and child group meetings, and parent-child dyads

Parent report on SCARED showed significant decrease in severity of anxiety symptoms in treatment group
White et al
(2009) 27
14 year old male with ASD, 14 yr old female with PDD-NOS,12 year old male with ASD, 12 year old female with ASD ADIS MCIT 12-13 individual therapy modules delivered over 11 weeks. On the CASI-20 parent rated measure of anxiety, 3 out of 4 participants demonstrated significant improvement from baseline to endpoint.

CY-BOCS children’s Yale-Brown Obsessive Compulsive Scare, SAD- Separation Anxiety Disorder, OCD- Obsessive Compulsive Disorder, GAD- Generalised Anxiety Disorder, HFA – High Functioning Autism, ADIS – Anxiety Disorder Interview Schedule, CGI – Clinical Global Scale, MASC – Multidimensional Anxiety Scale for Children, CBCL – Child Behavioural Checklist, SSRS –Social Skills Rating System, VABS – Vineland Adaptive Behaviour Scales, SWQ – Social Questionnaire, MCIT – Multi- Component Integrated Treatment, PARS – Paediatric Anxiety Rating Scale, RCMSA- Revised Children’s Manifest Anxiety Scale, SRS- Social Responsiveness Scale, CASI-Anx - Child and Adolescent Symptom Inventory-4 ASD Anxiety Scale

Review of Randomised Control Trials

There have been eight studies that have met criteria for a randomised controlled trial that identified CBT as a treatment for anxiety in children with ASD. See table 2 for published randomised controlled trials.

Table 2: Published randomised controlled trials of cbt

AUTHOR (year) Age range/
Sample size
Anxiety Measure Characteristics of intervention Characteristics of Controlled Outcome
Sofronoff, Atwood, Hinton (2005) 28 age 10-12

(n=71)

SCAS, SCAS-Parent,

child report measure

a 6 week CBT

child based (n=23) or combined child and parent (n=25) intervention

a waiting list group Significant decreases Parent reports SWQ at follow-up and a significant increase in the child’s ability to generate positive strategies in an anxiety-provoking situation.
Chalfant, Rapee, and Carroll (2006) 29 age 8-13

(n=47)

ADIS, SCAS, Revised Children’s Manifest Anxiety Scale, Children’s Automatic Thoughts Scale, SDQ-Parent, SCAS-Parent a 12 week group CBT based on ‘Cool Kids’ program(n=28) Approx. 7 months waiting list (n=19) 71.4% of the treated children no longer met criteria for an anxiety disorder compared to 0% in the wait list condition (n=19)
Wood et al
(2009) 30
ages 7-11
(n=40)
Anxiety symptom checklists at baseline and post treatment/ post waitlist 16 sessions of standard CBT augmented with multiple treatment components (n=17) A 3 month wait list (n=23) 78.5% CGI improved compared to only 8.7% of the waitlist group, Remission of anxiety in CBT group, but child reported anxiety had no significant effect
Sung et al
(2011) 31
age 9–16

(n=70)

SCAS-C,CGI-S a 16-week CBT

program
(n = 36)

a Social Recreational (SR) program on anxiety
(n =34)
Children in both programs showed significantly lower levels of generalized

anxiety and total anxiety symptoms at 6-month follow-up on SCAS-C

Reaven et al (2012) 32 age 7-14

(n=50)

ADIS-P modified CBT (n=24) TAU (n=26) 50% in the CBT compared to 8.7% TAU group had a clinically meaningful positive treatment response, group CBT intervention specifically developed for children with ASD may be effective in decreasing anxiety
White et al (2012) 33 age 12-17
(n=30)
ADIS-C/P,SRS,
CASI-Anx
CGI-I, PARS
Multimodal

Anxiety &Social Skills Intervention (MASSI) (n=15, 13 completed)

wait-list control (n=15, 12 completed) 16 % improvement in ASD social impairment MASSI is a feasible treatment program and further evaluation is warranted

On the CGI-I, 6 of 15 (40 %) MASSI participants were rated as responders compared to 3 of 15 (20 %) of WL participants

Storch et al (2013) 34 age 7- 11
(n=45)
ADIS IV C/P, PARS,CGI, MASC-P, RCMAS BIACA –CBT; child & parent focused sessions (n=22) TAU(n=21) 18 (75 %) of CBT arm, were treatment responders, versus only 3 of 21 (14%) in the TAU arm. CBT adapted for anxious youth with high-functioning ASD demonstrates large effects in reducing anxiety symptoms.
McNally et al (2013) 35 age 8-14

(n=22)

ADIS-P, SCAS-P, SCAS a modified version of the Coping Cat program CBT package(n=12) waiting-list

(n=10)

ADIS-P 58% of children with CBT had no anxiety / 36% after 2 month follow up. A modified version of the Coping Cat program may be a feasible and effective program for reducing clinically significant levels of anxiety in children with ASD.

Sofronoff, Atwood, and Hinton (2005) 28 evaluated the impact of a six week cognitive-behavioural intervention for anxiety in 71 school children aged between 10 to 12 with Asperger’s Syndrome. The authors also looked at the potential impact of parent involvement on outcome. The diagnosis of Asperger’s Syndrome was confirmed by semi-structured telephone interview and anxiety symptoms were based on parent report in the initial telephone interview. Children were randomly assigned to one of three groups: child based intervention, combined child and parent intervention or a waiting list group. The intervention focused on teaching the children strategies to manage feelings and expanding emotional knowledge and was delivered weekly in a group format. The focus was on teaching the children strategies to effectively manage feelings and expanding emotional knowledge. Parents served as co-therapists in the combined parent-child intervention as they were trained in all aspects of the intervention.

Using the Spence Child Anxiety Scale-Parent report, children in the combined parent-child intervention reported fewer symptoms of anxiety post–treatment and at a six week follow up than children in the child-only intervention. A child report measure (James and the Maths Test) was used to identify the number of strategies the child could identify for coping with anxiety. Compared to children on the waiting list, children who received either intervention were able to develop more coping strategies. Those in the combined intervention generated significantly more coping strategies at endpoint compared to those in the child only intervention.

Parental involvement is an important aspect of treatment of young people with ASD in ensuring better generalisation and therapy outcome. Authors of this study found that children whose parents were involved in treatment were significantly more improved at follow up than those whose parents were not involved. There are different models of parents involvement and include either only direct participation in each session or with a separate parent only component or both. It seems that regardless of which approach is used parent involvement increases the sustainability and success rate of CBT. Involvement of parents helps to improve their understanding of exposure and practice and helping the young person to learn how to master the skills on their own.

Limitations of this study include the reliance on the parent report of anxiety symptoms and both Asperger’s Syndrome and anxiety symptoms were not formally diagnosed. Parents who were involved in the delivery of treatment may have had a more vested interest in their children’s progress with higher expectations for improvement affecting outcome measure reports. However, no independent (blinded) ratings of anxiety were gathered.

Chalfant, Rapee, and Carroll (2006) 29 evaluated a 12 week group delivered cognitive –behavioural treatment for anxiety in 47 school children aged between 8 to 13 with ASD and no intellectual disability. The intervention was adapted from the ‘Cool Kids’ program (Lyneham et al, 2003), a 12 week group based activity for treatment of childhood anxiety. Cognitive strategies were simplified in the intervention, with a greater focus on visual aids, structured worksheets and homework and exposure and the programme was extended over a 6 month period of time.

The authors randomly assigned participants to either the CBT (n=28) or waiting list (n=19) before beginning of each treatment group. Those under waiting list condition were offered treatment after approximately 7 months, when the waiting list period ended. Multi-modal and Multi-person assessment of anxiety were used. At pre-treatment, over 75% of the sample met criteria for more than one anxiety disorder.

Structured diagnostic measures used in the study included the ADIS (Albano& Silverman, 1996), Spence Children’s Anxiety Scale (Spence, 1998), The Revised Children’s Manifest Anxiety Scale (Reynolds & Richmond, 1978), and Children’s Automatic Thoughts Scale (Schniering& Rapee, 2002). Parent report measures included the SDQ-Parent Report (Goodman, 1997), and SCAS-Parent Report (Spence, 1998).

At post treatment, 71.4% of the treated children (n=28) no longer met criteria for an anxiety disorder compared to 0% in the wait list condition (n=19). It was also found that children in the CBT condition were largely able to identify their automatic thoughts indicating some theory of mind ability and had a significant reduction in automatic thoughts, in comparison to the wait list condition.

Limitations of this study include the small sample size so the data may not be reflective of the wider population with high functioning autism and anxiety. Also the lack of confirmation of the diagnosis of ASD by the investigating clinicians reduced the validity of the participant’s diagnostic status. Participants were accepted based on previous evaluations completed within the community setting.

There was no time spent with the waiting list group to help ensure that the benefits of treatment could be attributed to the treatment alone and not to time spent with the therapist. Also the issue of the waiting list group being aware of the treatment programme and knowledge of future treatment may have attenuated the response of those on the waiting list. Clinicians who implemented the CBT groups and collected the relevant pre-and post-treatment data were not blind to the study’s aims.

Wood et al (2009) 30 used a standard CBT program augmented with multiple treatment components as a randomised controlled trial for 40 children aged between 7 to 11. It was designed to accommodate the social and adaptive skill deficit of children with ASD that could pose barriers to anxiety reduction. They also used a family based intervention program adapted for use with children with ASD. Enhancements included addressing of poor social skills, adaptive skill deficits, circumscribed interests and stereotypes, poor attention and motivation, common co-morbidities as well as school based problems. During modules, children were given social coaching by the therapist, parents and available school providers on appropriate ways to enter interactions and maintain conversation with peers.

Children were randomly assigned to 16 sessions of CBT (n=17) or a 3 month wait list (n=23). Independent evaluators blind to treatment condition, were involved in structured diagnostic interviews. Parents and children completed anxiety symptom checklists at baseline and post treatment/ post waitlist.

The Clinical Global Impressions Improvement Scale (CGI) criteria showed that 78.5% of the CBT group showed positive treatment response at post treatment as compared to only 8.7% of the waitlist group.

Children randomised to CBT had primary outcomes comparable to those of typically developing children receiving CBT for anxiety disorder, which were remission of all anxiety disorders for over half the children in immediate treatment at post treatment and follow up and a high rate of positive treatment response on the CGI. However child- reported anxiety did not yield a significant treatment effect.

Limitations of this study include the small sample size which precluded tests of moderation. The study was also undertaken by researchers who developed the intervention and would need independent replication to validate the intervention.

Also using measures not designed for children with ASD had major impact on the outcomes. The child report of Multidimensional Anxiety Scale for Children (MASC) scores did not yield a significant effect for treatment group largely due to a decrease in MASC scores from pre to post treatment for children in both groups. This may have been due to the MASC being not particularly effective in this population and children’s scores at baseline were relatively low on average. Parental scores showed less of a change from pre to post treatment in the waiting list group. The MASC does not specifically measure OCD and GAD symptoms and as there was a wide range of anxiety symptoms, the type of change that some children may have experienced may not have been properly assessed.

Sung et al (2011) 31 compared the effects of a 16-week cognitive-behavioural therapy program and a Social Recreational (SR) program for 70 children with ASD aged between 9 to16. 36 of them were randomised to CBT and 34 to Social Recreational program. Children in both programs showed significantly lower levels of generalized anxiety and total anxiety symptoms at 6-month follow-up on SCAS-C. They suggest factors such as regular sessions in a structured setting, consistent therapists, social exposure and the use of autism-friendly strategies are important components of an effective framework in the management of anxiety in children and adolescents with ASD.

Reaven et al (2012) 32 used a modified CBT intervention for anxiety in 50 children aged between 7 to 14 with high-functioning ASD and anxiety, who were randomized to group CBT (n=24) or treatment-as-usual (TAU) (n=26) for 12 weeks. Independent clinical evaluators blind to condition, completed structured ADIS-P pre- and post-intervention condition. They found a significant difference between CBT and TAU group.

47 children completed either the CBT or TAU condition. They also had 3 and 6 month follow-ups. Results indicated markedly better outcomes for the CBT group. Clinician Severity Ratings, diagnostic status, and clinician ratings of global improvement showed significant differences by group. In the intent-to-treat sample, the CBT group, 10 of 20 children (50%) had a clinically meaningful positive treatment response, compared to 2 of 23 children (8.7%) in the TAU group. Initial results from this randomized, designed treatment study suggest that a group CBT intervention specifically developed for children with ASD may be effective in decreasing anxiety.

Limitations of this study include small sample size, lack of an attention control group, use of outcome measures normed with typically developing children, and no use of teacher or child measures. TAU remained variable, and the study did not mention the situation of the children in TAU as were or weren’t receiving any treatment.

White et al (2012) 33 combined treatment approaches, and evaluated the feasibility and preliminary outcomes of the Multimodal Anxiety and Social Skills Intervention (MASSI) program in 30 adolescents aged between 12 to 17 with ASD and anxiety symptoms of moderate to greater severity who were randomised to CBT (n=15) or Wait list group (n=15). A 16 % improvement in ASD related social impairment (within-group effect size = 1.18) was observed on a parent-reported scale. Although anxiety symptoms declined by 26 %, the change was not statistically significant. These findings suggest MASSI as a feasible treatment program and further evaluation is warranted. High subject adherence and therapist fidelity demonstrate the treatment was acceptable to families.

Storch et al (2013) 34 examined the efficacy of the Behavioural Interventions for Anxiety in Children with Autism (BIACA), a modular cognitive behavioural therapy protocol, relative to treatment as usual (TAU) among 45 children with ASD aged between 7 to 11. Children with clinically significant anxiety (including OCD), and no intellectual disability, were randomised to receive 16 sessions of weekly CBT (n=22, 2 drop out) or TAU (n=21). After screening, assessments were conducted at baseline, post-treatment, and 3-month follow up for only CBT group which was not blind. The raters were blind to treatment condition. They did also use both child- and parent-report versions of ADIS. Children receiving CBT showed substantial improvement relative to TAU on primary anxiety outcomes. Of 24 children randomised to the CBT group, 18 (75 %) were treatment responders, versus only 3 of 21 children (14%) in the TAU group. Treatment gains were generally maintained at 3-month follow up for CBT responders. They concluded that relative to usual care, CBT adapted for anxious youth with high-functioning ASD demonstrates large effects in reducing anxiety symptoms.

The limitations of this study include that only about 75% of the TAU children were in fact getting treatment of any kind at all, as 25% of their TAU weren’t getting anything. Also TAU group was extremely variable, therefore the control group were getting a variety of treatments, or none, making comparisons with the children who received CBT difficult.

McNally et al (2013) 35 used a modified version of the Coping Cat Program in reducing anxiety in children with ASD. They randomly assigned 22 children with ASD aged between 8 to14, with clinically significant anxiety and no intellectual disability, to 16 sessions of the Coping Cat cognitive-behavioural therapy (CBT) program or a 16-week wait list group.

They used ADIS-parent at pre-treatment and post-treatment phases, and they also video-recorded therapy sessions to check for treatment fidelity. Children in the CBT condition evidenced significantly larger reductions in anxiety than those in the waitlist. Treatment gains were largely maintained at two-month follow-up. Results provide preliminary evidence that a modified version of the Coping Cat program may be a feasible and effective program for reducing clinically significant levels of anxiety in children with high-functioning ASD.

The limitations of this study include small sample size which recommended statistical and effect size to be interpreted with caution, and also the outcome measures were largely based on parent- ADIS reports by parents who were not blind to the treatment. Also, examining treatment response was limited to the primary author who delivered all of the treatment. Similarly, with waiting list as a comparison, there was a danger of getting placebo effects with the intervention arm, especially with parent-report measures, as most parents were very keen to get any help at all for their children.

Discussion and future perspective

It is clear from the 8 randomised controlled studies that young people on the autistic spectrum benefit from some form of CBT when modified as part of a therapeutic package. Unfortunately it is not clear what specific aspect of the therapy is making the difference. Cognitive Behavioural Therapy has many components to it as well as the actual cognitive, i.e. ‘thinking’ part and behavioural part. Which bit of the therapy is making a difference to the anxiety? Is it the cognitive reframing, the relaxation, the exposure, the parental involvement, or simply the therapeutic relationship with a therapist? As with CBT studies which are delivered as part of a package, positive results are often obtained when there is no control group or when compared to a waiting list.

Other limitation to research papers cited above include fairly small sample sizes, and outcome measures that are normed with a non ASD cohort.

Only 2 studies had non waiting list comparison 32, 34. These studies did show significant clinical improvement in anxiety levels. These studies have shown that CBT can be effective if modified for the ASD population. Many clinics often fail to pick up associated anxiety difficulties in the ASD cohort and if present, often are under the impression that CBT would not work in this population due to misunderstanding and ill informed prejudices about the ASD population. As there is such a high comorbidity with anxiety disorders, young people on the autistic spectrum should be offered effective interventions such as CBT. Research should focus on modifications of the CBT package to enable better engagement and better understanding of the CBT constructs.

Practice Points

  • Children with high-functioning Autism Spectrum Disorder (ASD) are at high risk for developing significant anxiety
  • Anxiety can adversely impact on functioning across school, home and community environments
  • Cognitive Behavioural Therapy (CBT) is frequently used with success for children with anxiety symptoms
  • Standard CBT treatments need modification to address the anxiety difficulties associated with ASD
  • Modified CBT interventions for anxiety in children with ASD have also yielded promising results
Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
HADI SHAKER NAEENI MRCPSych, Bedfordshire CAMHS, UK. TRINISHA GOVENDER MRCPsych, Bedfordshire CAMHS, UK. UTTOM CHOWDHURY MRCPSYCH, Bedfordshire CAMHS, UK.
Corresponding Author Details: 
Dr Hadi Shaker Naeeni, Beech Close Resource Centre, 5 Beech Close, Dunstable LD6 3SD.
Corresponding Author Email: 
hadi.shakernaeeni@nhs.net
References
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Prevalence of Psychiatric Disorders Following Brain Injury

Authors
Nismen Lathif, Emily Phipps, Philip Alton, Devena Tyagi Sharma
Article Citation and PDF Link
BJMP 2014;7(3):a722
Abstract / Summary
Abstract: 

Brain injury is a major cause of mortality and morbidity all over the world and in Europe there is an estimated incidence of 235 brain injury inpatients per 100,000 population. Over the years, the medical care of brain injuries has developed with a resultant fall in mortality. However, with this fall in death rates the proportions of people with complications, especially the neuro-behavioural effects of brain injury, has risen. Of the complications, psychiatric disorders have a significant impact on the patient’s quality of life and rehabilitation prognosis and so are an important consideration from both a care delivery and public health perspective. This paper analyses current literature, demonstrating a high prevalence of psychiatric disorders amongst this patient group. It also demonstrates the significant impact they have on patients, carers and families through an insightful case series. 

Introduction

Brain injury is a major cause of mortality and morbidity all over the world and in Europe there is an estimated incidence of 235 brain injury inpatients per 100,000 population 1. Over the years, the medical care of brain injuries has developed with a resultant fall in mortality. However, with this fall in death rates the proportions of people with complications, especially the neuro-behavioural effects of brain injury, has risen 2. Of the complications, psychiatric disorders have a significant impact on the patient’s quality of life and rehabilitation prognosis3 and so are an important consideration from both a care delivery and public health perspective. This paper therefore aims to analyse the prevalence of psychiatric disorders following brain injury and highlight the practical and personal implications of these through an illustrative case series.

Depression Following Brain Injury

Jorge et al in 20044 conducted a prospective case controlled study on a sample of 91 patients with traumatic brain injury (TBI). Patients with penetrating head injury, spinal cord injury and severe deficits of comprehension was excluded and 27 patients without brain injury but with other trauma was included as controls. The sample was analysed at 3, 6 and 12 months with Present State Examination (PSE), structured clinical interview for DSM1V, and analysed with Mann Whitney and chi squared tests. The results showed that 33% of the TBI group had major depression compared to 22 % in the control group. Neuropsychological testing also demonstrated that depressed patients had a greater degree of impaired cognitive function. An earlier study with a larger sample was conducted by Kreutzer in 20015, studying 722 TBI patients (average time post injury for evaluation 2.5 years). Data was collected via survey, using the Neurobehavioral Functioning Inventory to identify depression; the response was studied by trained neuropsychologists and compared with DSM-IV Criterion for depression. A significant proportion (42%) of survey respondents met the DSM-IV criterion for depression. Fatigue, low concentration and frustration were most commonly reported symptoms. A similar study done by Seel et al in 20036, where 666 TBI outpatients from 17 centres was reviewed using DSM-IV Criterion, showed rates of major depression to be 27%.

Mania Following Brain Injury

Jorge in 19937 reviewed 66 patients with brain injury at 3, 6 and 12 month intervals to evaluate the prevalence of mania. The inclusion criteria was age above 18 years and absence of delirium, no previous history of mood disorder and absence of grave injuries to other areas of the body. Using the Present State Examination to gather data, 9% of the sample had symptoms in correlation with the DSM III criteria for mania.

Van Reekum in 19968 recruited 18 TBI patients attached to a rehabilitation unit for a study to evaluate mental illness in this population. 44% of patients had severe TBI while 56% had mild/moderate TBI; the average duration since TBI was 4.9 years. 27% met the DSM II criteria for bipolar affective disorder and 61% met criteria for depressive illness. The rate of anxiety disorder was 38% but psychosis was not reported.

Psychosis & Other Mental Illness Following Brain Injury

Fann et al in 20049 conducted a large prospective cohort study involving 1939 randomly selected TBI patients 1 year pre injury and 3 years post injury to study rates of psychiatric illness including psychosis. The sample was divided into the moderate/severe TBI and mild TBI compared to matched controls. The presence of psychiatric illness was detected by utilisation of mental health services by subjects, usage of psychotropic medication and presence of a psychiatric diagnosis in the records. Psychotic disorders were seen in 49% of the moderate to severe TBI patient group and for the mild TBI group psychosis was seen in 34% of the sample. This is significantly greater than the rate seen in the control group. However the lack of definitive diagnostic criteria and confounding factors such as social circumstances and other physical health issues which may have strong associations with mental illness were not accounted for.

Another observational prospective study done by Rao et al in 200910 looked into prevalence rates of aggression in the 3 months following brain injury. Overt Aggression Scale was used by trained examiners in the assessment of aggression in a sample of 107 TBI patients. Comorbidities were analysed using General Medical Health Rating scale; psychosocial functioning was analysed by Social Functioning Exam and the Social Ties Checklist. Results showed the prevalence of aggression in the sample to be 28.4% and this subgroup was also associated with new-onset major depression. Only 63% of the already small sample completed the study and the drop out group was unaccounted for; this may negatively impact the results.

Keenan et al in 200811 studied prevalence of attention-deficit hyperactivity disorder(ADHD) in 2782 post TBI children and demonstrated chance of a diagnosis of ADHD two folds higher amongst children with a head injury before age 2. Jellinger in 200412 studied links between brain injury and dementia, and found that although cognitive deficit was associated with brain injury, there was no established link between development of dementia and brain injury. Oquendo et al in 200413 studied 325 depressed patients to analyse the link with mild TBI and suicidal behaviour; 44% of the sample had mild TBI and suicidal behaviour was more common in this subgroup. Suicide Intent Scale and the Lethality Rating Scale was used to measure suicidal behaviour. However, exclusion of moderate to severe TBI and inclusion of only inpatients in this study would affect any generalisability of the results.

Case series: Psychiatric Disorders Following Brain Injury

Case 1- Patient A: Epilepsy, interictal psychosis and organic personality disorder following head injury

Patient A is a 37 year old female under mental health services with a diagnosis of organic personality disorder and interictal psychosis. She suffered from epilepsy from the age of 9 but coped well at school and went on to work successfully as a hairdresser. However, in 1998 at the age of 22 she was admitted to ITU with status epilepticus as a result of encephalitis of unknown cause, and remained severely unwell for several months. She recovered but was left with residual tonic clonic and complex partial seizures.

Since this episode, marked changes in her personality were noted. She developed mood swings with recurrent episodes of low mood, and expressed paranoid beliefs about people in the street talking about her. These beliefs resulted in her being agitated and physically aggressive, resulting in harm to both herself and others. She has required numerous admissions to acute wards and rehabilitation units because of her paranoid and suspicious behaviour and aggressive outbursts that her family were not able to manage in the community. She required restraint under Section 3 of the Mental Health Act in 2010, believing that care staff were poisoning her. Psychotic symptoms are most marked around seizures, with her displaying self harming behaviour such as cutting off hair or painting face with nail polish. She frequently accuses staff and family of acting against her in these periods and her behaviour is very difficult to manage.

Her case has been challenging to manage successfully in the community by family and community teams, and she has needed several short and long term stays in acute wards and residential units. Her care has been coordinated jointly between neurological and psychiatric services. She currently lives with her parents and has carers to support her. Her epilepsy is yet to be successfully controlled; antipsychotics can lower the seizure threshold and so a delicate balance between these and her antiepileptic medication is warranted. There is an on-going concern that further mental health problems may develop in light of this.

Case 2- Patient B: Schizophrenia following head injury

Patient B is a 43 year old female with a diagnosis of schizophrenia, learning difficulties and epilepsy. She suffers from epilepsy in the form of absence and tonic-clonic seizures from the age of 7 months, when there is high suspicion that she sustained a head injury whilst in the care of extended family. Patient B has difficulties with numeracy and literacy, identified through psychological assessment, and an IQ of around 70. She has required three admissions under Section 2 of the MHA due to her paranoid delusions and poor self care. Patient B frequently reports feeling monitored by cameras, suspicions that her food has been poisoned and that her personal belongings are being tampered with. She has attempted to take her own life due to feeling unable to cope with these delusions, laying in the road to be run over by a bus.

She is currently managed well in the community on oral risperidone for her psychosis and sodium valproate for her epilepsy; she resides in supported accommodation and has required stints in long term residential and rehabilitation beds due to her mental health problems and learning difficulties.

Case 3- Patient C:Depression and Personality disorder after head injury

Patient C first came in to contact with psychiatric services in 2007 and was diagnosed with depression and organic personality disorder. At the age of 16 this gentleman was knocked off his bicycle and sustained a severe head injury, from which he was left in a coma for over three weeks, but recovered well enough to go home. In 1994 he started having blackouts, was investigated extensively by neurology, and diagnosed with non-epileptic attack disorder. As part of these investigations, Patient C underwent an MRI which demonstrated significant brain damage including traumatic damage to the frontal lobes. This was likely due to his accident at age 16. From his first assessment by psychiatric services, he eluded to thoughts and behaviours that were of serious concern to his team. He reported feeling emotionally detached from his family, gaining little pleasure from life, getting in to fights frequently and allegedly having stabbed someone in an altercation several years ago. He described to practitioners only getting excitement out of reading and watching programmes about serial killers, and occasionally became sexually aroused by this. He had made extensive written plans on how he would capture, torture and kill the couple he believed were responsible for his accident at 16. He also struggles with auditory command hallucinations telling him to harm himself and others. He frequently self harms, often using a Stanley knife to cut his arms and legs. Patient C has been jointly managed by adult psychiatry and neuropsychiatry on an outpatient basis. His risks of aggression and violence have been carefully managed through regular assessment and involvement of forensic services.

Conclusion:

The literature search indicates that the prevalence of psychiatric disorders in patients with brain injury is much higher compared to general population. The significance of the results are however greatly affected by response bias, the impact of patients’ cognitive impairment on their study participation, observer biases and the small study population sizes; however, we believe that these short-fallings should be seen as a trigger to stimulate more comprehensive and wide-scale research in to this field. The methodologies used by authors described in the literature review demonstrate the wide variance in the tools used to assess psychiatric illness in patients following TBI; we therefore argue that universal case definitions need to be agreed on and implemented to standardise studies and reduce bias. The economic impacts and impacts on quality of life have often been neglected by researchers and warrant formal assessment. From a service delivery perspective, rehabilitation programs need to identify patients with signs of psychiatric illness post TBI earlier and involve psychiatric service in the development of integrated care plans to improve the total outcome and quality of life of the patient. The impact on the patient’s family and carers also need to be explored further to provide an evidence base for more effective and holistic interventions.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
NISMEN LATHIF, Consultant Psychiatrist, Five Boroughs Partnership, Merseyside, UK. EMILY PHIPPS, Foundation Year 2 Doctor, Mersey Deanery, Merseyside, UK. PHILIP ALTON, Medical Student, Liverpool University, Merseyside, UK. DEVENA TYAGI SHARMA, CT1 Psychiatry, Mersey Deanery, Merseyside UK.
Corresponding Author Details: 
Dr Emily Phipps, Royal Liverpool and Broadgreen University Hospital Trust, Prescot Street, Liverpool UK L7 8XP.
Corresponding Author Email: 
emily.phipps87@gmail.com
References
References: 
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  12. Jellinger KA. Head injury and dementia. Curr Opin Neurol 2004;17(6):719-23.
  13. Oquendo MA, Friedman JH, Grunebaum MF, Burke A, Silver JM, Mann JJ. Suicidal behavior and mild traumatic brain injury in major depression. J Nerv Ment Dis 2004;192(6):430-4.

Cholestatic hepatitis: An unusual presentation of lisinopril induced hepatotoxicity

Authors
Gurpinder Singh, Amit Kachalia, Jaspreet Kaur, Kinjal Kachalia, Shaojun Liu and Vincent Rizzo
Article Citation and PDF Link
BJMP 2014;7(3):a721
Abstract / Summary
Abstract: 

Previously published case reports have shown direct hepatocellular injury as the mechanism for lisinopril induced hepatotoxicity. We report case of a 47 year old female who presented with jaundice, diagnosed as cholestatic hepatitis;two years after initiation of lisinopril. Extensive work up was negative for other causes of hepatitis. Liver biopsy showed portal inflammation by lymphocytes without centrilobular necrosis, which is similar to earlier case reports. Discontinuation of angiotensin converting enzyme inhibitors (ACE-I) usually leads to normalization of liver enzymes, however continuation or re-initiation can be potentially fatal.

This is the first reported case of lisinopril induced hepatotoxicity via cholestatic mechanism. Some reports hypothesize a metabolic idiosyncratic reaction as the molecular mechanism but currently there is no validated literature. This case highlights the need for further research to explore mechanisms for ACE-I mediated hepatotoxicity and to create awareness amongst physicians to consider ACE-I as an etiology for drug induced liver injury.

Abbreviations: 
ACE-I: Angiotensin converting enzyme inhibitors; DILI: Drug induced liver injury; AST: Aspartate transaminase; ALT: Alanine transaminase; GGT: Gamma-glutamyl transferase; ALP: Alkaline phosphatase; ANA: Anti nuclear antibody; AMA: Anti mitochondrial antibody; ANCA: Anti-neutrophil cytoplasmic antibody; CKD: Chronic kidney disease
Keywords: 
Angiotensin coverting enzyme inhibitor, Hepatotoxicity, Cholestatic hepatitis, Lisinopril

Introduction:

Various classes of medications have been known to cause drug induced liver injury (DILI), however not much literature has been published regarding angiotensin converting enzyme inhibitors (ACE-I) causing DILI. Recent years have seen tremendous increases in ACE-I prescriptions for coronary artery disease, diabetic nephropathy and hypertension. We report the first case of lisinopril induced hepatitis via a cholestatic mechanism.

Case:

A 47 year old female with history of diabetes mellitus type 2, hypertension, chronic kidney disease (CKD)stage III, non-obstructive coronary artery disease was admitted with complains of generalized weakness, lack of appetite, yellow discoloration of skin and eyes, dark urine and white stools for 1 week prior to admission. She denied history of alcohol abuse, past liver disease, illicit drug use, recent sick contacts, fever, chills, travel. Current patient medications included lisinopril, pioglitazone, furosemide, atenolol, metformin and detemir. Patient was started on these medications about 2 years prior to admission. Patient received enalapril for 5 months before switching to lisinopril about 2 years prior to presentation.

Physical examination was positive for icteric sclera, icteric skin; negative for spider nevi, palmar erythema and asterixis. Exam did not reveal hepatomegaly or splenomegaly. Labs showed hemoglobin 8.7 gm/dl, normal white count and platelet, normal C-reactive protein, alkaline phosphatase (ALP) 750 U/L, aspartate transaminase (AST) 169 U/L, alanine transaminase (ALT) 210 U/L, gamma-glutamyl transferase (GGT) 813 U/L, total bilirubin 13.4mg/dl with conjugated fraction 7.7mg/dl, ammonia level 64. Prior to initiation of lisinopril ALP was 87 U/L, GGT 53 U/L, with AST18 U/L, ALT 11 U/L and normal bilirubin fractions. Hepatitis A, B, C and D serologies were negative. Serum acetaminophen level was normal. Anti nuclear antibody (ANA), anti- mitochondrial antibody (AMA), anti-endomysial antibody, c-anti-neutrophil cytoplasmic antibody (ANCA), p-ANCA was negative. Anti smooth muscle antibody was weakly positive in titre of 1: 40. Creatine kinase, ceruloplasmin and alpha -1 antitrypsin level were normal. Quantiferon gold was negative. Lipid panel was deranged with cholesterol level 1017 and low density lipoprotein 1006, triglycerides 255.

Ultrasonography and magnetic resonance imaging abdomen showed hepatomegaly 17.5cms but was negative for fatty infiltration of liver, stones, cirrhotic features or dilation of biliary tree. Liver biopsy was done which showed mild portal chronic hepatitis with lymphocytic infiltration (Fig: 1), cholestasis (Fig: 2), mild portal fibrosis (Fig: 3), negative for bile duct damage (Fig: 4), negative for cytoplasmic inclusion. Congo red stain was negative for amyloid.


Figure 1: Mild hepatitis with portal tract lymphocytic infiltration.


Figure 2: Cholestasis.


Figure 3: Trichrome stain showing portal tract fibrosis.


Figure 4: Normal bile ducts in portal tract.

Patient was treated with fluids, anti-histaminic, ursodeoxycholic acid. Patient was unable to tolerate coleveselam. Impression was drug induced hepatitis, lisinopril was discontinued and patient improved clinically and biochemically. Discharge labs two weeks after discontinuation of lisinopril showed AST 80 U/L, ALT 70 U/L, ALP 1045 U/L and GGT 1212 U/L; total bilirubin of 3.93 mg/dl with conjugated fraction 2.43mg/dl. Patient was discharged uneventfully with follow up in Hepatology clinic. Six months after discontinuation of lisinopril ALP was 199 U/L, GGT 168 U/L with AST 19 U/L, ALT 17 U/L, total bilirubin 0.9mg/dl and conjugated bilirubin 0.21mg/dl. Patient is currently asymptomatic and icterus has resolved.

Discussion:

ACE-I has been used widely for coronary artery disease, hypertension and diabetic nephropathy and approximately 159 million prescriptions for ACE-I are written annually. Recent JNCC guidelines recommended ACE-I to be used as first line anti-hypertensives for patients with CKD and diabetes. The common side effects known about ACE-I use are cough and angioedema, hypersensitivity. However not much awareness exists regarding ACE-I induced hepatotoxicity. It is important to consider ACE-I as an etiology for drug-induced liver injury (DILI) since continuation of the ACE-I beyond onset of hepatitis is fatal1.

Literature review shows multiple reports of DILI with captopril2, 3, ramipril4, fosinopril5, 6 and enalapril.2,7 Most commonly implicated ACE-I are enalapril and captopril. The usual presentation for ACE-I induced hepatotoxicity is cholestasis mediated hepatitis. Till date there have been four case reports published reporting lisinopril as cause of hepatitis 1, 8, 9 All 4 cases of lisinopril induced hepatotoxicity have shown a hepatocellular pattern of liver injury and did not show any cholestatic features. We report the first case of lisinopril induced cholestasis mediated hepatotoxicity.

In our case, patient had received enalapril for 5 months before initiation of lisinopril; however patient developed symptoms 2 years after initiation of lisinopril. The patient had no past medical history of liver or biliary tract disease. A thorough investigative workup was negative for autoimmune and other viral causes of hepatitis. Older case reports of lisinopril induced toxicity have shown similar histopathological findings of portal inflammation by lymphocytes without centrilobular zonal necrosis.9 There are various theories regarding possible mechanisms for DILI with lisinopril, namely terminal proline ring mediated bile stasis8, 10 and hypersensitivity to the sulfhydryl group.2 Discontinuation of metformin, pioglitazone, furosemide, atenolol and detemir did not result in clinical or biochemical improvement. Patient was initially continued on lisinopril since suspicion was low and then later discontinued. Similarity in histopathological findings along with a strong temporal relationship between lisinopril withdrawal and improved biochemical and clinical scenario, with absence of other constitutional symptoms and eosinophilia strongly point toward lisinopril-induced hepatotoxicity.

Our case had a long period of latency between drug intake and onset of hepatic injury which is consistent with other published reports of lisinopril induced hepatocellular injury9, 10, 11; however the mechanism responsible for latency or hepatotoxicity remains unclear. Earlier report postulate metabolic idiosyncratic reaction as a possible molecular mechanism for hepatocellular injury9. However our case is unique as the primary mode of injury appears to be cholestatic. Since our patient received enalapril before initiation of lisinopril without any adverse events, this case adds further controversy as to whether this patient could have been safely continued on other ACE-I except lisinopril or whether she would have developed hepatotoxicity if enalapril was continued. This case highlights further need for research to evaluate ACE-I induced hepatotoxicity. Currently the awareness for ACE-I induced liver injury is low and there are no guidelines guiding physician to monitor for possible hepatic adverse events. Further research is needed to delineate the mechanism by which ACE-I cause hepatotoxicity and to define possible risk factors.

Conclusion:

Discontinuation of ACE-I beyond recognition of DILI hepatitis usually leads to normalization of liver enzymes, however continuing or reinitiating ACE-I can be severe and potentially fatal. Thus, it is important to be aware of ACE-I as a possible cause of DILI, which can present with either hepatocellular or cholestatic mechanism and to promptly discontinue ACE inhibitor use. Currently there are no guidelines in place for monitoring of liver enzymes following initiation of ACE-I and more research is required to delineate possible mechanisms and prevent further DILI in such patients.

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
None
Competing Interests: 
None
Details of Authors: 
GURPINDER SINGH, MD MBBS PGDHHM. Icahn School of Medicine at Mount Sinai Queens Hospital Center, 82-68 164 street, Jamaica, NY-11432, USA. AMIT KACHALIA, MD MBBS.Icahn School of Medicine at Mount Sinai Queens Hospital Center, 82-68 164 street, Jamaica, NY-11432, USA. JASPREET KAUR, MBBS. Icahn School of Medicine at Mount Sinai Queens Hospital Center, 82-68 164 street, Jamaica, NY-11432, USA. KINJAL KACHALIA, DNB MBBS.Icahn School of Medicine at Mount Sinai Queens Hospital Center, 82-68 164 street, Jamaica, NY-11432, USA. SHAOJUN LIU, MD. Icahn School of Medicine at Mount Sinai Queens Hospital Center,82-68 164 street, Jamaica, NY-11432, USA. VINCENT RIZZO, MD MBA, FACP. Icahn School of Medicine at Mount Sinai Queens Hospital Center,82-68 164 street,Jamaica, NY-11432, USA.
Corresponding Author Details: 
GURPINDER SINGH, Icahn School of Medicine at Mount Sinai Queens Hospital Center, 82-68 164 Street, Jamaica, NY 11432, USA.
Corresponding Author Email: 
drgurpinder@yahoo.co.in
References
References: 
  1. Larrey D, Babany G, Bernuau J, et al. Fulminant hepatitis after lisinopril administration. Gastroenterology. 1990; 99:1832–3.
  2. Shionoiri H, Nomura S, Oda H, et al. Hepatitis associated with captopril and enalapril but not with delapril in a patient with congestive heart failure receiving chronic hemodialysis. CurrTher Res. 1987; 42:1171–6.
  3. Schattner A, Kozak N, Friedman J. Captopril-induced jaundice: report of 2 cases and a review of 13 additional reports in the literature. Am J Med Sci 2001; 322:236–240.
  4. Douros A, Kauffmann W, Bronder E, et al. Ramipril-induced liver injury: case report and review of the literature. Am J Hypertens. 2013 Sep;26(9):1070-5.
  5. Nunes AC, Amaro P, Mac AF, et al.Fosinopril-induced prolonged cholestatic jaundice and pruritus: first case report. Eur J GastroenterolHepatol 2001; 13:279–282.
  6. Chou JW, Yu CJ, Chuang PH, et al.Successful treatment of fosinopril-induced severe cholestatic jaundice with plasma exchange. Ann Pharmacother. 2008 Dec;42(12):1887-92.
  7. Da Silva GH, Alves AV, Duques P, et al. Acute hepatotoxicity caused by enalapril: a case report. J Gastrointestin Liver Dis. 2010 Jun;19(2):187-90.
  8. Hillburn RB, Bookstaver D, Whitlock WL. Angiotensin-converting enzyme inhibitor hepatotoxicity: further insights. Ann Pharmacother. 1993; 27:1142–3. Letter.
  9. Zalawadiya SK, Sethi S, Loe S, et al. Unique case of presumed lisinopril-induced hepatotoxicity. American Journal of Health-System Pharmacy August 15, 2010 vol. 67 no. 16 1354-1356.
  10. Hagley MT, Hulisz DT, Burns CM. Hepatotoxicity associated with ACE inhibitors. Ann Pharmacother. 1993; 27:228–31.
  11. Droste HT, de Vries RA. Chronic hepatitis caused by lisinopril. Neth J Med. 1995; 46:95–8.

BJMP June 2014 Volume 7 Number 2

BJMP June 2014 Volume 7 Number 2

Full Issue Booklet   PDF
Case Reports/Series
Medical Images
Tracheo esophageal fistula
M Suresh Babu, Deepak Suvarna, Chandrashekhar Shetty and Aditya Nadella
Full Text  PDF
The twitching leg
Jose A Egido and Ana M Garcia
Full Text  PDF
Spotted Bone - A Spot Diagnosis
Abdul Rehman Arshad, Asif Rahman, Shafqat Hussain
Full Text  PDF
Miscellaneous

“Of Psychosis" - A Poem by Dr Javed Latoo

Authors
Javed Latoo
Article Citation and PDF Link
BJMP 2014;7(2):a719
Abstract / Summary
Abstract: 

This poem was written with the intention of increasing awareness of psychosis amongst the medical fraternity and general public.  It is written in jargon free English language and highlights the important features of this medical condition.

When our beautiful mind feels all muddled up

   With a tendency to draw bizarre conclusions;

When the difference between a reality 

   And an imagination becomes all blurred. 

 

When one hears people, hears things, hears a god,

     That can't be explained. When one sees images, 

Sees aliens, sees prophets, that can't be accounted for. 

       When one smells, tastes, feels things that can't be untangled.

 

When one worries about other's intentions,

   Their innocent words, their innocent actions; 

When one is preoccupied with a belief 

   That they are not driving their body or their mind.

 

When one holds an inflated view

    Of being able to communicate with aliens, 

Of possessing powers to heal, 

   Of being a royal, of being able to control the weather.

 

When the energy of youth is replaced by 

    A lack of motivation, an idleness, an apathy.

When one ignores daily personnel cleanliness, 

   Daily chores, daily social interactions.

 

When you are in this perplexed state of mind 

    Remember it is an illness called psychosis, 

 Not a curse or black magic or witchcraft.

    Remember, treatment is available, from the experts who care.

 

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
JAVED LATOO MBBS DPM MRCPsych, Consultant Psychiatrist and Honorary Lecturer, 5 Borough Partnership NHS Foundation Trust, Warrington, United Kingdom.
Corresponding Author Details: 
Dr JAVED LATOO MBBS, Consultant Psychiatrist, 5 Borough Partnership NHS Foundation Trust, Hollins Park, Hollins Lane, Warrington, United Kingdom.
Corresponding Author Email: 
javedlatoo@gmail.com

A Very Important Doctor

Authors
Francis J Dunne
Article Citation and PDF Link
BJMP 2014;7(2):a720

Once upon a time there lived a quite wealthy young man - in the sense that he was quite smug and comfortable, never really wanting for anything. ‘Wealthy people don’t have to concern themselves about others or indeed material matters, he used to say to himself, blissfully unaware of the dramatic irony in his statement. He had tons of clothes (which made it difficult to decide what to wear each day), lived on his own in a big house almost the size of a mansion, went on lots of holidays to exotic places, ate in the best restaurants, and by all accounts had no worries whatsoever. He was a man of modest intelligence, quite tall and stout with an arrogant (or should I say confident) manner. He could quite easily win an argument because he would literally wear his opponent down with the ferocity of his delivery, even though it bore little substance. 'I could be a politician because I am so good at debating sensitive issues which affect ordinary people, he would reflect when on his own, which was frequent.

His parents had so much money (from their banking business) to fritter away and therefore had no trouble finding him a suitably big house (almost as large as a mansion as stated) in a fashionable area of London. He also owned a house in Richleymanor, a wealthy, prosperous suburb of Richleyshire.  ‘Because I have no worries and am in perfect health', he said when he was only 16, 'I am going to become a doctor and heal people who are not rich enough to see me privately and who are a million times less fortunate than me.'  Such was his altruistic spirit. And so he studied as hard as he could because he had to (he was not the brightest card in the pack). With the help of his parents' influential circle of friends in the whole of Richleyshire who knew people in high places, he managed to secure a place in an elite medical school where only top doctors were trained - even though he did not possess any outstanding qualifications on leaving school. But that sort of thing doesn’t really matter if you possess an altruistic spirit. 'I mean', he reasoned, – 'Lots of famous people (including entrepreneurs) did not pass their final school year exams with Honours and I am just like them in that respect - really down-to-earth, a man of the people.'

On the first day of entry to the Royal Breedington University Medical School he was already planning his future career. Not for him the humdrum life of a family doctor. No - he was aiming for prestige and acclaim. He did not need the money though extra money would help 'because you can never have enough, especially if you want to help others less fortunate than yourself', he would say to himself. Such was his determination. 'Should I become a great brain surgeon', he pondered one evening. Should I become an eminent cardiologist or a revered obstetrician? You see, for him it was not enough to be an ordinary doctor - one had to be special in some way. These careers and others (the field of Medicine is huge) he considered. Then one day he decided: 'I know now what to do'; I will get my basic qualifications out of the way and then embark on a career in Mentalology - a subject which was gaining great interest in the popular press. Even students at the University were talking about it. It was a higher degree than Neurodevelopmental Psychobabble (another much sought-after career, normally the reserve of doctors studying cerebrotherapy). So after lots and lots of postgraduate courses in Mentalology he finally passed the higher degree, becoming a member of the Royal College of Mentalologists (MRCM), spent 5 more years in training and became a Consultant Mentalologist at a very prestigious hospital, one which had links to a university, as it happened. His ultimate ambition was to become a Doctor in Medical Politics because he wanted to be in charge of doctors and patients but without the encumbrance of having to care for patients per se or to actually meet doctors. Not for him the drudgery of life in a hospital or general practice – no - one needs to earn as much as possible by doing the least work, rather like Business Executives, he would ruminate.

Initially he enjoyed seeing a few patients here and there as par for the course, but because he felt he was a very important doctor, he needed to move up the ladder to the higher echelons, managing other doctors who might in turn benefit from his great wisdom and enormous insight, accrued in just 8 years training! He decided that he was too important to be seen hanging around hospital wards or in the outpatient department and so spent nearly all his time in the library and at meetings, apart from breakfast and lunch. He always had breakfast in the hospital canteen to show he had the common touch, and sometimes he would make a point of staying on longer after lunch in order to mix with other not-so-important doctors, who would laugh and grovel obsequiously at his every spoken word. Then suddenly he was off, and would be seen bustling and rushing through the canteen doors on his way to a very important event at the prestigious headquarters of the Organization, where he would sit three seats away from the Lord High Superexecutive Chief of the Organization (LHSCO), a very long title indeed but when one is important one usually has imposing if not long titles. Such was the circle the very important doctor was mixing, it explained why he was hardly ever seen in the hospital outside lunch hours or breakfast. Because, you see, in his estimation or rather esteemed opinion, if one is not around much then one must be a very important person indeed.

Sometimes he was seen rushing off to other very important meetings at a top-class hotel where there would be a special Conference Room; sometimes he was at meetings all day. However, often it was difficult to find out exactly what he was doing or where he was because many of the meetings were high level top-secret meetings; for example, a Superexecutive meeting lasting a whole hour might have on the agenda a motion to close down the hospital outpatient department because patients were costing the Organisation too much money. That superfluous-to-requirements money could be better spent on holidays and pay rises for other but not-so-important medical chums as well as serious-minded managers who in turn might do him a favour later on. 'You never know what's around the corner', he always used to say in one of his contemplative moments. The Organization often talked about very big issues such as Doctor Management Downcasting (how to keep those grasping medics in line) and Patient Empowerment, even though patients were never included in any discussions about where they would go when their hospital closed down.  Sometimes meetings would extend until the early hours of the morning, which suited the very important doctor because he had no family to worry about or other personal commitments and could come and go as he pleased. Others had to stay on at the very important meetings regardless of their personal circumstances. Sometimes he was so exhausted attending meetings he would spend the following afternoon on the golf course relaxing before attending another evening conference. 'I don't know how he does it', his reverential colleagues would mutter, in hushed tones. 'He deserves another award for taking time off to recharge his batteries for the next meeting'. 'It is quite astonishing how much energy some people have', he would say contentedly to himself.' 'What would the Organisation do without someone of my great leadership skills’?, he asked himself many times in a semi-congratulatory tone.

Nothing would deter the very important doctor from achieving his goals and pleasing the Organisation. After all, this was the way to the top of the medical hierarchy – Doctor of Medical Politics (DMP) and Chief Scientist and Supervisor of the Faculty of Mentalology (CSSFM for short) was his goal. First he set out some decrees or edicts. These would all come under the rubric 'Management Directives', or put in another way, informing his colleagues in a polite but firm manner how he would  delegate them to do ‘this and that', and therefore no one would blame the very important doctor for say, dismantling any part of the service; besides, his sheer tenacity and doggedness (character traits which he had cultivated from his seniors) gained him further admiration from the legions of subdoctors (doctors who were under his control) who had to yield to his commands. He would sometimes act very humble when questioned about his ruthless tactics and would feign innocence (or was it impotence) in the face of criticism. No, it was the Organization 'calling the shots', as he used to describe it, callously ignoring the plight of his colleagues and patients.

It was strange that he could never recall or at least did not seem to know any of the names of people in the Organization who were responsible for the targets to be achieved. 'Anyway, most patients are not really ill, they just complain and they can jolly well go back to their own general practitioner if they want to bother someone', he would argue in one of his rare insights into the human condition, particularly when colleagues challenged him. His doctor 'associates' (he could never really truthfully call them friends) were stupefied by his perspicacity and visionary zeal and were in no doubt that in order to achieve a change in their practice it was better they were paid less and worked more intensely between 9am and 5pm. They could come in earlier or stay later if they wanted to of course, but no extra money was available for overtime because it was costing the Organization thousands of pounds annually. Best to give the bonuses to those who really deserved them - those Manager Doctors who were extremely busy writing protocols about Best Practice and Risk Assessments - real life-and - death issues, and spending at least 4 hours every six months at very special high-powered meetings drafting 'outcome protocols'. So many emails to send out. This agenda was 'all in a day's work' for the very important doctor who needed to supervise this superhuman task in between meals.

But even the very important doctor himself needed resources and time to carry out all this work. 'I know what', he said to himself one bright sunny Sunday morning on the golf course, -  'I will reduce the amount of time doctors spend seeing patients and cut costs further in this way for all those dedicated doctors because dedication is costing too much'. One hospital in-patient could cost the Organization £1000 a week, even more. 'The doctors can still attend meetings in the hospital (no costs incurred) and do extra administrative work.' 'The bonuses will only go to those who have achieved a special distinction in doing the work of Managers and follow the party line'. 'Yes, that's the way forward', he thought to himself, in one of his rare flashes of brilliance. 'From now on doctors will only have to work 9-5pm'. 'The on-call commitments can be covered by NHS Indirect', the latter being a new company set up to replace doctors and nurses at night-time and weekends, usually manned by staff from one of the local supermarkets. Surgeons would be then free to down tools at 5pm instead of wasting time (and the Organization's money) battling through endless hours of unnecessary exhaustive operations such as cardiac bypasses or hip replacements, which could easily be carried out in the patients' homes anyway. Psychobabble experts could use tick-box rating scales or instruments to assess new referrals (no need to see patients, too costly).

 There is no way to describe the tumultuous reception these ideas received at the Managers Annual Conference in Bristol, and the very important doctor received even more accolades. In fact, he was considered for a Rhodium Medal, the highest award in the land given to any doctor. Before being conferred with this precious and prestigious medal (because it can only be worn around your neck, or else it lies on the mantelpiece where nobody really notices it) he was given two lots of pay rises - one for services to the Organisation, the other for keeping the common grasping subdoctors in line by forcing them to sign in and out of work every day and by reducing their salaries. After all, there were rumours that the grasping, greedy subdoctors were beginning to think that perhaps the very important doctor was becoming too very very important. But they kept quiet in any event.

His great achievement was the setting up of SCRAP (Strategic Commission for Rapid Abolition Programme) which set out a one-year plan of how to prevent any patient being seen by a doctor. The patient could be seen by any number of people, from the tea lady to the hospital porter, who were already working flat out on the minimum wage. At least they were not so expensive to keep on the pay roll. The next brilliant idea he concocted was to replace the word 'patient' with 'customer'. 'Patient', he did not like. It gave the impression that someone was ill and needed to see a doctor. But with the New Opinion About Hospital Patients (NOAHPS in short) charter, the word 'patient' did not fit the profile of an enterprising Organisation and so NOAHCS (New Opinion About Hospital Customers) sounded much better. All staff were thence ordered to use this terminology or face the consequences. It was rumoured that it was a sacking offence to use the word patient. He even sent an email to the same effect around the whole Organisation. No one spoke out for fear of reprisal and possible instant dismissal. He was applauded at every Organization meeting from that time on and was rewarded by being given Freedom of the Hospital. This meant he did not have to do anything really - just walk around shaking hands with everybody, telling them what a great job they were doing, and so forth. He used the phrase 'Congratulations on a job well done' as many as four times a day to different staff in the hospital. In private he would be irritated because he had to praise other people for what he truly believed were his achievements.

By the end of each week he was so exhausted from sitting on comfortable chairs (some were so comfortable it was a real effort to get out of them) at the many meetings he attended that he would fly off to some far away country for a rest, though of course would endeavour to find out how that country dismantled its health service. Because of his enterprising attitude on behalf of the Organization these trips would be paid for and the very important doctor would not have to spend a penny. 'I deserve it because of all the hard work I am putting in', he used to say, to justify his huge salary and the enormous expenses paid for by the Organization. 'They obviously think very highly of me.' Besides, they know I would get a better salary elsewhere if they did not pay me such gigantic sums of money here', he would rationalise. But this suits me for the time. I have a big house in London near the University and an even bigger house in Richleyshire where I can play golf on the weekends and charge all my expenses to the Organization, even the Golf Club fees. 'Why not? Politicians were doing it', he would argue, in a rare utterance of cognitive dissonance (or pangs of conscience others might think) a term he had picked at one of the many important half-hour psychology conferences he attended (he was much too busy to stay to the end of any conference.

As time passed he was beginning to think he needed a higher salary because time off and holidays were costing him money (domestic shopping, clothes, food, heating bills) despite the freebies. During his days off he would spend lots of time going to museums, visiting the theatre, eating in expensive restaurants and staying in luxury hotels not too far from home, say 10 miles or less. However, for him a real holiday was travelling abroad in a first class seat on a prestigious airline to faraway places. This gave him an edge over his less wealthy colleagues and he would often spend hours on his return recounting his great adventures and experiences abroad in exotic lands. 'He is so broadminded and well-travelled', his managerial associates would say with a feeling of unrequited envy.  It is quite remarkable how he manages to be in so many places at the same time - if only he could do the same at this hospital, we would be top of the League Tables for Hospital Risk (LTHR) and gain the recognition we deserve'. 'For all his hard work spent travelling abroad researching better ways of closing down wards and hospitals he now deserves a huge rise in salary'.

And so it came to be. The very important doctor was given an extra allowance (EA for short) worth half his salary and a Credit for Working Hard Allowance (CWHA), both linked to his pension. He was also given a bonus allowance (BA) for sitting twice yearly on a Doctors Work Review Panel (DWRP) set up to deal with those doctors who were not pulling their weight or taking more than one day sick leave or 2 days annual leave at a time. Study leave had already been dropped because the very important doctor argued that if he did not need study leave then no one else did. Besides, ‘Who needs study leave when you can look things up on the internet – even how to carry out open heart surgery’. He would argue. Commitment to the Organization was his raison d'être.

And so it continued. After 10 years nearly all the patients had been discharged from the hospital and family doctors were sending them elsewhere into more luxurious, expensive, private hospitals for 'reviews, assessments, and second, third, even fourth opinions'. The Organization would pay for all this from the money it saved closing down the local hospital. This was the very important doctor's finest hour and for his services to the Organization he was awarded the Rhodium Medal at the Annual Convention of Supermanagers Conference. This award was inevitable, given all the time both home and abroad he had invested in this venture. Now the entire hospital could be closed down thereby saving the Organization millions of pounds.

However, there was a problem with this way of operating, he began to think: ‘If the hospital were to close down there would be no need for an Organization to run it.  There would be no management posts and my post as MDP and CSSFM might be superfluous to requirements. 'I know what I will do' - he decided - 'When that happens I will apply for another post in a different Organisation and I am sure I will be successful given all the accolades I have received, and when that Organisation closes down with my help I will get an even bigger salary and move on to the next post'  -   maybe Minister for Health?

To be continued 

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
FRANCIS J DUNNE, FRCPsych, Consultant Psychiatrist and Honorary Senior Lecturer, University College London, North East London Foundation Trust, United Kingdom.
Corresponding Author Details: 
FRANCIS J DUNNE, FRCPsych, Consultant Psychiatrist and Honorary Senior Lecturer, University College London, North East London Foundation Trust, United Kingdom.
Corresponding Author Email: 
francis.dunne@nelft.nhs.uk
References
References: 

None

Extended spectrum beta lactamase positive uropathogenic E. coli - Epidemiological Factors and Resistance

Authors
Priya Datta, Varsha Gupta and Shailpreet Sidhu
Article Citation and PDF Link
BJMP 2014;7(2):a718
Abstract / Summary
Abstract: 

Introduction: There is increasing incidence ofESBL producing E. coli causing community urinary tract infections.The primary objective of this study was to study the epidemiological factors associated with ESBL (Extended spectrum beta lactamases) positive community acquired uropathogenic E. coli isolates and to determine their susceptibility to newer oral drugs including mecillinam.
Materials & Method: In this prospective study, from total of 140 community isolates of E. coli causing UTI, ESBL was detected by CLSI criteria. Drug susceptibility was done by Kirby-Bauer method disc diffusion method for various oral antimicrobial agents. Various epidemiological factors associated with ESBL for each patient were recorded on individual forms. This included age, presence of diabetes mellitus, renal calculi, pregnancy, history of urinary instrumentation, recurrent UTI and antibiotics intake.
Results: Out of total of 140 strains of E. coli, which were screened for ESBL production, 30 (21.4%) isolates were positive. High-level resistance 94 (70%) was seen for many antimicrobial agents. Only 4.5% of uropathogenic E. coli were resistant to Mecillinam. Various epidemiological factors associated with ESBL causing infections were female patients, H/o antimicrobial intake, elderly age > 60 years, renal calculi and H/o recurrent UTI.
Conclusions: The epidemiology of ESBL positive uropathogenic E. coli is becoming more multifaceted.

Abbreviations: 
ESBL( Extended spectrum beta lactamases), UTI( Urinary tract infection)
Keywords: 
ESBL, Community UTI, E.coli, epidemiology

Introduction

Community acquired urinary tract infection (UTI) due to Escherichia coli is one of the most common form of bacterial infections, affecting people of all ages. Originally ESBL (extended spectrum β-lactamases) producing E. coli was isolated from hospital setting but lately this organism has begun to disseminate in the community.1

In India community presence of ESBL producing organisms has been well documented. However, various epidemiological factors associated with ESBL producing strains need to be documented. This will allow clinicians to separate patients with community UTI with these factors so that appropriate and timely treatment can be given.A community UTI when complicated may be a potentially life-threatening condition. In addition, for deciding the empirical treatment for patients with a UTI a thorough knowledge of local epidemiology is required. Therefore, the primary objective of this study was to determine the epidemiological factors associated with ESBL positive community acquired uropathogenic E. coli isolates and to determine their susceptibility to newer oral drugs. Mecillinam is a novel β-lactam antibiotic that is active against many members of family Enterobacteriaceae. It binds to penicillin binding protein (PBP 2), an enzyme critical for the establishment and maintenance of bacillary cell shape. It is given as a prodrug that is hydrolyzed into active agent. It is well tolerated orally in the treatment of acute cystitis.3

Material and Methods

This prospective study was conducted, from Jan 2012- July 2012, in our tertiary care hospital, which caters to medical needs of the community in North India.

Study Group:

The study group included patients diagnosed as having a UTI in outpatient clinic, or the emergency room or patients diagnosed within 48 hrs after of hospitalization. These patients and were labeled as patients having a community UTI. A diagnosis of symptomatic UTI was made when patient had at least one of the following signs or symptoms with no other recognized cause: fever ≥ 38.8˚C, urgency, frequency, dysuria or suprapubic tenderness and a positive urine culture (i.e. ≥10microorganisms/ml of urine).Various epidemiological factors for each patient were recorded on individual forms. This included age, presence of diabetes mellitus, renal calculi, pregnancy, history of urinary instrumentation, recurrent UTI (more than 3 UTI episodes in the preceding year) and antibiotics intake (use of β-lactam in the preceding 3 months).2

Patients with a history of previous or recent hospitalization were excluded from study.

Antibiotic susceptibility testing was carried out following Clinical Laboratory Standards Institute (CLSI) guidelines using the Kirby-Bauer disc diffusion method.The antibiotics, which were tested included Amoxyclav (30/10µg), Norfloxacin (10µg), Ciprofloxacin (5µg), Tetracycline (30µg), Nitrofurantoin (300µg), Trimethoprim-sulfamethoxazole (23.75/1.25µg), Cephalexin (30µg), Cefaclor (30µg), Cefuroxime (30µg), Mecillinam (10µg) (Hi-Media, Mumbai, India).

Detection of ESBL

ESBL detection was done for all isolates according to latest CLSI criteria.5

Screening test - According to latest CLSI guidelines, zone diameter of E. coli strain for Ceftazidime <22mm and for Cefotaxime < 21mm is presumptively taken to indicate ESBL production.

Confirmatory test - As per CLSI guidelines, ESBLs were confirmed by placing a disc of Cefotaxime and Ceftazidime at a distance of 20mm from a disc of Cefotaxime /Clavulanic acid (30/10µg) and Ceftazidime/Clavulanic acid (30/10µg) respectively on a lawn culture of test strain (0.5 McFarland inoculum size) on Mueller-Hinton agar. After overnight incubation at 37° C, ESBL production was confirmed if there was a ≥5mm increase in zone diameter for either antimicrobial agent tested in combination with Clavulanic acid versus its zone when tested alone

Control strain - Standard strain of Klebsiella pneumonia ATCC 700603 was used as ESBL positive controland Escherichia coli ATCC 25922 was used as ESBL negative control.

Results

Out of total of 140 strains of E. coli, which were screened for ESBL production, 30 (21.4 %) isolates were found to be positive. High-level resistance was seen for many antimicrobial agents like Cephalexin (92.8%), Cefaclor (90%), Amoxy-clavulanate (88.57%), Cefuroxime (75.7%), Sulfamethoxazole-trimethoprim (72.8%), Norfloxacin (75.71%) and Ciprofloxacin (70%). Sensitivity to Nitrofurantoin was found to be 90%. Only 4.5% of uropathogenic E. coli were resistant to Mecillinam.

Various epidemiological factors seen in ESBL producers include female patients (n =24, 80%), history of antimicrobial intake (n = 17,57 %), elderly age >60 years (n =16 53%), renal calculi (n =15, 50%), history of recurrent UTI (n =11, 37 %), pregnancy (n = 11,37%), diabetes mellitus (n = 7, 23%) and history of urogenital instrumentation (n = 7, 23%).

Discussion

The epidemiology of ESBL positive uropathogenic E. coli is becoming more multifaceted, with increasingly indistinct boundaries between the community and hospital.6 In addition, infection with an ESBL producing organisms causing community UTI is associated with treatment failure, delayed clinical response, higher morbidity and mortality. These organisms are multi-resistant to other antimicrobials like Aminoglycosides, Quinolones and Co-trimoxazole. Therefore, empirical therapy with Cephalosporins and Fluoroquinolones often fail in patients with community UTI.7

The rate of ESBL producers in our study is lower than that described by other authors. In a similar study Mahesh E et al. reported higher rate (56.2%) of ESBL positivity from E. coli, which were causing UTIs from a community setting.8 Additionally Taneja N et al. described a higher rate (36.5%) of ESBL positivity in uropathogens. 9,10

A high rate of resistance was seen to almost all antimicrobial agents. This is in agreement with other authors like Mahesh et al. and Mandal J et al.8,11 Mecillinam showed very good results with only 4.5% resistance. Wootton M et al. reported similar high activity of Mecillinam against E. coli(93.5%).3 Auer S et al. reported that Mecillinam can be a good oral treatment options in patients with infections due to ESBL organisms.7

A limitation of our study was that being a developing country with limited resources, molecular typing and determination of antimicrobial resistance profiles of the isolates was not done. In our study female patients, elderly, patients with a history of antimicrobial intake, renal calculi and history of recurrent UTI were important factors for infection due to ESBL producers. These findings are similar to risk factors studied by other authors.2 In conclusion; this study confirms that ESBL-producing E. coli strains are a notable cause of community onset infections especially in predisposed patients. The widespread and rapid dissemination of ESBL-producing E. coli seems to be an emerging issue worldwide. Further clinical studies are needed to guide clinicians in the management of community onset infections caused by E. coli.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
PRIYA DATTA, MD, Assistant Prof, Dept Of Microbiology, Govt Medical College Hospital, Sec 32, Chandigarh, India. VARSHA GUPTA, MD DNB, Professor, Dept Of Microbiology, Govt Medical College Hospital, Sec 32, Chandigarh, India. SHAILPREET SIDHU, MD, Senior Resident, Dept Of Microbiology, Govt Medical College Hospital, Sec 32, Chandigarh, India.
Corresponding Author Details: 
DR SHAILPREET SIDHU, Senior Resident, Dept Of Microbiology, Govt Medical College Hospital, Sec 32, Chandigarh, India.
Corresponding Author Email: 
shailpreet78@hotmail.com
References
References: 
  1. Rodríguez BJ,  Alcalá CJ, Cisneros MJ, Grill F, Oliver A, Juan P et al. Community Infections Caused by Extended-Spectrum β-Lactamase-Producing Escherichia coli. Arch Intern Med. 2008; 168: 1897-1902.
  2. Azap OK,  Arslan H, Serefhanoglu K, Colakoglu S, Erdogan H, Timurkaynak F et al. Risk factors for extended-spectrum  β -lactamase positivity in uropathogenic Escherichia coli isolated from community-acquired urinary tract infections. Clin Microbiol Infect .2010;16: 147-51.
  3.  Wootton M, Walsh TM, Macfarlane L, Howe R. Activity of mecillinam against Escherichia coli resistant to third-generation cephalosporins. J Antimicrob Chemother. 2010; 65: 79-81.
  4. Dong SL, Chung BL, Seung-JL. Prevalence and Risk Factors for Extended Spectrum Beta-Lactamase-Producing Uropathogens in Patients with Urinary Tract Infection. Korean J Urology. 2010; 51:492-7.
  5. Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing: Twenty First Informational Supplement M100-S21. CLSI, Wayne, PA, USA, 2011.
  6. Nesher L, Novack V, Riesenberg F, Schlaeffer F. Regional community-acquired urinary tracts in Israel; diagnosis, pathogens, and antibiotics guidelines adherence: A prospective study. International J Infect Dis 2007; 11:245-50.
  7. Auer S, Wojna A, Hell M. Oral Treatment Options for Ambulatory Patients with Urinary Tract Infections Caused by Extended-Spectrum beta-Lactamase-Producing Escherichia coli. Antimicro Agents Chemo. 2010,54: 4006-8.
  8. Mahesh E, Ramesh D, Indumathi VA, Khan MW, Kumar PS, Punith K. Risk Factors for Community Acquired Urinary Tract Infection caused by ESBL-producing Bacteria. J Indian acad  clinl med.. 2010; 11:271-6.
  9. Taneja N, Rao P, Arora J, Dogra A. Occurrence of ESBL & Amp-C β-lactamases & susceptibility to newer antimicrobial agents in complicated UTI. Indian J Med Res 2008; 127: 85-8.
  10.  Taneja N, Singh G, Singh M, Madhup S, Pahil S, Sharma M .High occurrence of bla CMY-1 Amp C lactamase producing Escherichia coli in cases of complicated urinary tract infection (UTI) from a tertiary health care centre in north India. Indian J Med Res 2012; 136: 289-91.
  11.  Mandal J, Acharya NS, Buddapriya D, Parija SC.Antibiotic resistance pattern among common bacterial uropathogens with a special reference to ciprofloxacin resistant Escherichia coli. Indian J Med Res 2012; 136: 842-9.

Tracheo esophageal fistula

Authors
M Suresh Babu, Deepak Suvarna, Chandrashekhar Shetty and Aditya Nadella
Article Citation and PDF Link
BJMP 2014;7(2):a717
Abstract / Summary
Abbreviations: 
TEF - Tracheoesophageal fistula
Keywords: 
TEF - Tracheoesophageal fistula

A 40 year old patient presented to the hospital outpatient department with one year history of cough, choking sensation following swallowing, hoarseness of voice and loss of weight. History revealed his previous hospital admission 1 year back for management of organophosphorus poisoning during which he was intubated and put on mechanical ventilator for 10 days. Patient developed the symptoms a month after his discharge from the hospital. Cranial nerve examination was within normal limits. What is the possible diagnosis?

  1. Gastro-oesophageal reflux disease
  2. Tracheo-oesophageal fistula
  3. Oesophageal diverticula
  4. Oesophageal rupture


Fig 1: Barium swallow illustrating a dilated oesophagus and the TOF with resultant contamination of the trachea and bronchial tree


Fig 2: Oesophagoscopy showing TOF

Correct answer:

2. Tracheo-oesophageal fistula

Discussion:

A tracheo-oesophageal fistula (TOF) is a communication between the trachea and oesophagus which can be congenital or acquired. Congenital and acquired TOFs are associated with multiple complications, including poor nutrition, recurrent pneumonia, acute lung injury, acute respiratory distress syndrome, lung abscess, bronchiectasis from recurrent aspiration, respiratory failure, and death. Acquired TOFs occur secondary to malignant disease, infection, ruptured diverticula, and trauma.1, 2 Acquired TOFs are quite rare, and incidence rates have not been well documented. Post intubation TOFs uncommonly occur following prolonged mechanical ventilation with an endotracheal or tracheostomy tube. TOFs caused by endotracheal tube intubation depend on several factors, including prolonged intubation, an irritating or abrasive tube, and pressure exerted by the cuff. Pressures exceeding 30 mm Hg can significantly reduce mucosal capillary circulation and result in tracheal necrosis. Cuff pressure is particularly risky when exerted posteriorly against a rigid nasogastric tube in the oesophagus. Poor nutrition, infection, and steroid use cause tissue alteration, which predisposes patients for the development of TOFs. As a result of laryngeal bypass, spillage of oesophageal contents occurs into the trachea. Saliva, food and gastric juice contaminate the airways. This leads to congestion, infection, pneumonia, bronchial obstruction, atelectasis and respiratory distress. The severity of contamination depends on the width and length of the fistula as well as the posture of the patient. Spontaneous closure of non-malignant TOFs is exceptional.

Patients with acquired TOFs have high mortality and morbidity rates because of critical illnesses and co-morbidities. Acquired TOFs may occur in individuals of any age, and elderly individuals are at increased risk if they become ventilator dependent because of respiratory failure. Acquired TOFs can be diagnosed by instillation of contrast media into the oesophagus (Fig.1) or during direct visualization by flexible oesophagoscopy (Fig.2) or bronchoscopy. A high index of suspicion is needed to diagnose tracheo-oesophageal fistula in a post intubated patient presenting with symptom of cough following deglutition. Since acquired TOFs do not close spontaneously, surgical repair is needed if the patient is stable enough.3, 4 Critically ill patients are managed conservatively until stable enough for a major surgical procedure.

Typical oesophageal symptoms of gastro-oesophageal reflux disease include heartburn, regurgitation and dysphagia. The classic presentation of spontaneous oesophageal rupture is chest pain and subcutaneous emphysema after recent vomiting or retching (Mackler’s triad) in a middle-aged man with a history of dietary over-indulgence and over consumption of alcohol. Oesophageal diverticula presents with oropharyngeal dysphagia, usually to both solids and liquids, which is the most common symptom. Retention of food material and secretions in the diverticulum, particularly when it is large, can result in regurgitation of undigested food, halitosis, cough, and even aspiration pneumonia. The patient may note food on the pillow upon waking up in the morning.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
M SURESH BABU, MBBS MD FCCP FICP FICS FIMSA FIACM FISE FACP(USA), Associate Professor, Department of Internal Medicine, JSS Medical College and Hospital, JSS University, Mysore, Karnataka, India. DEEPAK SUVARNA, MBBS MD DNB(Gastroenterology), Professor, Department of Gastroenterology, JSS Medical College and Hospital, JSS University, Mysore, Karnataka, India. CHANDRASHEKHAR SHETTY, MBBS MD(Radiology), Professor and Head of Department, Department of Radiology, JSS Medical College and Hospital, JSS University, Mysore, Karnataka, India. ADITYA NADELLA, MBBS, Junior Resident, Department of Internal Medicine, JSS Medical College and Hospital, JSS University, Mysore, Karnataka, India.
Corresponding Author Details: 
Dr. M. Suresh Babu MBBS, MD, FCCP, FICP Associate Professor, Department of Internal Medicine, JSS Medical College and Hospital, JSS University, Mysore, Karnataka, India-570004 PH: +91-9448052680 Email :drmsureshbabu@yahoo.co.in Postal Address: #739, E and F Block, Kuvempunagar, Mysore-570023, Karnataka, India
Corresponding Author Email: 
drmsureshbabu@yahoo.co.in
References
References: 
  1. Diddee R, IH Shaw IH Continuing Education in Anaesthesia, Critical Care & Pain | Volume 6 Number 3 2006
  2. Sharma S  Tracheoesophageal fistula -  e medicine.medscape.com/article Medscape reference  2012
  3. Reed MF and Mathisen DJ “Tracheoesophageal fistula,” Chest Surgery Clinics of North America, vol. 13, no. 2, pp. 271–289, 2003.
  4. Chauhan SS, Long JD, “Management of tracheoesophageal fistulas in adults,” Current Treatment Options in Gastroenterology, vol. 7, no. 1, pp. 31–40, 2004

The twitching leg

Authors
Jose A Egido and Ana M Garcia
Article Citation and PDF Link
BJMP 2014;7(2):a716
Abstract / Summary
Abstract: 

A 87-year-old man was admitted to the Acute Stroke Unit and incidental spontaneous movements were seen at rest. Differential diagnosis and ancillary tests are discussed in this article.

Abbreviations: 
ALS: amyotrophic lateral sclerosis EMG: electromyography MRI: magnetic resonance imaging
Keywords: 
Fasciculation, neurological examination, radiculopathy

Clinical Scenario / Question

An 87-year-old gentleman was admitted after sudden dysarthria and left facial palsy due to a right internal carotid artery occlusion. On examination, incidental spontaneous movements were seen at rest in the left leg (video), with bilaterally diminished Achilles reflexes. Patient was unaware of this finding. Muscle atrophy and hypoesthesia were not present. When walking on heels, left foot dorsiflexion was impaired.

What kind of physical finding is shown in this video?

A. Myoclonus
B. Dystonia
C. Tremor
D. Chorea
E. Fasciculation
F. Myokymia

Answer / Discussion

Focal fasciculations in the tibialis anterior muscle are shown. When walking on heels, left foot dorsiflexion was slightly impaired.

Fasciculation is a brief, twitching, spontaneous involuntary contraction affecting muscle fibres served by one motor unit, which may be visible under skin. When present, they reflect denervation.

A complete history intake and neurological examination will lead to a sensible diagnostic work-up and to set a prognosis. Clinical differential diagnosis is presented in table 1.

Table 1: Key points for clinical diagnosis

Myoclonus Brief, shocklike involuntary contraction of a muscle or group of muscles
Dystonia Involuntary muscle contraction that can cause slow repetitive movements or abnormal postures
Tremor Involuntary rhytmic contraction of antagonistic muscles
Chorea Involuntary irregular movement that starts in one part of the body and moves unpredictably and continously to another part, like “dancing”
Myokymia Involuntary spontaneous quivering, writhing movements within a single muscle not extensive enough to cause a movement of a joint

Localization helps in diagnosis: fasciculations can be generalised, in metabolic-toxic conditions, the benign fasciculation syndrome and degenerative disorders of anterior horn of spinal cord, as amyotrophic lateral sclerosis; segmental, as in syringomyelia; or focal, affecting the muscles controlled by a nerve or spinal root. When fasciculations are in a distribution that cannot be explained by plexus, root or nerve lesion amyotrophic lateral sclerosis (ALS) must be ruled out as soon as possible.

Evolution findings are also pivotal. The absence of muscle atrophy suggests that an acute or subacute nerve lesion is present, although a limited chronic nerve lesion cannot be excluded based on that observation alone. A clinical examination should be repeated at least every six months to assess progression, muscle weakness, upper motor neuron signs and other findings, such as bilateral wasting of the tongue, the “split hand”, head drop, emotionality and cognitive or behavioral impairment1

It is also very important to rule out any possible metabolic disorder, as toxic conditions. Earl Grey tea intoxication has been reported as a cause of widespread fasciculations and cramps2

Electromyography (EMG) is the recording of the electrical activity of the muscles. It supports the clinical suspicion and helps in the topographic diagnosis. If ALS is suspected, a systematic examination of clinically uninvolved muscles has to be done for 2 minutes as fasciculations are the hallmark of this condition. As fasciculation potentials in ALS and benign fasciculation syndrome are indistinguishable on grounds of waveform parameters3 and there is not a reliable biological marker of the disease, a minimum follow-up of 6 months is required before setting a prognosis. When non-progressive isolated fasciculations of the tibialis anterior muscle, it has to been examined the 5th lumbar root and the deep peroneal nerve, as localizer sensory symptoms may be absent4, and to rule out any more diffuse neurogenic processes.

Magnetic resonance imaging (MRI) is supportive to EMG findings as it is very sensitive in detecting anatomic changes that could be responsible for the radiculopathy, but there are other causes of radiculopathy besides nerve root compression. Moreover, lumbar disk protrusions can be found in asymptomatic patients independent of age5. Therefore, MRI is not appropriate if pain or foot drop are not present.

Finally, an isolated chronic left L5 radiculopathy was diagnosed related to lumbar spondyloarthrosis.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
JOSE A EGIDO, MD MPHIL FESO, Stroke Unit and Neurosonology Laboratory Clinical Lead, Hospital Clinico San Carlos, Madrid, Spain. ANA M GARCIA, MD MPHIL, Consultant Neurologist and Stroke Physician, Worcestershire Royal Hospital, Worcester, United Kingdom.
Corresponding Author Details: 
ANA M GARCIA, Consultant Neurologist and Stroke Physician, Worcestershire Royal Hospital, Worcester, United Kingdom.
Corresponding Author Email: 
amgarciagarcia@gmail.com
References
References: 
  1. Turner MR, Talbot K. Mimics and Chamaleons in Motor Neuron Disease. Practical Neurol 2013; 13 (3): 153 – 164, doi: 10.1136/practneurol-2013-000557
  2. Finsterer J. Earl Grey Tea Intoxication. Lancet 2002; 359 (9316): 1484, doi: 10.1016/S0140-6736(02)08436-2
  3. Mills KR. Characteristics of Fasciculations in Amyotrophic Lateral Sclerosis and the Benign Fasciculation Syndrome. Brain: a Journal of Neurology 2010; 133 (11): 3458–3469, doi:10.1093/brain/awq290.
  4. Garland H and Moorhouse D. Compressive Lesions of the External Popliteal (Common Peroneal) Nerve. British Medical Journal 1952; 2 (4799):1373–1378.
  5. Jensen MC, Brant-Zawadzki MN, Obuchowski N, et al. Magnetic Resonance Imaging of the Lumbar Spine in People Without Back Pain. New England Journal of Medicine 1994; 331 (2): 69–73, doi:10.1056/NEJM199407143310201.

Health care quality and hospital acquired infection in Intensive care: Bundles and checklists

Authors
Sandeep Tripathi
Article Citation and PDF Link
BJMP 2014;7(2):a715

Hospital acquired infections (HAI) are one of the most common complications involving hospital care and are the leading cause of death in U.S. Central line associated Blood stream Infection (CLABSI), Ventilator Associated Pneumonia (VAP), Surgical site infection (SSI) and Catheter associated urinary tract infection (CAUTI) represent 75% of all HAI1 . HAI prevention is one of the 20 ‘priority areas’ identified in the Institute of Medicine (IOM) 2003 report ‘transforming health care quality’2. Certain HAI are preventable, but as the prevention efforts become more defined, there remains a lack of evidence of a strong return of investment for hospitals and health care payers in preventing these infections. This lack of evidence presents potential obstacles in advancing efforts to prevent infections.

Central Line Associated Blood Stream Infection (CLABSI)

CLABSI is a primary blood stream infection that develops in a patient with a central line in place within the 48 hour period before the onset of blood stream infection, which is not related to infection at another site. Central line associated blood stream infection occurs up to 80,000 times per year resulting in 28,000 deaths among patients in the Intensive Care unit (ICU). Average cost of CLABSI is approximately $ 45,000 per incidence3. CLABSI reduction is also one of the success story of how inexpensive interventions, grouped as a checklist could reduce the rate of nosocomial infections to a median rate of zero. Although quality control interventions in many areas of ICU have been studied, the idea of integrating quality indicators with group of interventions known as bundles has been validated in the ICU most successfully in CLABSI. The landmark study on reduction of CLABSI was the ‘Keystone ICU’ project funded by the Agency for Health care Research and Quality (AHRQ) 4. One hundred and three ICUs in Michigan participated in this state wide safety initiative. The study intervention recommended five evidence based procedures that were identified as having the greatest effect on the rate of catheter related BSI and the lowest barriers to implementation. The interventions were remarkably successful, nearly eliminating CLABSI entirely in most ICUs over an 18 month follow up period.

Although in short term intensive training and monitoring can lead to improved outcomes, in long term the biggest impact on decreasing HAI, is of the safety climate of the unit. Studies have linked safety climate to clinical and patient outcomes in addition to showing that the safety climate is responsive to interventions. A large study targeting the culture of safety was a follow up of the Michigan Keystone study. The study was a prospective cohort study to improve quality of care and safety culture by implementing and evaluating patient safety interventions in participating ICUs and showed large scale improvements in safety climate among diverse organizations5. As part of the national effort to reduce the HAI, the Department of Health and Human Services (HHS) launched the HHS action plan to reduce the health care associated infections in 2009. The project was titled ‘On the cusp: Stop BSI’, designed to apply the principles of comprehensive unit based safety program (CUSP) to improve the culture of patient safety and implement evidence based best practices to reduce the risk of infection. The initiative ultimately reduced mean rates of CLABSI in participating units by an average of 40%, preventing more than 2000 CLABSI, saving more than 500 lives and avoiding more than $34 million in excess health care costs6.

Ventilator Associated Pneumonia

Optimizing the care of mechanically ventilated patients is an important goal of health care providers and hospital administrators. An easily acquired and reliable marker for medical quality has been elusive for this patient population. VAP has historically been used as a marker of the quality of care associated with mechanically ventilated patient and is associated with worse outcomes7. However the diagnosis of VAP is non-specific, the clinical diagnosis by the widely used American College of Chest Physicians (ACCP) criteria includes a new progressive consolidation on chest radiography plus at least two of the following clinical criteria: fever > 38, leucocytosis or leucopenia and purulent secretions. Unfortunately, all these findings alone or in combination can occur in other non-infectious conditions, making the diagnosis of VAP subjective and prone to bias. In fact, for the last many years, the surveillance rates of VAP are decreasing, whereas the clinical diagnosis of VAP and tracheobronchitis as well as antibiotic prescribing remains prevalent. External reporting pressures may be encouraging stricter interpretation of the subjective signs that can cause artifactual lowering of the VAP rates. The result is that, it is almost impossible to detangle the relative contribution of quality improvement efforts in the ICU versus surveillance efforts as explanation for the currently observed lower rates of VAP8.

To eliminate the subjectivity and inaccuracy and to create an objective , streamlined and potentially automatable criteria, Center of Disease Control (CDC) now recommends surveillance of ventilator associated events (VAE) as a more general marker and defines it as sustained increase in patient’s ventilator settings after a period of stable or decreasing support . There are three definition tiers within the VAE algorithm; 1) Ventilator Associated Condition (VAC); 2) Infection Related Ventilator Associated Complication (IVAC); and 3) Possible and probable VAP. The screening for VAC captures a similar set of complications to traditional VAP surveillance, but it is faster, more objective and potentially a superior predictor of clinical outcomes9. In a CDC funded study of 597 mechanically ventilated patients on use of VAC as an outcome predictor, it was noted that 9.3% of the study population had a VAP, whereas 23% had VAC. VAC was associated with increased mortality (odds ratio of 2.0) but VAP was not. VAC assessment was also faster (mean 1.8 minutes vs 3.9 minute per patient) 10.

Similar to the CLABSI bundles, prevention of VAP by utilization of evidence-based bundles of care has proved to be a very successful. Heimes and colleagues recently conducted a study examining 696 consecutive ventilated patients in a level 1 trauma center to evaluate a VAP prevention bundle with 7 elements. They found a VAP rate of 5.2/1000 days of ventilator support in the pre intervention phase, while a 2.4 /1000 and 1.2/1000 days (p= 0.085) in the implementation and enforcement periods respectively11.

Catheter Associated Urinary Tract Infection (CAUTI)

Health care associated UTI account for up to 40% of infections in hospitals and 23% of the infections in the ICU. The vast majority of UTIs are related to indwelling urinary catheters. CAUTI result in as much as $ 131million excess direct medical costs nationwide annually12. Since October 2008, Center of Medicare Services (CMS) no longer reimburses hospitals for the extra costs of managing a patient with hospital acquired CAUTI.

There are certain factors like Diabetes mellitus, old age or severe underlying illness that places patients at a greater risk of CAUTI, but there also are modifiable factors like non adherence to aseptic catheter care recommendations and duration of catheterization that can be targeted by quality improvement efforts, to decrease the risk13. The key strategies for prevention of CAUTI include avoiding insertion if possible, early removal by implementation of checklists, nurse based interventions or daily electronic reminders, utilization of proper techniques for insertion and maintenance and considering alternatives to indwelling catheters like intermittent catheterization, condom catheters and portable bladder ultrasound scanner. Most of these strategies have been utilized in quality improvement efforts to decrease CAUTI. Assessment of the need is essential as Munasinghe et al have found urinary catheter placed in 21 to 50% of patients for inappropriate reasons14. A nurse based reminder to physician to remove unnecessary urinary catheters in a Taiwanese hospital resulted in reduction of CAUTI from 11.5 to 8.3 /1000 catheter days15. Similarly utilization of electronic urinary catheter reminders system and stop orders have been shown to reduce the mean duration of catheters by 37% and CAUTI by 2%16. Utilization of condom catheter has also been shown to be effective in reducing bacteriuria, symptomatic UT and mortality as compared to indwelling catheter17.

Final word

Health care is often compared with airline industry with six sigma efficiency. This would translate to 0.002 defective parts or errors/million, obviously we are not close to that and may not be realistic. However this also cannot be an excuse to rationalize poor practice culture. As in any industry, in health care to establish change it is essential to regulate interpersonal interactions. With behaviors change leading to changes in processes of care, change is not only possible, it is sustainable.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
SANDEEP TRIPATHI, MD, Consultant, Pediatric Intensive Care Unit, Assist Professor of Pediatrics, Mayo Clinic, Rochester, MN.
Corresponding Author Details: 
DR SANDEEP TRIPATHI, 3107 Avalon Cove Court NW, Rochester, MN 55901
Corresponding Author Email: 
sandeeptripathi2000@yahoo.com
References
References: 
  1. Klevens RM, Edwards JR, Richards CL Jr, et al. Estimating health care associated infections and deaths in U.S. hospitals, 2002. Public Health Rep 2007;122:160–166.
  2. National Research Council. Priority Areas for National Action: Transforming Health Care Quality. Washington, DC: The National Academies Press, 2003.
  3. Pittet D, Tarara D, Wenzel RP. Nosocomial bloodstream infections in critically ill patients. Excess length of stay, extra costs, and attributable mortality. JAMA 1994;271:1598–601.
  4. Pronovost P, Needham D, Berenholtz S, et al. An intervention to decrease catheter-related bloodstream infections in the ICU. N Engl J Med 2006;355(26): 2725–2732.
  5. Sexton JB, Berenholtz SM, Goeschel CA, et al. Assessing and improving safety climate in a large cohort on intensive care units. Crit Care Med 2011;39:934–9.
  6. AHRQ Patient Safety Project Reduces Bloodstream Infections by 40 Percent. September 2012. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/news/newsroom/press-releases/2012/20120910.html
  7. Kollef MH, Hamilton CW, Ernst FR. Economic impact of ventilator-associated pneumonia in a large matched cohort. Infect Control Hosp Epidemiol 2012;33: 250–6.
  8. Klompas M. Is a ventilator-associated pneumonia rate of zero really possible? Curr Opin Infect Dis 2012;25:176–82.
  9. Marin H. Kollef. Ventilator-associated Complications, Including Infection-related Complications:The Way Forward. Crit Care Clin 2013;29:33–50.
  10. Klompas M, Khan Y, Kleinman K, et al. Multicenter evaluation of a novel surveillance paradigm for complications of mechanical ventilation. PLoS One 2011;6: e18062.
  11. Heimes J, Braxton C, Nazir N, et al. Implementation and enforcement of ventilator-associated pneumonia prevention strategies in trauma patients. Surg Infect (Larchmt) 2011;12:99–103.
  12. Burton DC, Edwards JR, Srinivasan A, et al. Trends in catheter-associated urinary tract infections in adult intensive care units-United States, 1990-2007. Infect Control Hosp Epidemiol 2011;32:748–56.
  13. Umsheid CA, Mitchell MD, Doshi JA, et al. Estimating the proportion of healthcare-associated infections that are reasonably preventable and the related mortality costs. Infect Control Hosp Epidemiol 2011;32:101–14.
  14. Munasinghe RL, Yazdani H, Siddique M, et al. Appropriateness of use of indwelling urinary catheters in patients admitted to the medical service. Infect Control Hosp Epidemiol 2001;22(10):647–9.
  15. Huang WC, Wann SR, Lin SL, et al. Catheter-associated urinary tract infections in intensive care units can be reduced by prompting physicians to remove unnecessary catheters. Infect Control Hosp Epidemiol 2004;25:974–8.
  16. Meddings J, Rogers MAM, Macy M, et al. Systematic review and metaanalysis: reminder systems to reduce catheter-associated urinary tract infections and urinary catheter use in hospitalized patients. Clin Infect Dis 2010; 51:550–60.
  17. Saint S, Kaufman SR, Rogers MA, et al. Condom versus indwelling urinary catheters: A randomized trial. J Am Geriatr Soc 2006;54:1055–61.

Lamotrigine-induced hallucination in patient with bipolar disorder and no history of epilepsy or psychosis: a case report and literature review

Authors
Yasir Hameed and Jacobus Hamelijnck
Article Citation and PDF Link
BJMP 2014;7(2):a714
Abstract / Summary
Abstract: 

We report a rare case of hallucinations in a patient with bipolar affective disorder BAD without any history of psychosis or epilepsy following the introduction of lamotrigine as an add-on medication to her current treatment with lithium carbonate. 

The patient has been on two previous medications (quetiapine and sodium valproate) without significant improvement and only showed partial response to lithium.

Lamotrigine was introduced as an adjunctive medication with her lithium carbonate. Her dose of lithium was 800 mg once daily with satisfactory lithium levels.

She started to report complex auditory and visual hallucinations which started two days after starting lamotrigine (25 mg once daily) and increased with its dose increase to 50 mg once daily two weeks later and resolved completely with stopping it.

Hallucinations following lamotrigine treatment in non-epileptic patients is extremely rare reaction and only few similar case reports are reported in literature.

Awareness of this rare but serious side effect is important to avoid confusion with other psychotic symptoms related to mental illness and avoid unnecessary treatment.

Abbreviations: 
BAD: Bipolar affective disorder. ICD 10: International Classification of Disesases. Tenth Edition. DSM 5: Diagnostic and Stastical Manual. Fifth Edition.
Keywords: 
Anticonvulsants; Bipolar Affective Disorders; Drug interactions and side effects; Education and training; Mood stabilisers

Case Presentation:

We report the case of 36 year old white Caucasian female who used to work as a driving instructor and living with her parents.

She has a diagnosis of congenital adrenal hyperplasia (21 hydroxylase deficiency) and is on long term corticosteroid replacement (prednisolone 4 mg once daily and fludrocortisone

100 mcg once daily) and she is under the care of an endocrinologist.

She was referred for psychiatric evaluation with “anxiety and depressive symptoms” and failure to respond to antidepressant treatment which was prescribed by her General Practitioner.

During the psychiatric assessment, she reported long history of recurrent episodes of elevated mood and depression dating back to her late teens with clear description of distinct periods of mood elevations lasting for few weeks and longer periods of persistent low mood. There was no history of psychotic symptoms and no family history of mental illness.

She was diagnosed with bipolar affective disorder and failed to achieve remission of symptoms on two different antipsychotic medications (quetiapine and olanzapine) and anticonvulsant medication (sodium valproate) before starting lithium carbonate.

The introduction of lithium and gradual titration resulted in significant improvement in her symptoms and mood stability. However, few months later, she reported relapse in her symptoms (mainly reporting features of bipolar depression) despite adequate lithium levels.

She agreed on the introduction of lamotrigine as an adjunctive medication to lithium. The initial dose of lamotrigine was 25 mg daily for two weeks in line with dose recommendation from manufacturer and drug guides.

On the same day of lamotrigine introduction, the patient started to experience visual hallucinations that she never had before (please see patient’s perspective for detailed description of her hallucinations).

With the dose of lamotrigine increased to 50 mg daily after the initial two weeks, she started to report worsening of these abnormal perceptions which developed into more complex visual and auditory hallucinations.   

More importantly, there was no evidence of accompanying manic symptoms or severe depressive symptoms to explain these symptoms and also no alcohol or drug use.

Following a psychiatric review, the dose of lamotrigine was reduced to 25 mg which resulted in immediate reduction in the intensity of the abnormal perceptions. When the lamotrigine was eventually stopped after one week, there was complete cessation of abnormal perceptions.

Lamotrigine was never re-started again and she was maintained on a combination of lithium and quetiapine with good effect.

Investigation:

We used the Naranjo Adverse Drug Reaction Probability Scale (1) to determine the likelihood of whether an adverse drug reaction is related to this specific drug or may be related to other factors. This tool examine factors such as the temporal association of drug administration and event occurrence, alternative causes for the event, drug levels, dose – response relationships and previous patient experience with the medication.

The probability of the adverse drug reaction is concluded from the total score (Definite if the overall score is 9 or greater, Probable for a score of 5-8, Possible for 1-4 and Doubtful if the score is 0).

Questionnaire

1. Are there previous conclusive reports on this reaction? Yes (+1)

2. Did the adverse events appear after the suspected drug was given? Yes (+2)

3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was given?

Yes (+1)

4. Did the adverse reaction appear when the drug was re-administered? Do not know or not done (0)

5. Are there alternative causes that could have caused the reaction? No  (+2)

6. Did the reaction reappear when a placebo was given? Do not know or not done (0)

7. Was the drug detected in any body fluid in toxic concentrations?

No (0)

8. Was the reaction more severe when the dose was increased or less severe when the dose was decreased?

Yes (+1)

9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure?

No (0)

10. Was the adverse event confirmed by any objective evidence? Do not know or not done (0)

Scoring 7 (Probable Adverse drug reaction)

Discussion:

Lamotrigine is a phenyltriazine derivative used as an anticonvulsant drug with established mood stabilising properties. In the United Kingdom, it is recommended for use in bipolar affective disorder according to the guidelines from the National Institute of Health and Care Excellence (2) and the British Association for Psychopharmacology (3).

We performed a literature search to find similar case reports. We searched the following databases using the keywords (lamotrigine AND hallucinations): Complementary Medicine (AMED), British Nursing Index BNI), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Excerpta Medica Database (EMBASE), Health Business Elite (HMIC), Medline, PsycINFO and Health Management Information Consortium (HMIC).

The search returned 57 results. Only 8 articles discussed hallucinations and other psychiatric symptoms as side effects associated with lamotrigine and therefore were included in this review.

Psychotic symptoms have been reported with the use of lamotrigine (both as an anticonvulsant or mood stabiliser) but this reaction is mainly seen in patients with history of epilepsy. One study reported 4.8% incidence of psychiatric and behavioural side effects with lamotrigine in 546 patients with epilepsy. (4)

Another study on paediatric patients showed that reversible visual and auditory hallucinations were reported in one patient among 9 patients with epilepsy who received lamotrigine treatment (mean age 5 years). (5) 

Villari et al published a literature review on psychiatric symptoms related to lamotrigine and included case reports documenting full acute psychotic episodes hallucinations and affective switching in patients with and without history of epilepsy.(6)

They found one case report on hallucination with lamotrigine in bipolar patient without epilepsy. In patients with epilepsy, they reported two cases reports and one case series (total number of patients 9) developing psychotic symptoms following lamotrigine and one randomised controlled trial in which four out of 216 patients stopped lamotrigine due to psychotic symptoms (including hallucinations and delusions).

The authors concluded that majority of the case reports concluded that these symptoms were lamotrigine-induced due to the temporal association with lamotrigine treatment and favourable outcome following drug withdrawal. It also appeared that more case reports were from patients with epilepsy, suggesting lower incidence in patients without this condition.

Chistyakova and Amos (7) reported a case of delirium associated with lamotrigine use. The dose of lamotrigine was increased from 200 to 400 mg over two weeks prior to her admission. The patient reported visual and auditory hallucination with confusion. She took an accidental overdose of her medication (200 mg of fluoxetine and 2800 mg of lamotrigine) due to her confusion and medications were stopped.

The authors concluded that delirium may result from lamotrigine toxicity or drug interaction with fluoxetine.

Uher and Jones in 2006 (8) reported a case of a 42-year-old woman with bipolar affective disorder with comorbid alcohol abuse and no history of  neurological illness.

The patient tolerated an initial dose of lamotrigine 50 mg/day but following a dose increase to 100 mg/day, she reported vivid dream-like experiences and subsequently she reported visual hallucinations. These symptoms subsided over a few days when the dose was decreased to 50 mg/day.

The authors suggested a causal association through this dose dependent effect but also pointed out that the concurrent alcohol abuse may have been a contributing factor.

They also highlighted the paucity of case reports documenting this rare adverse reaction and identified two similar case reports in their references (which we were unable to get their full text) and a third paper reporting hallucination in 2 out of 108 patients with epilepsy on a combination of lamotrigine and sodium valproate (9)

Hallucination with lamotrigine when combined with valproic acid was also reported in a case report by Roberts et al (10) in 14 year old girl with epilepsy when it was added to valproic acid and it was suggested that this adverse effect may be due to an interaction between the two medications causing lamotrigine half-life to triple with valproic acid.

Learning points:

  • Lamotrigine is an anticonvulsant with an established role in management of bipolar affective disorder, particularly for the treatment and prevention of depressive episodes.
  • However, it appears to be associated with variable incidence of psychiatric symptoms which should be known to the prescriber and patient.
  • These adverse effects are mainly seen in patients with history of epilepsy but can occur in patients with mental health problem without epilepsy.
  • Different mechanisms for inducing these psychiatric symptoms have been suggested, including idiosyncratic reaction, lamotrigine toxicity as a result of concomitant use of another drug that affect lamotrigine metabolism (e.g., valproic acid) and delirium.
  • Examples of these psychiatric symptoms including affective switches in depressed patients with bipolar disorder, hallucinations in depressed patients, delirium and psychotic symptoms (mainly hallucinations and delusions) in patients with or without epilepsy.
  • Reversible and severe psychiatric disturbances associated with lamotrigine therapy are rarely reported in literature and more research is needed to identify population at risk.
  • Patient education about these rare but frightening side effects is essential to improve medication adherence and better outcome of the management of the mental disorder.

Patient perspective:

“The first hallucination I had was one hour roughly after taking lithium and lamotrigine. It was the Pope which appeared as bright light on my wall. He was wearing a white gown and he had gold jewellery. The picture was so clear and very detailed. I’m not religious and this image would not be something I would think of.

Every day on lamotrigine I had black spots moving quickly around the walls. They were in size of about an inch, 20-30 moving around at one time. Like spiders but without legs. I was really scared at first because I hate spiders. It was very unsettling and I changed my whole bed, away from my wall, and had trouble sleeping.

There was another night when I had similar to the black dots, where instead I had smaller black dots like bees moving into the corner of my room. They were all slightly moving as if they were getting their places. There were hundreds of them.

The scariest incident that happened was hearing voices downstairs. I was so sure that people had broken into the house; I went downstairs armed with razors. I was going to cut DNA from the burglars to give to the police as evidence. When I checked the house, there was no one there.

When I was taking lamotrigine with the lithium, it made me very unsettled, more anxious and mentally unstable. I was so tiered for not sleeping and my decisions irrational. It wasn’t a pleasant place to be for me personally.”

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared.
Details of Authors: 
Yasir Hameed (MRCPsych), Specialist Registrar, Old Age and General Adult Psychiatry, Norfolk and Suffolk NHS Foundation Trust. Jacobus Hamelijnck (MRCPsych), Consultant Psychiatrist, Northgate Hospital, Norfolk and Suffolk NHS Foundation Trust, Great Yamrouth, Norfolk, UK, NR30 1BU.
Corresponding Author Details: 
Yasir Hameed (MRCPsych), Specialist Registrar, Old Age and General Adult Psychiatry, Norfolk and Suffolk NHS Foundation Trust, Northgate Hospital, Great Yamrouth, Norfolk, NR30 1BU.
Corresponding Author Email: 
yasirmhm@yahoo.com
References
References: 
  1. Naranjo CA, Busto U, Sellers EM et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981. 30 (2): 239–245.
  2. National Institute of Health and Clinical Excellence. Bipolar disorder. The management of bipolar disorder in adults, children and adolescents, in primary and secondary care. NICE clinical guideline CG38. http://guidance.nice.org.uk/CG38
  3. Goodwin GM. Evidence-based guidelines for treating bipolar disorder: revised second edition-recommendation from the British Association for Psychopharmacology. Journal of Psychopharmacology 2009;23(4):346–388. 
  4. Weintraub D, Buchsbaum R, Resor Jr SR, et al. Psychiatric and behavioural side effects of the newer antiepileptic drugs in adults with epilepsy. Epilepsy Behav 2007; 10: 105-10
  5. Cardenas J.F.,Rho J.M.,Ng Y.-T. Reversible lamotrigine-induced neurobehavioral disturbances in children with epilepsy. Journal of Child Neurology 2010; 25 (2): 182-187. 
  6. Villari V. Roccab P, Frieria T, Bogettob F. Psychiatric symptoms related to the use of lamotrigine: a review of the literature. Funct Neurol 2008. 23(3):133-136.
  7. Chistyakova Y, Amos J. Delirium associated with lamotrigine and fluoxetine treatment. Am J Psychiatry2008;165(7):918.
  8. Uher R, Jones HM. Hallucinations during lamotrigine treatment of bipolar disorder. Am J Psychiatry 2006;163:749-750.
  9. Faught E, Morris G, Jacobson M, et al. Adding lamotrigine to valproate: incidence of rash and other adverse effects: Postmarketing Antiepileptic Drug Survey (PADS) group. Epilepsia 1999; 40:1135–1140.
  10. Roberts C, Davenport R, Patel H, et al. Hallucinations during lamotrigine treatment. The Nurse Practitioner 2008;33:12-13.

Spotted Bone - A Spot Diagnosis

Authors
Abdul Rehman Arshad, Asif Rahman, Shafqat Hussain
Article Citation and PDF Link
BJMP 2014;7(2):a713
Abstract / Summary
Abstract: 

A young male was incidentally diagnosed to have a rare disorder on X rays done to rule out a bony injury after trauma to his left wrist. The radiological findings and differential diagnosis are briefly discussed.

Keywords: 
bone dysplasia, osteosclerosis, osteopoikilosis

Clinical Scenario / Question

A 26-year-old previously healthy male presented with a two day history of pain in his left wrist following trauma inflicted while playing volleyball. It was aggravated by movements around the affected joint. Clinical examination revealed mild tenderness over the left wrist with full range of movements and absence of any swelling. Distal neurovascular status was intact. X-ray of the left hand and wrist was done to rule out an injury to the bones (Fig. 1).

Fig. 1: X-Rays of left hand and wrist

What diagnosis does the X-ray findings indicate?

  1. Fracture of left scaphoid bone
  2. Osteoblastic metastases
  3. Osteopathia striata
  4. Tuberous sclerosis
  5. Osteopoikilosis

Answer / Discussion

The X-ray in Fig. 1 shows multiple small hyperdense oval and circular lesions scattered in all small bones of the left hand, with preservation of cortical thickness. These findings are suggestive of osteopoikilosis. Similar lesions were also present in the contralateral hand and wrist, as well as the pelvis (Fig. 2), on X-rays done subsequently.


Fig. 2: X-Ray Pelvis showing bone islands

Patient was counselled and reassured about the radiological findings. He was prescribed oral Paracetamol and topical Piroxicam for three days and asked to rest the affected joint. Osteopoikilosis (also called spotted bone) is a benign, possibly autosomal dominant dysplasia of bones, occurring in 1 per 50,000 people.1 Small bones of hand and feet, long tubular bones and pelvis are most frequently affected. The condition is asymptomatic and is diagnosed incidentally on radiographs taken for other problems. The diagnosis is straightforward, based on the typical radiological appearances of small (up to 10mm) hyperdense opacities distributed symmetrically. No further investigations or any specific treatment are indicated. Patients need to be reassured about the benign nature of radiological findings.

Osteoblastic metastases occur in the older age group, are generally larger in size and do not have such a uniformly symmetric distribution. Osteopathia striata is another rare bone dysplasia, characterized by long hyperdense striations mainly in the metaphyses of long bones and pelvis.2 Sclerotic bone lesions in tuberous sclerosis are frequently seen in the axial skeleton especially calvarias and spine, are at times distributed focally and have irregular borders and variable size.3 Subperiosteal new bone formation may be present and other clinical features like epilepsy may also provide a clue. As seen in Fig. 1, there is no break in the continuity of scaphoid bone, thus ruling out a fracture.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
ABDUL REHMAN ARSHAD, MCPS, FCPS(Pak). 1 Mountain Medical Battalion, Bagh, AJK Pakistan. ASIF RAHMAN, MCPS, FCPS(Pak). Combined Military Hospital Bannu, Pakistan. SHAFQAT HUSSAIN, MBBS. 1 Mountain Medical Battalion, Bagh, AJK Pakistan.
Corresponding Author Details: 
Dr ABDUL REHMAN ARSHAD, Classified Specialist in Medicine, 1 Mountain Medical Battalion (MDS), Bagh 12500, Azad Kashmir, Pakistan.
Corresponding Author Email: 
maj.abdulrehman@gmail.com
References
References: 
  1. Meena S, Saini P, Chowdhary B. Multiple spots on bone: diagnostic challenge or spot diagnosis? Osteopoikilosis. Neth J Med 2013; 71(7):372, 376.
  2. Perdu B, de Freitas F, Frints SG, et al. Osteopathia striata with cranial sclerosis owing to WTX gene defect. J Bone Miner Res 2010; 25(1):82-90. doi: 10.1359/jbmr.090707.
  3. Umeoka S, Koyama T, Miki Y, et al. Pictorial review of tuberous sclerosis in various organs. Radiographics 2008; 28(7):e32. doi: 10.1148/rg.e32. Epub 2008 Sep 4.

Carbimazole induced ANCA Positive Vasculitis

Authors
Yasmeen Ajaz and Sameem Matto
Article Citation and PDF Link
BJMP 2014;7(2):a712
Abstract / Summary
Abstract: 

Anti-throid drugs like propylthiouracil and carbimazole are the main drugs prescribed for hyperthyroidism worldwide. Vasculitis related to anti-thyroid medication is very rare and can be potentially life threatening, if not recognized early. We report a female patient with Graves’ Disease who developed ANCA positive vasculitis due to carbimazole. The episode was characterized by a Raynaud’s Phenomenon of hands and feet and small joint arthritis. To our knowledge this is the first ANCA positive carbimazole induced vasculitis case reported from United Arab Emirates.

Abbreviations: 
TSH-Thyroid stimulating hormone, FT3-Freetri-iodothyronine, FT4-Free thyroxine, ANCA-Antineutrophilic cytoplasmic antibodies, CRP-C reactive protien, ESR-Erythromicin sedimentation rate, ECG-electrocardiogram, ATD-Antithyroid drugs, PTU-Proplythiouracil, ANTI-TPO-thyroperoxidase, MPO-Myeloperoxidase
Keywords: 
Carbimazole, ANCA, Vasculitis, Hyperthyroidism, Raynauds Phenomenon, Graves Disease, Antithyroid Drugs.

Introduction

Hyperthyroidism is a common endocrine disorder and is mainly treated with anti-thyroid medications like propylthiouracil (PTU) and carbimazole. These medications have a large number of adverse effects, the commonest being skin rashes, and some are rare like agranulocytosis. Vasculitis is uncommon, but ANCA positivity is reported more in propylthiouracil and rarely with carbimazole or methimazole (1).We report a female patient with Graves’ disease who developed ANCA associated vasculitis while on carbimazole treatment.

Case report

A 29 year old female Filipino patient came to us with history of palpitations, tremors and weight loss for the last one month. Her thyroid profile showed severe hyperthyroidism (TSH <0.005, FT3-11.5, FT4-45.6) She was diagnosed with Graves’ disease as her anti-TSH receptor positive and was started on carbimazole 10mg tds. After three weeks of treatment, she developed macular rash over arms and legs and swelling of small joints of both hands. She noticed pain and colour change of both the hands and experienced typical Raynaud’s phenomenon. She had no renal or lung involvement.

On examination her blood pressure was 120/84mmHG, pulse 104 beats per min, temperature -37.1̊C. She had a mild diffuse goiter. Her X-ray chest, ECG and urine dipstick routine were all normal. Her CRP and ESR were raised. X-rays of the hands were normal. P-ANCA was positive. Antimyeloperoxidase antibody was positive. Anti-TPO and TSH receptor antibodies were positive.

Diagnosis of carbimazole induced vasculitis was made. The patient was treated with prednisolone 40mg daily once daily which was tapered over three weeks. She improved within 48hours and was asymptomatic after three weeks. She was treated successfully with radioiodine ablation. Her MPO-ANCA after 6 months was negative.


Figure 1. Pictures of the hands showing Raynaud’s phenomenon


Figure 2. Pictures of the hands showing Raynaud’s phenomenon

Discussion

ANCA positive vasculitis in association with antithyroid drugs was first reported in 1992 (2).There has been 32 cases of ANCA positive vasculitis associated with antithyroid medications reported up until now (3). The presenting symptoms are variable and may include renal involvement (67%), arthralgias (48%), fever (37%), skin involvement (30%), respiratory tract involvement (27%), myalgias (22%), scleritis (15%) and other manifestations (18%) (3).

In these patients the underlying thyroid disease is most commonly Graves’ disease but ANCA positive vasculitis has also been seen with association with toxic multinodular goitre (4). Recent studies have shown high frequency of ANCA positivity in patients with Graves’ disease treated with antithyroid medications, especially with PTU. Most cases of ANCA positivity are seen in patients on long term therapy (greater than 18 months) or in those with recent commencement of therapy as seen in our patient. However, a small percentage of these go on to develop features of vasculitis (3).

The majority of cases of vasculitis (88%) have been reported in association with PTU, vasculitis associated with carbimazole is very rare (5, 6, and 7). The pathogenesis of ATD associated vasculitis is not clearly understood. PTU has been shown to accumulate within neutrophils (8) and bind myeloperoxidase (9). The binding alters the configuration of myeloperoxidase (9) and may promote formation of autoantibodies in susceptible people. There has been no data with regards to whether carbimazole can alter the configuration of myeloperoxidase. ANCA positive vasculitis may be more common in patients of Asian ethnic origin, with half of cases reported from Japan (3). Our patient was from Philippines.

Wadw et al have reported 25% of patients were positive for MPO-ANCA in PTU group whereas in methimazole group 3.4% were positive (10).

This case highlights the awareness of this relatively rare adverse effect of a thyroid medication which may lead to fatal renal and pulmonary complications. Early diagnosis and withdrawal of the offending medication is important. In asymptomatic patients the significance of ANCA positivity is not clear but early definitive therapy in the form of radioiodine ablation or surgery should be considered.

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
NONE
Competing Interests: 
None declared
Details of Authors: 
YASMEEN AJAZ (M.D, F.A.C.E, PGDD, SCE) Specialist Internal Medicine And Endocrinology, Belhoul Speciality Hospital, Dubai, UAE. SAMEEM MATTO (M.D, PGDD, SCE) Specialist Internal Medicine And Endocrinology, Canadian Specialist Hospital, Dubai, UAE.
Corresponding Author Details: 
DR SAMEEM MATTO, Canadian Specialist Hospital, Abuhail Deira, PO BOX 15881, Dubai, UAE.
Corresponding Author Email: 
sameematto@hotmail.com
References
References: 
  1. Sera N, Ashizawa K, Ando T, et al. Treatment with propylthiouracil is associated with appearance of antineutrophil cytoplasmic antibodies in some patients with Graves’ disease. Thyroid 2000; 10:595-9.
  2. Stankus SJ & Johnson NT. Propylthiouracil-induced hypersensitivity vasculitis presenting as Respiratory failure. Chest 1992 102, 595–1596.
  3. Gunton JE, Stiel J, Clifton-Bligh P, et al. Prevalence of positive antineutrophil cytoplasmic  antibody   (ANCA) in patients receiving antithyroid medication. Eur J Endocrinol 2000; 142: 587-96.
  4. Gunton JE, Stiel J, Caterson RJ & McElduff A. Anti-thyroid drugs and antineutrophil cytoplasmic antibody positive vasculitis. A case report and review of the literature. Journal of Clinical Endocrinology and Metabolism1999 8413–16.
  5. Day C, Bridger J, Rylance P, et al. Leukocytoclastic vasculitis and interstitial nephritis with Carbimazole treatment. Nephrol Dial Transplant 2003; 18: 429-31.
  6. Sève P, Stankovic K, Michalet V, et al. Carbimazole induced eosinophilic granulomatous vasculitis localized to the stomach. J Intern Med 2005; 258: 191-5.
  7. Calañas-Continente A, Espinosa M, Manzano-García G, et al.Necrotizing glomerulonephritis and pulmonary hemorrhage associated with carbimazole therapy. Thyroid 2005; 15: 286-8.
  8. Lam DCC & Lindsay RH. Accumulation of 2-[14C]-propylthiouracil in human polymorphonuclear leukocytes. Biochemical Pharmacology 1979 282289–2296.
  9. Lee H, Hirouchi M, Hosokawa M, Sayo H, Kohno M & Kariya K.Inactivation of peroxidase of rate bone marrow by repeated administration of propylthiouracil is accompanied by a change in the heme structure. Biochemical Pharmacology 1988 372151–2153.
  10. Bonaci-Nikolic B, Nikolic MM, Andrejevic S, et al. Antineutrophil cytoplasmic antibody (ANCA)-associated autoimmune diseases induced by antithyroid drugs: comparison with idiopathic ANCA Vasculitides. Arthritis Res Ther 2005; 7:1072-81. 

Liver Veno-Occlusive Disease (VOD) in a patient given 6-Thioguanine for Crohn’s Disease

Authors
Agata Salerno, Marco Vacante, Donatella Pollina, Benedetta Stancanelli, Silvia Martini, Ezio David, Lorenzo Malatino
Article Citation and PDF Link
BJMP 2014;7(2):a711
Abstract / Summary
Abstract: 

6-Thioguanine (6-TG) is being given to patients with Crohn's disease failing conventional immunosuppression, but cases of hepatotoxicity have been reported. We report the case of a patient who developed acute sinusoidal obstruction syndrome after 3 months of successful 6-TG treatment. A complete regression of liver injury was observed after withdrawal of 6-TG. Our case-report underscores the risk of hepatic injury due to the administration of 6-TG for Crohn’s disease. We strongly recommend alternative therapeutic options in patients intolerant or resistant to conventional thiopurines.

Keywords: 
6-thioguanine, Crohn’s disease, hepatotoxicity, veno-occlusive disease.

A 44-yr-old patient with history of ileal Crohn’s disease was admitted to our Department because of asthenia, subclinical jaundice, painful hepatomegaly, fluid retention and ascites. In 2008 the patient was diagnosed with bladder cancer and was treated by surgical resection of the cancer and intravesical chemotherapy with mitomicyn C. In 2010 he was given azathioprine (AZA) at 2 mg/kg for Crohn’s disease and 3 months later he developed an increase in serum alkaline phosphatase, gamma-glutamyl transpeptidase and transaminases. He was then started on 1.5 mg/kg 6-mercaptopurine (6-MP) once daily. After 9 months he stopped 6-MP because of nausea, vomiting and abnormal liver function tests; 6-MP was therefore discontinued until the normalisation of markers of liver function. Two months later, when the transaminases were within the normal range, he received 6-thioguanine (6-TG) 25 mg a day, that was progressively increased to 80 mg a day. Three months later, the patient was referred to our Department with painful hepatomegaly, ascites and asthenia. Laboratory tests on admission revealed an elevation in AST 198 U/l and ALT 209 U/l. Total bilirubin was 3 mg/dl (direct bilirubin 1.5 mg/dl), LDH 784 U/l, alkaline phosphatase 191 U/l and ammonia 112 umol/l. Virological markers (HBsAg, HBcAb, anti HCV, HBV DNA) were negative. Patient was apyrexial, showed normal blood pressure (130/80 mmHg), tachycardia (110 bpm) and 97% SaO2 on room air. Physical examination revealed right hypochondrial tenderness, abdominal distension and shifting dullness, suggesting the presence of ascites. The rest of the physical examination was unremarkable. An echo-Doppler evaluation revealed thin linear suprahepatic veins and confirmed the presence of ascites. A CT scan of the abdomen showed hepatomegaly with dishomogeneous enhancement after dye injection (mosaic pattern). There was no evidence of any venous thrombosis or splenomegaly (Figure 1A); 6-TG was withdrawn empirically and the patient was started on therapy with albumin 25 g/day and spironolactone 200 mg/day. The average serum Na+ level during diuretic treatment was 134 mEq/l. An abdominal paracentesis of two litres was necessary, due to the progressive increase of ascites.


FIGURE 1A. CT scan of the abdomen on admission: Dishomogeneous enhancement of the liver after dye injection (mosaic pattern) (arrow). Suprahepatic veins are not detectable.


FIGURE 1B. Histological pattern of the liver biopsy specimen: marked centrilobular congestion (arrows) with hepatocyte dropout. There is no evidence of centrolobular veins thrombosis.

A routine laboratory investigation of ascitic fluid showed < 500 leukocytes/µL and < 250 polymorphonuclear leukocytes (PMNs)/µL. The ascitic fluid total protein level was 2.1 g/dl and serum-ascites albumin gradient (SAAG) was > 1.1 g/dL. No neoplastic cells were found. A transjugular liver biopsy was then performed, showing marked centrilobular hemorrhage with hepatocyte necrosis. There was mild ductular reaction, with no evidence of centrilobular vein thrombosis. The histologic diagnosis confirmed veno-occlusive disease (VOD) (Figure 1B). Screening for thrombophilia was also done, showing low levels of serum protein C and protein S. There was no mutation of JAK-2 V617F. The patient was then treated with a hyposodic diet, mild hydric restriction, enoxaparin,spironolactone, lactulose and omeprazole. He was discharged two weeks later, and after 3 months a complete regression of ascites and hepatomegaly occurred, and echography of the liver was unremarkable (Figure 2A and 2B).


FIGURE 2A. Echography of the liver at follow up. No evidence of ascites.


FIGURE 2B. Echography of the liver at follow up. No evidence of ascites. Suprahepatic veins are detectable (arrow)

Discussion

Although VOD was known among complications of 6-TG in childhood, this case-report emphasises the occurrence of VOD in adults with Crohn’s disease, as first described by Kane et al. in 20041. The thiopurine drugs were developed more than 50 years ago, and 6-MP was first used as a drug in 19522. Since then, 6-MP and 6-TG have been widely used to treat acute lymphoblastic leukemia in children. VOD mimicking Budd-Chiari like disease was then described as a frequent complication of 6-TG in pediatric patients given the drug for lymphoblastic leukaemia. Later on, in 1976, Griner et al. described the cases of two adult male patients with acute leukaemia developing a fatal Budd-Chiari-like disease while receiving 6-TG3. Since patients were given 6-TG plus cytosine arabinoside, authors were unable to ascribe this complication solely to 6-TG3. VOD exclusively related to 6-TG was first described by Gill et al., who observed a clinically reversible liver VOD developing in a young man with acute lymphocytic leukemia after 10 month administration of 6-TG4. Furthermore, sinusoidal obstruction was also reported in a patient with psoriasis treated with 6-TG and other cytotoxic therapy5. In 2006, a European 6-TG Working Party established that 6-TG should be considered a rescue drug in stringently defined indications in inflammatory bowel diseases (IBD). The indication for administration of 6-TG should only include its use for maintenance therapy as well as intolerance and/or resistance to aminosalicylates, azathioprine, 6-mercaptopurine, methotrexate and infliximab. Moreover, 6-TG must be withdrawn in case of overt or histologically proven hepatotoxicity6. Although Ansari et al 7 found no nodular regenerative hyperplasia (NRH) in the liver of patients given 6-TG, Dubinsky et al.8 described NHR as a common finding in 6-TG-treated patients with inflammatory bowel disease in the absence of VOD. By contrast, in our case report we showed histological pattern of VOD and, in accord with Gisbert et al.9, would suggest that 6-TG should not be administered out of a clinical trial setting. Given that the proportion of patients with Crohn’s disease achieving an improvement of symptoms during 6-TG treatment is similar to that after methotrexate10 or infliximab6, these drugs should therefore be considered as second line therapy in patients intolerant or resistant to azathioprine and 6-mercaptopurine.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
AGATA SALERNO MD, Department of Internal Medicine, University of Catania, c/o Cannizzaro Hospital, Via Messina 829, 95126 Catania, Italy. MARCO VACANTE, MD, Department of Internal Medicine, University of Catania, c/o Cannizzaro Hospital, Via Messina 829, 95126 Catania, Italy. DONATELLA POLLINA, MD, Department of Internal Medicine, University of Catania, c/o Cannizzaro Hospital, Via Messina 829, 95126 Catania, Italy. BENEDETTA STANCANELLI, MD, Department of Internal Medicine, University of Catania, c/o Cannizzaro Hospital, Via Messina 829, 95126 Catania, Italy. SILVIA MARTINI, MD,SSCVD Insufficienza Epatica e Trapianto, Azienda Ospedaliera Città della Salute e della Scienza – Molinette, C.so Bramante 88, 10126 Turin, Italy. EZIO DAVID, MD,SCDU II Anatomia Patologica, Azienda Ospedaliera Città della Salute e della Scienza – Molinette, C.so Bramante 88, 10126 Turin, Italy. LORENZO MALATINO, MD, PROFESSOR OF MEDICINE Department of Internal Medicine, University of Catania, c/o Cannizzaro Hospital, Via Messina 829, 95126 Catania, Italy.
Corresponding Author Details: 
MARCO VACANTE, Department of Internal Medicine, University of Catania, c/o Cannizzaro Hospital, Via Messina 829, 95126 Catania, Italy.
Corresponding Author Email: 
marcovacante@yahoo.it
References
References: 
  1. Kane S, Cohen SM, Hart J. Acute sinusoidal obstruction syndrome after 6-thioguanine therapy for Crohn's disease. Inflamm Bowel Dis. 2004;10:652-4.
  2. Elion G, Burgi E, Hitchings G. Studies on condensed pyrimidine systems, IX. The synthesis of some 6-substituted purines. J Am Chem Soc 1952;74:411-4.
  3. Griner PF, Elbadawi A, Packman CH. Veno-occlusive disease of the liver after chemotherapy of acute leukemia. Report of two cases.Ann Intern Med. 1976;85:578-82.
  4. Gill RA, Onstad GR, Cardamone JM, Maneval DC, Sumner HW. Hepatic veno-occlusive disease caused by 6-thioguanine.Ann Intern Med. 1982;96:58-60.
  5. Kao NL, Rosenblate HJ. 6-Thioguanine therapy for psoriasis causing toxic hepatic venoocclusive disease. J Am Acad Dermatol. 1993;28:1017-1018.
  6. de Boer NK, Reinisch W, Teml A, van Bodegraven AA, Schwab M, Lukas M, et al; Dutch 6-TG working group. 6-Thioguanine treatment in inflammatory bowel disease: a critical appraisal by a European 6-TG working party.Digestion. 2006;73:25-31.
  7. Ansari A, Elliott T, Fong F, Arenas-Hernandez M, Rottenberg G, Portmann B, et al. Further experience with the use of 6-thioguanine in patients with Crohn's disease.Inflamm Bowel Dis. 2008;14:1399-405.
  8. Dubinsky MC, Vasiliauskas EA, Singh H, Abreu MT, Papadakis KA, Tran T, et al. 6-thioguanine can cause serious liver injury in inflammatory bowel disease patients.Gastroenterology. 2003;125:298-303.
  9. Gisbert JP, González-Lama Y, Maté J. Thiopurine-induced liver injury in patients with inflammatory bowel disease: a systematic review. Am J Gastroenterol. 2007;102:1518-27.
  10. Feagan BG, Rochon J, Fedorak RN, Irvine EJ, Wild G, Sutherland L, et al. Methotrexate for the treatment of Crohn's disease. The North American Crohn's Study Group Investigators. N Engl J Med. 1995;332:292-7.

BJMP March 2014 Volume 7 Number 1

BJMP March 2014 Volume 7 Number 1

Full Issue Booklet   PDF

Review Articles

Case Reports/Series
Medical Images
Photo Quiz: Palatal swelling with pain
Segun Adeoye, Sylvester Sarfraz and Kiranmayi Korimerla
Full Text  PDF
Miscellaneous

Winners Vs. Losers: Are the Patients the Real Winners in this Game?

Authors
Juan S. Barajas-Gamboa
Article Citation and PDF Link
BJMP 2014;7(1):a710

It cannot be denied that healthcare services have become an attractive business for any party involved, whether it be government, insurance companies, hospitals and doctors, to look out for their own interest and leave aside the real priority of this system – the patients’ healthcare and welfare.1

Recent proposed changes in the health system (i.e. healthcare reform) have commanded the attention of all people involved. If nothing else, it has provided an avenue in which each detail can be scrutinized and assessed. And, ultimately, it can be used to optimize the balance of clinical outcomes with resource requirements.

As expected, each guild has its own theories and proposals for improving the delivery of care. However, coming to a consensus will be a difficult task given the economic interests at stake. It should be obvious that the most important guild affected by the changes is the guild formed by patients.2

From the physician’s point of view, achieving optimal patient care has become more difficult. In part, this is due to how the government has chosen to assess and improve the delivery of healthcare services, which is by implementing patient surveys to assess the quality of care and level of satisfaction. Basically, the government has hired private companies to prepare and distribute these assessments. Based on the results of these surveys, the government will allocate various economic resources. As a strategy to face these measures, hospitals have established annual incentive plans to motivate doctors to get good scores in patient satisfaction surveys, including offering higher salaries and compensations.2-3

This impasse pushes the system to operate in an inappropriate manner. For example, hospitals and physicians have increased the number of diagnostic tests, surgical interventions, use of medications, and number of hospitalizations with the sole purpose of making their patients happier. By showing more interest in their patients’ diseases, the hospital and physicians expect to get better scores on the surveys. However, this excess of interventions and expenses does not always ensure the best clinical outcomes. Instead, increased monetary investments can directly affect the finances of the health system.3-4

Currently, 66% of physicians are sheltered under an annual incentive plan; this leads to the idea that "more satisfaction of patients = higher salary.” Many authors consider this to be the silent murderer of the healthcare system since it does not guarantee increased patient satisfaction but it surely guarantees high monetary investment strategies.5

There are two key questions to address as a result of the problems generated by the survey results: How reliable are these surveys? Must we, as healthcare providers, modify our daily clinical practice based on these results? To start, I should mention that from my perspective as a physician, I do not agree that wage benefits and salaries of medical staff should be defined based on these results. More importantly, it should not determine the amount of money provided by the government to the health system and as aid to hospitals.5

Up to today, many scientific studies have been conducted to determine the impact of these assessments on the quality of the service in terms of clinical outcomes and patient satisfaction. The findings are controversial because some studies support the hypothesis that there is direct relationship between the scores of the surveys and the quality of healthcare services provided to patients. However, other studies have shown opposite results. There are some key points to be considered to reach a more objective conclusion regarding the implementation of these evaluation systems for medical staff and hospitals.2-4

There are many factors involved in each patient's experience that can affect the general opinion on the quality of his or her medical treatment and how satisfied he or she was with the treatment. Many observers argue that the number of treatments directly correlates with a better perception of the quality of patient care, regardless of the final outcome of the disease. On the other hand, some authors argue that there is a direct relationship between the expected and actual results achieved, thus fulfilling levels of patient expectations.

Based on this relationship, patients judge the effectiveness of physicians and medical staff according to their levels of satisfaction. However, it should be noted that patients receiving a greater number of interventions and treatments do not always get maximum level of satisfaction in spite of all the effort from the physicians and their teams. In fact, better results have been found on surveys when patients are encouraged to take the leadership of their medical treatment. This leads to better clinical outcomes and a reduction of resources used.

Other factors that may influence the assessment outcomes are: the number of events evaluated per patient (since many of them are chronic patients and have different experiences to be evaluated), the number of physicians involved in the patient care (i.e. different specialties working together), the time between medical care, and the evaluation of that care.3

Despite the variety of studies available in this particular area of knowledge, there is no clear definition of patient satisfaction in healthcare. In turn, many authors are concerned with the patients’ lack of medical knowledge. Therefore, if they receive negative patient comments, they cannot adequately judge and modify their medical practice.

In conclusion, the government must design healthcare reform strategies with all parties in mind. The ultimate goal of these strategies should be to safeguard the healthcare and welfare of patients, not to implement controversial evaluation systems that create conflicts within the system and ultimately lead to detrimental changes in physicians’ clinical practices.

Acknowledgements / Conflicts / Author Details
Acknowledgement: 
None
Competing Interests: 
None declared
Details of Authors: 
Juan S. Barajas-Gamboa, MD, University of California, San Diego School of Medicine, 9500 Gilman Dr, 92093, La Jolla, California, United States.
Corresponding Author Details: 
Juan S. Barajas-Gamboa, MD, University of California, San Diego School of Medicine, 9500 Gilman Dr, 92093, La Jolla, California, United States.
Corresponding Author Email: 
jbarajasgamboa@gmail.com
References
References: 
  1. Fu AZ, Wang N. Healthcare expenditures and patient satisfaction: cost and quality from the consumer's perspective in the US. Curr Med Res Opin. 2008 May;24(5):1385-94. doi: 10.1185/030079908X291994 . Epub 2008 Apr 2.
  2. Fenton JJ, Jerant AF, Bertakis KD et al. The cost of satisfaction: a national study of patient satisfaction, health care utilization, expenditures, and mortality. Arch Intern Med. 2012 Mar 12;172(5):405-11. doi: 10.1001/archinternmed.2011.1662. Epub 2012 Feb 13.
  3. Manary MP, Boulding W, Staelin R et al. The patient experience and health outcomes. N Engl J Med. 2013 Jan 17;368(3):201-3. doi: 10.1056/NEJMp1211775. Epub 2012 Dec 26.
  4. Jha AK, Orav EJ, Zheng J, et al. Patients' perception of hospital care in the United States. N Engl J Med. 2008 Oct 30;359(18):1921-31. doi: 10.1056/NEJMsa0804116.
  5. Falkenberg K. Why Rating Your Doctor Is Bad For Your Health.Forbes. (2013, Jan 21). Retrieved from http://www.forbes.com/sites/kaifalkenberg/2013/01/02/why-rating-your-doctor-is-bad-for-your-health

“Of the depression" - A Poem by Dr Javed Latoo

 

Cite this as: BJMP 2014;7(1):a709

 

When aquamarine sky looks grey to our eyes
  And golden rays of sunlight disappear from the skies.
When stars no longer adorn the heavens or shine bright
  And silver moon looks like a phantom of the night.
 
When we feel imprisoned in a dark place,
  Sorrowful eyes stare into a cold empty space.
When dazzling beauty looks like an old wrinkled face,
  Oblivious of the loved ones, their beauty and grace.
 
When we feel abandoned by the angel of sleep,
  Soul is drained, our eyes are eager to weep.
When our favourite food loses all its allure,
  Foggy brain cannot concentrate anymore.
 
When our mind tricks us to believe we are worthless,
  All consolations about the future seem fruitless.
When our heart is eaten by guilt over the trivialness,
  Soul is overwhelmed by stabbing hopelessness. 
 
When our mind ruminates about the days of yore,
  Life seems devoid of vigour, shine and decor. 
When reassurance fails to dampen our agitation
  And thoughts of optimism are replaced by suicidal ideation.
 
When we are in such a dark place of despair,
  Remember, It is a condition called Depression. Beware, 
It is a transitory phase, not an everlasting snare, 
  And help is available from the experts who care.
 
 
Competing Interests
None declared
Author Details
JAVED LATOO MBBS DPM MRCPsych, Consultant Psychiatrist and Honorary Lecturer, 5 Borough Partnership NHS Foundation Trust, Warrington, United Kingdom.
CORRESSPONDENCE: Dr JAVED LATOO MBBS, Consultant Psychiatrist, 5 Borough Partnership NHS Foundation Trust, Hollins Park, Hollins Lane, Warrington, United Kingdom.
Email: javedlatoo@gmail.com

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