Internal Medicine

Efficacy of Fixed High Dose Radioiodine Therapy for Hyperthyroidism – a 14 year Experience: A focus on Influence of Pre-treatment Factors on Outcomes

Y Khalid, D M Barton, V Baskar, H Kumar P Jones, T E T West and H N Buch
Article Citation and PDF Link
BJMP 2011;4(3):a435
Abstract / Summary

Radioiodine therapy (RAI) is commonly used as a definitive treatment for hyperthyroidism. However there is no agreement on the regime or the dose of RAI used and success rate is quite variable. In addition, the literature on the factors governing the success of the initial dose is conflicting.
We have adopted a standard 550 MBq dose for all patients with hyperthyroidism. The aims of our study were (1) to assess the success rate of this regime in terms of cure of hyperthyroidism and (2) to evaluate the role of pre-treatment factors including age, gender, use of antithyroid medication prior to RAI, aetiology of hyperthyroidism and free thyroxine levels at diagnosis, as predictors of response to RAI. 
Patients and methods
The study is a retrospective analysis of 584 patients treated at this centre over a 14 year period. All patients received a fixed 550MBq dose following withdrawal of antithyroid medication for 7 days. Repeat dose was administered if patients remained hyperthyroid at the end of one year after the initial dose. Success rate in terms of cure of hyperthyroidism was calculated. The association of pre-treatment factors and failure to respond to the first dose of RAI was studied using univariate and multivariate analyses.
Mean age was 56 years (range 20-90 years) with female preponderance (82%). Of the 478 patients in whom the aetiology could be ascertained by the criteria used, 344(72%) patients had Graves’ disease and 134(28%) patientshad toxic nodular disease. At the end of one year 545(93%) patients were either hypothyroid (411(70%)) or euthyroid (134(23%)) and were considered to be cured, while 39(7%) patients remained hyperthyroid and required further doses of RAI. Free thyroxine level at the time of diagnosis was the only pre-treatment factor, which independently influenced post-RAI outcome and a higher free thyroxine level predicted a lower cure rate. 
A standard 550MBq dose of RAI has a low failure rate when used for the treatment of hyperthyroidism. In our experience, only high free thyroxine levels at diagnosis was associated with a lower cure rate.


Hyperthyroidism is one of the most frequently encountered conditions in clinical endocrinology.1 The modes of treatment available are antithyroid drugs, surgery and radioiodine (RAI) and although each of these is highly successful in controlling or curing hyperthyroidism none leads to permanent euthyroidism on a consistent basis. 2 Although over the last three decades RAI therapy has replaced surgery as the leading form of definitive treatment 3, 4, 5 there is no universally accepted dose or regime for its use. Previous attempts to individualise the dose of RAI to reduce the rate of post-RAI hyper- or hypothyroidism have been unsuccessful 6, 7. Fixed dose RAI administration has therefore become the most commonly used regime although the actual dose of RAI used varies considerably and ranges between 185MBq to 600MBq 8, 9. For the last two decades we have used a fixed RAI dose of 550MBq for all patients. Others have used this regime with a high success rate 10 and a prospective head to head comparison with the calculated dose method found the fixed dose regimen to be superior for curing Graves’ hyperthyroidism 11.

Conflicting results have been produced in several studies that have attempted to predict outcome following RAI therapy by correlating cure rate with various pre-treatment factors including age, gender, aetiology of hyperthyroidism, goitre size, use of antithyroid drugs, free thyroxine levels at diagnosis and thyroid antibody status. Various forms of calculated or low fixed dose RAI therapy have been used in these studies but no study used a high fixed dose of 550MBq. In this study we have evaluated the overall success rate of high fixed dose RAI therapy and attempted to identify simple clinical predictors of failure to respond the initial RAI dose. 

Patients and Methods

The study is a retrospective analysis of 584 consecutive patients referred to the Shropshire endocrinology service (Princess Royal Hospital and Royal Shrewsbury Hospital) over a 14 year period for the treatment of hyperthyroidism. These patients received RAI therapy at Royal Shrewsbury Hospital, which is the only centre providing facilities for RAI administration in the county of Shropshire and also draws referral from adjoining trusts in Powys, North Wales. Information for this study was obtained from the thyroid database which is maintained on all patients who have received RAI since 1985 at the above hospitals.

RAI was administered both as a primary (53%) and as secondary (47%) treatment. A majority of patients with moderate to severe hyperthyroidism were rendered euthyroid by antithyroid drugs (ATD). Ninety percent (518/584) patients were pre-treated to euthyroidism by antithyroid drugs (carbimazole in 95% and propylthiouracil in 5%) before RAI therapy. Carbimazole was withdrawn one week and propylthiouracil 4 weeks prior to RAI therapy. A standard RAI dose of 550MBq was administered to all patients without a prior uptake study. Thyroid function was measured at 6 weeks and at 3, 6 and 12 months following RAI therapy. ATD drugs were not recommenced routinely following RAI therapy and were reserved for patients who were persistently and significantly hyperthyroid following RAI administration. Patients who developed clinical and biochemical hypothyroidism after the initial 6-8 weeks were commenced on thyroxine. Patients with high free thyroxine level (FT4) and a suppressed thyroid stimulating hormone (TSH) level and those on antithyroid medication were defined as being hyperthyroid, those with low FT4 or on thyroxine as hypothyroid and those with normal FT4 and a normal or low TSH as euthyroid. At the end of one year if a patient remained hyperthyroid, another RAI dose of 550MBq was administered. The patient was considered to have been “cured” if euthyroidism or hypothyroidism was achieved during the first year following RAI therapy and “not cured” if patient remained persistent hyperthyroidism at the end of this period.

 Information recorded on the database included age, gender, aetiology, indication (primary or secondary), dose of RAI, number of RAI doses, name and duration of antithyroid drugs used, if any, and FT4 and TSH levels at diagnosis, at the time of RAI therapy and at 6 weeks, 3, 6 and 12 months after RAI therapy. Diagnosis of Graves’ disease was based on the presence of Graves’ ophthalmopathy or a combination of a diffuse goitre and a significant titre of thyroid peroxidase antibodies or if radionuclide scan showed diffuse uptake. Toxic nodular disease was diagnosed on the grounds of a nodular goitre and a focal increase in radionuclide uptake. Patients who could not be classified to either of the groups on clinical grounds and where a radionuclide scan could not be performed for a variety of reasons, were categorised as “unclassified” on aetiological grounds.

Statistical analysis

Continuous random variables were compared using t-tests and association of categorical variables by using chi-squared tests. The effect on outcome (cure of hyperthyroidism) of all variables was assessed by using logistic regression analysis and a step-wise routine was applied to choose the best set of predictors. All analyses were carried out by using NCSS2000.


Data on 584 patients was included with a mean age of 56 years (range 20-90) and a female preponderance (82%). Assessment of the aetiology of hyperthyroidism was made by the above-mentioned criteria. In 110(15%) patients precise aetiological diagnosis could not be made. 344/474 (72%) patients had hyperthyroidism secondary to Graves’ disease and 134/474(28%) had toxic nodular disease. 518 patients received pre-RAI antithyroid medications. Mean free thyroxine level at time of diagnosis was 45.4pmol/L in 259 patients in whom this information was available.  Data for thyroid status at 3, 6, and 12 months post-radioiodine were available in 97, 94 and 100% patients respectively (see Table 1).

Table 1: Thyroid status at 3, 6 and 12 months

  Euthyroid (%) Hypothyroid (%) Hyperthyroid (%)
3 months 308 (54%) 176 (31%) 87 (15%)
6 months 210 (38%) 280 (51%) 59 (11%)
12 months 134 (23%) 411 (70%) 39 (7%)

FT4 values were entered onto the database more recently and this result was available in 259 patients. The group of patients where FT4 data was available was comparable to the group where this information was not available in all respects apart from age (mean age (SD) 54 (±15) vs 58 (±14) years respectively, p<0.02). Similarly, the group of patients in whom the aetiology could not be ascertained was not different from the group where the aetiology could be identified in any respect apart from the age (mean age (SD) 60 (±13) vs 55 (±15) respectively).

Table 2 – Forward Stepwise (Wald) logistic regression analysis to identify factors independently associated with failure to respond to first dose of RAI

Variables P value Adjusted r2; OR (95% CI)
Free T4 at diagnosis 0.005 0.084; 1.04 (1.01-1.07)
Free T4 > 45 pmol/l at diagnosis* 0.02 0.056; 3.43 (1.17-10.04)
Age 0.81 N/A
Gender 0.18 N/A
Aetiology 0.23 N/A
Pre RAI use of anti-thyroid drugs 0.42 N/A

* Regression analysis carried out with free T4 as a continuous variable and separately as a categorical variable at a cut off of 45pmol/l

One year following RAI treatment, 543(93%) patients were either euthyroid (162;28%) or hypothyroid (383;65%) and considered “cured”; 39(7%) patients remained hyperthyroid and required further doses of RAI, with 34(6%) patients requiring two doses and 5(1%)  patients three doses. At 3 months, 484 out of 571 (85%) patients, and at 6 months, 490 out of 549 (89%) patients were “cured” (table 2). On univariate analysis no correlation could be established between the failure to respond to the first dose RAI and age, gender, aetiology or use of antithyroid medication (p = ns for all) although the rate of hypothyroidism was significantly higher at the end of one year in patients with Graves’ disease as compared to those with toxic nodular disease (77.1% vs. 50.3%, p<0.01). These results were not affected by limiting the analyses to any of the following groups: only those patients in whom the aetiological diagnosis could be made (n=478), only those patients in whom FT4 value was available (n=259) or only those patients where both FT4 was available and aetiology could be ascertained (n=209). On univariate analysis FT4 at diagnosis was associated with the outcome when it was used as a continuous variable (p<0.05) or as a categorical variable with the cut off set at mean FT4 value of 45pmol/L (p=0.01) and high values were associated with failure to respond to the first dose of RAI (mean ± SD, 57.28±20.1 v 44.58±16.1 pmol/L, p<0.05). On multivariate analysis with all variables, FT4 was found to be independently associated with outcome and again this association was seen when FT4 was used as a continuous variable (p=0.01) as well as a categorical variable (p=0.02). On using step-wise selection routine only FT4 could be chosen as a predictor when criterion for selection was set at p=0.05 and a value of over 45pmol/L predicted failure to respond to the first dose of RAI.


The use of a standard fixed-dose RAI therapy is gaining increasing popularity and several studies have now shown that formal estimation of the required dose based on the thyroid size and iodine kinetics does not lead to a higher cure rate 6,7,10,11 or a lowerhypothyroidism rate 7. For several years we have used 550MBq dose for all patients of hyperthyroidism. The overall success rate with this regime was 93% and only 7% of patients required a repeat RAI dose. These figures are comparable to those from most other centres, which have used a similar dose of RAI 10. In addition to achieving a high cure rate, hyperthyroidism was controlled rapidly with 85% of the patients becoming either euthyroid or hypothyroid within 3 months of treatment. Early onset of hypothyroidism (>70% at 12 months) facilitated institution of thyroxine replacement therapy during the first year during which the patients were being closely followed.

The use of a relatively higher dose of RAI leads to more stringent restrictions to the normal life of patients and these have to be followed for a longer period of time than is the case with the use of a lower dose. Majority of patients accept these restrictions at the prospect of a cure of hyperthyroidism. However, even at this dose, 7% of patients required repeat dosing which in turn led to another restrictive period for these patients. In view of this it is useful to be able to predict failure of the first dose in an individual patient. This would enable us to warn these patients about the higher possibility of requiring repeat dosing, further period of post-RAI restrictions and target them for a closer follow up. To allow us to make this prediction we correlated simple clinical pre-treatment variables to the need for repeat dosing. We found that there was no statistically significant correlation between age, gender, aetiology and the use of anti-thyroid medication prior to RAI and the outcome following RAI therapy although a high free thyroxine level at diagnosis predicted a failure of the first dose to achieve a cure of hyperthyroidism. There are several conflicting reports in the literature on the correlation between these factors and the response to RAI therapy. Most of the studies have failed to show a significant association between the age of the patient and the outcome irrespective of whether the age was used as a continuous or a categorised variable 12-15 although in a study where a standard 150 gray RAI was used age >50 was found to be associated with a higher failure rate 16. In one study, male gender was associated with a lower cure rate following a single dose of RAI in patients with Graves’ disease 12 although others have failed to confirm this association 13,14. Use of antithyroid drugs prior to RAI has been shown to independently reduce the success rate of RAI 17, 18 while other studies have shown such an association with the use of propylthiouracil but not with carbimazole 19, 20. Literature on the association between the aetiology of hyperthyroidism and the outcome is even more confusing. Patients with toxic nodular disease have been considered to be more radio-resistant as compared to patients with Graves’ disease 21 although opposite results have also been noted 22. In other studies no correlation could be established on multivariate analysis between the aetiology and outcome following RAI 14, 18. Our study is the only one which analyses the influence of these factors on the outcome following the use of a standard 550MBq RAI dose and the above studies which have attempted to identify clinical predictors of outcome have either used various forms of the calculated dose regime or a lower fixed-dose RAI regime. We feel that this is the reason for the inconsistencies in the results and when a 550MBq dose RAI is used only FT4 value at diagnosis could predict the failure of RAI therapy to achieve cure. This dose of RAI appears to override the variations in the response induced by the remaining pre-treatment variables studied.

Studies using smaller doses or calculated doses of RAI have shown the outcome to be inversely associated with the thyroid size 14, 16 although this could not be ascertained in our study due to the lack of consistent documentation of the size ofgoitre in the clinical notes. In addition there are several possible confounding factors. Firstly the overall cure rate could have been influenced by the long period of time over which patients have been included (15 years) and the resulting changes in the criteria and threshold for the use of RAI. However if we divide the figures into 3 time periods of 5 years each, the findings remain consistent during each of these periods. Secondly, in over 50% of our patients, RAI was administered as a primary measure and it could be argued that a larger number of patients with milder hyperthyroidism may have been included in our cohort as compared to the patients at other centres where RAI is mainly reserved for patients who fail to respond to ATD. However there was no significant difference in the cure rate between those patients who received RAI as a primary measure and those in whom RAI was administered as a secondary treatment (94% v 93%). Thirdly in 15% of patients the aetiology could not be ascertained by using our well-defined criteria, mainly because of the practical difficulty of performing radionuclide scans in some of the patients where the diagnosis could not be made clinically. We do not feel that our results on the association between the aetiology and the cure rate were affected, as the patients with undefined aetiology were comparable to the remaining patients in all respects apart from age and had similar outcomes. Lastly the information on the FT4 value at diagnosis was available in only 259 patients. To exclude a selection bias this group was compared to the group of patients where this information was not available. Again the only difference between the two groups was the age distribution. In both instances this difference was not large (though statistically significant) and we do not feel it affected the outcome, especially as age does not appear to influence the outcome following RAI therapy. We could not assess the impact of post-RAI use of antithyroid drugs as these were not routinely restarted following RAI therapy at our centre.


In conclusion, high fixed dose RAI therapy is a very effective treatment for patients with hyperthyroidism and has a high success rate. Failure to respond to this dose cannot be predicted by most of the pre-treatment variables apart from the severity of the hyperthyroidism as judged by the FT4 value at diagnosis. Patients who present with severe hyperthyroidism should be warned regarding the higher possibility of requiring further doses of radioiodine even when treated with a dose of 550MBq.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
Y KHALID, V BASKAR, New Cross Hospital, Wolverhampton, UK. D M BARTON, H KUMAR, T E T WEST, H N BUCH, Princess Royal Hospital, Telford, UK. P JONES, Keele University, Stoke on Trent, UK.
Corresponding Author Details: 
YASMEEN KHALID, Clinical Fellow, Diabetes and Endocrinology, New Cross Hospital Wednesfield Road, Wolverhampton WV10 0QP
Corresponding Author Email:


1. Furszyfer J, Kurland LT, McConahey WM et al. Epidemiologic aspects of Hashimoto’s thyroiditis and Graves’ disease in Rochester, Minnesota, 1935-1967. 1972 Metabolism: 21:197-204

2. Douglas S. Ross, M.D.Radioiodine Therapy for Hyperthyroidism, N Engl J Med 2011;364:542-50.

3. Solomon B, Gilinoer D, Lagasse R and Wartofsky L Current trends in the management of Graves’ disease Journal of Clinical Endocrinology and Metabolism 1990. 70:1518-1524

4. Becker DV Choice of therapy for Graves’ disease. New EnglandJournal of Medicine 1984 311: 464-6

5. Farrar JJ, Toft AD.  Iodine –131 treatment of hyperthyroidism: current issues. Clinical Endocrinology(Oxf) 1991; 35: 207-12

6. Jarlov AE, Hegedus L, Kristensen LO, Nygaard B, Hansen JM  Is calculation of the dose in radioiodine therapy of hyperthyroidism worthwhile?Clinical Endocrinology 1995; 43: 325-29

7. Sridama V, McCormick M, Kaplan EL, Fauchet R, DeGroot LJ Long term follow up study of compensated low dose131iodine therapy for Graves’ disease. New EnglandJournal of Medicine 1984; 311: 426-31

8. Sanyal D, Mukhhopadhyay P, Pandit K, Chatterjee J, Raychaudhuri M, Mukherjee S, Chowdhury S. Early treatment with low fixed dose (5 mCi) radioiodine therapy is effective in Indian subjects with Graves' disease J Indian Med Assoc.2008 Jun;106(6):360-1, 372

9. Radioiodine in the management of benign thyroid disease, clinical guidelines Royal College of Physicians 2007.

10. Kendall-Taylor P, Keir M, Ross WM Ablative radioiodine therapy for hyperthyroidism: long-term follow up study. British Medical Journal 1984; 289: 361-3

11. Peters. H, Fischer C., Bogner U, Reiners C, Schleusener H  Radioiodine therapy of Graves’ hyperthyroidism: standard vs. calculated 131iodine activity.     Results from a prospective, randomised, multicentre study. European Journal of Clinical Medicine 1995; 25: 186-93

12. Allahabaida A, Daykin J, Holder R, Sheppard M, Gough SCL, Franklyn JA  Age and gender predict the outcome of treatment for Graves’ hyperthyroidism  Journal of Clinical Endocrinology and Metabolism 2000; 85: 1038-1042

13. Nordyke RA, Gilbert FI Optimal iodine-131 dose for eliminating hyperthyroidism in Graves’ disease. Journal of Nuclear Medicine 1991; 32(3): 411-410

14. Jarlov AE, Christensen E, Hegedus L, Kristensen LO, Nygaard B, Hansen JM Factors associated with recurrence of hyperthyroidism after 131I treatment: the inadvertent influence of antithyroid drug administration after 131I treatment of hyperthyroidism Thyroidol Clin Exp 1997; (9): 55-59

15. Allahabadia A, Daykin J, Sheppard MC, Gough SC, Franklyn JA  Radioiodine treatment of hyperthyroidism-prognostic factors for outcomeJournal of Clinical Endocrinology and Metabolism  2001 86(8):3611-7.

16. Pfeilschifter J, Elser H, Haufe S, Zeigler R, Georgi P. Impact of pre-treatment variables on the outcome of standardised 131I therapy with 150 gray in Graves’ disease. Nuclearmedizin 1997 36(3): 81-86

17. Sabri O, Schulz G, Zimny M et al Determination of factors affecting the therapeutic outcome of radioiodine therapy in patients with Graves’ disease Nuclearmedizin 1998 37(3): 83-89

18. Franklyn JA, Daykin J, Holder R, Sheppard MC Radioiodine therapy compared in patients with toxic nodular or Graves’ hyperthyroidism Quarterly Journal Medicine 1995; 88: 175-180

19. Hancock LD, Tuttle RM, LeMar H, Bauman J, Patience T The effect of propylthiouracil on subsequent radioactive iodine therapy in Graves’ disease. Clinical Endocrinology 1997; 47(4): 425-430

20. Imseis RE, Vanmiddlesworth L, Massie JD, Bush AJ, Vanmiddlesworth NR. Pre-treatment with propyluracil but not methimazole reduces the therapeutic effeicacy of Iodine-131 in hyperthyroidism. Journal of Clinical Endocrinology and Metabolism 1998; 83: 685-687

21. Farrar JJ, Toft AD Iodine –131 treatment of hyperthyroidism: current issues. Clinical Endocrinology (Oxf) 1991; 35: 207-12

22. Delgrange E, Weber E, Michel L, DeCoster P, Buysschaert M, Donckier J. Status of three years of hyperthyroidism treatment with iodine 131 Acta Clinica Belgica 1994; 49(5): 200-2007

Painful legs and moving toes – Case report and Review of literature

Roy Liu, Mohammed Moizuddin and Serena Hung
Article Citation and PDF Link
BJMP 2011;4(3):a431
Abstract / Summary

Objective: Painful legs and moving toes (PLMT) is a syndrome consisting of pain in the lower legs with involuntary movements of the toes or feet. Its incidence and prevalence remain largely unknown since it is still a relatively rare disorder. We are reporting a case of PLMT along with the first review of literature on all previously reported cases and a discussion on its clinical management.

Methods: A review of published literature on PLMT was done using MEDLINE and PubMed databases. Searches were conducted to find articles from 1971 – 2010. Medical subject headings used to search the databases included PLMT with subheadings of painful legs/moving toes, electromyography, polysomnography, as well as keyword search using “PLMT”. Single author reviewed titles and abstracts of potentially relevant articles.

Results: We reviewed approximately 19 PLMT articles that have been published to date, with a total of 72 patients: 30.5% males and 69.5% females (median age 55 & 64 yrs, respectively). The most common predisposing conditions were neuropathy and radiculopathy. Numerous treatments including antiepileptics, benzodiazepines, antispasmodic agents, and antidepressants have been tried with little success. GABAergic agents such as gabapentin and pregabalin were the most effective in attenuating the pain and the movements, possibly via both central and peripheral mechanisms.

Conclusion: Physicians should be aware of this rare debilitating condition. Though much progress has been made in elucidating its etiology, the exact mechanism still remains a mystery. It is important to consider PLMT in a patient with painful legs and/or restless leg syndrome without any significant history of neurological disease or trauma. Diagnosis is essentially clinical and treatment is complex, which includes different combinations of medications and invasive techniques that generally produce a poor outcome.

Painful legs, Moving toes, GABA agonists, Peripheral Neuropathy


First described in 1971 by Spillane et al.1, painful legs and moving toes (PLMT) is a syndrome consisting of pain in lower legs with involuntary movements of the toes or feet. Pain varies from moderate discomfort to diffuse and deep and usually precedes movements by days to years. The movements themselves are often irregular and range from flexion/extension, abduction/adduction to clawing/straightening and fanning/ circular movements of the toes.1,2 This syndrome may affect one leg or spread to involve both legs.3

PMLT incidence and prevalence remain largely unknown since it is still a relatively rare disorder worldwide. Age of onset is between the second and seventh decades of life. It has been postulated that lesions of the peripheral or central nervous system after nerve or tissue damage might lead to impulse generation that subsequently causes the symptoms seen in PLMT.4 We report a case of PMLT that presented to our Neurology Movement Disorder Clinic along with a discussion on the pathophysiology, differential diagnosis and clinical management of this rare debilitating condition.

Case report

63 year old, morbidly obese (BMI 41.7) Caucasian male patient with past medical history of stroke 10 years ago, on long term anticoagulation, hypertension, type II controlled diabetes mellitus, asbestos exposure, bilateral hip and knee osteoarthritis, left total knee replacement 2 years ago, and non-traumatic ruptured Achilles tendon; presented with complaints of involuntary movements in both legs over the last 8-10 years. He had unprovoked flexion and extension of the toes along with feet movement at all times with no diurnal variation. He admitted to having a constant severe pain described as 'twisting a rubber band' with 10/10 intensity that radiated up to his calf accompanied by numbness and dorsal swelling of both feet for many months. He claimed to have partial relief whilst walking but had difficulty walking without a cane as he ‘“could not balance with constantly moving [his] feet”’. Tylenol 500mg as required and amitriptyline 20mg at night prescribed by his primary care physician provided no relief.

He also has a history of snoring, daytime fatigue, and non-restorative sleep with frequent nocturnal awakenings due to bilateral feet pain. He recalled having a stroke with transient confusion and focal hand weakness along with visual problems about 10 years previously. All laboratory and radiological investigations were negative and he recovered fully. He had previously served with the US armed forces and had been exposed to ‘Agent Orange’ in Vietnam.

He had no medical allergies and his current medications include amitriptyline 25mg at night, hydrochlorothiazide 25mg once daily, lisinopril 10mg once daily, loradatine 10mg once daily, metoprolol tartrate 20mg twice daily, simvastatin 20mg once daily, vitamin B complex one tablet once daily and warfarin once daily. He denied any history of alcohol, tobacco, or recreational drug abuse in the past. His mother had a history of hypertension and chronic low back pain; no members of his family had any neurological or movement disorders.

Physical examination revealed an alert, awake, and well oriented male with bilateral lower extremity varicose veins. He was observed to have semi-rhythmic flexion-extension and occasionally abduction movements of the phalanges, especially in the great toes. There was a profound decrease in vibration sense below both knees and it was almost absent on both feet, decreased reflexes in both feet, and absent proprioception in the phalangeal joints. He was also observed to have decreased pinprick and monofilament sensation in both legs below the knee. Bilateral ankle reflexes were diminished with negative Babinski sign. Both lower extremity dorsalis pedis and posterior tibial pulsations were palpable. He did not have any cerebellar signs. He did have pitting oedema up to his shins in both lower extremities, extending from his feet to upper one third of the legs. There were no abnormalities noted on the bilateral lower extremity EMG and there was no electrodiagnostic evidence of large-fiber neuropathy.

He was diagnosed with painful legs and moving toes syndrome and started on a trial of gabapentin 300mg at night. He was advised to increase it to 1200mg and to continue taking his amitriptyline 25mg at night. Scheduled MRI of the brain could not be done due to his morbid obesity. He was arranged follow up in three months in the clinic.


A review of published literature on PLMT was done using MEDLINE and PubMed databases. Searches were conducted to find articles from 1971 – 2010. Medical subject headings used to search the databases included PLMT with subheadings of Movement disorder, Electromyography, and Polysomnography as well as keyword search using ‘PLMT’. Single author reviewed titles and abstracts of potentially relevant articles.

Review of current literature

We reviewed approximately 19 PLMT articles that have been published to date with a total of 72 patients: 30.5% males, 69.5% females (median age 55 & 64 years,

respectively). Clinical presentations in the majority of the cases were burning pain in lower extremities and involuntary movements of the toes. The most common predisposing conditions were neuropathy and radiculopathy (see Table 1).

Table 1 - Painful Legs & Moving Toes Syndrome ~ Review of Literature (1971- 2010)

Author Year Sex/
Subject age # of cases Clinical presentation
Spillane et al 1971 M (4)
F (2)
51, 52, 52, 53
66, 68
6 Burning/throbbing LE pain followed by writhing/clawing and flexion/extension movements of the toes
Dressler et al 1994 M (4)
F (16)
28, 36, 54, 73
20 Pain in LE followed by involuntary flexion/extension and abducion/adduction of the toes
Shime et al 1998 F (1) 63 1 Involuntary flexion/extension of the toes bilaterally and aching/crampy pain in both feet
Schott et al 1981 M (1)
F (4)
56, 57, 69, 77
5 Crushing pain in both feet followed by involuntary writhing and flexion/extension of the toes; burning pain in foot followed by writhing toe movements
Montagna et al 1983 M (1)
F (2)
74, 76
3 Burning pain in one or both LE followed by involuntary flexion/extension, abduction/adduction, and fanning/clawing of the toes
Shime et al 1998 F (1) 63 1 Involuntary flexion/extension of the toes bilaterally and aching/crampy pain in both feet
Villarejo et al 2004 M (1) 66 1 Paresthesias/burning pain in both feet followed by involuntary flexion/extension and abduction/adduction of the toes
Aizawa et al 2007 F (1) 73 1 Tingling pain in both feet followed by involuntary abduction/adduction of the toes
Guimaraes et al 2007 M (1) 60 1 Wringing-like pain in in L foot and R leg followed by flexion/extension and abduction/adduction of the toes
Eisa et al 2008 M (1)
F (1)
2 Burning pain in bilateral LE followed by semirhythmic flexsion/extension of the toes
Alvarez et al 2008 M (6)
F (8)
25-84 (mean 69) 14 Burning pain of LE followed by involuntary flexion/extension, abduction/adduction, fanning, or clawing of the toes
Tan et al 1996 F (1) 57 1 Severe burning pain in both LE followed by involuntary flexion/extension and abduction of the toes
Dressler et al 1994 M (4)
F (16)
28, 36, 54, 73
20 Pain in LE followed by involuntary flexion/extension and abducion/adduction of the toes
Yoon et al 2001 F (1) 56 1 Burning pain in R foot with flexion and lateral deviation of the toes
Miyakawa et al 2010 M (1)
F (1)
2 Burning pain in R arm followed by involuntary flexion/extension of R thumb; pain in L leg accompanied by flexion/extension and abduction/adduction of L toes
Schoenen et al 1984 M (2)
F (4)
49, 74
68, 69, 71, 80
6 Burning/aching pain in LE followed by involuntary flexion/extension and writhing of the toes
Sanders et al 1999 F (1) 76 1 Deep/throbbing pain in L leg followed by invloluntary flexion/extension and abduction/adduction of L toes
Ikeda et al 2004 F (1) 75 1 Involuntary flexion/extension of the toes bilaterally followed by pain in both legs
Kwon et al 2008 F (1) 75 1 Painless wriggling movements of the toes in both feet

Total Number of articles reviewed = 19
Total Number of Cases: Male = 22 (Median Age = 55 years); Female = 50 (Median Age = 64 years)
Author/Article References in chronological order (Top to below): 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 16, 17, 23, 24, 25, 29, 31, 32, 33

In 1981 Schott GD et al reported that in 3 PLMT patients the EMG revealed evidence of denervation in the affected muscles. Montagna et al of the University of Bologna, Italy reported 3 cases of PLMT that exhibited evidence of peripheral neuropathy on EMG. Polysomnography (PSG) studies on these patients showed reduced movements during sleep with increase in slow wave or rapid eye movement sleep.5 This suggested the movements could have arisen centrally.

Guimaraes et al of the Universidade Nova Lisboa, Portugal reported one patient with a history of Hashimoto’s disease whose lower extremity EMG showed spontaneous arrhythmic bursts of the affected muscles during wakefulness which disappeared during sleep6. Both suggested the movements could have arisen centrally.

Alvarez et al of the Mayo Clinic described 14 cases of PLMT in 2008 in which burning pain often preceded the movements. PSG studies confirmed these movements would also persist in light stages of sleep which pointed to a central origin.7 Eisa et al of Yale University School of Medicine, Connecticut described 2 cases of PLMT in which one patient had a past history of lumbosacral root injury and the other systemic lupus erythematosus with peripheral neuropathy on EMG.8 Interestingly, in the latter patient her pain occurred years after the onset of involuntary toe movements.8


Spinal cord and cauda equina diseases, neuropathies, radiculopathies, drugs and other systemic diseases are the main cause of this syndrome although many cases are still idiopathic. The most common predisposing conditions were neuropathy (i.e. polyneuropathy from alcoholism, hypertrophic mononeuritis, or tarsal tunnel syndrome) and radiculopathy.7 Other etiologies include nerve root lesions, peripheral nerve trauma, spinal ganglia lesions, cauda equina lesion, Wilson’s disease, herpes zoster myelitis, HIV, neuroleptics, and chemotherapeutic agents.9-19

The involuntary movements appeared bilaterally in the toes in our patient, which suggests that central reorganization (especially in the spinal level) is the cause of PLMT. EMG and nerve conduction studies have proven helpful in demonstrating spontaneous arrhythmic bursts of affected muscles and underlying neuropathy in some patients. Although the exact mechanism remains elusive, it has been proposed that impulses generated in lesioned peripheral nerve, posterior nerve root/ganglion, or afferent fibers pass into the spinal cord - some to higher areas to cause pain, while others into the local interneuron and motor neurons to generate involuntary movements of the toes.5

In patients with clinical or electrophysiological evidence of peripheral nerve or root problem, these lesions can initiate or even alter afferent input to the spinal cord and cause subsequent central and efferent motor reorganization, which may explain the limited

success these patients had with nerve blocks or lumbar sympathetic blockade.2 Similarly, some have suggested that even though the radiation of pain following local trauma seemed to resemble causalgia,20 there was a lack of hyperpathia and changes in the soft tissue, bones, and blood vessels as well as a poor response to sympathetic blockade, thus making clinical features of PLMT inconsistent with known radicular disorders.3

Interestingly, some believed that the central nervous system played an essential role in PLMT via a central oscillator.21 It has also been proposed that hyper-excitability of the damaged peripheral nerves could cause symptoms of PLMT by way of the sympathetic nervous system. More specifically, the sympathetic nervous system could potentially serve as a bridge between injured afferent fibers and sympathetic nerve fibers,22 allowing abnormal afferent impulse to travel to efferent fibers and ultimately leading to continuous pain with involuntary movements. This was evident in the fact that lumbar sympathetic ganglion blockade provided moderate symptomatic relief for some patients even though it was short-lived.4 Interestingly, one of the explanations put forth was the possibility of spinal/supraspinal reorganization,23 which coincided with the hypothesis of central reorganization mentioned above.

Clinical Management

Numerous treatments including antiepileptics, benzodiazepines, antispasmodic agents, and antidepressants have been tried with little success.1,2,24,25 However, temporary success was observed with local anesthetic nerve blocks, epidural blocks, sympathectomy/sympathetic blockade, neurectomies, botulinum toxin type A injection, transcutaneous electrical nerve stimulation, vibratory stimulation, and epidural spinal cord stimulation.1,2,15,26,27 Analgesics, steroids, anti-inflammatory agents, vitamin B12 injections, propranolol, quinine sulphate, and local anesthetics only offered temporary relief as well.3 GABAergic agents such as gabapentin and pregabalin were the most effective in attenuating the pain and the movements, possibly via both central and peripheral mechanisms.7,24,25 It has been reported that gabapentin as high as 600mg three times daily could control symptoms of PLMT long-term.25

Treatment of PLMT has also been attempted with botulinum toxin A at the level of lumbosacral roots and peripheral nerves with moderate relief of symptoms, although toe movements did return after a few months.8 It was suggested that botulinum toxin A might have acted via reduction of muscle spindle discharge leading to decreased central sensitization, as well as antisympathetic, antiglutamergic, or anti-inflammatory effects.28

Differential Diagnosis

The syndrome of PLMT exhibits certain features similar to the restless leg syndrome (RLS). In RLS the sensation in the legs could be burning, creeping, or tingling coupled with an urge to move them, especially early in the night. Movements such as walking or stretching relieve the symptoms whereas rest makes them worse. However, in PLMT pain is severe, constant, unrelated to the sleep-wake cycle, and is not relieved by

movements or walking.23 In addition, its involuntary movements of the toes or feet also differ from the myoclonic jerks of RLS.

In conditions such as thalamic syndrome and limb pain with myoclonus, patients may experience pain and involuntary movements as well but they often occur simultaneously as opposed to in PLMT where pain often precedes the movements.17 In disorders such as Parkinson’s disease and dystonia, sustained involuntary movements in the feet can be present and pain can be an associated feature. But the movements are typically sustained muscle contractions, which are different from the typical movements associated with PLMT.


PLMT is a newly discovered syndrome and since there has not been a systematic study following these patients long-term, it is currently quite difficult to predict the outcome of this syndrome and its effect on lifespan, though there has yet been a report of a patient actually dying from this syndrome. However, it is known that PLMT is a debilitating condition that greatly reduces patients’ quality of life.


Since Spillane et al first described it in 1971, there have been more reported cases of PLMT and its variants over the years. Though much progress has been made in elucidating its etiology, its exact mechanism still remains a mystery. Similarly, even though EMG and nerve conduction studies have proven helpful in demonstrating spontaneous arrhythmic bursts of affected muscles and underlying neuropathy in some patients, diagnosis of PLMT remains largely on history and clinical presentation.

Physicians should be aware of this rare debilitating condition. It is important to consider PLMT in a patient with painful legs and/or restless leg syndrome without any significant history of neurological disease or trauma. Treatments such as different combinations of medications and invasive techniques are complex and generally lead to a poor outcome.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
No sources of funding were used to assist in the preparation of this case report. Dr Serena Hung is a full time employee of Biogen Idec and owns stock in the company. The authors have no conflict of interests that are directly relevant to the content of this case report and review of literature.
Details of Authors: 
ROY LIU, MOHAMMED MOIZUDDIN, MD FACP Department of Sleep Medicine, Medical College of Wisconsin, Wisconsin. SERENA HUNG, MD. Biogen Idec, Inc. Cambridge, MA
Corresponding Author Details: 
MOHAMMED MOIZUDDIN, MD FACP, Department of Sleep Medicine, Medical College of Wisconsin, 8701 West Watertown Plank Road, Milwaukee, WI 53226-3548
Corresponding Author Email:


1. Spillane JD, Nathan PW, Kelly RE, Marsden CD. Painful legs and moving toes. Brain. 1971; 94(3): 541-556. 2. Dressler D, Thompson PD, Gledhill RF, Marsden CD. The syndrome of painful legs and moving toes. Mov Disord. 1994; 9(1): 13-21.3. Schott GD. "Painful legs and moving toes": The role of trauma. J Neurol Neurosurg Psychiatry. 1981; 44(4): 344-346.4. Shime N, Sugimoto E. Lumbar sympathetic ganglion block in a patient with painful legs and moving toes syndrome. Anesth Analg. 1998; 86(5): 1056-1057.5. Montagna P, Cirignotta F, Sacquegna T, Martinelli P, Ambrosetto G, Lugaresi E. "Painful legs and moving toes" associated with polyneuropathy. J Neurol Neurosurg Psychiatry. 1983; 46(5): 399-403.6.  Guimaraes J, Santos L, Bugalho P. Painful legs and moving toes syndrome associated with hashimoto's disease. Eur J Neurol. 2007; 14(3): 343-345.7. Alvarez MV, Driver-Dunckley EE, Caviness JN, Adler CH, Evidente VG. Case series of painful legs and moving toes: Clinical and electrophysiologic observations. Mov Disord. 2008; 23(14): 2062-2066.8. Eisa M, Singer C, Sengun C, Russel A, Jabbari B, Papapetropoulos S. Treatment of painful limbs/moving extremities with botulinum toxin type A injections. Eur Neurol. 2008; 60(2): 104-1069. Schott GD. "Painful legs and moving toes": The role of trauma. J Neurol Neurosurg Psychiatry. 1981; 44(4): 344-34610. Gastaut JL. Painful legs and moving toes. A drug-induced case. Rev Neurol (Paris). 1986; 142(6-7): 641-642. 11. Ikeda K, Deguchi K, Touge T, et al. Painful legs and moving toes syndrome associated with herpes zoster myelitis. J Neurol Sci. 2004; 219(1-2): 147-150. 12. Malapert D, Degos JD. Painful legs and moving toes. neuropathy caused by cytarabine. Rev Neurol (Paris). 1989; 145(12): 869-871. 13. Mattos JP, Rosso AL, Correa RB, Novis SA. Movement disorders in 28 HIV-infected patients. Arq Neuropsiquiatr. 2002; 60(3-A): 525-530. 14. Mitsumoto H, Levin KH, Wilbourn AJ, Chou SM. Hypertrophic mononeuritis clinically presenting with painful legs and moving toes. Muscle Nerve. 1990; 13(3): 215-221.15. Okuda Y, Suzuki K, Kitajima T, Masuda R, Asai T. Lumbar epidural block for 'painful legs and moving toes' syndrome: A report of three cases. Pain. 1998; 78(2): 145-147.16.  Pla ME, Dillingham TR, Spellman NT, Colon E, Jabbari B. Painful legs and moving toes associates with tarsal tunnel syndrome and accessory soleus muscle. Mov Disord. 1996; 11(1): 82-86. 317.  Sanders et al. An ‘annoying’ foot: unilateral painful legs and moving toes syndrome. Pain Vol 82 (1), 1999; 103-10418. Sandyk R. Neuroleptic-induced "painful legs and moving toes" syndrome: Successful treatment with clonazepam and baclofen. Ital J Neurol Sci. 1990; 11(6): 573-576.19. Touge T, Ishibashi T, Kamoda M, Tsukaguchi M, Takeuchi H. "Painful legs and moving toes" and muscle cramps spreading to the bilateral legs in a patient with alcoholic polyneuropathy. Rinsho Shinkeigaku. 1998; 38(8): 762-766. 20. Sunderland S. Pain mechanisms in causalgia. J Neurol Neurosurg Psychiatry. 1976; 39(5): 471-480.21. Jabbari B, Molloy FM, Erickson M, Floeter MK. Bilateral painful hand-moving fingers: Electrophysiological assessment of the central nervous system oscillator. Mov Disord. 2000; 15(6): 1259-1263.22. Seltzer Z, Devor M. Ephaptic transmission in chronically damaged peripheral nerves. Neurology. 1979; 29(7): 1061-1064.23. Miyakawa T et al. Case Reports: Painful limbs/Moving Extremities. Clin Ortho & Related Research 2010 Vol 468 (12); 3419-342524.  Aizawa H. Gabapentin for painful legs and moving toes syndrome. Intern Med. 2007; 46(23): 1937. 25. Villarejo A, Porta-Etessam J, Camacho A, Gonzalez De La Aleja J, Martinez-Salio A, Penas M. Gabapentin for painful legs and moving toes syndrome. Eur Neurol. 2004; 51(3): 180-181.26. Nathan PW. Painful legs and moving toes: Evidence on the site of the lesion. J Neurol Neurosurg Psychiatry. 1978; 41(10): 934-93927. Takahashi H, Saitoh C, Iwata O, Nanbu T, Takada S, Morita S. Epidural spinal cord stimulation for the treatment of painful legs and moving toes syndrome. Pain. 2002; 96(3): 343-345.28. Lang AM. Considerations for the use of botulinum toxin in pain management. Lippincotts Case Manag. 2006; 11(5): 279-282.29. Verhagen WI, Horstink MW, Notermans SL. Painful arm and moving fingers. J Neurol Neurosurg Psychiatry. 1985; 48(4): 384-385. 30. Yoon et al. Syndrome of painful legs and moving toes. Journal of Amer Podiatric Med Assoc Vol. 91 (7), 2001; 361-36431. Schoenen J, Gonce M, Delwaide PJ. Painful legs and moving toes: a syndrome with different pathophysiologic mechanisms. Neurology. 1984; 34:1108–111232.  Tan AK, Tan CB. The Syndrome of painful legs and moving toes – case report. Singapore Med J 1996 Aug; 37 (4): 446-733. Seon-Joo Kwon, MD, Jong-Min Kim, MD, and Beom S. Jeon, MD: A case report of painless moving toes syndrome. J Clin Neurology 2008; 4(1): 33-35

Thyrotoxic Periodic Paralysis

M Suresh Babu, H Basavanna Gowdappa, M R Aiyappa and Sasidharan Sameer
Article Citation and PDF Link
BJMP 2011;4(3):a430
Abstract / Summary

Thyrotoxic periodic paralysis (TPP) is an alarming and potentially lethal complication of hyperthyroidism characterised by muscle paralysis and hypokalaemia. It is often not recognised when first seen because of lack of familiarity with the disorder and partly due to the subtleness of thyrotoxicosis. Early diagnosis and treatment can prevent severe cardiopulmonary complications. We hereby report a male patient who was evaluated and diagnosed to have TPP.

Thyrotoxic Periodic Paralysis, hypokalaemia, thyrotoxicosis


Thyrotoxic periodic paralysis (TPP) is an uncommon disorder characterised by simultaneous thyrotoxicosis, hypokalaemia, and paralysis that occurs primarily in males of South Asian descent.1 Many affected patients do not have obvious symptoms and signs of hyperthyroidism and hence may be misdiagnosed or overlooked on presentation.2 We hereby report a male patient who presented to us with weakness of all four limbs. The patient was evaluated and diagnosed to be having TPP.

Case History

A 30-year-old male patient, who was an agriculturist by profession, presented with weakness of all four limbs of one-day duration. The weakness first appeared in his lower limbs and then in the upper limbs. There were no sensory symptoms or bladder involvement. He was not a known hypertensive, diabetic or thyrotoxic patient. He was not on any medication for any significant illness.

On general physical examination, there was no pallor, icterus, cyanosis, clubbing, lymphadenopathy or pedal oedema. Multinodular goitre was noted on thyroid examination. There was no exopthalmos, lid lag, pretibial myxoedema or other signs of thyrotoxicosis.  Thyroid bruit was absent.  Pulse rate was 96/minute, blood pressure of 140/80mmHg, and respiratory rate 18/minute. On central nervous system examination, the higher mental functions and cranial nerve examination were within normal limits. Motor system examination showed the presence of flaccid quadriparesis with areflexia. Sensory system examination was within normal limits. Cardiovascular and respiratory system examination were normal.

Investigations revealed: haemoglobin (Hb) -13.1 gm%, total count (TC) - 11,400/cmm, platelet count - 49,000/cmm, random blood sugar (RBS) - 110mg/dl, blood urea - 29 mg/dl, serum creatinine - 0.8 mg/dl. Serum electrolyte profile showed sodium - 143 mEq/L, potassium - 2.2mEq/L, chloride - 112mEq/L. Serum calcium and magnesium levels were within normal limits. Electrocardiogram (ECG) was normal. Human Immunodeficiency Virus (HIV) ELISA was non reactive. Bone marrow biopsy and ultrasonography of abdomen were normal. Fine Needle Aspiration Cytology (FNAC) of thyroid showed features of hyperplastic colloid goitre. Ultrasonography of thyroid showed hyperechoic small nodules in both lobes as well as isthmus suggestive of multinodular goitre. Thyroid profile was: total T3 - 2.34 (normal: 0.60 - 1.81ng/ml), total T4 - 13.9 (normal: 4.5 - 10.9 mcg/dl), thyroid-stimulating hormone (TSH) - 0.01 (normal: 0.35 - 5.5IU/ml). Antithyroid antibodies and antiplatelet antibodies were negative. Nerve conduction study was normal. A final diagnosis of TPP with idiopathic thrombocytopenia was made.

The patient was administered 40mmol potassium chloride intravenously.  He was treated with tablet carbimazole 10mg three times a day and tablet propanolol 10mg twice a day. The patient’s weakness in all four limbs improved dramatically within an hour after potassium chloride administration. As he had persistent thrombocytopenia during his stay in hospital, he was commenced on tablet prednisolone (1mg/kg body weight). His platelet count normalized in one month after which the steroid dose was tapered and stopped.


TPP is an uncommon disorder characterised by simultaneous thyrotoxicosis, hypokalaemia and paralysis that occurs primarily in males of South Asian descent. The overall incidence of TPP in Chinese and Japanese thyrotoxic patients is 1.8% and 1.9% respectively.3, 4 Sporadic cases have been reported in non-Asian populations such as Caucasians, Afro-Americans, American Indians and Hispanics. With population mobility and admixture, TPP is becoming more common in Western countries. Many affected patients are in the age group of 20 - 40 years and do not have obvious symptoms and signs of hyperthyroidism.5 The attack is characterised by recurrent, transient episodes of muscle weakness that range from mild weakness to complete flaccid paralysis. The proximal muscles are affected more severely than distal muscles.  Attacks usually first involve the lower limbs, and progress to the girdle muscles and subsequently the upper limbs. Sensory function is not affected. Although patients can present with quadriparesis that resembles Guillain-Barre Syndrome or transverse myelitis, the bladder and bowel functions are never affected. Patient may experience recurrent episodes of weakness that last from a few hours up to 72 hours with complete recovery between the attacks. In the majority of patients, deep tendon jerks are markedly diminished or absent although some patients may have normal jerks.

Patients with TPP usually experience the attacks a few hours after a heavy meal or in the early morning hours upon waking. More than two-thirds present to the emergency department between 2100 and 0900 hours; hence it was initially described as nocturnal palsy or night palsy.6 It has been shown that plasma glucose and insulin responses to meals are markedly higher in the evening than in the morning in control subjects. Such a phenomenon suggests a possible mechanism for the nocturnal preponderance of TPP. Another explanation could be the circadian rhythmicity of many hormones reaching their peak levels during sleep. Hypokalaemia is considered to be the most consistent electrolyte abnormality in TPP and a hallmark of the syndrome along with hyperthyroidism. It has been demonstrated that hypokalaemia is a result of potassium shift into cells and that it is not caused by total body potassium depletion.7 Patients with thyrotoxic periodic paralysis have an underlying predisposition for activation of Na+/K+-ATPase activity either directly by thyroid hormones or indirectly via adrenergic stimulation, insulin or exercise. Increased Na+-K+ ATPase activity is postulated to contribute to hypokalaemia.8

The majority of cases of hyperthyroidism associated with thyrotoxic periodic paralysis are due to Graves disease although other conditions including thyroiditis, toxic multinodular goitre, toxic adenoma, TSH secreting pituitary tumour, ingestion of T4 and inadvertent iodine excess have also been implicated.9 Assaying of thyroid function in patients with hypokalaemic paralysis distinguishes thyrotoxic periodic paralysis from other forms of hypokalaemic periodic paralysis. Thyrotoxic periodic paralysis occurs only in the presence of hyperthyroidism and is abolished when thyroid hormones are normalised.

Immediate therapy with potassium supplementation and beta-adrenergic blockers can prevent serious cardiopulmonary complications and may hasten recovery of periodic paralysis.10 Potassium chloride is given intravenously and/or orally. Regular potassium supplementation as prophylaxis against further paralysis when the patient has normal serum potassium level is ineffective. Effective control of hyperthyroidism is indicated to prevent recurrence of paralysis.


To conclude, although the association of thyrotoxicosis and periodic paralysis has been well known, TPP is often not recognised when first seen because of lack of familiarity with the disorder and partly because of the subtleness of thyrotoxicosis. When a young male of South Asian descent is initially seen with severe lower limb weakness or paralysis, TPP should be considered in the differential diagnosis and investigated for its presence since it is a curable disorder that resolves when euthyroid state is achieved.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
M SURESH BABU, M.D., F.C.C.P. Associate Professor of Internal Medicine, J.S.S.Medical College, Mysore, India.. H BASAVANNA GOWDAPPA, M.D.,F.I.C.C., Principal & Professor of Internal Medicine, J.S.S.Medical College, Mysore, India.. M R.AIYAPPA, M.B.B.S. Resident, Internal Medicine, J.S.S.Medical College, Mysore, India. SASIDHARAN SAMEER, Intern, Internal Medicine, J.S.S.Medical College, Mysore, India.
Corresponding Author Details: 
M. Suresh Babu, M.D., F.C.C.P. Associate Professor of Internal Medicine. J.S.S.Medical College, J.S.S.University, Mysore, Karnataka, India.
Corresponding Author Email:


1. Pooja Pothivala, Steven N Levine. Analytic Review: Thyrotoxic Periodic paralysis:

A Review. J Intensive Care Med 2010;25:71-77.

2. Mariam Arakian Manoukian, Julie A Foote, Lawrence M Crapo. Clinical and Metabolic features of thyrotoxic periodic paralysis in 24 episodes. Arch Intern Med 1999;159:601-06.

3. McFadzean AJS, Yeung R. Periodic paralysis complicating thyrotoxicosis in Chinese. Br Med J 1967;1:451-455.

4. Okinaka S, Shizume K, Lino S et al. The association of periodic paralysis and hyperthyroidism in Japan. J Clin Endocrinol Metab1957;17:1454-1459.

5. Kung AW. Clinical review: Thyrotoxic Periodic paralysis: a diagnostic challenge. J Clin Endocrinol Metab 2006; 91(7):2490-5.

6. Talbott JH. Periodic Paralysis. Medicine 1941;20:85-142.

7. Feely J. Potassium shift in thyrotoxic periodic paralysis. Postgrad Med J. 1981;57:238–39.

8. Chan A, Shinde R, Chow CC et al. Invivo and invitro sodium pump activity in subjects with thyrotoxic periodic paralysis. Br Med J 1991;303:1096–99.

9. Yeo PPB, O’Neill WC. Thyrotoxicosis and periodic paralysis. Med Grand Rounds 1984;3:10–25.

10. Fisher J. Thyrotoxic periodic paralysis with ventricular fibrillation. Arch Intern Med 1982;142:1362–64.

Prevalence and Pattern of Self Medication use in coastal regions of South India

Balamurugan E and Ganesh K
Article Citation and PDF Link
BJMP 2011;4(3):a428
Abstract / Summary

Aim:Self medication (SM) is proportionately increasing in both urban and rural communities. The prevalence and pattern of SM use is not well established, hence a cross sectional survey was undertaken which recruited a sample size of 200 participants randomly from the coastal regions of south India.
Method: Each participant underwent a face to face interview with the help of a structured questionnaire; data collected was analyzed using descriptive and inferential statics in SPSS.
Result: SM use was reported by 71% of the subjects, which ranged from a frequency of at least one time to a maximum of 5 times and above. Lack of time (41.5%), minor illness (10.5%) and quick relief (10%) was cited as the most common reason for SM use. The majority of the participants (93.5%) were not aware about the side effects of SM. Findings revealed females and people living in urban areas are more likely to use SM than males and people in rural areas (P<0.001). 
Conclusion: there maybe a larger role for a training programme to empower people about safety and side effects of SM use, to achieve a greater sense of self control

Self-medication, Rural, Urban, over the counter drug, Medicines


William Osler has said that "A desire to take medicine is perhaps the great feature which distinguishes man from animals" This desire, however may play havoc when a person starts taking medicines on their own (i.e. self-medicating), forgetting that all drugs are toxic and their justifiable use in therapy is based on a calculable risk 1.

Self-medication (SM) can be defined as obtaining and consuming drugs without the advice of a physician2. There is a lot of public and professional concern about the irrational use of drugs in SM. In developing countries like India, easy availability of a wide range of drugs coupled with inadequate health services result in increased proportions of drugs used as SM compared to prescribed drugs2. Although, over-the-counter (OTC) drugs are meant for SM and are of proved efficacy and safety, their improper use due to lack of knowledge of their side effects and interactions could have serious implications, especially in extremes of ages (children and old age) and special physiological conditions like pregnancy and lactation 3, 4. There is always a risk of interaction between active ingredients of hidden preparations of OTC drugs and prescription medicines, as well as increased risk of worsening of existing disease pathology 5 . As very few studies have been published in our community regarding usage of self medication we conducted this cross-sectional study in the coastal region of Pudhucherry, South India, t assess the prevalence and pattern of SM use.

Materials and methods:

The present study was a cross-sectional survey conducted in coastal region of pudhucherry, south India. For this study we recruited 200 patients randomly from both urban and rural communities (100 each) for a period of six months during 2009. Patients who were = 18 years of age and who were able to read and write the local language (Tamil) or English were included in the study after informed consent explaining the purpose of the study. Participants with intellectual, psychiatric and emotional disturbances that could affect the reliability of their responses were excluded from the study. To collect data regarding SM usage a structured questionnaire was prepared, after an extensive literature review.. The structured questionnaire contained 25 items in the form of closed and open ended questions. Initially the tool was validated by a panel of experts in the field of public health for the appropriateness of each item and assessment of content validity (0.91) and re-test reliability coefficient (0.89). Approval to conduct the study was granted by the Institute ethics committee prior to data collection. Each participant underwent a face to face interview to collect data followed by an informal educational counseling about potential adverse effects of consuming common SM. Data collected was analyzed using SPSS for windows statistical software version 14 (SPSS Inc., Chicago, Il, USA). Data was presented using descriptive statistics (i.e. numbers, percentage) and inferential statistics (i.e. Chi-square). A probability value of < 0.05 was considered to be significant.


Basic demographic details:

The majority of the participants were female (56%). Most of the participants (60%) were between 26-45 years of age. There were an equal number of participants from the rural and urban community. Among the total 200 participants 70% were literate.

Findings related to usage of SM:

Overall, out of 200 participants, 71 % of them reported that they have used SM in the past. The frequency of SM use varied among the subjects with a minimum of at least one time to maximum of 5 times and above See Figure 1. When the participants were asked about the reasons for SM use, the majority of them - 41.5% - stated lack of time to visit a doctor as the main reason followed by minor illness and quick relief. See Table 1.   The major source through which the participants learned to use SM were as follows, directly from pharmacist (57.3%), prescription of previous illness (21.5%), friends (12.5%), television (5.5%) and books (3%).See Table 2. The main indications for SM use were fever (36%), headache (35%), then cough/cold/sore throat (20%). See Table 3 for detailed data.

Figure 1: Frequency of self medication Use

Table 1: Reasons for Self Medication Use

Reasons Number (%)
Lack of time 41.5
Minor illness 10.5
Economical 14
Quick relief 10
Learning opportunity 2
Ease and convenience 10.5
Avoiding crowd in visiting doctor 6
Unavailability of doctor 5.5

Table 2: Sources of Self Medication Use

Sources for self medication use Number (%)
Directly from pharmacy without prescription 57.3
Prescription of previous illness 21.5
Friends prescription 12.5
Television media 5.5
Book 3

Table 3: Indications for Self Medication Use

Indications for self medication use Number (%)
Headache 35
Stomach ache 3
Vomiting 1
Eye symptoms 0.73
Diarrhoea 2
Cough, cold, sore throat 20
Fever 36
Skin symptoms 0.27
Ear symptoms 2

While calculating chi-square to find out the association between usage of SM and selected demographic variables we found an association between residence (i.e. rural or urban) and gender; urban people were more likely to use SM than rural people (urban, 60/100 vs. rural 82/100, p value = .006). In relation to gender females were more likely to use SM in comparison to males (female, 78/112 vs. 43/88, p value= .002). Other variables were not significantly associated with SM use. Finally, when the subjects were asked about the side effects of their used self medications 93.5% of them said that they are not aware of the side effects and only the remaining 6.5% of them said they are aware of the side effects.


The current study examined the prevalence and pattern of SM use in a coastal region of South India. The study findings revealed 71% of the people reporting SM use in the past,  this prevalence rate in our study is consistent with previous finding3,6,7,8,9,10,11 The figure of participants who use SM is very high, which requires immediate attention. The frequency of self medication use in our study ranged from a minimum of one time to a maximum of 5 times and above, this finding was in line with the findings of a study by Nalini (2010)12.

Participants cited multiple reasons for use of SM like lack of time , quick relief from illness and ease and convenience, a similar reasons were cited  in an another Indian study13. In the current study participants reported SM use in a variety of conditions like headache, stomach ache, cough and fever, this these finding are comparable with those of Sontakke et al (2011) 14. The reason for SM use may be mufti-factorial, in our study an association was found between gender and residence, i.e. female and rural people reporting more  SM use, this finding was similar to two previous studies15,16 To establish the reasons why requires further research. One potential limitation of this study is the limited sample size, which we tried to overcome by adopting a random sampling method so as to generalize findings.


Factors influencing SM include patient satisfaction with the healthcare provider, cost of the drugs, educational level, socioeconomic factors, age and gender 17. Interactions between prescribed drugs and the drugs taken for SM is an important risk factor of which healthcare providers must be aware of.17,2

Easy availability of wide range of drugs without a prescription is the major factor responsible for irrational use of drugs in SM as, thus resulting in impending health problems (antimicrobial resistance, increased load of mortality and morbidity) and economic loss. The need for promoting appropriate use of drugs in the health care system is not only for financial reasons, with which policy makers and manager are usually most concerned, but also for health and medical care of patients and the community. There is need for authorities to strengthen existing laws regarding OTC drugs to ensure their rational sale and use. Also, specific pharmacovigilance is needed and the patient, pharmacist and physician must be encouraged to report any adverse events. Periodic studies on the knowledge, attitude about and practice of SM may give insight into the changing pattern of drug use in societies.

Acknowledgements / Conflicts / Author Details
The author is grateful to all study participants who willingly participated in the study.
Competing Interests: 
None declared
Details of Authors: 
BALAMURUGAN E. (R.N, R.M, M.Sc.), Research Scholar, College of Nursing, All India Institute of Medical Science, New Delhi, India. GANESH K. (R.N, R.M, M.Sc), Research Scholar, College of Nursing, All India Institute of Medical Science, New Delhi, India
Corresponding Author Details: 
Balamurugan E., Research Scholar, College of Nursing, All India Institute of Medical Science, Ansari Nagar, New Delhi -110029, India
Corresponding Author Email:


  1. Phalke VD, Phalke DB, Durgawale PM. Self-medication practices in rural Maharashtra. Indian J Community Med .2006; 31:34-5.
  2. Montastruc JL, Bagheri H, Geraud T, Lapeyre MM. Pharmacovigilance of self-medication. Therapie 1997;52:105-10
  3. Shankar PR, Partha P, Shenoy N. Self-medication and non-doctor prescription practices in Pokhara valley, Western Nepal; a questionnaire based study. BMC Fam Pract. 2002;3:17
  4. Murray MD, Callahan CM. Improving medication use for older Adults: An integrated research agenda. Ann Intern Med 2003;139:2425-9
  5. Choonara I, Gill A, Nunn A. Drug toxicity and surveillance in children. Br J Clin Pharmacol. 1996;42:407-10
  6. Sharma R, Verma U, Sharma CL, Kapoor B. Self-medication among urban population of Jammu city. Indian J Pharmacol. 2005;37:40-3
  7. Kasilo OJ, Nhachi CF, Mutangadura EF. Epidemiology of household medications in urban Gweru and Harare. Cent Afr J Med. 1991;37:167-71
  8. Awad A, Eltayeb I, Matowe L, Thalib L. Self-medication with antibiotics and antimalarials in the community of Khartoum State, Sudan. J Pharm Pharm Sci. 2005 Aug 12;8(2):326-31.
  9. Al-Azzam SI, Al-Husein BA, Alzoubi F, Masadeh MM, Al-Horani MA. Self-medication with antibiotics in Jordanian population. Int J Occup Med Environ Health. 2007;20(4):373-80.
  10. Richman PB, Garra G, Eskin B, Nashed AH, Cody R. Oral antibiotic use without consulting a physician: a survey of ED patients. Am J Emerg Med. 2001 Jan;19(1):57-60.
  11. Cagri Buke A, Ermertcan S, Hosgor-Limoncu M, Ciceklioglu M, Eren S. Rational antibiotic use and academic staff. Int J Antimicrob Agents. 2003 Jan;21(1):63-6.
  12. Berzanskyte A, Valinteliene R, Haaijer-Ruskamp FM, Gurevicius R, Grigoryan L. Self-medication with antibiotics in Lithuania. Int J Occup Med Environ Health. 2006;19(4):246-53.
  13. Nalini GK. Self Medication Use Among allopathic Medical Doctors in Karnataka, India. British Journal of Medical Practioner. 2010; 3(2):325.
  14. Kayalvizhi S, Senapathi R. International Journal of Enterprise and Innovation Management Studies.2010; 1(3): 40-44.
  15. Sontakke SD , Bajait CS , Pimpalkhute SA, Jaiswal KM, Jaiswal SR. International Journal of Biological & Medical Research. Int J Biol Med Res. 2011; 2(2): 561-564
  16. Figueiras A, Caamano F, Gestal OJJ. Sociodemographic factors related to self-medication in Spain. Eur J Epidemiol. 2000;16:19–26
  17. Hebeeb GE, Gearhart JG. Common patient symptoms: patterns of self-treatment and prevention. J Miss State Med Assoc. 1993; 34:179–181.

‘Well the doctors should check the side-effects shouldn’t they?’ A case of Nitrofurantoin-induced liver injury

Louise Macdougall, Kate Armitage, Richard Thomson and Robert Stirling
Article Citation and PDF Link
BJMP 2011;4(3):a429
Abstract / Summary

This case report discusses an interesting case of drug- induced autoimmune hepatitis following the long term use of nitrofurantoin for recurrent urinary tract infections (UTIs).  Recurrent UTIs are common and the evidence for long term antibiotics are discussed along with the difficulty in deciding whether drugs are implicated as the cause of deranged liver function tests. 

An 80-year old lady was referred to a gastroenterology clinic in August 2009 with deranged liver function tests; alkaline phosphatase 180 IU/L (35-120), alanine transferase 147 IU/L (<40), gamma glutamyl transferase 384 IU/L (<45) and globulins 45 g/L (20-35).  She had initially presented to her general practitioner with symptoms of lethargy and malaise four months previously. She denied any symptoms of obstructive jaundice and there were no risk factors for hepatitis; she seldom consumed alcohol. 

Past medical history included osteoarthritis, migraines and recurrent urinary tract infections; these had been investigated by urology and the patient had undergone cystoscopy and urethral dilatation in September 2003; despite this she continued to experience urinary tract infections and was therefore commenced on prophylactic nitrofurantion by her General Practitioner with approval by the Urologist.  This was initially commenced at 50mg at night.  This regime was continued for approximately three years however during this time she had a further three treatment courses of nitrofurantoin.  In October 2005 her prophylactic dose was therefore increased to 100mg at night. Other medication included lansoprazole 30mg daily, pizotifen 500 micrograms at night, metoprolol 100mg twice daily, simvastatin 10mg at night, senna 15mg at night and furosemide 40mg daily.

On examination there was evidence of palmar erythema and Dupuytren’s contractures but no other stigmata of chronic liver disease.  The liver was tender and palpable 4 cm below the costal margin. A liver ultrasound was performed which was normal.  Liver screen and autoimmune profile are shown in table 1; notably a positive nuclear antibody was found (1 in 1280 IgG) with Hep 2 cell staining showing a homogenous (ANA) pattern at 1:320 IgG, and a nuclear lamin pattern at 1:1280 IgG;.  Due to the positive ANA and raised globulins a suspected diagnosis of nitrofurantoin-induced autoimmune hepatitis was made and a liver biopsy performed.

Test Result
Hepatitis C antibody Negative
Hepatitis B surface antigen Negative
Ferritin 85 ug/L (15-300)
Caeruloplasmin 0.33g/L (0.19-0.71)
Double-stranded DNA antibody 4.44 IU/ml (<10)
Nuclear antibody 1 in 1280 IgG
Mitochondrial antibody Negative
Smooth muscle antibody Negative
Reticulin antibody Negative
ENA- Ro/La/RNP/Sm/Jo-1/Scl-70 Negative
Liver kidney microsomal antibody Negative
Soluble liver antigen antibody Borderline
Liver cytosol antibody Negative

Table 1: liver screen and autoimmune profile

Figure 1a. Liver biopsy showing portal-based interface hepatitis


Figure 1b. Liver biopsy showing portal-based interface hepatitis

Figure 2. Serial LFTs over time

Liver biopsy (figure 1) indicated a moderate hepatitis which was mainly portal based with multifocal interface hepatitis; these morphological appearances were consistent with those of an autoimmune hepatitis. The patient was advised to immediately stop nitrofurantoin and was commenced on prednisolone 30mg which caused a rapid improvement in LFTs (figure 2). This improvement was maintained following a step-wise reduction in steroid dose and prednisolone was discontinued after eight months of treatment. LFTs are currently normal one month following cessation of steroids


This case raises two points of discussion.   The first is whether the long term use of nitrofurantoin as prophylaxis for urinary tract infections is appropriate and based on solid evidence. Nitrofurantoin has many side effects and is well documented to cause liver derangement1,2,3. The patient described in this case had been taking nitrofurantoin for seven years and had received a large cumulative dose, on the basis that this was effective prophylaxis. The continuous, long term use of antibiotics as prophylaxis for urinary tract infections is debatable.  Madersbacher et al4 recommend the use of prophylactic antibiotics  but only after or alongside additional measures including behavioural change, the use of topical oestrogens and the use of alternative therapies; this view is supported by the European Association of Urology5.A Cochrane Review6  in 2004 found that antibiotic use did decrease the number of urinary tract infections compared to placebo but only for the duration of treatment; antibiotics  do not alter the natural history of the underlying condition7. There is no clear evidence for duration of treatment and any trials have only been continued for six or twelve months6.  It has been noted that all antibiotics had a worse adverse event profile compared to placebo. There was no consensus as to which antibiotic should be used although nitrofurantoin has been associated with a greater withdrawal rate6. One study8 comparing nitrofurantoin and trimethoprim revealed no significant difference in recurrence rates or side effects between the two antibiotics, although this involved a lower dose of nitrofurantoin than was used in this case, and a treatment duration of just 6 months. We would argue that due to the side effect profile of nitrofurantoin and the evidence base available, it is not appropriate to continue it for a duration beyond 6 months.

The second discussion point is whether nitrofurantoin was actually the cause for liver derangement in this case. As documented in a recent review article on the diagnosis of drug-induced liver injury, establishing with any certainty whether liver injury is drug induced can be very difficult3.   The key issues are whether there is a temporal relationship between the drug and the onset of liver injury, and whether other causes have been excluded.  In this case the patient had negative viral serology and a normal ferritin and caeruloplasmin but her positive autoantibodies raise the possibility of autoimmune hepatitis.  Guidelines from the American Association for Liver Diseases9 suggests that the diagnosis of autoimmune hepatitis should be made on the following criteria

  • laboratory abnormalities (serum AST or ALT,  and increased serum total IgG or gamma-globulins)
  • positive serological markers including ANA,SMA, anti-LKM1 or anti- LC1
  • histological changes consistent with autoimmune hepatitis i.e. interface hepatitis

This case meets these above criteria for autoimmune hepatitis however the presence of nitrofurantoin does confound the issue. Other case reports10  have reported nitrofurantoin to have caused autoimmune hepatitis based on the relationship between the timing of the drug and the onset of biochemical abnormalities.  Bjornsson et al11 performed a comparative study of patients with autoimmune hepatitis and found drugs, particularly nitrofurantoin and minocycline were causally implicated in 9% of cases.  When they compared the two groups no significant differences were found in the diagnostic parameters of biochemical, serological and histological abnormalities.  In fact the only difference was that no drug-induced cases relapsed on withdrawal of steroids whereas nearly two third of those with non-drug-induced hepatitis relapsed. Bjornsson et al therefore argue in favour of autoimmune immune hepatitis being induced by drugs such as nitrofurantoin; rather than particular drugs simply unmasking sporadic cases based on these management differences. 

The patient in this case so far has shown no signs of relapse following steroid withdrawal.  We believe that this case does represent one of nitrofurantoin-induced autoimmune hepatitis. In view of the above we would urge readers to consider their use of nitrofurantoin for recurrent urinary-tract infection prophylaxis.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
LOUISE MACDOUGALL, Teaching and Research Fellow, North Tyneside General Hospital, UK. KATE ARMITAGE, Teaching and Education Fellow, North Tyneside General Hospital, UK. RICHARD THOMSON, Consultant Gastroenterologist and Clinical Subdean, North Tyneside General Hospital, UK. ROBERT STIRLING, Consultant Histopathologist, North Tyneside General Hospital, UK.
Corresponding Author Details: 
LOUISE MACDOUGALL, Teaching and Research Fellow, Northumbria Healthcare NHS Trust, North Tyneside General Hospital, Rake Lane, North Shields, Tyne and Wear, NE29 8NH
Corresponding Author Email:
  1. Haukekeete ML Hepatoxicity of antibiotics. Act Gastroenterologica Belgica 2003 ; 58 (3): 290-6
  2. Chalasani N, Fontana R. Causes, clinical features and outcomes from a prospectve study of drug-induced liver injury in the United States 2008;135:1924-34
  3. Verma S, Kaplowitz Diagnosis, management and prevention of drug-induced liver injury 2009;58: 1555-1564
  4. Madersbacher S, Thalhammerb F and Marbergera MPathogenesis and management of recurrent urinary tract infection in women Current opinion in Urology 2000; 10:29-33
  5. Grabe M., Bjerkland-Johansen T.E., Botto H. Guidelines on Urological Infections. European Association of Urology 2010.  Available at December 2010)
  6. Albert X, Huertas I, Pereiro II et al. Antibiotics for preventing recurrent urinary tract infection in non-pregnant women. Cochrane Database Syst Rev 2004(3):CD001209
  7. Madersbacher S, Thalhammerb F and Marbergera MPathogenesis and management of recurrent urinary tract infection in women Current opinion in Urology 2000; 10:29-33
  8. Vahlensick W Jr, Westenfelder M Nitrofurantoin versus trimethoprim for low dose long-term prophlaxis in patients with recurrent urinary tract infections.  A prospective randomized study. International Journal of Urology and Nephrology 1992; 24(1): 3-10
  9. Manns M.P., Czaja A.J., Gorham J.D. et al Diagnosis and Management of Autoimmune Hepatitis. Hepatology 2010; 51(6): 1-31
  10. Koulaouzidis A., Bhat S., Moshos J. et al. Nitrofurantoin-induced lung and hepatotoxicity. Annals of Hepatology 2007; 6(2): 119-121
  11. Bjornsson E., Talwalkar J, Treeprasertsuk S. et al Drug-induced autoimmune hepatitis: clinical characteristics and prognosis. Hepatology 2010; 51 (6): 2040-8

Diagnosis and Management of Stable COPD

Katerina M Achilleos and Duncan J Powrie
Article Citation and PDF Link
BJMP 2011;4(3):a427

Chronic obstructive pulmonary disease (COPD) is a debilitating condition resulting in significant morbidity and mortality. It is the fifth leading cause of death in the UK 1, estimated to be the third by 2020 2.


  1. COPD is a preventable and treatable disease with some extra-pulmonary effects that may contribute to the severity in individual patients Its pulmonary component is characterised by airflow limitation that is progressive and not fully reversible. There is an abnormal inflammatory response of the lung to noxious gases and particles, most commonly cigarette smoke 3.
  2. Airflow obstruction is defined as post-bronchodilator FEV1/FVC ratio (where FEV1 is the forced expiratory volume in one second and FVC is the forced vital capacity) of less than 0.7 If FEV1 is ≥ 80% predicted, a diagnosis of COPD should only be made in the presence of respiratory symptoms 4.

Incidence/ Prevalence:

Within the UK it is estimated that 3 million people are affected with COPD 4. However, only 900,000 are diagnosed -4An estimated two million people who have COPD remain undiagnosed 4.


90% of cases are smoking related 4, particularly those with >20 pack year smoking histories 5. Environmental and occupational factors can also play a role, including exposure to biomass fuels such as: coal, straw, animal dung, wood and crop residue which are used to cook in some countries and heat poorly ventilated homes COPD occurs in 10-20% of smokers, suggesting there is an element of genetic susceptibility 2-3, 5.


To make a diagnosis of COPD an obstructive deficit must be demonstrated on spirometry in patients over the age of 35 years with risk factors (mainly smoking) and signs and symptoms of the disease 4.

Signs and Symptoms:

  1. Progressive dyspnoea on exertion
  2. Chronic cough
  3. Chronic sputum production
  4. Wheeze
  5. Frequency of exacerbations – particularly during winter months 4
  6. Functional status – bearing in mind gradual progression of disability, effort intolerance and fatigue.
  7. Features suggestive of Cor pulmonale 5:
    1. Peripheral oedema
    2. Elevated jugular venous pressure
    3. Hepatomegaly
    4. Right ventricular heave
    5. Tricuspid regurgitation

Investigations/ Tests to consider:

  1. Post-bronchodilator Spirometry – essential in confirming the diagnosis of COPD.
    1. Demonstrating an obstructive picture.
    2. FEV1 is used to assess the progression and severity of COPD, but correlates poorly with the degree of dyspnoea 3-6. (Table 1)
  1. Pulmonary functions tests – Markers suggesting the presence of emphysema include:
    1. Reduced TLCO and KCO due to a reduced surface area for gaseous exchange 5.
    2. Raised Total lung capacity, residual volume and functional residual capacity due to air trapping 5.
  1. Chest radiograph – Is not required for the diagnosis, but is recommended to exclude other conditions such as interstitial lung disease, pleural effusions or pneumothorax. It may demonstrate features of the condition, such as 3, 5:
    1. Hyperinflated lung fields
    2. Flattened diaphragms
    3. Bullous changes, particularly at the apices
  1. BODE index prognostic indicator – This is grading system shown to be better than FEV1 at predicting the risk of hospitalisation and death in patients with COPD. Patients are scored between 0 and 10, with higher scores having an increased risk of death. It encompasses 3, 5-7: (Table 2)
    1. BMI
    2. Airflow Obstruction – taking into account the FEV1
    3. Dyspnoea – in accordance with the Medical Research Council (MRC) scale 5.
    4. Exercise capacity – measured by the distance walked in 6 minutes. (Table 3)

Table 1. Severity of airflow obstruction 4

Stage Severity post-bronchodilator FEV1 (%) Predicted Comments
1 Mild ≥ 80% Only diagnosed in the presence of symptoms
2 Moderate 50- 79% Managed within the community
3 Severe 30-49% TLCO usually Low
Hospitalization may be needed only with exacerbations
4 Very Severe <30% Or FEV1 <50% with respiratory failure

Table 2. BODE Index 3, 5-8

  1 2 3  
FEV1 Predicted (%) ≥ 65 50- 64 36- 49 ≤ 35
Distance walked in 6 minutes (meters) ≥ 350 250- 349 150- 249 ≤ 149
MRC dyspnoea scale 0-1 2 3 4
BMI ≥ 21 ≤ 21    

Table 3. Medical research council (MRC) Dyspnoea scale 5, 8

1 Dyspnoeic only on strenuous activity
2 Dyspnoeic on walking up a slight incline or when hurrying
3 Walks slower than contemporaries on the flat, or has to stop for breath, or has to stop for breath when walking at own pace
4 Stops for breath on walking 100m or after a few minutes on walking on the flat
5 Breathless on minimal exertion e.g. dressing/ undressing. To breathless to leave the house

Differential Diagnosis:

  1. Asthma – the most important differential diagnosis to consider.
    1. This is steroid and bronchodilator responsive
    2. Indicative of reversible airway obstruction.
    3. It is not associated with smoking.
    4. Patients with asthma may exhibit 3, 9: chronic non-productive cough, variability in breathlessness, diurnal /day-to-day variation, nocturnal wheeze and dyspnoea
    5. However both conditions may coexist creating diagnostic uncertainty.
  1. Alpha1 antitrypsin deficiency is an autosomal dominant condition associated with an increased risk of developing emphysema at an early age 3, 5, 9.
    1. It can occur in non-smokers
    2. Can be asymptomatic and thus under-diagnosed with an estimated 1 in 2000-5000 individuals being affected 5.
    3. The disease is worse in smokers
    4. COPD can develop in patients < 35years of age
    5. It is associated with liver cirrhosis.
    6. All patients with COPD should be screened.
    7. Emphasis should be made to avoid smoking, including passive smoking.
  1. Other conditions to consider include:
    1. Bronchiectasis
    2. Interstitial lung disease
    3. Cardiac failure.


Goals of management include:

  1. Early and accurate diagnosis
  2. Improve symptoms and quality of life
  3. Reduce the number of exacerbations
  4. Improve mortality

Non-pharmacological management:

  1. Smoking cessation – an accurate smoking history should be obtained, including the number of pack years smoked. All current smokers with COPD should be encouraged to stop at every opportunity, and offered smoking cessation advice. Advising the patient alone will help a certain proportion to stop, whilst referral to smoking cessation services has been shown to further increase in quit rates. There are a range of nicotine and other pharmacological therapies available such as Bupropion (Zyban®) and Varenicline (Champix®) 3-4, 7, 8.
  2. Vaccinations – A once off Pneumococcal and annual Influenza vaccine should be offered.
  3. Pulmonary rehabilitation – Should be offered to patients who have had a recent exacerbation requiring hospitalisation and those that have an MRC score of ≥ 3, but are still able to mobilise and thus have the potential for further rehabilitation. It is not suitable for those patients that are immobile or limited in their mobility due to symptoms of unstable angina or a recent cardiac event. Benefits are seen in terms of reduced hospital admission, improved quality of life and exercise tolerance Commitment to the programme should be relayed to the patient, and each programme should be tailored to their individual needs. This usually includes 3-5:
    1. Disease education – which can improve the ability to manage their illness.
    2. Exercise – tailored programmes to prevent de-conditioning and improve functional exercise capacity, dyspnoea and quality of life 4. This includes strength and endurance training of upper limbs and respiratory muscles Benefits may be seen even after 6 months.
    3. Physiotherapy – to teach active cycle breathing techniques or to use positive expiratory pressure masks in patients with excessive sputum production.
    4. Nutritional support – in the form of supplementation or dietician advice in patients with a suboptimal BMI. A low BMI is associated with increased mortality as it is associated with poor exercise capacity, reduced diaphragmatic mass and impaired pulmonary status. Alternatively, weight loss is recommended in patients who are in the obese range.
    5. Psychological – Assessment for support at home, introduction of patients to day centres, assessing for features of depression and anxiety, and aiding in the obtainment of a car disability badges may require referral to occupational therapy and social services.
  1. Travel advice – Patients who are planning air travel and have FEV1 <50%, Sa02 < 93%, or are on long term oxygen therapy (LTOT) should undergo formal assessment -4Patients with bullous disease should be informed that they are at increased risk of pneumothorax during high altitude flights 4.

Pharmacological management:

  1. Bronchodilators – Provide long term benefit in reducing dyspnoea. This is not reflected in improvements in FEV1 as it may not show reversibility 4.
    1. Start with an inhaled SABA (short-acting beta2-agonist) or a SAMA (short-acting muscarinic antagonist) on an as required basis for symptomatic relief. If symptoms remain despite regular SABA therapy (i.e. four times a day), then treatment will need to be stepped up.
    2. If symptoms persist or if the patient is having recurrent exacerbations add in a LABA (long-acting beta2 agonist) or a LAMA (long acting muscarinic antagonist).
    3. If symptoms continue, add in a LAMA if already on a LABA (or vice versa).
    4. If FEV1 <50% add in an inhaled corticosteroid (ICS). This can be offered as a combination inhaler.

Inhaled therapy should offer sufficient bronchodilator response. A spacer can be used for those with poor technique. Nebulisers are reserved for patients who demonstrate respiratory distress despite maximal inhaled therapy, and for those that show an improvement in symptoms or exertional capacity 4.

Diagram 1: Summary of step-by-step management 4

  1. Corticosteroids – A short course of oral steroids may be used during exacerbations. A maintenance course however is not recommended Any patients on long term steroids should be weaned off.
  2. Mucolytic agents – May be considered in patients with a chronic cough who have difficulty expectorating. They should only be continued if symptomatic benefit is evident, otherwise they can be stopped. There is no evidence to show that they reduce the exacerbation frequency.
  3. Theophylline – Should only be offered in people that are unable to use inhaled therapy or after trials of SA and LA bronchodilators 4. The same generic brand should be prescribed as individual brands will have different efficacy. It is usually used as an adjunct to beta2-agonists and muscarinic antagonists. Interactions with macrolides and fluroquinolones and other drugs are also common, and as such the theophylline dose should be reduced if interactions are known. Caution should be taken in prescribing theophylline in the polypharmacy patient 3, 5. Little evidence has been shown to support theophylline usage in COPD (compared to asthma), however it is used for its anti-inflammatory effects As such levels are only performed if toxicity is suspected and should not be adjusted if in the sub-therapeutic range.
  4. Oxygen therapy – Patients should be assessed for long-term oxygen therapy (LTOT) if they exhibit 4:
    1. Severe airflow obstruction
    2. Features of Cor pulmonale
    3. Hypoxaemia (Sa02 ≤ 90%)
    4. Cyanosis
    5. Polycythaemia

Patients with stable COPD who are receiving maximum medical therapy are assessed by measuring arterial blood gases taken on two separate occasions at least 3 weeks apart. To meet the criteria patients must have 4:

  1. A Pa02 < 7.3 kPa when stable, or
  2. A Pa02 >7.3 but < 8.0 kPa when stable and:
    1. Pulmonary hypertension or
    2. Peripheral oedema or
    3. Secondary polycythaemia or
    4. Nocturnal hypoxaemia

LTOT should be used for a minimum of 15L per day, including during sleep 3-4.

Patients who continue to smoke should be made aware of the serious risk of facial injuries due to the highly flammable nature of oxygen.

When to refer:

Referrals for specialist advice or specialist investigations may be appropriate at any stage of the disease.

Other possible reasons for referral 4

§ Diagnostic uncertainty § Suspected severe COPD
§ Onset of Cor pulmonale § Rapid decline in FEV1
§ Assessment for LTOT, home nebulisers or oral corticosteroid therapy § Symptoms that do not correlate to lung function deficit
§ Pulmonary rehabilitation assessment § Frequent infective exacerbations
§ Family history of alpha-1-antitrypsin deficiency § Haemoptysis
§ Onset of symptoms < 40 years § Bullous lung disease
§ Assessment for lung volume reduction surgery/ lung transplantation § Dysfunctional breathing


Patients with stable mild-moderate COPD should be reviewed by their general practitioner at least once a year and those with severe COPD twice yearly.

At each visit 4:

  1. An opportunity should be taken to ask about their current smoking status and the desire to stop.
  2. Assessment of adequate control of symptom: dyspnoea, exercise tolerance and the estimated number of exacerbations per year.
  3. Assessment of inhaler technique.
  4. To assess the effects/side effects of each drug treatment.
  5. The need for pulmonary rehabilitation.

For those patients with very severe airflow obstruction (FEV1 < 30%), the above still remains, in addition to the assessment of 4:

  1. Features of Cor pulmonale
  2. Nutritional status
  3. The need for LTOT
  4. Signs of depression
  5. The need for occupational therapy and social services input
  6. Referral to specialist and their services
  7. Measurements of:
    1. FEV1 and FVC
    2. BMI
    3. MRC dyspnoea scale
    4. Sa02 via pulse oximetry

Those patients requiring long term non-invasive ventilation will be reviewed by a specialist on a regular basis.

Patient Information:


Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
KATERINA M ACHILLEOS, MBBS BSc (Hons), Southend University Hospital, Prittlewell chase, Westcliff-on-sea, SS0 0RY DUNCAN J POWRIE, MB ChB, Consultant Respiratory Physician, Heart and chest clinic, Southend University Hospital, Prittlewell chase, Westcliff-on-sea, SS0 0RY
Corresponding Author Details: 
KATERINA M ACHILLEOS, ST1 Respiratory Medicine, Southend University Hospital, Prittlewell chase, Westcliff-on-sea, SS0 0RY
Corresponding Author Email:

1.      National statistics (2006) Health Statistics Quarterly 29.

2.      European Respiratory society (2003) European White Lung Book.

3.      Global Strategy for Diagnosis, Management, and Prevention of COPD.  Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines 2010.

4.      Chronic obstructive pulmonary disease. Management of chronic obstructive pulmonary disease in adults in primary and secondary care. NICE guidelines 2010.

5.      Chapman S, Robinson G, Straddling J, West S. Oxford handbook of  respiratory medicine, 2e, Oxford university press, 2009

6.      Celli BR.  Update on the management of COPD. Chest 2008;133:1451-1462.

7.      Celli BR, et al. The Body-Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity Index in Chronic Obstructive Pulmonary Disease. NEJM 2004; 350: 1005-12.

8.      Todd DC et al. Approach to chronic obstructive pulmonary disease in primary care. Can Fam Physician 2008; 54:706-11.

9.      Celli BR, MacNee W et al. Standards for the diagnosis and treatment of patients with COPD. A summary of the ATS/ESR position paper.Eur Respir J 2004; 23: 932–946

10.  Barnes PJ. Theophylline for COPD. Thorax 2006; 61: 742-743.

Dabigatran: A look before we leap

Naseer A Masoodi and Bilal Ahmad
Article Citation and PDF Link
BJMP 2011;4(2):a423

Warfarin is the most commonly used oral anticoagulant and has established efficacy for more than 50 years for the prevention of thromboembolic events, but its use is limited by fear of bleeding, drug-drug and drug-food interactions, and routine monitoring of international normalized ratio (INR). In patients with atrial fibrillation (AF), warfarin prevents 64% of strokes in research studies but the real-world effectiveness drops to 35% because of various factors leading to its suboptimal use.1 In October 2010 the United States (US) Food and Drug Administration (FDA) approved Pradaxa capsules (dabigatran etexilate) as the first new agent to prevent stroke and systemic emboli in patients with non-valvular AF. In this article we will discuss some of the evidence for and against the use of dabigatran.

In the RE-LY study2 (Randomized Evaluation of Long-term Anticoagulant Therapy), high-dose dabigatran (150mg twice a day) was found to be superior to warfarin for the prevention of stroke and systemic emboli, required no routine INR monitoring, and had few food and drug interactions. James Freeman and colleagues,3 using data from the RE-LY trial, found that high-dose dabigatran (150mg twice a day) was the most efficacious and cost-effective strategy compared with adjusted-dose warfarin among adults older than 65 with AF.

Dabigatran has been shown to specifically and reversibly inhibit thrombin, the key enzyme in the coagulation cascade. Studies in healthy volunteers4 and in patients undergoing orthopaedic surgery have indicated that dabigatran has a predictable pharmacokinetic/pharmacodynamic profile, allowing for a fixed-dose regimen. Peak plasma concentrations of dabigatran are reached approximately two hours after oral administration in healthy volunteers, with no unexpected accumulation of drug concentrations upon multiple dosing. Excretion is predominantly via the renal route as unchanged drug. Dabigatran is not metabolized by cytochrome P450 isoenzymes. Though use of dabigatran for non-valvular AF and venous thromboembolism (VTE) is gaining practice,5 it remains far from being the standard of care. 

What are the concerns with use of dabigatran? In the RE-LY study the INR control was relatively poor (64% TTR (time in the therapeutic range)) but, probably more importantly, the relationship between events and individual’s INR control was not reported. The use of centre’s time in therapeutic range (cTTR) in the RE-LY study as a surrogate for INR control may not truly reflect TTRs for individual patients. Also in RE-LY study, randomization was stratified for centre and by the centre-based analyses, and the quality of oral anticoagulant services was the basis for the comparisons in this report. A subgroup analysis6 concluded that relative effectiveness of dabigatran versus warfarin was mainly seen at centres with poorer INR control. For example, Swedish centres had good TTR and the relative effectiveness and safety of dabigatran was virtually the same as with warfarin; thus, it is only the price difference that counts. It also highlights how local standards of care affect the benefits of use of new treatment alternatives and hence further limits the generalizability of any ‘overall average’ cost-effectiveness of dabigatran,  raising the question that if an intervention does not do more, why should a payer pay more for it? There are several other factors that could impact on the cost-effectiveness7 of dabigatran such as patient medication adherence, dosing frequency, and the potential effect of new efficient methods of warfarin management improving INR control by patient self-testing.

The other shortcomings of dabigatran include lack of antidotes when patients do bleed and lack of any alert to physicians that patients are not compliant with dabigatran (INR serves this purpose for warfarin). Additionally, in the RE-LY trial, dabigatran was used twice daily thus raising compliance issues compared to once daily warfarin (the rates of discontinuation of dabigatran were higher at 15% and 21% at one and two years, respectively); 11.3% reported dyspepsia (twice the rate of warfarin group); high rate of gastrointestinal bleed compared with warfarin; patients in the dabigatran cohort were at slightly higher risk of myocardial infarction (not sure how it will translate in real world practice); and contraindication of dabigatran in severe renal dysfunction raises some more questions about its use and cost effectiveness. In addition, the RE-LY trial excluded patients who had: contraindications to anticoagulation, severe heart-valve disorder, stroke within 14 days or severe stroke within six months before screening, a condition that increased risk of haemorrhage, creatinine clearance of less than 30ml per minute, active liver disease, and pregnancy.  Clinicians will need to use their judgement to weigh and balance the risk for bleeding with this new agent in a setting of an acute stroke versus the risk of having another ischaemic stroke in someone with AF if not given anti-coagulation therapy immediately. Safety and efficacy at extremes of body weight is not well established with current FDA approved doses of dabigatran either.

In summary dabigatran is a very exciting new agent with significant advantages over warfarin. However, in view of dabigatran’s higher non-adherence rate and greater risk of non-haemorrhagic side effects, patients already taking warfarin with excellent INR control have little to gain by switching to dabigatran.1 Until more studies and post-marketing data become widely available, we should advocate tight INR control for which there is a wealth of evidence for benefits, and promote strategies to improve the management of therapy with warfarin.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None Declared
Details of Authors: 
NASSEER A MASOODI MD, MBA, FACP, CMD, CPE, Associate Professor Clinical Sciences, FSU College of Medicine, Tallahassee, FL-32060, USA; Medical Director Health Services, ACV Inc., Dowling Park, FL-USA BILAL AHMAD MD, Clinical Instructor, Internal Medicine/Geriatrics, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157, USA
Corresponding Author Details: 
NASSEER A MASOODI, Associate Professor Clinical Sciences, FSU College of Medicine, Tallahassee, FL-32060, USA


  1. Gage BF. Can we rely on RE-LY? N Engl J Med. 2009; 361:1200-1202.
  2. Connolly SJ, Ezekowitz MD, Yusuf S et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009; 361:1139-1151.
  3. Freeman JV, Zhu RP , Owens DK , Garber AM , Hutton DW , Go AS , Wang PJ , Turakhia MP. Ann Intern Med. 2011 Jan 4;154(1):1-11.
  4. Stangier J, Rathgen K et al. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol. 2007 September; 64(3):292-303.
  5. Clayville LR, Anderson KV et al. New options in anticoagulation for the prevention of venous thromboembolism and stroke. P T. 2011 February; 36(2):86-88, 93-99.
  6. Wallentin L, Yusuf S, Ezekowitz MD et al; RE-LY investigators. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalized ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet. 2010; 376:975-83.
  7. Masoodi NA. Compared with warfarin, high-dose dabigatran might be cost-effective for preventing stroke in older patients with nonvalvular AF (Comment). ACP Journal Club. 2011 Jun 21; 154:JC6-12.

An unusual case of Lactic Acidosis

Muhammad Badar Ganaie and Rodney Hughes
Article Citation and PDF Link
BJMP 2011;4(2):a420
Abstract / Summary
Lactic Acidosis, Metabolic Acidosis, Severe Asthma, Salbutamol, Albuterol


Lactic acidosis is an important cause of metabolic acidosis in hospitalised patients. This usually occurs either due to over production or under utilisation of lactate1 . Most cases of lactic acidosis are due to marked tissue hypoperfusion or hypoxia in systemic shock.

Asymptomatic lactic acidosis has been reported previously during acute severe asthma and attributed to fatiguing respiratory muscles, hypoxaemia and liver ischaemia. It has also been linked to β2 agonist therapy in asthma, although lactic acidosis causing increasing dyspnoea in the asthmatic patient has only been recorded rarely.

Case presentation

We present a case of lactic acidosis in a patient with acute severe asthma who did not have any overt signs of sepsis or tissue hypoperfusion.

Mr IL was a 49 years old male who was known to have moderate asthma. He had multiple previous admissions to hospital with exacerbation of asthma but had never required an intensive care admission and had never been intubated. His other comorbidities included atrial fibrillation, ischaemic heart disease and depression.

His usual medications included salbutamol, budesonide and salmeterol inhalers, aspirin, atorvastatin and digoxin. He was a mechanic by trade with no obvious occupational sensitisation. He had no pets at home. He was a smoker with a 20 pack year history. Recent lung function tests showed an FEV1/FVC of 0.68 with a post bronchodilator FEV1 of 4.17 L (95% predicted).

He was admitted with a 1 week history of worsening shortness of breath, dry cough and wheeze. His baseline blood tests including full blood count, C reactive protein, liver and renal function were normal. Chest radiograph was unremarkable. Arterial blood gas showed no evidence of hypoxia or acidosis.He was treated as acute severe asthma with back to back nebulisers, intravenous hydrocortisone and magnesium sulphate resulting in gradual improvement in bronchospasm and peak expiratory flow rate.

Despite optimal treatment, his breathing started to deteriorate. Arterial blood gas at this time showed lactic acidosis with normal oxygenation (Table 1). There was no clinical or biochemical evidence of haemodynamic compromise or sepsis. A presumptive diagnosis of lactic acidosis secondary to salbutamol was made. The nebulisers were withheld and he has transferred to high dependency unit for closer monitoring. The acidosis completely resolved in the following 12 hours on stopping salbutamol and the patient made an uneventful recovery.

Table 1: Serial Arterial Blood Gases (On admission, 4 hours later and on stopping salbutamol)





07:42 *

















pH (7.35-7.45)










pCO2 (4.5-6.0 kPa)










pO2 (11-14 kPa)










HCO3 (22-28 mmol/L)










BE (2- -2)










Lactate (0.5-2 mEq/L)










* Salbutamol witheld


Lactate is a product of anaerobic glucose metabolism and is generated from pyruvate. Normal plasma lactate concentration is 0.5-2 meq/L. Most cases of lactic acidosis are due to marked tissue hypoperfusion or hypoxia in systemic shock2 .

Lactic acidosis can occur in acute severe asthma due to inadequate oxygen delivery to the respiratory muscles to meet an elevated oxygen demand3 or due to fatiguing respiratory muscles4 . A less recognised cause of lactic acidosis is treatment with salbutamol. The mechanism of this complication is poorly understood.

Salbutamol is the most commonly used short acting βagonist. Stimulation of β adrenergic receptors leads to a variety of metabolic effects including increase in glycogenolysis, gluconeogenesis and lipolysis5 thus contributing to lactic acidosis.

Table 2 shows an assortment of previously published case reports and case series of lactic acidosis in the context of acute asthma.

Table 2: Details of etiology and consequences of lactic acidosis in previously published case reports 




Suggested etiology of lactic acidosis

Effect of lactic acidosis

Roncoroni et al, 1976 [6]


Uncertain: increased respiratory muscle production, decreased muscle or liver metabolism

None observed

Appel et al, 1983 [7]


Increased respiratory muscle production, decreased muscle or liver metabolism

8 out of 12 developed respiratory acidosis, 6 required invasive ventilation

Braden et al, 1985 [8]


β2 agonist, steroid and theophylline therapy


O’Connell & Iber, 1990 [9]


Uncertain: intravenous β2 agonist versus severe asthma


Mountain et al, 1990 [10]


Hypoxia and increased respiratory muscle production


Maury et al, 1997 [11]


β2 agonist therapy

Inappropriate intensification of β2 agonist therapy

Prakash and Mehta, 2001 [2]


β2 agonist therapy

Contributed to hypercapneic respiratory failure

Manthous, 2001 [12]


β2 agonist therapy


Stratakos et al, 2002 [3]


β2 agonist therapy


Creagh-Brown and Ball, 2008 [13]


β2 agonist therapy

Patient required invasive ventilation

Veenith and Pearce, 2008 [14]


β2 agonist therapy


Saxena and Marais, 2010 [15]


β2 agonist therapy



In this case, the patient developed lactic acidosis secondary to treatment with salbutamol nebulisers. The acidosis resolved spontaneously without any specific treatment.

Lactic acidosis secondary to β agonist administration may be a common scenario which can be easily misinterpreted and confuse the clinical picture. Acidosis itself results in hyperventilation which could be mistaken for failure to treat the  response. This may in turn lead to inappropriate intensification of treatment.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
MUHAMMAD BADAR GANAIE, LAT Specialist Registrar, Blackpool Victoria Hospital, UK RODNEY HUGHES, Consultant Respiratory Physician, Northern General Hospital, Sheffield, UK
Corresponding Author Details: 
MUHAMMAD BADAR GANAIE, LAT Specialist Registrar, Blackpool Victoria Hospital, UK
Corresponding Author Email:


  1. Forsythe SM, Schmidt GA. Sodium bicarbonate for the treatment of lactic acidosis. Chest 2000; 117:260–267
  2. Prakash S, Mehta S: Lactic acidosis in asthma: Report of two cases and review of the literature. Canadian Respiratory Journal. 2002, 9(3):203-208
  3. Stratakos G, Kalomenidis J, Routsi C, Papiris S, Roussos C. Transient lactic acidosis as a side effect of inhaled salbutamol. Chest. 2002 Jul;122(1):385-6
  4. Mountain RD, Heffner JE, Brackett NC Jr, Sahn SA. Acid-base disturbances in acute asthma. Chest. 1990 Sep;98(3):651-5
  5. Haffner CA, Kendall MJ. Metabolic effects of β2 agonists. J Clin Pharm Ther 1992; 17:155–164
  6. Roncoroni AJ, Adrougué HJ, De Obrutsky CW, Marchisio ML, Herrera MR. Metabolic acidosis in status asthmaticus. Respiration. 1976;33(2):85–94
  7. Appel D, Rubenstein R, Schrager K, Williams MH., Jr. Lactic acidosis in severe asthma. Am J Med. 1983 Oct;75(4):580–584 
  8. Braden GL, Johnston SS, Germain MJ, Fitzgibbons JP, Dawson JA. Lactic acidosis associated with the therapy of acute bronchospasm. N Engl J Med. 1985 Oct 3;313(14):890-1
  9. O'Connell MB, Iber C. Continuous intravenous terbutaline infusions for adult patients with status asthmaticus. Ann Allergy. 1990 Feb;64(2 Pt 2):213-8
  10. Mountain RD, Heffner JE, Brackett NC, Jr, Sahn SA. Acid-base disturbances in acute asthma.Chest. 1990 Sep;98(3):651–655
  11. Maury E, Ioos V, Lepecq B, Guidet B, Offenstadt G. A paradoxical effect of bronchodilators.Chest. 1997 Jun;111(6):1766–1767
  12. Manthous CA. Lactic acidosis in status asthmaticus : three cases and review of the literature.Chest. 2001 May;119(5):1599–1602
  13. Creagh-Brown BC, Ball J. An under-recognized complication of treatment of acute severe asthma. Am J Emerg Med. 2008 May;26(4):514.e1-3
  14. Veenith TV, Pearce A. A case of lactic acidosis complicating assessment and management of asthma. Int Arch Med. 2008 Apr 15;1(1):3
  15. R Saxena, G Marais. Salbutamol: beware of the paradox! BMJ Case Reports 2010; doi:10.1136/bcr.01.2010.2665

Tumefactive Multiple sclerosis

Potjana Jitawatanarat, Bhatraphol Tingpej and Paul Deringer
Article Citation and PDF Link
BJMP 2011;4(2):a419
Abstract / Summary
Multiple sclerosis, Tumefactive multiple sclerosis


Tumefactive multiple sclerosis (MS) is a rare variant of MS.  This form of MS can masquerade as neoplasm or infectious etiology.  Understanding of the disease is limited to case report but it is associated with high morbidity and mortality.

Case report

A 44 year old man presented with a 2-month history of progressive right upper extremity weakness, confusion and visual change.  Physical exam revealed weakness, hyperreflexia on the right side and right homonymous hemianopia.  MRI of the brain showed multiple ring-enhancing lesions located in both cerebral hemispheres.  CSF analysis disclosed elevated protein with positive oligoclonal bands and myelin basic protein.  Stains and cultures for bacteria and mycobacteria were negative.  Serologies including HIV, Toxoplasmosis, and Lyme were all negative.  Patient was treated with high-dose IV corticosteroid and clinically improved.  One month later, he presented with increasing confusion, aphasia and progressive weakness.  Repeat MRI of the brain revealed worsening multiple ring-enhancing lesions with surrounding vasogenic edema in most lesions.  High-dose corticosteroid was promptly started.  There was also concern about infection, especially brain abscess; hence, intravenous ceftriaxone, vancomycin, and metronidazole were empirically given.  Due to uncertainty of diagnosis, first brain biopsy at right frontal lobe lesion yielded non-specific gliosis.  Repeat MRI brain showed increasing number of ring-enhancing lesions in both cerebral hemispheres.  As a result, a second brain biopsy was performed, which showed an active demyelinating process consistent with multiple sclerosis.  Patient experienced severe disability and was discharged to long-term facility with slowly tapered schedule of corticosteroid. He was readmitted several times and eventually family decided hospice care.


Multiple sclerosis is diagnosed by demonstrating clinical and/or radiographic evidence of dissemination of disease in time and space1.  Tumefactive MS is a term used when the clinical presentation and/or MRI findings are indistinguishable from a brain tumor2.  Not all case of tumefactive MS are fulminant.  Marburg variant MS is an acute rare variant of MS which has a rapidly progressive course with frequent, severe relapses leading to death or severe disability within weeks to months3.  The tumefactive demyelinating lesions are defined as large (>2 cm.) white matter lesions with little mass-like effect or vasogenic edema, and post-gadolinium magnetic resonance imaging (MRI) typically showing an incomplete ring enhancement2,4.  The clinical and imaging characteristics of these demyelinating lesions may mimic primary and secondary brain tumors, brain abscess, tuberculoma, and other inflammatory disorders e.g. sarcoidosis, primary sjogren’s syndrome5. As a result, tumefactive MS is frequently misdiagnosed. There are some MRI characteristics that are more suggestive of tumefactive demyelinating lesions than of other etiologies.  These include incomplete ring enhancement, mixed T2-weighted iso-and hyperintensity of enhanced regions, absence of a mass effect and absence of cortical involvement2,6.   Differential diagnosis of rapidly progressive neurological deficit with ring-enhancing lesions include brain abscess, primary brain neoplasm or brain metastasis, acute disseminated encephalomyelitis (ADEM) and tumefactive multiple sclerosis.  Careful clinical history, CSF study, serial MRI evaluation and follow-up are usually sufficient to make a diagnosis. Some cases pose considerable diagnostic difficulty owing to clinical and radiographical resemblance to brain tumor, for which biopsy may be warranted.  Pathologically, the lesions are characterized by massive macrophage infiltration, acute axonal injury, and necrosis.  No specific histological features distinguished specimens derived from patients developing classic multiple sclerosis from those who had tumefactive form7.  A limited number of cases of Marburg’s variant MS have been reported in the literature whereby most patients died within a period of weeks to months.  Only two cases survived after one year7,8.  There is no current standard treatment for this condition.  Plasma exchange and Mitoxantrone are reportedly showed some promising options9,10.

Figure A: FLAIR imaging at first presentation showed lesion in both hemisphere. Figure B: FLAIR imaging at one month later showed progression of multiple lesion in both hemisphere. Figure C: T1 Post contrast imaging showed intense ring enhancement pattern in almost all lesions  with mild edema and minimal mass effect. Figure D: Showed lesion view as sagittal section.

Our patient presented somewhat like a stroke with visual field defect and right hemiparesis which is unusual in MS, but MRI and CSF exam yielded a diagnosis of probable MS.  Because of his abrupt clinical deterioration and impressive worsening of his MRI, concern was raised about possibility of infection or neoplasm.  Hence, he received two brain biopsies, the second of which showed active demyelination, confirming the diagnosis of severe tumefactive multiple sclerosis and can be consider as a Marburg variant multiple sclerosis.


Marburg variant multiple sclerosis carries a high morbidity and mortality.  This disease notoriously mimics other conditions leading to delay diagnosis and treatment.  Absence of definitive diagnosis test apart from brain biopsy makes diagnosis, prognosis and treatment decisions difficult. 

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
POTJANA JITAWATANARAT, MD Internal Medicine Resident, Bassett Medical Center, Cooperstown, NY BHATRAPHOL TINGPEJ, MD Internal Medicine Resident, Bassett Medical Center, Cooperstown, NY PAUL DERINGER, MD Neurology Attending, Bassett Medical Center, Cooperstown, NY
Corresponding Author Details: 
POTJANA JITAWATANARAT, MD Internal Medicine resident, Bassett Medical Center, Cooperstown, NY
Corresponding Author Email:


1.  McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the Diagnosis of multiple sclerosis. Ann Neurol.2001; 50: 121–7.2.  Dagher AP, Smirniotopoulos J. Tumefactive demyelinating lesions. Neuroradiology. 1996; 38: 560–5.3.  Canellas AR, Gols AR, Izquierdo JR, et al. Idiopathic inflammatory-demyelimating disease of central nervous system. Neuroradiology.2007; 49:393-409.4.  Lucchinetti CF, et al. Clinical and radiographic spectrum of pathologically confirmed tumefactive multiple sclerosis. Brain.2008; 131:1759-75.5.  Sanahuja J, Ordonez-Palau S, Beque R, Brieva L, Boquet D. Primary Sjogren syndrome with tumefactive central nervous system involvement. Am J Neuroradiol.2008 Nov; 29(10):1878-79.6.  Kim DS, et al. Distinguishing tumefactive demyelinating lesions from glioma or central nervous system lymphoma: Added value of unenhanced CT compared with conventional contrast-enhanced MR imaging. Radiology. 2009; 251:467-75.7.  Turatti M, Gajofatto A, Rossi F, et al. Long survival and clinical stability in Marburg variant multiple        sclerosis. Neurol Sci. 2010; 31(6):807-11.8.  Giubilei F, Sarrantonio A, Teisei P, et al. Four-year follow-up of a case of acute multiple sclerosis of the Marburg type. Ital J Neurol Sci.1997; 18:163-166.9.  Jeffery DR, Lefkowitz DS, Crittenden JP. Treatment of Marburg variant multiple sclerosis with mitoxanthrone. J Neuroimaging. 2004; 14:58-6210.  Rodriguez M, Karnes WE, Bartleson JD, Pineda AA Plasmapheresis in acute episodes of fulminant CNS inflammatory demyelination. Neurology.1993; 43 (6):1100-4.

Malignant Hypertension Masquerading as Thrombotic Thrombocytopenic Purpura

Muhammad Zohaib Bawany, Zeeshan Tariq, Thomas Sodeman and Anand Mutgi
Article Citation and PDF Link
BJMP 2011;4(2):a418
Abstract / Summary

Hypertension is common, but with early detection and treatment, it is rare to see malignant hypertension.  Malignant hypertension is a medical emergency with an incidence of 1% in hypertensive patients.  We report on a patient who presented with signs suggestive of Thrombotic Thrombocytopenic Purpura and severe hypertension, which resolved with the treatment of hypertension.

Malignant Hypertension, Thrombotic Thrombocytopenic Purpura


Hypertension is common but, with early detection and treatment, it is rare to see malignant hypertension. We report a patient who presented with signs suggestive of thrombotic thrombocytopenic purpura and severe hypertension, which resolved with the treatment of hypertension.


A 34 year old African American male presented to the emergency department (ED) having experienced nausea, vomiting and diarrhoea for two days.  He denied haematochezia, meleana or sick contacts at home.  He complained of blurred vision without photophobia, headache and mild chest discomfort.  His past medical history was unremarkable.  The patient did not have any significant family history. Smoking history was significant for a pack of cigarettes daily for seven years.  He reported occasional alcohol intake, and denied use of recreational drugs.  On presentation, this patient’s blood pressure was 201/151 mmHg, with a mean of 168 mmHg.  Pulse 103 beats per minute, respirations 20 per minute and temperature 98.4F.  Physical examination was otherwise unremarkable, including absence of focal neurological deficits.

Blood tests showed: Haemoglobin 12.6 g/dl, White cell count 13.9 g/dl, Platelets 67000, Sodium 136, Potassium 3.4, BUN 24, Creatinine 2.56 and LDH 556. Chest x-ray showed cardiomegaly.  A non-contrast computed tomography scan of the brain did not show any sign of stroke (haemorrhage).  Urinalysis was positive for proteins 4+, a large amount of blood, 0-2 white blood cells/high power field (HPF) and 0-2 red blood cells/HPF.

Figure 1

The patient’s initial treatment whilst in the ER consisted of a Labetalol drip.  His mean arterial pressure decreased to approximately 115 mmHg during the first hour, and his chest pain and headache improved with the control of elevated mean arterial pressure.  Furthermore, over the next 24 - 48 hours, the patient’s blood pressure was brought down to 138/86 mmHg and his blurred vision improved significantly.  Subsequently, intravenous medications were switched to an oral regimen.  Blood peripheral smear from the day of admission was significant for the schistocytes (Figure 1) suggesting ongoing haemolysis.  Renal ultrasound was unremarkable.  His cardiac ultrasound revealed an enlarged left ventricle, however no valvular abnormality was seen.  Serum calcium and thyroid stimulating hormone levels were normal, as were urine catecholamines and vanillylmandelic acid level.  On two week follow up in the outpatient clinic, the patient’s platelet count and creatinine had returned back to baseline and peripheral smear did not reveal any schistocytes as the blood pressure came under better control. [Table 1]

Variable On day 1 Day 3 Day 5 Day 6 Follow-up in 2 weeks
Haemoglobin 12.6 9.3 9.3 10.3 11.4
Platelets 67, 000 65,000 90,000 125,000 204,000
Retic. count 3.9 -- -- 4.3 --
Creatinine 3.06 2.86 2.69 2.4 2.3
BUN 29 27 28 27 27
LDH 556 370 333 240 --
Troponin 0.10 0.08 0.06 0.05 --
Peripheral Smear Schistocytes -- -- -- No Schistocytes

Table 1


Malignant hypertension is a medical emergency with an incidence of 1% in hypertensive patients1and is more common in the African American population2.  Depending on the clinical presentation, it must be differentiated from thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulation (DIC), glomerulonephritis and vasculitis.

Suspicion for TTP was initially high in this patient because of haemolysis, thrombocytopaenia, central nervous system (CNS) manifestations and renal insufficiency.  However, TTP did not explain the presence of elevated blood pressure3,4nor the improvement in symptoms and signs with the management of this, which clearly supports our diagnosis.  Rapidly progressive glomerulonephritis did not explain the CNS symptoms, and a normal prothrombin time and activated partial thromboplastin time ruled against disseminated intravascular coagulation5.  The patient did not have a history of preceding diarrhoea6, which could possibly direct towards haemolytic uraemic syndrome (HUS)4.  There was no history of prosthetic valves, nor clinical evidence of vasculitis. The patient’s symptoms of severe hypertension, haemolysis, thrombocytopaenia and renal failure were consistent with malignant hypertension, and treating the hypertension7gradually resolved the thrombocytopaenia, haemolysis and renal failure8


This case report highlights that malignant hypertension is a medical emergency which can present with features resembling a wide variety of diseases, including TTP and HUS.  Using appropriate management to control the elevation in blood pressure can help reveal the underlying diagnosis.

Acknowledgements / Conflicts / Author Details
Competing Interests: 
None declared
Details of Authors: 
Muhammad Zohaib Bawany MD, Zeeshan Tariq MD, Thomas Sodeman MD FACP, Anand Mutgi MD FACP, University of Toledo Medical Center, Toledo, OH
Corresponding Author Details: 
Muhammad Zohaib Bawany, University of Toledo Medical Center, 3000 Arlington Ave Mail stop 1150, Toledo OH, USA 43614
Corresponding Author Email:


1.    Kitiyakara C, Guzman NJ. Malignant hypertension and hypertensive emergencies. J Am Soc Nephrol 1998;9:133-42.2.    Khanna A, McCullough PA. Malignant hypertension presenting as hemolysis, thrombocytopenia, and renal failure. Rev Cardiovasc Med 2003;4:255-9.3.    Patel A, Patel H. Thrombotic thrombocytopenic purpura: the masquerader. South Med J 2009;102:504-9.4.    Shibagaki Y, Fujita T. Thrombotic microangiopathy in malignant hypertension and hemolytic uremic syndrome (HUS)/ thrombotic thrombocytopenic purpura (TTP): can we differentiate one from the other? Hypertens Res 2005;28:89-95.5.    Kitchens CS. Thrombocytopenia and thrombosis in disseminated intravascular coagulation (DIC). Hematology Am Soc Hematol Educ Program 2009:240-6.6.    Hertig A, Ridel C, Rondeau E. [Hemolytic uremic syndrome in adults]. Nephrol Ther 2010;6:258-71.7.    Varon J, Marik PE. The diagnosis and management of hypertensive crises. Chest 2000;118:214-27.8.    Gassanov N, Pollok M, Er F. Acute renal failure associated with malignant hypertension. Dtsch Med Wochenschr 2009;134:2224-7.

Syndicate content