No

Incidence and Prevalence

The incidence and prevalence of hypertension is rife among first and second world countries and arguably, could be labelled the most common chronic disease in the UK¹. It is estimated that a quarter of all adults in the UK have hypertension². This is alarming in light of the incredible contribution of hypertension to mortality and morbidity. Evidence shows that for each 2mmHg rise of systolic blood pressure, mortality from ischaemic cardiac events rises by 7% and mortality from ischaemic intracranial events rises by 10%^3-4. The key to reversing this lies in diagnosing hypertension accurately and quickly and knowing how to best treat each patient.

Understanding hypertension

It is still not entirely clear what mechanisms cause hypertension. Evidence has proven that systolic blood pressure increases in a linear fashion with age, which is due to the loss of elastic tissue in arteries with age^1,5. This is known as ‘essential hypertension’. The majority of patients who are diagnosed with hypertension have ‘essential hypertension’, in other words, there is no clear cause found besides increasing age^1-2. Research has shown that other factors can be associated with hypertension but alone may not necessarily cause it. Unalterable risk factors include genetic predisposition, age, sex and race. Other factors which have proven to raise blood pressure include environmental factors such as lifestyle and diet, obesity (randomised control trials have shown that a weight loss of one kilogram can be attributed to one mmHg fall in diastolic blood pressure⁵), excessive alcohol intake, smoking, stress at work or in the home, socio-economic status and recent major life events^1-2,6.

How to take the perfect blood pressure

In the clinic setting, make sure the patient is relaxed, sit the patient comfortably with their arm outstretched, resting on the table and wait a few minutes.  Make sure the sleeves are not too tight as this will alter the readings^1,5. Be careful that the blood pressure cuff is the correct size for the patient as small cuffs can give a false high reading for larger patients and larger cuffs can give a false low reading for smaller patients^3,5. Check the pulse is regular as irregular pulses can give incorrect readings from automated devices - if in doubt perform it manually⁵. Take the blood pressure in both arms and repeat several times, discard the first reading and always record the lowest reading in the patient’s file¹.

The well recognised ‘white coat syndrome’ has a prevalence of about 10% in the UK and according to NICE data, the syndrome can cause a difference of 20/10mmHg between readings in a clinical setting and those at home^1,3,5. In light of this, NICE altered the guidelines in 2011, stating that any patient with a reading close to 140/90mmHg is to be sent home with an Ambulatory Blood Pressure Monitor (ABPM)³. This is a device attached to the patient for a minimum of 24 hours and it records the patient’s blood pressure every 30 minutes of the patient’s waking day. The idea behind this is to rule out any ‘white coat syndrome’ and to get a range of readings as the patient goes about their usual day to day activities. In this way, when the readings are analysed (an average of at least 14 readings are taken by the clinician), it confirms diagnosis immediately and treatment can be initiated^1,3.

The value of repeated measurements in different settings has been shown in evidence from as early as the 1970s^2,5. Research has also shown that patients usually have a high blood pressure reading initially which drops after subsequent measurements, hence the new guidelines are in place to allow for a range of readings before diagnosing and treating hypertension^1,3.

Investigations

While the patient is still in the clinic, assess the patient’s overall cardiovascular risk score using the cardiovascular risk assessment tool³.  Perform a thorough physical examination, including looking for evidence of target organ damage, for example, left ventricular hypertrophy, renal disease, peripheral vascular disease and changes in the retina from raised blood pressure^1,3,5. If there is suspicion of hypertension, send the patient home on an ABPM³. While waiting for the results of the ABPM, any patient under investigation for hypertension needs to have a baseline set of tests^1,7-8. This includes a full blood count, renal function tests, liver function tests, a fasting glucose and cholesterol blood test, an ECG (electrocardiogram) and a urine dip. These tests are a basic screen for assessment of target organ damage^6,9. If these investigations are not adequate, a patient can be referred for more extensive investigation for target organ damage, for example, an echocardiogram or a renal ultrasound/angiography^1,3,5.

Any patient that is young or presenting with persistent hypertension, especially that which does not respond to treatment, needs further investigation for other causes, such as renal disease, adrenal disease, alcoholism or steroid use (not to forget the oral contraceptive pill can also cause hypertension^1,7,9.

In general, a patient should be treated if their blood pressure readings are persistently 140/90mmHg or higher. For those that have borderline readings, for example, 135/85mmHg, clinicians must assess their cardiovascular risk score and look for target organ damage. If there is evidence for either of these, a patient should be started on treatment immediately¹.

Treatment

Non-pharmacological

First line treatment of hypertension is always non-pharmaceutical; also known as ‘lifestyle changes’ ^1,3,5,9. Attempt to find out the details of the patient’s diet, weight, employment, stress levels at work/home, exercise, alcohol intake and smoking habits. Once established, assist the patient in altering their lifestyle choices in order to lower their blood pressure. Patients often feel overwhelmed and many benefit from group activities, such as smoking cessation and weight loss groups³. Other ideas include a dietician referral, counsellors if they are struggling with motivation and low moods, gym sessions/personal trainers. Encourage the patient in that if they succeed in altering their lifestyle and therefore bringing down their blood pressure, they can avoid prescription medication.

Lifestyle changes can delay hypertension for many years but if the blood pressure continues to creep upwards in subsequent multiple visits and lifestyle options have been exhausted, it would then be appropriate to start pharmacological management^1,3,5.

Pharmacological Treatment

In general terms, always start with monotherapy and increase the dose according to patient response. According to NICE guidelines from 2011, if a patient is over 55 years of age and/or Afro-Caribbean in origin, start with a calcium channel blocker, such as Amlodipine³. If these are contra-indicated, start with a thiazide diuretic³. In regards to thiazide diuretics, the new NICE guidelines state that Chlortalidone (12.5–25.0 mg once daily) or Indapamide (1.5 mg modified-release or 2.5 mg once daily) should be used in preference to what clinicians have been prescribing for years, namely Bendroflumethiazide and Hydrochlorothiazide³. For those who are already on these conventional thiazide diuretics, NICE state that if the patient’s blood pressure is stable, to continue with Bendroflumethiazide or Hydrochlorothiazide³.

Patients diagnosed with hypertension who are under 55 years of age, should be started on an ACE inhibitor (Angiotensin Converting Enzyme inhibitor), for example, Ramipril³, but if this is not tolerated, replace it with an ARB (Angiotensin II Receptor Blocker) such as Losartan³.

Review the patient every few weeks initially and extend the reviews to 6 months once the blood pressure is within therapeutic range⁶.Do not forget to check the patient’s renal function in the first few months of starting a new drug and always be aware that if a patient’s blood pressure drops drastically after starting an ACE inhibitor this suggests underlying renal disease and must be investigated^1,3,5,9.

Continue to titrate the dose of the drug until the patient’s blood pressure is satisfactory. Consider adding in a second agent when the patient is nearing maximum dose of the first agent and the blood pressure is rising again^3,5. Depending on what the patient is on, add in either an ACE inhibitor, ARB or a calcium channel blocker, for example, if patient is on Ramipril, add in Amlodipine and vice versa³. If a calcium channel blocker is not tolerated as second line, consider using thiazide diuretics. Afro-Caribbean patients who are already on calcium channel blockers, add in an ARB, rather than an ACE inhibitor³.

Following that, if the blood pressure is still not within therapeutic range, consider adding in a third agent or alternatively, discontinue the first agent and continue with the second and add a third from among an ACE inhibitor, ARB or calcium channel blocker. Consider a thiazide diuretic if patients are intolerable to any of the above³.

Beta-blockers should not be considered in treating hypertension, according to NICE, unless the patients are very young or intolerant to ACE inhibitors, ARBs or calcium channel blockers³.

Beware and monitor closely any elderly patients who are on antihypertensives as the physiology of ageing interferes with the drugs, for example, decreased clearance of drugs from the kidney or liver, decreased sensitivity to baroreceptors (postural hypotension), chronic sodium retention and reduced cardiac reserve. Do not forget communication and compliance issues with the elderly also^1,7.

Make sure there is an annual review for each patient that has been diagnosed with hypertension in order to get blood pressure readings, medication review and how the patient is coping with lifestyle changes or side effects of the antihypertensives.

When to Refer

Resistant hypertension is defined as a patient remaining hypertensive despite being on triple or quadruple drug therapy^3,7. Consider starting a low dose of Spironolactone (if the serum potassium is less than 4.5mmol/l) and refer to a specialist for advice^3-4.

If subsequent readings are 180/110mmHg or more, start antihypertensives immediately and refer the patient to hospital. Also refer immediately if retinal haemorrhages or papilloedema are seen^1,3.

Summary

If a patient is suspected to have hypertension, send them home with an ABPM and perform baseline tests^1,3.

Start treatment if blood pressure is 140/90mmHg and ABPM average is 135/85mmHg and/or patient has one of the following:

• target organ damage
• established cardiovascular disease
• renal disease
• diabetes
• 10-year cardiovascular risk equivalent to 20% or greater (NICE guidelines, 2011)³

Start on monotherapy and review every few months, until blood pressure is stable³.

Review yearly after stability has been reached and consider adding in further antihypertensives if the blood pressure rises again.

Book patients in for annual reviews of end organ damage as this is an excellent overview of disease progression.

Hypertension is to be respected in light of its incredible contributor to morbidity and mortality. Never underestimate the importance of keeping a patient’s blood pressure within the desired range⁴.

Introduction

Prolactin is a polypeptide hormone that is secreted by lactotrophs of the anterior pituitary gland. Prolactin secretion shows a circadian rhythm¹, with highest levels occurring during the night and the nadir occurring during the afternoon and eveningThe best known function of prolactin is the stimulation and maintenance of lactation.

Normal basal levels of serum prolactin are approximately 20 to 40 ng/ml in women (depending on the phase of their menstrual cycle), and 15 ng/ml in men. However, these concentrations can also vary with ageHyperprolactinemia is diagnosed when serum prolactin concentrations are >20-25 ng/ml (400-500 mU/l) on two separate occasions³.

Hyperprolactinemia is the most common disorder of the hypothalamic-pituitary-gonadal (HPG) axis⁴ and can have physiological causes - pregnancy, nursing, sleep, stress, sexual intercourse or pathological causes - tumor called prolactinomaMultiple factors are involved in prolactin secretion (Figure 1). However, hyperprolactinemia is also a common side-effect of traditional antipsychotics (e.g. haloperidol) and is associated with the use of some newer second generation agents^{2, 6}.

Figure 1: Factors involved in Prolactin secretion

The prevalence of hyperprolactinemia is low in the general population (0.4%), but it can be as high as 9 to 17 % in women with reproductive disordersThe disease occurs more frequently in women than in men, multiple signs and symptoms associated with hyperprolactinemia (Table 1).

Multiple variables affect probability of development of breast cancer (Table 2) and a number of important factors determine the risk for breast cancer, and the most important of these seem to be related to estrogen and possibly prolactin (Table 3).

Methods

Pubmed.gov searched by using keywords

Antipsychotics and Hyperprolactinemia

Hyperprolactinemia is caused by these agents by blocking D2 receptors on lactotrophs and thus preventing inhibition of prolactin secretion. Furthermore, it has been suggested that the degree of elevation of prolactin correlates with the degree of occupation of D2 receptors in excess of 50%⁸.

Most studies have shown that conventional antipsychotics are associated with a two to tenfold increase in prolactin levels^{9, 10}. In general, second generation antipsychotics produce a lower increase in prolactin than conventional agentsAmong second generation antipsychotics associated with increased prolactin are amisulpride, zotepine and risperidone^{11, 12, 13}.

Antipsychotic induced Hyperprolactinemiaand Breast cancer

Prolactin is known to increase the incidence of spontaneously occurring mammary tumors in mice¹⁴ and increase the growth of established carcinogen-induced mammary tumors in rats¹⁵.

Prolactin and other sex hormones such as, estradiol and progesteroneare important in normal mammary gland growth and developmentas well as lactation. Both animal and in vitro data suggestthat prolactin is involved in tumorigenesis by promotingcell proliferation, increasing cell motility,and improving tumor vascularization. Whereas prolactinand its receptor are found in normal and malignant tissues,concentrations of both are generally higher in malignant tissue¹⁶.

Several studies have linked hyperprolactinemia to an increased risk of breast cancer in women^{17, 18}. Mechanisms that have been suggested to explain this possible action of prolactin include the increased synthesis and expression of prolactin receptors in malignant breast tissue and a prolactin-induced increase in DNA synthesis in breast cancer cells in vivo¹⁸.

One of the hypothesized roles of prolactin in the development of mammary tumors is to create mammary gland conditions favorable for the action of carcinogens through its stimulation of the rate of mammary gland DNA synthesis, a measure of the frequency of mammary gland cell division¹⁹.

Several epidemiological studies have investigated whether female psychiatric patients receiving treatment with antipsychotics have a higher incidence of breast cancer but results have been conflicting. However, the most recent and methodologically strong study, found that antipsychotic dopamine receptor antagonists conferred a small but significant risk of breast cancer. This study had a retrospective cohort design and compared women who were exposed to prolactin-raising antipsychotics with age-matched women who were not²⁰.

Conversely, other studies have shown no correlation between hyperprolactinemia and breast cancer^{21, 22}. Furthermore, as most breast cancers are thought to be fueled by estrogen²³, and hyperprolactinemia causes estrogen deficiency²⁴, it is perhaps surprising that hyperprolactinemia has been linked with an increased risk of breast cancer. Indeed, post-operative hyperprolactinemia in breast cancer patients has been shown to improve disease free and overall survivalObviously, more studies are necessary to define any possible links between hyperprolactinemia and breast cancer.

In view of these problems it would be of interest to go around the contentious issue of possible carcinogenic effects of dopamine antagonists using a classical condition of dopamine loss or attenuation as in Parkinson's disease (PD). Using computerized registers of death data of the National Center of Health Statistics for years 1991 through 1996, estimated 12,430,473 deaths of persons over forty, and extracted 144,364 cases with PDTellingly, PD patients showed a highly significant reduction of overall cancer incidence. PD resistance to breast cancer might conceivably be attributed to dopaminergic treatment antagonizing hyperprolactinemia^{26, 27, 28}.

Another recent study showed that dopaminergic therapy inhibits angiogenesis thereby acting as an anti-tumor agent²⁹.

Epidemiological studies of women who have received prolactin-releasing drugs such as reserpine and perphenazine have not disclosed increased risk³⁰.

Antipsychotic induced Hyperprolactinemia and Other cancers

Antipsychotics have been hypothesized to account for the reduced cancer occurrence observed in patients with schizophrenia in a number of studies. This reduction has been found primarily in men in smoking-related cancers, and in prostate and rectal cancer.

In addition, a study found a reduced risk of rectal cancer in both men and women as well as indications of a reduced risk of colon and prostate cancer in this population-based cohort of neuroleptic users. Reassuringly, they observed no increased risk of breast cancer in female users³¹.

Comments and recommendations

• Hyperprolactinemia results from treatment with any drug that disrupts dopaminergic function on the HPG axis and is not limited to the use of antipsychotics.
• Management of supposed anti-psychotic associated hyperprolactinemia should exclude all other causes, involve regular monitoring of adverse effects and include a regular risk-benefit discussion with patient.
• Switching the patient to prolactin-sparing antipsychotic (i.e. Aripiprazole, Olanzapine, Quetiapine or Clozapine) usually proves effective, though there is also a risk of relapse.
• It seems prudent to avoid prescribing prolactin-raising antipsychotics in patients with past history or family history of breast cancer.
• It is premature to mandate warning patients of an unknown and undemonstrated increase in the risk of developing breast cancer associated with neuroleptic treatment.
• Before initiating antipsychotic treatment a careful examination of patient is necessary.
• One should examine the patient for evidence of sexual adverse events, including menorrhagia, amenorrhoea, galactorrhoea and erectile/ejaculatory dysfunction. If evidence of any such effects is found, then the patient's prolactin level should be measured.
• Patient history, physical examination, pregnancy test, thyroid function test, blood urea and creatinine level can help determine if other etiologies are responsible.
• Presence of headache and visual field defects is suggestive of a sellar space-occupying lesion (MRI indicated), but the absence of these features does not exclude such pathology.
• History of menstrual cycling (duration, amount and intervals of menstruation) as well as lactation and sexual functioning should be taken before antipsychotic medication is initiated.
• Obtain a pretreatment prolactin level, which one can compare with subsequent samples if the patient develops symptoms associated with relatively modest hyperprolactinemia.
• The risk-benefit ratio for treatment of antipsychotic-induced hyperprolactinemia needs to be assessed on an individual basis.
• If there is doubt about the cause of the hyperprolactinemia, patient should be referred to an endocrinologist.

Current recommendation

A rise in prolactin concentration should not be of concern unless complications develop, and until such time no change in treatment is required.²⁰

Conclusions

There is no definitive data suggesting increased risk of breast cancer available at this time, thus author concludes:

• Further prospective studies are needed in this area, with large number of patients, before a more definitive answer can be provided.
• Detection of existing mammary tumor by breast examination or studies (mammogram) is recommended prior to administration of neuroleptics.
• Development of newer antipsychotic drugs that do not increase serum prolactin level may be indicated.

Strengths

• Each article found by search term was reviewed
• Data were extracted from each article to find answer of research question
• Pubmed.gov is a huge database for search.

Limitations

• This literature review has been conducted by a single author, thus bias on part of author cannot be ruled out
• Author was limited by time to review articles available in other databases.

Claiming historic triumph, that has defined his presidency ever since, President Barak Obama signed the $ 1 trillion Patient Protection and Affordable Care Act (in short called as ACA) in a highly visible white house ceremony on Tuesday March 23, 2010 (using 20 different pens) thereby establishing health care as a ‘right’ of every American for the first time. It took all the legislative and political skills from him to get the bill passed through both houses of Congress as was suggested on these pages previously.¹

Soon after President Obama signed the landmark legislation, 26 States filed law suit contesting that the health care legislation, which earned the nickname of “Obamacare” from its opponents, was unconstitutional for several reasons. The legal challenge created significant uncertainty about the viability and future implementation of the legislation. There was also growing concern about the law’s impact on the national debt that became, and continues to be, an extremely divisive issue between the Democrats and the Republicans in the US Congress.

The law suit finally, as expected, made its way to the Supreme Court of the United States. The Court was looking at the legislation from three angles. First, at the core of the legislation, was the requirement that nearly all Americans obtain health insurance by 2014 or face a financial penalty- a provision that came to be known as the ‘individual mandate’ . The penalty would be recycled into “health exchanges” providing alternate options to low income Americans and small businesses for purchase of health care. The ‘individual mandate’ was the backbone of the legislation that wouldcover millions of uninsured Americans, majority of whom would be healthy young individuals. And, if this ‘individual mandate’ were to be struck down by the Court (as was expected by many), then the second question would be what happens to the rest of the ACA as insurance industry was supporting the legislation since it would provide them with tens of millions of new healthy ‘customers’. If such healthy individuals were left out, the pool would have mostly sicker individuals compromising the profitability, and perhaps the very viability, of the insurance industry. The third issue related to the mandate for the states to accept a large number of individuals into Medicaid program that provides health care for the poor and those with income of up to 133 % of the federal poverty level.²

The Supreme Court, mercifully for President Obama, upheld virtually the entire legislation in its historic decision on June 28, 2012. The four ‘liberal justices’ ( Justices Stephen Breyer, Ruth Ginsburg, Elena Kagan and Sonia Sotomayor) were joined by the conservative Chief Justice John Roberts in upholding the ‘individual mandate’. In what many observers of the court called a surprising twist, the justices held that the mandate was not constitutional under the ‘interstate commerce clause’, as argued by the administration, but was constitutional under Congress’ power of taxation. The other four dissenting conservative justices (Justices Samuel Alito, Anthony Kennedy, Antonin Scalia and Clarence Thomas) held that the Congress had exceeded its authority on several levels.

The reaction to the ruling was prompt and mixed. Dr. Jeremy A. Lazarus, President American Medical Association said “The AMA has long supported health insurance coverage for all, and we are pleased that this decision means millions of Americans can look forward to the coverage they need to get healthy and stay healthy”. The President and CEO of American Hospital Association, Mr Rich Umbdenstock, said “The decision means that hospitals now have much-needed clarity to continue on their path toward transformation”Perhaps the President of the American College of Physicians stated it best “We hope that a day will come when the debate will no longer be polarized between repeal on one hand, or keeping the law exactly as it is on the other, but on preserving all of the good things that it does while making needed improvements.”

The President of the U.S. Chamber of Commerce, Thomas J. Donohue, lamented that “While we respect the court’s decision, today’s Supreme Court ruling does not change the reality that the health care law is fundamentally flawed. It will cost many Americans their employer-based health insurance, undermine job creation and raise health care costs for all.” And in a scathing statement, the President of National Federation of Independent Business, Dan Danner, echoing the sentiments of a growing number of small businesses said “Under [the ACA], small-business owners are going to face an onslaught of taxes and mandates, resulting in job loss and closed businesses. We will continue to fight for the repeal of [the ACA] in the halls of Congress; only with [the ACA’s] full repeal will Congress have the ability to go back to the drawing board to craft real reform that makes reducing costs a No. 1 priority.” ³

This line of argument, apart from bringing some uncertainly, provided politicians fodder as they move closer to the Presidential elections. And as expected, the Republicans (who control the House of Representatives) passed legislation repealing the law but the bill died in the US Senate (controlled by Democrats). And the Republican Presidential candidate, Gov. Mitt Romney, framed the decision as a political call to arms. “What the Court did not do on its last day in session, I will do on my first day if elected President of the United States. And that is I will act to repeal Obamacare.” While both President Obama and Gov. Romney agree that Medicare costs have to be reined in but there is fundamental difference in their approach to cost cutting. President Obama’s plan relies on a powerful board to reduce payments to service providers and gradually changing how hospital and doctors are paid in order to eliminate fee for service and establish pay for performance (pay for the quality, not quantity). Gov. Romney would limit the amount future retirees would receive from the federal government to approximately $ 7000 (also called as Voucher System) and relying on the private industry to find an efficient solution.

It is clear that Gov. Romney, who previously implemented ‘Obamacare’ type of legislation as the governor of Massachusetts, flipped his position to appease extreme right wing of the Republican Party. As usual politics trumps policy. This drama continues to play out as we get closer to the election on November 6, 2012.

As identified by an independent nonpartisan educational institute based in Washington, The Centre for American Progress (CAP), some of the popular provisions of the law are ⁴:

• The law provides for young adults to stay on their parents’ insurance to age 26 enabling 2.5 millionyoung Americans toenrol on their parents policies (73 % of young adults now have coverage as a result of this provision);
• For seniors living on fixed income (Medicare patient population), one of the immediate benefits of the ACA was the closure of prescription drug coverage gap (known as the ‘donut hole’) saving 4 million seniors about$ 2 billion on prescription drugs or approximately $604 per person, in 2011 alone;
• The law provides $11 billion to support and expand community health centres nationwide. More than 350 new community health centres were established in 2011 serving 50 million Americans in medically underserved areas;
• Starting in 2014, the law prohibits health insurance carriers from excluding and/or denying coverage or charging higher premiums and limiting benefits to those with pre-existing medical conditions (as happens currently in too many cases);
• 50,000 Americans have already enrolled in the Pre-existing Condition Insurance Plan (PCIP) that ensures medical services including prescription drugs for those with pre-existing conditions as soon as possible ;
• Provision of $200 million to expand school-based health centres for primary care, dental care, behavioural health services and substance abuse counselling;
• In 2011 alone, 85 million Americans benefitted from preventive services included in the legislation. Many more will benefit since a major provision of the preventive services for women took effect in August 2012;

However, several components of the legislation remain unclear and their impact rather unknown. As an example the Obama administration fought hard for formation of the Independent Payment Advisory Board (IPAB) to address the inordinate influence of stakeholders in Congressional decisions over Medicare. This group of 15 nonpartisan experts is responsible for developing payment and related Medicare policy changes to assure that Medicare spending does not exceed budget targets tied to economic growth. Although now the law, the IPAB may never be formed because the Senate is unlikely to find 60 votes required to confirm IPAB members (unless the election brings unforeseen changes in the makeup of the Senate). Politics may again triumph policy. The payment approaches that need to evolve from “volume” to “value,” remain vexing. The Centre for Medicare & Medicaid Innovation charged with developing the pilot programs that may result in a reformed delivery system, have no pilots that focus on developing alternative models to reimburse physicianservices.^{5, 6}

And the “invisible problem” of physician shortage! While there is growing bipartisan appreciation that the primary care workforce is insufficient to handle increasing demand for primary care services, the problem has not been fully addressed. The Association of American Medical Colleges estimates that in 2015 the country will have 62,900 fewer doctors than needed and those numbers will more than double by 2025. ^{7, 8}

In coming months the States may become the battleground for implementing the “health exchanges”. By 2014 States are required to establish American Health Benefits exchanges and small business health operations program (SHOP) exchanges. These exchanges called in short, “health exchanges”, are basically subsidized market places with tax credits for consumers to shop for their health insurance at very competitive rates. Individuals who will not be eligible for Medicaid and with income of up to 400% of the Federal poverty level will have access to these health exchanges to purchase insurance. Such subsidies and tax credits will also be available to businesses with less than 100 employees. ⁹

It is also becoming apparent that the financial burden of the legislation will be significantly higher than initially estimated.For example the non-partisan Congressional Budget Office (CBO) estimates that 80 % of Americans who will face penalty for lack of health insurance under the ‘individual mandate’ would be those with yearly income of $ 55, 250 (for individuals) and $ 115, 250 (for couples). This is in contrast to the statements of President Obama who continues to pledge that he will not raise taxes on individuals making less than $ 200,000 and couples making less than $ 250, 000. And the Republican side of the Senate Budget Committee estimates that Obamacare will cost $2.6 trillion dollars in its first real decade since the bill does not fully go into effect until 2014. ¹⁰

Fortunately for President Obama, the prestigious Institute of Medicine released a report,last month on September 6, confirming what has been suggested by him and others, that the US health care system wastes almost 30 % ($750 Billion) each year on unnecessary procedures, fraud and waste. Therefore, the administration has redoubled its efforts to check the waste and fraud in order to pay for the cost of ACA. However, the real battle will begin as soon as the Congress reconvenes in January 2013. They are immediately faced with dealing with “Sequestration”. Originally a legal term referring to the act of valuable property being locked away for safe keeping by an agent of the court, the term has been adapted by Congress in 1985 for fiscal discipline. Under this rule, an amount of money equal to the difference between the cap set in the Budget Resolution and the amount actually appropriated is "sequestered" by the department of Treasury and not handed over to the departments it may have been appropriated originally by the Congress. The balanced budget act of 2011established a Congressional task force (called ‘Super Committee’) that was charged to make recommendations to cut the US Budget deficit by $ 1.5 trillion by November 23, 2011. Failure to do so would automatically trigger “Sequestration”. On November 21, 2011, the committee issued a statement that it had failed to reach agreement. This failure is viewed by most as a triumph of political ideology over genuine leadership. But the prospect of ‘sequestration’ has come to be seen so catastrophic that key members of Congress and the Presidentare expected to abandon brinkmanship and come to an agreement in early 2012.

So, as the drama and the debate continue vigorously in the days leading up to the November 6 elections, it is clear that “Obamacare” will continue to divide the US congress and the country. Irrespective of the party that will control the Congress and who becomes the next President of the US, “Obamacare” is here to stay. And, no matter how hard the Republican Party may try, they will face a monumental task in reversing the course of the history. There will be bickering, name calling, finger pointing and horse trading. But, the warring factions will realize that the escalating costs and complexities of the health care system demand that the legislators and the President come together to find real solutions to keep the American health care system as the best in the world. The real challenges will remain the same no matter who is elected as President: to stem the unsustainable tide of national health expenditure as percentage of the gross national product (rising from 7.2 % in 1970 to over 17 % in 2010), rapidly increasing number of Americans without health insurance (approaching almost 50 million), exploding national debt and, more immediately, the looming threats from sequestration.

Introduction

Alopecia areata is a non-scarring autoimmune, inflammatory hair loss affecting the scalp and/or body. Although the etiopathogenesis of alopecia areata is still unknown, the most widely accepted hypothesis is that it is a T-cell mediated autoimmune condition that occurs in genetically predisposed individuals. The term ‘alopecia areata’ was first used for this disorder by Savages¹.Alopecia areata has a reported incidence of 0.1-0.2%, with a life-time risk of 1.7%^2-4. The disease can begin at any age, but the peak incidence is between 20 and 50 years of age⁵. Both the sexes are equally affected and there is no racial variation reportedClinically, alopecia areata may present as a single well demarcated patch of hair loss, multiple patches, or extensive hair loss in the form of total loss of scalp hair (alopecia totalis) or loss of entire scalp and body hair (alopecia universalis). Histopathologically, alopecia areata is characterized by an increase in the number of catagen and telogen follicles and the presence of perifollicular lymphocytic infiltrate around the anagen phase hair follicles. The condition is thought to be self-limited in majority of cases, but in some the disease has a progressive course and needs active treatment in the form of oral or topical therapeutic options. Progressive alopecia areata is associated with severe social and emotional impact.

Clinical features

Alopecia areata mostly presents as a sudden loss of hair in well demarcated localized areas. The lesion is usually a round or oval flat patch of alopecia with normal skin colour and texture involving the scalp or any other region of the body. The patch of alopecia may be isolated or there may be numerous patches. It usually has a distinctive border where normal hair demarcates the periphery of the lesion. In acute phases, the lesions can be slightly erythematous and oedematous.

The patches of alopecia areata are usually asymptomatic, although several patients may sometimes complain of local paraesthesia, pruritus or pain. The affected hairs undergo an abrupt conversion from anagen to telogen, clinically seen as localized shedding. Characteristic hairs, known as ‘exclamation point hairs’ may be seen within or around the areas of alopecia. The hairs are tapered towards the scalp end with thickening at the distal end. These hairs may also demonstrate deposition of melanin pigment in the distal extremity, also known as Wildy’s sign. Although not absolutely pathognomonic, it strongly suggests the diagnosis of alopecia areata. Hair pull test conducted at the periphery of the lesion may be positively correlated (six or more) with disease activity. In the chronic phases, the test is negative, since the hair is not plucked as easily as in the acute phases.

Another important clinical sign that can aid in the diagnosis is the presence of ‘cadaverous hair’. These are the hairs in which there occurs a fracture of the shaft inside the hair follicle, producing blackened points inside the follicular ostia resembling comedones. In alopecia areata, the hair loss progresses in a circumferential pattern. Often, distinct patches merge to form large patches. Upon regrowth, hairs will often initially lack pigment resulting in blonde or white hairs⁷.

Extrafollicular involvement in alopecia areata:

a) Nail changes: Nail changes are more frequent in children (12%) than in adults (3.3%)⁸.The prevalence of nail changes is greater in the more severe forms of alopecia areata such as alopecia universalis and alopecia totalisFinger nails are more commonly involved than the toe nails. Pitting is the most common finding. Other nail changes include koilonychias, onycholysis, onychomadesis, punctuate leukonychia, trachyonychia, Beau’s lines and red lunulae^8-11.

b) Ocular changes: Various ocular changes have been reported to occur in alopecia areata. These include focal hypopigmentation of the retina¹², lens opacities, posterior subcapsular cataracts¹³ decrease in visual acuity, Horner’s syndrome, heterochromia of the iris¹⁴, miosis and palpebral ptosis.

Treatment of alopecia areata

Treatment of alopecia areata is not mandatory in every affected patient because the condition is benign in majority and spontaneous remission is common. Treatment is mainly directed towards halting the disease activity as there is no evidence that the treatment modalities influence the ultimate natural course of the disease. Treatment modalities are usually tailored as per the extent of hair loss and the patient’s age. Addressing the impressive inflammatory process occurring in alopecia areata, corticosteroids have by far been the most commonly used treatment modality^-16Few treatments have been subjected to randomized control trials and except for contact immunotherapy, there is a paucity of published data on their long term outcomes. Currently, new treatments targeting the immune system are being explored for the use in alopecia areata.

Topical treatment options

Topical corticosteroids:

Several topical corticosteroids with varying levels of efficacy have been used to treat alopecia areata. These include fluocinolone acetonide cream¹⁷, fluocinolone scalp gel, betamethasone valerate lotion¹⁸, clobetasol propionate ointment¹⁹, dexamethasone in a penetration-enhancing vehicle and halcinonide cream²⁰. They are a good option in children because of their painless application and wide safety margin²¹. Topical corticosteroids are ineffective in alopecia totalis/universalisFolliculitis is a common side effect of corticosteroid treatment, appearing after a few weeks of treatment. Telangiectasia and local atrophy have also been reported. Treatment must be continued for a minimum of 3 months before regrowth can be expected and maintenance therapy often is sometimes necessary.

Intralesional corticosteroids:

Intralesional corticosteroids are widely used in the treatment of alopecia areata. In fact, they are the first-line treatment in localized conditions involving <50% of the scalp²². Hydrocortisone acetate (25mg/ml) and Triamcinolone acetonide (5-10mg/ml) are commonly used. Triamcinolone acetonide is administered usually in the concentration of 5mg/ml using a 0.5 inch long 30-gauge needle in multiple 0.1 ml injections approximately 1 cm apart^22-23. The solution is injected in or just beneath the dermis and a maximum of 3 ml on the scalp in one visit is recommended²³. Lower concentrations of 2.5mg/ml are used for eyebrows and face. Regrowth usually is seen within 4-6 weeks in responsive patients. Treatments are repeated every 3-6 weeks. Skin atrophy at the sites of injection is a common side effect, particularly if triamcinolone is used, but this usually resolves after a few months. Repeated injections at the same site or the use of higher concentrations of triamcinolone should be avoided as this may lead to prolonged skin atrophyPain limits the practicality of this treatment method in children who are less than 10 years of age. Severe cases of alopecia areata, alopecia totalis, alopecia universalis as well as rapidly progressive alopecia areata respond poorly to this form of treatment²⁵.

Anthralin:

Dithranol (anthralin) or other irritants have been used in the treatment of alopecia areata. The exact mechanism of action is unknown, but is believed to be through immunosuppressant and anti-inflammatory properties with the generation of free radicals. It is used at concentrations ranging from 0.5 to 1 % for 20-30 minutes after which the scalp should be washed with shampoos in order to avoid excessive irritant effects. The applications are made initially every other day and later on daily. Adverse effects include pruritus, erythema, scaling, staining of treated skin and fabrics, folliculitis, and regional lymphadenopathy^26-27. In an open study, 25% patients with severe alopecia areata were shown to respond positively to local applications of 0.5-1% anthralinMore placebo control studies are needed to justify the use of anthralin in alopecia areata.

Minoxidil:

Minoxidil appears to be effective in the treatment of alopecia areata. It’s mechanism of action has yet to be determined, but it is known to stimulate DNA synthesis in hair follicles and has a direct action on the proliferation and differentiation of the keratinocytes²⁸. In one clinical study, hair growth was demonstrated in 38% and 81% of patients treated with 1% and 5% minoxidil respectively. Thus 5% minoxidil solution is usually recommended as a treatment option in alopecia areata. No more than 25 drops are applied twice per day regardless of the extent of the affected area. Initial regrowth can be seen within 3 months, but continued application is needed to achieve cosmetically acceptable regrowth. Minoxidil has also been studied in combination with anthralin²⁹, topical betamethasone propionate³⁰ and prednisolone³¹. Minoxidil is of little benefit to patients of severe alopecia areata, alopecia totalis or alopecia universalisThe possible side effects from minoxidil are allergic and irritant contact dermatitis and hypertrichosis which is usually reversible with the interruption of the treatment.

Topical immunotherapy:

Topical immunotherapy is the best documented treatment so far for severe and refractory cases of alopecia areata. Topical immunotherapy is defined as the induction and periodic elicitation of allergic contact dermatitis by applying a potent contact allergen³³. In 1965, the alkylating agent triethyleneimino benzoquinone was the first topical sensitizer used to treat cutaneous disease, but it was abandoned on account of its mutagenic potential. Later nitrogen mustard, poison ivy, nickel, formalin, and primin were tried, mainly as topical immunotherapy, for alopecia areata and warts. Contact immunotherapy was introduced in 1976, by Rosenberge and Drake. Later, potent contact allergens namely dinitrochlorobenzene (DNCB) and diphenylcyclopropenone (DPCP) replaced the allergens that were used earlier³³. DNCB is mutagenic against Salmonella tymphimurium in the Ames test and is no longer usedNeither SADBE, nor DPCP are mutagenic. DPCP is more stable in solution and is usually the agent of choice.

Mechanism of action: Topical immunotherapy acts by varied mechanisms of action. The most important mechanism is a decrease in CD4 to CD8 lymphocyte ratio which changes from 4:1 to 1:1 after contact immunotherapy. A decrease in the intra-bulbar CD6 lymphocytes and Langerhan cells is also noted. Happle et al, proposed the concept of ‘antigenic competition’, where an allergic reaction generates suppressor T cells that non-specifically inhibit the autoimmune reaction against a hair follicle constituent. Expression of class I and III MHC molecules, which are normally increased in areas affected by alopecia areata disappear after topical immunotherapy treatment³⁴.A ‘cytokine inhibitor’ theory has also been postulated³⁴.

Method of sensitization: The protocol for contact immunotherapy was first described by Happle et al in 1983 The scalp is the usual sensitization site. For the initial sensitization a cotton-tipped applicator saturated with 2% DPCP in acetone is applied to a small area. Patients are advised to avoid washing the area and protect it from sunlight for 48 hours. After 2 weeks 0.001% solution of DPCP is applied on the scalp and then the application of contact allergen is repeated weekly with increasing concentrations. The usual concentration of DPCP that ultimately causes mild contact eczema is 0.01-0.1% and this is repeated weekly till a response is seen. An eczematous response indicates that sensitization has taken place. Only 1-2% of the patients fail to sensitize. It is important to remember that DPCP is degraded by light and should thus be stored in the dark and the patient should also wear a wig or hat during the day after application of DPCP. DPCP immunotherapy has even been combined with oral fexofenadine treatment with good effect³⁶.

Evaluation of efficacy: The clinical response after six months of treatment is rated as per the grading system proposed by Mcdonald Hull and Norris^37:

Grade 1- Regrowth of vellus hair.

Grade 2- Regrowth of sparse pigmented terminal hair.

Grade 3- Regrowth of terminal hair with patches of alopecia.

Grade 4- Regrowth of terminal hair on scalp.

If no regrowth is observed within six months of treatment, the patient is considered to be a non-responder. Evaluation of plucked hair is done using light microscopy, for evaluation of anagen/telogen ratio.

A review of most of the published studies of contact immunotherapy concluded that 50-60% of patients achieve a worthwhile response but the range of response rates was very wide (9-87%)Patients with extensive hair loss are less likely to respond. Other reported poor prognostic factors include the presence of nail changes, early onset disease and a positive family history³⁹.

Topical immunotherapy can lead to certain side effects such as persistent dermatitis, painfull cervical lymphadenopathy, generalized eczema, blistering, contact leukoderma, and urticarial reaction. Systemic manifestations such as fever, arthralgia and yellowish discoloration of hair are noted more often with DNCB.

In poor responders to DPCP, squaric acid dibutylester (SADBE) can be tried as a contact sensitizer. The method of application is the same as with DPCP but the applications are done once or twice weekly⁴⁰.

Good care should be taken to avoid contact with the allergen by handlers, including pharmacy and nursing staff. Those applying the antigen should wear gloves and aprons. There is no available data on the safety of contact immunotherapy during pregnancy and it should not be used in pregnant women or in women intending to become pregnant.

Tacrolimus:

Tacrolimus is a topical calcineurin inhibitor that inhibits transcription following T-cell activation of several cytokines including IL-2, IFN-gamma and TNF-α. Yamamoto et al reported in their findings that tacrolimus stimulated hair growth in mice⁴¹, although subsequent studies have shown conflicting resultsRecently, Price et al reported an 11-patient study in which none of the patients had terminal hair growth in response to tacrolimus ointment 0.1 % applied twice daily for 24 weeks⁴³.

Topical garlic

Garlic is a very commonly used home remedy in the treatment of alopecia areata in India and even in the rest of the world. One study analyzed the effect of a combination of topical garlic gel and betamethasone valerate ointment in alopecia areata in a double-blind study. The study found the combination useful in majority of the patients with a statistically significant difference between the treatment and control groups⁴⁴.

Topical retinoids:

Among topical retinoids, tretinoin and bexarotene have been tried in alopecia areata with mixed results^-46Irritation of the skin is a very common side effect and the efficacy is doubtful in the absence of double-blind randomized trials.

Prostaglandin analogs:

The propensity of certain prostaglandin analogues used as anti-glaucoma eye drops to cause hypertrichosis has been employed in the treatment of alopecia areata. These prostaglandin analogues include Latanoprost and Bimatoprost and they are used in the treatment of alopecia areata involving the eyelashes^-48However, the results obtained with these drugs have not been really encouraging⁴⁹.

Systemic treatments

Systemic treatments, as a rule, are used only in progressive forms of alopecia areata and going by the immune nature of the disease, majority of these treatment options are immunosuppressants or immunomodulators in nature.

Systemic corticosteroids:

The use of systemic corticosteroids for the treatment of alopecia areata is under much debate. Some authors support a beneficial role of systemic steroids on halting the progression of alopecia areata, but many others have had poor results with this form of therapy. The suggested dosages are 0.5-1mg/kg/day for adults and 0.1-1 mg/kg/day for children⁵⁰. Treatment course ranges from 1-6 months, but prolonged courses should be avoided to prevent the side effects of corticosteroids. Side effects profile of corticosteroids in conjunction with the long-term treatment requirements and high relapse rates make systemic corticosteroids a more limited option. In addition to the daily oral administration of corticosteroids, there are several reports of high-dose pulsed corticosteroid treatments employing different oral and intravenous regimens^51-53. Many of these regimens have been tried in alopecia areata with encouraging results but the majority of these studies have been non-blind open studies. One such pulsed administration employs a high dose oral corticosteroid on two consecutive days every week with a gap of 5 days between the two pulses. This modality of treatment is known as oral minipulse therapy (OMP) and it has been tried in many skin diseases in addition to alopecia areata like vitligo^54-55 and lichen planusSome open label studies on corticosteroid OMP therapy have reported encouraging results in alopecia areata⁵³.

Sulfasalazine:

Because of its immunomodulatory and immunosuppressive actions, sulfasalazine has shown good hair regrowth in the treatment of alopecia areata. The drug is administered orally usually as enteric coated tablets to minimize the gastrointestinal side effects. The treatment is started at a lower dose, usually in the range of 500 mg twice daily and then the dose is gradually increased to 1 g three times a dayAdverse effects include gastrointestinal distress, liver toxicity and haemotological side effects. Sulfasalazine helps in alopecia areata because it causes inhibition of T cell proliferation, and natural killer cell activity and also inhibits antibody production. It also inhibits the secretion of interleukin (IL)-2, IL-1, TNF- and IFN-gamma and even IL-6⁶⁷.

A number of clinical studies have documented a positive effect of sulfasalazine in alopecia areata. In one clinical study, 23% patients showed a really good response with satisfactory hair growth after sulfasalazine therapyOther studies have also shown a beneficial effect of this treatment option in resistant cases of alopecia areata^66,69.

Azathioprine:

Azathioprine, being an immunosuppressive agent has also been tried in alopecia areata. The drug is used in many cutaneous disorders owing to its effect on circulating lymphocytes as well as Langerhan cells. In a limited study on 20 patients hair regrowth was demonstrated in about half of the patients with a dosage regimen of 2g/day⁷⁰.

Cyclosporine:

This drug has proven effective in the treatment of alopecia areata because of its immunosuppressive and hypertrichotic properties. The side effect profile and high rate of recurrence render the drug a poor choice for the use in alopecia areata. So the drug is to be attempted only in severe forms of alopecia areata not responding to treatment⁷¹.

Methotrexate:

Methotrexate either alone or in combination with prednisolone has been used in the treatment of alopecia areata in various studies with variable success rates⁷².

Oral zinc sulphate

Serum zinc levels have been found to be lower in patients with alopecia areata than in control populationIn a study on 15 patients, hair regrowth was observed in 9 patients (67%) after oral zinc gluconate administration⁷⁴.

Biological agents:

Tumour necrosis factor inhibitors such as Adalimumab, Infliximab and Etanercept have been tried in alopecia areata, but the results have not been encouraging^-76Clinical trials conducted till now have failed to demonstrate the efficacy of any biological agent in alopecia areata.

Photo-and photochemotherapy

Photochemotherapy:

Several uncontrolled studies regarding PUVA therapy for the treatment of alopecia areata exist. All types of PUVA (oral PUVA, topical PUVA, local or whole body UVA irradiation) have been used with success rates of up to 60-65%^57-59. The mechanism of action is considered to be the interference in the presentation of follicular antigens to T-lymphocytes by depletion of the Langerhan cells. The relapse rate following treatment is high, sometimes demanding repeated treatments for a prolonged period with implications for carcinogenic risks⁶⁰. To mitigate the side effects of systemic psoralens, PUVA-turban therapy is used for alopecia areata involving the scalp. In this form of photochemotherapy, very dilute solutions of 8-methoxy psoralen are applied on the scalp by utilizing a cotton towel as a turban. The patient’s scalp is exposed to UVA after keeping the ‘turban’ in contact with the scalp for about 20 minutesThe efficacy of this form of PUVA therapy has been seen to be about 70%⁶¹.

Phototherapy

Although narrowband UVB is among the most effective treatment options in a number of immune mediated skin diseases, the same efficacy has not been found in alopecia areata. Properly designed randomized trials are needed to elucidate whether NBUVB has any role in the management of alopecia areata^62-63.

Excimer laser and excimer light

Excimer laser and excimer light are two more recent additions to the phototherapeutic armamentarium for many skin and hair disorders. While the main use of these phototherapeutic modalities remains to be psoriasis and vitiligo, their immunomodulatory effect can be made use of in many other skin disorders. Some clinical studies have documented the efficacy of excimer laser and excimer light in alopecia areata^64-65. In one such study, 41.5% patches were shown to respond to excimer laser therapy administered over 12 weeks⁶⁴. Another study on childhood alopecia areata found regrowth in 60% lesions after a treatment period of 12 weeksThe treatment is well tolerated with erythema of the skin as the only adverse effect reported.

Miscellaneous therapies

Various non-conventional therapeutic agents have been used in alopecia areata with some degrees of success. These include fractional Er-Glass laser⁷⁷, topical azelaic acid⁷⁸, topical onion juice⁷⁹, topical 5-fluorouracil ointment⁸⁰ and photodynamic therapyThe efficacy and safety of these therapeutic agents need to be confirmed in large-scale, double-blind, placebo-controlled trials before they can be recommended for treatment of alopecia areata.

Non-pharmacological methods

Cosmetic treatments for patients with alopecia areata include the following:

a) Dermatography: It has been used to camouflage eyebrows of patients with alopecia areata. In this treatment tiny pigment dots of pigment are used on the skin on the region of the eyebrows to mask the underlying alopecia⁸¹.

b) Wigs or Hair pieces: These are useful for patients with extensive disease and allow them to carry on their usual social life.

Conclusion:

Alopecia areata is now regarded as an autoimmune disease involving the cellular immunity through the CD8 lymphocytes that act on follicular antigens. The pathogenesis of alopecia areata is being unravelled with various animal and human studies.

The localized forms often heal spontaneously or respond to simple treatments such as topical or intralesional corticosteroids. The severe forms have a reserved prognosis and are difficult to treat. In these cases the best results are achieved by topical immunotherapy technique.

Case Presentation: Reflex Anoxic Seizures and Anaesthesia

Reflex anoxic seizures (‘RAS’) may present, as potentially life threatening events, but these are often preventable. They are most common in preschool children (but can occur in any age) and more so in females.  As a cause of seizures they are not rare; one study estimated a frequency of 8 in 1000 preschool children¹, but they are often misdiagnosed. The pathophysiology of RAS is vagally mediated – a noxious stimulus causes a supranormal vagal discharge resulting in bradycardia and then astystole². This then results in cerebral under perfusion and hypoxia. During this time the patient is often noted to become very pale with dusky lips, initially flaccid and then tonic with rigid extension and clenched jaws. They may then have a generalised convulsion, often with rolling eyes and urinary incontinence. The patient spontaneously recovers (the whole episode lasting around 30 to 60 seconds) and will feel somnolent, often remaining pale for a while.

From this description it can be easily understood how such an event can be misdiagnosed as epilepsy; however it is not associated with the uncontrolled neuronal discharge of epilepsy and if monitored by EEG this is absent². It may also be mistaken as breath-holding attacks (where intra-thoracic pressure restricts cerebral perfusion) or Stokes- Adams attacks (where there is abnormal electrical function of the heart).

The noxious stimuli responsible can be many different things. Ocular pressure², venepuncture³, anaesthetics⁴, accidental trauma and fear have all been implicated. If these stimuli cannot be prevented, management is normally just supportive (positioning, protection from trauma, oxygen) and allowing the fit to self-resolve[U1] . Further management can involve atropine⁵ (either acutely of preventatively), maintenance anticonvulsants⁶ (though these often just stop the fitting but not the syncope) and even pacemaker [U2] insertion⁷.

The case we encountered was that of a 20 year old female student, presenting for a planned day case removal of a molar tooth. She was otherwise fit and well with no other past medical history, only taking the combined oral contraceptive pill. Her history with RAS started at age 1, when she was admitted to hospital following two seizures. The seizures occurred every few months and she was provisionally diagnosed as suffering from epilepsy, with prophylactic treatment started. However, as she grew older she was able to describe how the attacks were not associated with a preceding aura, but rather an unpleasant stimulus (such as accidental injury). A new diagnosis of RAS was made and the antiepileptics were stopped without the seizures becoming more frequent. As she entered late childhood and adolescence the frequency of the seizures became less, but (atypically) they did not stop entirely.  On preassessment she reported being seizure free for just over a year and was anxious that today could precipitate another.

After consideration, we decided to proceed with anaesthesia with the following measures. The patient was kept calm by having a clear explanation of what to expect before coming to theatre, and then was reassured by an affable theatre team (who had been informed of her condition). Atropine was drawn up and available if vagal over stimulation occurred, as was suxamethonium in case of emergency airway intervention. For cannulation, cold spray was used along with distraction. Induction was with propofol (under full monitoring) and anaesthesia was maintained with sevoflurane/nitrous oxide via LMA. To prevent pain as a potential trigger, fentanyl (at induction) and paracetamol (after induction) were given and local anaesthetic (lidocaine) was administered before any surgery. Emergence was kept as smooth as possible by removing the LMA prior to any gagging and coughing and manually supporting the airway until she was awake.

With these measures the procedure was uneventful and the patient could be discharged home as planned. We hope this case report will help improve awareness and understanding of RAS, and the steps that can be taken peri-operatively to help ensure safe anaesthesia.

Introduction:

In traumatic brain injury (TBI) the primary insult to the brain and the secondary insults as a result of systemic complications may result in a multitude of sequelae ranging from subtle neurological deficits to significant morbidity and mortality. As the brain recovers by repair and adaptation, changes become apparent and may result in physical, cognitive and psychosocial dysfunction. Rehabilitation is usually structured to recover physical ability, cognitive and social retraining with the aim of gaining independence in activities of daily living.

Case Report:

A 76 year old male patient was admitted to an intermediate neurorehabilitation unit following a traumatic brain injury(TBI) .He had fallen from a height of 11 feet resulting in intracerebral haemorrhage in the left parietal lobe and a left parietotemopral subarachnoid hemorrhage which was managed conservatively in the neurosurgical unit. He developed recurrent post traumatic seizures in the form of myoclonic jerks for which he was started on antiepileptic drugs (AEDs) sodium valproate ,clobazam and levetiracetam .During his stay in the acute neurorehabilitation unit, he was noted to be confused and wandering with a disrupted sleep wake cycle. Cognitive assessment showed global impairment across all cognitive domains suggesting that cognitive impairment was secondary to TBI with the chaotic sleeping pattern and fatigue having a significant effect on his cognition. He was then transferred to an intermediate neurorehabilitation unit four months post head injury for rehabilitation prior to discharge.

On admission he was confused, and disorientated. His neurological examination was normal except for mild expressive dysphasia. On the first night of his stay in the unit, he did not sleep at all, was restless, agitated and aggressive towards the staff. His initial agitation was attributed to the change of surroundings and general disorientation. However during his first week at the rehabilitation unit it was noted that his sleep wake cycle was completely disrupted .He would have short fragmented naps through the day and would regularly get agitated at night with threatening behaviour towards staff. On admission the Rancho Los Amigos scale^† was 4(confused-agitated) and he needed specialized supervision. Despite environmental modification and optimal pharmacotherapy to improve sleep and decrease agitation, the patient still continued to have aggressive outbursts and no identifiable sleep wake pattern. It was noted by the nursing staff that occasionally when very agitated, the patient refused to have his night time medications including all AEDs .On such occasions he was reported to have slept better at night and did not have any daytime naps. All blood investigations were within normal limits except for mild hyponatremia with a normal creatinine clearance and CT head showed changes consistent with previous TBI with no new pathology .A neurology opinion was sought and with a Naranjo adverse drug reaction probability score^†† of 7/10, a decision was taken to slowly decrease levetiracetam and wean it to stop, while continuing all other regular AEDs. The levetiracetam was reduced from an original dose of 750mg twice daily by 500mg every week with an aim to stop. This resulted in a considerable improvement in the patient’s agitation with a complete halt in the nighttime aggressiveness. His sleep wake cycle normalized and he started sleeping longer at night. His Ranchos Los Amigos scale improved from 4(confused-agitated) to 6(confused-appropriate). The patient could now participate more with the team of trained therapists in memory and attention exercises as well as regaining independence in activities of daily living.

Discussion:

TBI particularly in elderly aged over 64 years has a worse functional outcome as compared to non elderly.¹Closed head injury in older adults produces considerable cognitive deficits in the early stages of recovery² and there have been studies suggesting TBI to be a risk factor for developing Alzheimer’s disease.³Memory deficits, attention problems, loss of executive function and confusion are common after TBI.⁴This impaired cognitive function reduces the patient’s ability to recognize environmental stimuli often resulting in agitation and aggression towards perceived threats.TBI by itself may result in a variety of sleep disorders ranging from hypersomnia, narcolepsy, alteration of sleep wake cycle, insomnia to movement disorders^{. 5}Sleep wake schedule disorders following TBI are relatively rare and may clinically present as insomnia.⁶Often these sleep disorders result in additional neurocognitive deficits and functional impairment, which might often be attributed to the original brain injury itself and thus be left without specific treatment.

While dealing with disrupted sleep pattern and agitation in the elderly following TBI, treatable causes such as neurological, infectious, metabolic, and medications should be ruled out. This is imperative as they disrupt rehabilitation and achievement of functional goals. Long duration of agitation post TBI has been associated with longer duration of rehabilitation stay and persisting limitations in functional independence.⁷After ruling out all the treatable causes the first focus is on environmental management with provision of a safe, quiet, familiar, structured environment while reducing stimulation and providing emotional support. The next step is introduction of pharmacotherapy to reduce agitation. Though a variety of pharmacological agents are available, there is no firm evidence of efficacy of any one class and often the choice of drug is decided by monitoring its effectiveness in practice and watching for side-effects.⁸In pharmacotherapy, the general principle followed is start low and go slow while developing clear goals to help decide when to wean and stop medications. Atypical antipsychotics are often used for the agitation while benzodiazepines and non benzodiazepine hypnotics such as zopiclone are recommended for treatment of insomnia.⁹ However atypical antipsychotics carry a FDA black box warning being associated with increased risk of stroke and death among elderly.

But what does one do when all optimal non pharmacologic and pharmacologic measures fail? That brings us back to the drawing board which in this case led the team to rethink Levetiracetam, a novel new antiepileptic that has been used as monotherapy for partial seizures and adjunctive therapy for generalized tonic clonic and myoclonic seizures. Levetiracetam treated patients have been reported to have psychiatric adverse effects¹⁰ including agitation, hostility, anxiety, apathy, emotional lability, depersonalization, and depressionwith few case reports of frank psychosis ¹¹.While in healthy volunteers levetiracetam is noted to consolidate sleep¹²,in patients with complex partial seizures, levetiracetam has been noted to cause drowsiness decreasing day time motor activity and increasing naps without any major effects on total sleep time and sleep efficiency during night.¹³There has been an isolated report of psychic disturbances following administration of levetiracetam and valproate in a patient with epilepsy which resolved following withdrawal of valproate. ¹⁴However in practice it is used for recurrent post TBI seizures as it is a potent AED with a relatively mild adverse effect profile and no clinically significant interactions with commonly prescribed AEDs.¹⁵

Any adverse drug reaction (ADR) should be evaluated while keeping the patients clinical state in mind. This was, indeed, difficult in our case. With a history of TBI and cognitive decline, it became difficult to ascertain whether the neurocognitive issues were purely due to the nature of TBI or due to an ADR. Assigning causality to a single agent is difficult and fraught with errors. Using the Naranjo algorithm ¹⁶, with a score of 7/10(probable ADR) and a notable response on withdrawal of the offending drug as in this case helps establish possible causality.

This is a rare instance where sleep wake cycle disorder and agitation resolved following withdrawal of Levetiracetam in an elderly patient with TBI. This in turn led to the patient having a stable mood so that therapists could communicate and interact with him in order to improve basic cognitive functions such as attention, memory, thinking and executive control. This case illustrates the constant need to systematically and frequently reassess patients as they recover from TBI.

^†Appendix: Ranchos Los Amigos Levels of cognitive functioning.

^††Naranjo Adverse Drug Reaction Probability Score:

Score
<0 =Doubtful ADR
1-4=Possible ADR
5-8=Probable ADR
>9=Definite ADR

Introduction:

Sleep is a fundamental part of our lives and about one-third of it is spent sleeping. Sleep deprivation has been linked with such high profile public disasters, as Chernobyl, the Challenger shuttle disaster and the nuclear meltdown at Three Mile Island. According to the US Highway Traffic Safety Administration, approx. 100,000 motor vehicle accidents are the result of driver’s drowsiness and fatigue¹. There is an association of sleep disorders with anxiety and depression which may be bidirectional. Patients with insomnia for 2 weeks or longer, without current depression are at increased risk of developing major depression. Both insomnia and hypersomnia are considered independent predictors of depression and anxiety^2.

Key Milestones in the Development of American Sleep Medicine:

The history of treatment of sleep disorders dates back to at least the use of opium as a hypnotic reported in ancient Egyptian text. Sleep medicine, however did not emerge as a distinct discipline until the 1970’s. Drs. Kleitman and Dement were significant early contributors to this field in the United States. In 1957 they first described Non Rapid Eye Movement (NREM) sleep and Rapid Eye Movement (REM) sleep and proposed the 4 stages of NREM sleep. In 1972 Dr. Dement, a Professor of Psychiatry and Behavioural Sciences at Stanford University School of Medicine, contributed to the establishment of the first sleep disorder centre in Stanford. After Stanford, other centres in New York, Texas, Ohio and Pennsylvania started providing sleep evaluations for which patients stayed in the centre overnight. The Association of Sleep Disorders Centre (ASDC) was established in 1975 and Dr. Dement served as its first president for12 years. In 1999 ASDC was renamed American Academy of Sleep Medicine (AASM). The first textbook of sleep medicine “Principles and Practice of Sleep Medicine” was published in 80’s. The journal SLEEP started in 1978. In 1998 the AASM commissioned the fellowship training committee to develop guidelines for sleep medicine fellowship training. The first two programmes to be granted formal accreditation were Stanford University in California and the Centre for Sleep and Wake in Montefiore Medical Centre, New York. The American Medical Association recognized sleep medicine as a specialty in 1996. In 2004 the Accreditation Council on Graduate Medical Education (ACGME) took over the fellowship accreditation process and approved a one year training programme ^1,3,4,5.

Sleep Medicine training in Europe:

Unlike United States, there are no formal sleep medicine training programmes or qualification in the United Kingdom or Europe. Sleep medicine is restricted to a small group of respiratory physicians with a special interest in sleep medicine. Psychiatry trainees are exposed to very little formal teaching in sleep medicine. However in the last 3 years the neuropsychiatry section of the Royal College of Psychiatrists of the United Kingdom has formed the “sleep working group” under the leadership of Dr. Hugh Selsick, this group is responsible for increasing awareness of sleep medicine among British psychiatrists, by emphasizing the importance of sleep medicine in psychiatric practice and encouraging psychiatrists to contribute to the field of sleep medicine. This group has developed a competency based curriculum that incorporates the training of sleep medicine into the psychiatry curriculum, to organize sleep medicine symposia at annual conferences of the Royal College and to develop professional training (CPD) modules for psychiatrists. British Sleep Society is another forum that brings together physicians from various backgrounds interested in sleep medicine. Royal Society of Medicine also has a sleep medicine section which organizes various conferences. There are two, week long courses on sleep medicine, the Edinburgh and Cambridge courses. Recently the University of Glasgow started a Master’s of Science (MSc) in behavioural sleep medicine program for healthcare providers working in Scotland, the rest of the United Kingdom and Europe ^{6, 7, 8, 9}. There is a trans-European move to start a formal sleep medicine certification similar to what we have in the United States. European Sleep Research Society (ESRC), a professional body of sleep scientists in Europe responsible for promoting sleep research and sleep medicine is starting its “first ESRS certification examination” in sleep medicine; this examination is scheduled to take place on September 4^th, 2012 at the 21^st Congress of the European Sleep Research Society in Paris. Since there are no formal training programmes this will be for those without formal training ¹⁰.

Psychiatry and Sleep:

Asking about the patient’s sleep is an integral part of a psychiatric consultation. Almost all the medication that psychiatrists prescribe has an effect on sleep architecture. Some psychiatric medications are used to treat sleep disorders and others can cause sleep disorders like Restless Legs Syndrome and PMLD. Understanding sleep can help us understand the mechanism of psychiatric illness. Many psychiatric disorders have comorbid sleep disorders and several behavioural therapies have been used successfully for the treatment of sleep disorders. There is bidirectional association between sleep disorders and psychiatric disorders. With the growing population of military soldiers returning from Iraq and Afghanistan with post-traumatic stress disorder, sleep problems and depression, there is an increased need for psychiatrists who possess knowledge in both sleep disorders and comorbid psychiatric illness. Psychiatrists have a distinct advantage dealing with sleep disorders and can bring those skills to sleep medicine.

Are psychiatrists attracted towards sleep medicine? The answer is yes. In the recent years we have seen an increased interest among psychiatry trainees for a sleep fellowship in United States. In recognition of behavioural consequences of sleep problems and multidisciplinary approach in sleep disorders, fellowship programmes are increasingly taking applicants from various backgrounds and not just pulmonology and neurology. Many psychiatry trainees are choosing a sleep medicine elective earlier in residency. Currently there are more than 710 accredited sleep centres in the United States. Many major university medical centres have a one year fellowship programme accepting applications from physicians from various backgrounds including Psychiatry, Neurology, Internal Medicine, Pulmonology, Paediatrics, ENT and Anaesthesia ¹. There are more than 24 AGME approved sleep medicine fellowship programmes in the United States ¹¹. New fellowship programmes are being opened at the University of Kansas Medical Centre and the University of Texas Health Sciences Centre, San Antonio.

Conclusion:

Sleep medicine is a new and exciting field of medicine with potential to grow in future. It’s a multidisciplinary field. American sleep medicine has evolved greatly over the last 30 years and there appears to be much to learn from the American model. There is a need for the psychiatry training programs both in the United States and the Europe to encourage and prepare their trainees to consider training in sleep medicine. Psychiatry trainees in the United States interested in sleep medicine should speak with their programme directors early in their residency training to register their interest and residents should also contact the local sleep centre for more advice. Each year American Academy of Sleep Medicine (AASM) accepts 10 international physicians for its 4 week mini-fellowship programme. Three weeks of the fellowship are spent at an AASM-accredited U.S sleep centre with their last week of the fellowship spent at the annual SLEEP conference. A certificate of training is issued at the end of the mini fellowship ¹².

Introduction

Fibromyalgia (FM) is a challenging set of chronic, overlapping and debilitating syndromes with widespread pain, abnormal pain processing, sleep disturbance, fatigue and psychological distress.¹ The American College of Rheumatology (ACR) 1990 diagnostic guidelines were based primarily on tender point examination findings at 11 of 18 potential tender points;² however, lack of consistent application of these guidelines in clinical settings led the ACR in 2010 to develop new diagnostic criteria based on a Widespread Pain Index (WPI) and symptom severity (SS) scale with no requirement of a tender point examination.  Symptoms must have been present for at least three months with the absence of any other disorder that would otherwise explain the pain and other signs and symptoms.³

Type of pain and other symptoms vary widely in FM, complicating diagnosis and treatment.  A cross-sectional survey of 3,035 patients in Germany utilized cluster analysis to evaluate daily records of symptoms noted by patients on handheld computers. Five subgroups were described: four with pain evoked by thermal stimuli, spontaneous burning pain, pressure pain, and pressure pain combined with spontaneous pain; the fifth subgroup had moderate sensory disturbances, but greater sleep disturbances and the highest depression scores.⁴

Estimates of the prevalence of FM have varied based on case definitions and survey methods.  Using 1990 ACR guidelines, it was estimated to affect between 0.1 to 3.3% of populations in western countries and 2.0% in the United States. Greater prevalence occurs among females, with estimates ranging from 1.0 to 4.9%.^{1, 5}  Reasons for the gender difference have not been determined.^6-9 

Fibromyalgia Risk Factors

Identification of risk factors for FM has been complicated by the array of seemingly unrelated signs and symptoms. The United States Centers for Disease Control (CDC) notes  loose association with genetic predisposition,¹⁰ bacterial and viral infections, toxins, allergies, autoimmunity, obesity and both physical and emotional trauma.^{1, 11}  

Chronic fatigue syndrome and infection

Although chronic fatigue syndrome (CFS) has been defined as a separate syndrome, up to 70% of patients with FM are also diagnosed with CFS and 35-70% of patients with CFS have also been diagnosed with FM.¹²   Thus studies of patients with CFS may have clinical relevance to FM. Several case controlled studies of CFS and one of CFS/FM have been associated with chronic bacterial infections due to Chlamydia (Chlamydophila p.), Mycoplasma, Brucella, and Borrelia.^12-18  The most prevalent chronic infection found has been that of the various Mycoplasmaspecies.^15-23 

Mycoplasmas are commonly found in the mucosa of the oral cavity, intestinal and urogenital tracts, but risk of systemic illness occurs with invasion into the blood vascular system and subsequent colonization of organs and other tissues.^15-23  Mycoplasmal infections have been identified in 52 – 70% of CFS patients compared with 5 to 10% of healthy subjects in North America^{15-17, 19-22} and Europe (Belgium)²³.  For example, the odds ratio (OR) of finding Mycoplasma species in CFS was 13.8 (95% CL 5.8-32.9,  p< 0.001) in North America.¹⁷  A review by Endresen¹² concluded that mycoplasmal blood infection could be detected in about 50% of patients with CFS and/or FM.  A CDC case-control study attempted to replicate these findings based on the hypothesis that intracellular bacteria would leave some evidence of cellular debris in cell-free plasma samples.  Results were that the healthy subjects actually had evidence of more bacteria although the difference was not significant. The authors noted the complexity and limitations of this type of analysis and also postulated that since the CFS patients were years past the onset of illness, they might have previously cleared the triggering agent.²⁴  However, most studies found Mycoplasma DNA in intracellular but not extracellular compartments in CFS patients, and this could explain the discrepancy.^15-23  Other studies have found that 10.8% of CFS patients were positive for Brucella species (OR=8.2, 95% CL 1-66, p<0.01)¹⁶ and 8% werepositive for  Chlamydia pn. (OR= 8.6; 95% CL 1-71.1,p< 0.01)¹⁷.

The presence of multiple co-infections may be an especially critical factor associated with either initiation or progression of CFS.  Multiple infections have been found in about one-half of Mycoplasma-positive CFS patients (OR = 18.0, 95% CL 8.5-37.9, p< 0.001), compared with single infections in the few control subjects with any evidence of infection.¹⁷ A  North American study identified chronic infections in 142 of  200 patients (71%) with 22% of all patients having multiple mycoplasmal infections while just 12 of the 100 control subjects (12%) had infections (p<0.01) and none had multiple infections.¹⁵ Similarly, a European study reported chronic mycoplasmal infections in 68.6% of CFS and 5.6% of controls.  Multiple infections were found in 17.2% of the CFS patients compared with none in the controls (p<0.001).²³ Multiple co-infections were also associated with significantly increased severity of symptoms (p<0.01).^{15, 23} 

Viral infections associated with CFS have included Epstein Barr virus, human herpes virus-6, cytomegalovirus, enteroviruses and several other viruses.^{15, 25, 26}

Despite indications of single or multiple bacterial and/or viral infections in most patients with CFS, antibiotic or antiviral treatments have yielded inconsistent results.²⁷  Slow growing intracellular bacteria are relatively insensitive to most antibiotics and have inactive phases when they would be completely insensitive to any antibiotics.^{28 23}   Some treatments may actually have resolved the infections, but not the immune pathways that may remain in an activated state capable of producing symptoms. 

Fibromyalgia and infection

Bacterial infections associated with FM as a separate syndrome have included small intestinal bacterial overgrowth (SIBO)^{29, 30} and helicobacter pylori (HP)³¹.   Utilizing the lactulose hydrogen breath test (LHBT), investigators found SIBO in 100% of 42 patients with FM.   They noted that 30-75% of patients with FM have also been found to have irritable bowel syndrome (IBS).^{29, 30}  A confounding factor is that medications prescribed for FM often have gastrointestinal side effects.²⁹  HP diagnosed by positive immunoglobulin gamma (IgG) serum antibody was significantly higher in women with FM (44/65 or 67.7%) compared with controls (18/41 or 43.9%) (p=0.025) in Turkey³¹.

Viral infections associated with FM have included hepatitis C, in which two studies found an association,^32-34 and two studies found no association.^{35, 36} Associations with FM have also been found with hepatitis B, ³⁷ human immunodeficiency virus (HIV)^{38, 39} and human T cell lymphotropic virus type I (HTLV-1).⁴⁰

Fibromyalgia and non-infectious associations

Non-infectious triggers associated with FM have included toxins, allergens, and physical or emotional trauma. These triggers may not have been strictly “non-infectious” as allergens and toxins may also be produced by infections, and physical or emotional trauma may lead to the reactivation of previously controlled infections. Respondents to an internet survey of people with FM (n=2,596) also identified triggers as chronic stress (41.9%), emotional trauma (31.3%), acute illness (26.7%) and accidents (motor vehicle 16.1%, non-motor vehicle 17.1%).⁴¹ Physical trauma associated with FM has included cervical spine injuries as well as motor vehicle and other accidents.^42-44 

Fibromyalgia and autoimmunity

Three studies have found thyroid autoantibodies to be in greater percentages in subjects with FM compared with controls, in spite of normal thyroid hormone levels.  One study reported autoantibodies in 41% of FM patients versus 15% of controls.⁴⁵  The second study reported 16% in FM versus 7.3% in controls, p<0.01.⁴⁶ The third study reported 34.4% in FM versus 18.8% in controls (p=0.025)⁴⁷ and OR =3.87, 95% CL  1.54-10.13.⁴⁸  This could also have been the result of thyroiditis, because infections like Mycoplasma are often found in thyroiditis patients.¹⁵

Autoantibodies to serotonin were identified in 74% of 50 patients with FM compared with 6% of 32 healthy (blood donor) controls. Notably, serotonin levels were normal in 90% of the FM patients indicating serotonin receptor involvement.⁴⁹

Fibromyalgia and Metabolic Syndrome

Metabolic Syndrome consisting of abdominal obesity, high triglycerides, high blood pressure, elevated fasting glucose and decreased high-density lipids, was associated with FM in a U.S. study in which  cases were 5.6 times as likely to have Metabolic Syndrome as controls (C²_MH = 3.84, p = .047, 95% CL 1.25 – 24.74).⁵⁰ 

Fibromyalgia and emotional trauma

Although emotional trauma has been acknowledged as a contributing factor, most studies of CFS/FM have used recognized tests such as Beck’s Depression Index, Beck’s Anxiety Index and Minnesota Multi Personality Index (MMPI) to exclude potential subjects with actual psychiatric illnesses.^{51, 52}

Psychological and physiological subsets of fibromyalgia 

A Wisconsin cross sectional survey of 107 women with confirmed diagnoses of FM used validated psychological and physiological measures followed by cluster analysis. Four distinct subsets were identified: (I) history of childhood maltreatment and hypocortisolism with the most pain and disability; (II) “physiological dysregulation” described as “distinctive on nearly every biological index measured” with high levels of pain, fatigue and disability; (III) normal biomarkers with intermediate pain severity and higher global functioning; and (IV) psychological well-being with less disability and pain.⁵³

The “physiological dysregulation” of FM subset II  consisted of the highest antinuclear antibody (ANA) titers (t=4.06, p=0.001), highest total cholesterol levels (t=3.96, p<0.001), larger body mass index (BMI) values t=2.21, p<0.04), lowest Natural Killer (NK) cell numbers (t=3.95, p<0.001), lowest growth hormone (t=3.20, p<0.002), and lowest testosterone levels (t=3.80, p<0.001).  Trends were also indicated toward the highest erythrocyte sedimentation rate (ESR) (t=2.02, p=0.056), lowest creatinine clearance (t=1.85, p=0.067) and lowest cortisol (t=2.78, p<0.007).⁵³

Proposed Model of Fibromyalgia

The authors’ proposed model of FM develops a rationale for the “physiological dysregulation” indicated in subset II of the Wisconsin study.  In this model, various triggers are followed by prolonged immune activation with subsequent multiple hormonal repression, disrupted collagen physiology and neuropathic pain.

 Activation of immune response pathways

Innate immune responses begin with anatomical barriers, such as the epithelium and mucosal layers of the gastrointestinal, urogenital and respiratory tracts, and physiological barriers, such as the low pH of stomach acid and hydrolytic enzymes in bodily secretions. ⁵⁴ Breeching of these barriers activates cell-mediated immunity launched by leucocytes with pattern recognition receptors: neutrophils, macrophages and dendritic cells (DCs).⁵⁴ Insufficient or damaged anatomical or physiological barriers would necessarily keep this cell mediated level of innate defense in a constant state of alert and activity.

In contrast to the innate immune response, adaptive immunity has highly specific recognition and response activities resulting in lasting changes produced by leukocytes known as lymphocytes.   B lymphocytes (B cells) secrete plasma cells producing antibodies to specific pathogens. T lymphocytes (T cells), the other major cells of adaptive immunity, can be either cytotoxic (Tc) or helper cells (Th).  Tc cells produce progeny that are toxic to non-self peptides and Th lymphocytes secrete small proteins (cytokines) that mediate signaling between leukocytes and other cell types.  All types of lymphocytes retain memory so that subsequent invasions provoke faster and more rapid differentiation into effector cells. ^{54, 55}  Some Th cells respond to intracellular pathogens (Th1) and some to extracellular pathogens (Th2).  A third type (Th17) appears to respond to certain bacterial and fungal infections, tumor cells and are also involved in autoimmune diseases.⁵⁶  

In the presence of environmental stressors, cells may release stress proteins to alert the organism to potentially damaging conditions. These proteins can bind to peptides and other proteins to facilitate surveillance of both the intracellular and extracellular protein environment.  One form of stress proteins, heat shock proteins (HSP), can mimic the effects of inflammation and can be microbicidal.^{52, 57}

One of the earliest responses to intracellular viral or bacterial infections involves production of three types of interferon (IFNa, IFNb and IFNg).  Any of these can initiate a series of metabolic events in uninfected host cells that produce an antiviral or anti-bacterial state.^{58, 59} When IFN-γ targets genes in uninfected cells, the targeted genes become microbicidal by encoding enzymes generating oxygen (O₂) and nitric oxide (NO) radicals.⁵⁸  Activation of O₂ or NO radicals triggers another cascade involving IL-6, IL-1b, the cytokine Tumor Necrosis Factor-a (TNF-a) and the transcription nuclear factor kB (IKKb-NF-kB).  NF-kB can be activated by a variety of inflammatory stimuli, such as cytokines, growth factors, hormones, oncogenes, viruses and their products, bacteria and fungi and their products, eukaryotic parasites, oxidative and chemical stresses, therapeutic and recreational drugs, additional chemical agents, natural products, and physical and psychological stresses.⁶⁰ Activation of NF-kB releases its subunits; the p50 subunit has been associated with autoimmunity and the RelA/p65 unit with transcriptional activity involving cell adhesion molecules, cytokines, hematopoietic growth factors, acute phase proteins, transcription factors and viral genes.⁶¹  The authors propose that chronic infection or other stress would be a sustaining trigger of an immune cascade that includes NF-kB and resultant cell signaling processes that drive many of the symptoms of fibromyalgia.

The cytokine interleukin-6 (IL-6) can either activate or repress NF-kB through a switching mechanism involving IL-1ra and Interleukin 1b(IL-1b).   IL-6 first activates Interleukin 1b  (IL-1b), which then activates TNF-a, leading to the subsequent activation of NF-kB. ^{62, 63} Specifically, the release of the RelA/p65 subunit of activated  NF-kB switches on an inhibitory signaling protein gene (Smad 7) that blocks phosphorylation of Transforming Growth Factor Beta (TGF-b) resulting in the repression of multiple genes.  Alternatively, IL-6 activates IL-1ra, which allows TGF-b to phosphorylate and induce the expression of activating signaling protein genes Smad2 and Smad3, resulting in the full expression of multiple genes.⁶¹  

NF-kB plays a key role in the development and maintenance of intra- (Th1) and inter- (Th2) cellular immunity through the regulation of developing B and T lymphocytes. The p50 dimer of NF-kB has been shown to block B Cell Receptor (BCR) editing in macrophages, resulting in loss of recognition and tolerance of host cells (autoimmunity). T cells that are strongly auto-reactive are normally eliminated in the thymus, but weakly reactive ones are allowed to survive to be subsequently regulated by regulatory T-cells and macrophages.  Acquired defects in peripheral T-regulatory cells may mean failure to recognize and eliminate weakly reactive ones.^{54, 64}  The IL-17 cytokine associated with autoimmunity can activate NF-kB through a pathway that does not require TNF-a.⁵⁶ NF-kB activity can also be activated or repressed by the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (c AMP) in the early phases (3 days) of nerve injury through its main effector enzyme, protein kinase A (PKA).^{65, 66}  PKA decreases during later stages as the enzyme protein kinase C (PKC) increases.  PKC then plays important roles in several cell type specific signal transduction cascades.⁶⁷ An isoform of PKC within primary afferent nociceptive nerve fibers signals through IL-1b and prostaglandins E2 (PGE₂) as demonstrated in animal studies.⁶⁸  This process has been called “hyperalgesic priming,” and it has been described as responsible for the switch from acute to long-lasting hypersensitivity to inflammatory cytokines.⁶⁹

Figure 1 depicts key immune pathways leading to expression or repression of multiple genes proposed to be important in FM and neuropathic pain.

Fibromyalgia and immune - hormonal interactions

Reciprocity exists between the immune system and the hypothalamic-pituitary-adrenal (HPA) axis through its production of glucocorticoid signal transduction cascades. ^{63, 70, 71}. Hormones such as cortisol (hydrocortisone) produced by the adrenal cortex, affect metabolism of glucose, fat and protein.⁷²  The glucocorticoid receptor (GR), a member of the steroid/thyroid/retinoid super family of nuclear receptors is expressed in “virtually all cells”.  When the GR in the cytoplasm binds a glucocorticoid, it migrates to the nucleus where it modulates gene transcription resulting in either expression or repression of TNF-a, IL-1bβ and the NF-kB p65/Rel A subunit.  However, the RelA/p65 protein can also repress the Glucocorticoid Receptor. ^{63, 70, 71, 73}

Growth hormone (GH), an activator of NF-kB,⁷⁴  is usually secreted by the anterior pituitary, but changes found in FM may be hypothalamic in origin.  GH is needed for normal childhood growth and adult recovery from physical stresses.⁷⁵  Although low levels of GH were found in subset II of the Wisconsin study, ⁵³ functional deficiency may be expressed as low insulin-like growth factor 1 (IGF-1) combined with elevated GH, suggesting GH resistance.^{76, 77}   Defective GH response to exercise has been associated with increased pain and elevated levels of IL-1b, IL-6, and IL-8.^{77, 78}

The hormones serotonin and norepinephrine modulate the movement of pain signals within the brain.  Serotonin has been found to suppress inflammatory cytokine generation by human monocytes through inhibition of the NF-kB cytokine pathway in vitro;⁷⁹ however, NF-kB promotion of antibodies can repress serotonin.⁴⁹  Selective serotonin and norepinephrine reuptake inhibitors (SSNRIs), such as duloxetine and milnacipran, are key treatment options for fibromyalgia and have been approved of by the U.S. Food and Drug Administration (FDA).^{80, 81}  Although serotonin has been best measured in cerebral spinal fluid (CSF), recently improved methods of collection were utilized  (using rats and in 18 women) that yielded a high degree of correlation (r=0.97) between CSF and plasma, platelet, and urine measurements.⁸²

NF-kB activation has also been documented to interfere with thyroid hormone action through impairment of Triiodothyronine (T3) gene expression in hepatic cells. ⁸³  However, T3 administration has induced oxidative stress and activated NF-kB in rats.⁸⁴ 

Metabolic Syndrome, a confounding factor in Fibromyalgia

Leptin and insulin hormones interact to regulate appetite and energy metabolism.  Leptin, produced by adipose cells, circulates in the blood eventually crossing the blood-brain barrier to bond with a network of receptors within the hypothalamus.   Insulin, produced by beta cells in the pancreas, similarly crosses the blood brain barrier to interact with its own network of hypothalamic receptors.  Leptin and its receptors share structural and functional similarities to long-chain helical cytokines, such as IL-6, and it has been suggested that leptin be classified as a cytokine.^85-89

Metabolic syndrome can be a confounding factor in FM due to peripheral accumulation of fatty acids, acylglycerols and lipid intermediates in liver, bone, skeletal muscle and endothelial cells.  This promotes oxidative endoplasmic reticulum (ER) stress and the activation of inflammatory pathways involving PKC and hypothalamic NF-kB, leading to central insulin and leptin repression.^{85-87, 89-91}   Hyperinsulinemia further stimulates adipose cells to secrete and attract cytokines such as TNFa and IL-6 that trigger NF-kB in a positive feedback loop, which can be complicated by chronic over nutrition that increases the generation of reactive oxygen intermediates and monocyte chemoattractant protein-1 (MCP-1).^{87, 89}  When exposed to a chronic high fat diet, hypothalamic NF-kB was activated two fold in normal mice and six times in mice with the obese (OB) gene.⁸⁹

Fibromyalgia and indicators of immune-hormonal activity

Although most components of either innate or adaptive cell mediated immune responses exist for only fractions of seconds, some of their effects and products can be detected long after in the skin, muscle, blood, saliva or sweat^{92, 93}.  

One component,  nitric oxide (NO),  can suppress bacteria; however, endothelial damage causes dysfunction with impaired release of NO and loss of its protective properties.⁸⁶ The enzyme transaldolase acts as a counterbalance by limiting NO damage to normal cells.  Thus, high levels of transaldolase indicate elevated reactive oxygen species, reactive nitrogen species (ROS/RNS) and cellular stress. The “exclusive and significant over-expression of transaldolase” in the saliva samples of 22 women with FM compared with 26 healthy controls (77.3% sensitivity and 84.6% specificity, p<0.0001; 3 times greater than controls; p=0.02) was “the most relevant observation”; although there was no correlation between transaldolase expression and the severity of FM symptoms.⁹²  

High levels of NO have been associated with high levels of insulin, and insulin itself is a vasodilator that, in turn, can stimulate NO production.  Beta cells of the pancreas are quite susceptible to ROS/NOS damage .⁸⁶ When free radical damage of beta cells reaches critical mass, insulin production plummets with an associated decline in NO levels.  Thus, patients with FM who have high NO levels would likely be suffering from associated metabolic syndrome, and patients with low NO levels would likely be suffering from Type II diabetes.^{85, 88} 

Figure 2 illustrates the relationship of NF-kB to various hormone systems.

Fibromyalgia and immune-hormonal influences on connective tissue

Inflammation of muscles, tendons, and/or fascia is generally followed by proliferative and remodeling phases of healing initiated by fibroblasts which lay down an extracellular matrix (ECM) composed of collagen and elastin fibers. “Fibroblasts respond to mechanical strain by altering shape and alignment, undergoing hyperplasia and secreting inflammatory cytokines including IL-6.”  The extra cellular matrix is initially laid down in a disorganized pattern that is subsequently matured and aligned. Chronic and excessive mechanical tension from postural imbalance, hormonal disruption or other factors may interfere with collagen maturation. ⁹⁴  Remodeling of the extracellular matrix and collagen deposition around terminal nerve fibers may be compressive and contribute to neuropathic pain.⁹⁵

Oxidative stress in muscles accelerates the generation of advanced glucose (glycation) end products (AGEs).  AGE-mediated cross-linked proteins have decreased solubility and are highly resistant to proteolytic digestion.  Interaction of AGEs with their receptors leads to activation of NF-kB resulting in an increased expression of cytokines, chemokines, growth factors, and adhesion molecules.^{96 97}   

Two AGE products have been reported at significantly elevated levels in the serum of patients with FM: N-carboxymethyllysine (CML) (2386.56 ± 73.48 pmol/mL; CL 61.36-2611.76 versus controls 2121.97 ± 459.41 pmol/mL; CL 2020.39-2223.560; p<0.05)⁹⁶ and pentosidine (mean 190 ± 120 SD and median 164 versus controls mean 128 ± 37 SD and median 124; p<0.05)⁹⁷  Comparison of muscle biopsies showed “clear differences in the intensity and distribution of the immunohistochemical staining”. CML was seen primarily in the interstitial tissue between the muscle fibers where collagens were localized and in the endothelium of small vessels of patients.  Activated NF-kB was seen in cells of the interstitial tissue especially around the vessels of patients, but almost no activated NF-kB was seen in the control biopsies. AGE activation of NF-kB has been shown to be significantly more prolonged than the activation of NF-kB by cytokines.^{96 97} 

Fibromyalgia, the nervous system and pain

Sensory transmission in humans occurs through three primary afferentnerve fiber types: heavily myelinated mechanical afferent pathways (A Beta fibers) that transmit non-noxious tactile sensations, small-diameter myelinated fibers (A Delta fibers) that transmit sharp pain, and small diameter unmyelinated fibers (C fibers) that transmit dull aching pain.  The heavily myelinated non-pain Aβ fiber type has been shown to sprout axons that terminate on pain lamina in the posterior horn of the spinal cord resulting in the conversion of mechanical stimuli to pain.  Within the brain, sensitization of the N-methyl D-aspartate (NMDA) receptors can amplify pain signals between the thalamus and the sensory cortex.^{67, 98} 

Chronic damage or excitation of nociceptive afferent fibers from compressive collagen deposition may develop into spontaneous (ectopic) firing oscillating at frequencies sufficient to initiate cross (ephaptic) excitation of sympathetic and sensory fibers (myelinated A-delta and non-myelinated C fibers) within the dorsal root ganglia (DRG) of the central nervous system.⁹⁸ Normally, the DRG has little sympathetic innervation, but trauma can trigger sympathetic sprouting that forms basket-like structures within the DRG. Neurotrophins, in particular nerve growth factor (NGF), play an important role in sympathetic fiber sprouting of sensory ganglia in murine models. DRG can be reservoirs for latent viral infections such as Herpes Zoster, HIV and enteroviruses.  In addition, the Borrelia species has been identified in a non-human primate model of Lyme disease.  NGF also facilitates expression of Substance P (SP), a peptide neurotransmitter involved in the induction of the IL-6 - NF-kB pathway ^{60, 99, 100} and in the transmission of neuropathic pain.^{101, 102}  SP has been found to be elevated in the cerebrospinal fluid of patients with FM in comparison to normal values,¹⁰³ and control subjects.¹⁰⁴

Summary and Conclusions

Chronic unresolved infection, trauma, and/or emotional stresses that trigger immune pathways with subsequent chronic hormonal and nervous system responses is proposed to perpetuate chronic neuropathic pain. Figure 3 provides a summary model of immune-hormonal contributions to neuropathic pain in fibromyalgia.

The ACR criteria and severity scales have defined fibromyalgia and The Wisconsin study has identified psychological and physiological subsets that are critical steps in its characterization.   This type of testing could be further strengthened through the use of specific biomarkers.  Potential markers of FM status include the RelA/p65 and p50 subunits of NF-kB, which are currently the focus of several clinical trials of other chronic painful conditions.  Additional potential markers include: IL-6, IL-1b, TNF-a, PKC, transaldolase, CML, pentosidine and NGF.   Substance P has been previously identified as a marker of pain, but is problematic as a marker for FM, since it has only been measured in the CSF.    The search for markers that are truly specific to FM may continue to be a difficult task  due to their overlap with other metabolic conditions, such as CFS, metabolic syndrome, type II diabetes, and IBS.  Nonetheless, these markers remain important as they can indicate oxidative stress, cytokine activation, hormonal dysregulation and neuropathic pain.  These potential FM markers need to be evaluated in clinical trials where they can be measured over time and correlated with patient symptoms. 

Currently, family and general medical practice physicians are uniquely positioned to establish the FM diagnosis, determine subsets of FM patients, investigate potential triggers of chronic immune activation, advise patients, prescribe medications and refer patients to appropriate specialists or pain centers.  Establishment of the FM diagnosis requires use of the ACR Widespread Pain Index (WPI) and symptom severity (SS) scale, but no longer requires the tender point examination. ³ 

Determination of FM subsets can be accomplished using the approach used in  the Wisconsin cross sectional survey.⁵³  Investigation of potential triggers of chronic immune activation needs to include sources of underlying infection, unresolved physical or emotional trauma, toxins and food sensitivities.  These investigations may be accomplished through careful interviewing and well-designed questionnaires. Advising the patient should acknowledge the reality of their pain and other symptoms and provide rational approaches to resolution of those symptoms. Prescribing of medications needs to be sensitive to current and previous patient experience with medications, in addition to following current guidelines for stabilizing FM symptoms.  Referral to appropriate specialists and centers would include those with expertise in physical medicine, psychology and nutrition.  Physical medicine can address pain and functional deficits; psychology can address underlying emotional issues and trauma; and nutrition can focus on resolution of chronic inflammation, oxidative stress, and intestinal dysbiosis.

Where do we go from here for additional FM treatment options?  Immune modulators have been used successfully in other painful conditions, such as rheumatoid arthritis.  Immune modulators acting on the IL-6 - NF-kB cascade have considerable potential for FM, but only after ruling out or successfully treating any underlying infections.  Numerous pharmaceutical blockers of NF-kB exist, but most are associated with serious side effects.  Natural products may provide additional options as some are able to mediate pathways leading to NF-kB without the same side effects.¹⁰⁵  Medications that elevate individual hormone levels have been included in accepted treatment protocols in the case of serotonin and norepinephrine.  However, elevations of other hormones, such as cortisol and thyroid hormones, are under investigation and remain controversial.  Elevation of individual hormones may be problematic because of the number of different hormones influenced by the IL-6 - NF-kB pathway. 

In rheumatology clinics chronic painful conditions are the norm. Although many pain syndromes are associated with low mood and sometimes clinical depression, the mood disorder often goes unrecognised. Fibromyalgia is one such chronic pain syndrome, 'chronic' arbitrarily defined as lasting longer than six months. It is a common, poorly understood, musculoskeletal disorder which more often affects women between the ages of 25-50 years generally.

In nearly all patients three symptoms predominate, namely, neuropathic pain (nerve injury pain), fatigue and non-restorative sleep disturbance. The chronic neuropathic diffuse pain, described as whole body pain, is felt particularly in deep tissues such as ligaments, joints, and muscles of the axial skeleton in mainly the lower cervical and lumbar spine. The pain is often characterised by an exaggerated and prolonged response to a noxious stimulus (hyperalgesia). Patients may be considered to be malingering because there is no obvious explanation for the symptoms. Anxiety, stress and depression caused by fibromyalgia add insult to injury, with personality and cognitive factors coming into play in addition.¹ Paraesthesiae (abnormal sensory sensations) or dysaesthesiae (painful sensations) of the extremities may also occur. There is no objective muscular weakness or neurological disorder to account for the symptoms, which adds to the diagnostic dilemma. For example, fibromyalgia affecting the supraspinatus muscle of the shoulder would limit initial abduction of the arm because of pain, not because of any muscle weakness. Cognitive function is sometimes described as 'fibrofog' or 'conscious confusion' and may be a primary symptom of fibromyalgia, reflecting impairments in working memory (a form of short-term memory), episodic (memory for events), and semantic memory (memory for words, rules, language).

Nociception refers to the process of information about harmful stimuli conveyed by neuronal activity up to the point of perception in the dorsal horn of the spinal cord where primary afferents synapse.² Evidence is accumulating which shows that atypical sensory processing in the central nervous system (CNS) and dysfunction of skeletal muscle nociception are important in the understanding of fibromyalgia and other chronic pain syndromes^.3The concept of 'central pain sensitization' or 'central sensitivity syndrome' considers fibromyalgia to be a disturbance of nociceptive processing which causes a heightened experience of pain or pain amplification.⁴ Because pain signals are subject to variation in amplitude, the modulation of sensory processing may be the key to understanding the pain response not only in fibromyalgia but also in other conditions, such as irritable bowel syndrome. Descending spinal noradrenergic and serotonergic neurons inhibit the neurotransmitters noradrenaline and serotonin, released from primary afferent neurons and dorsal horn neurons. Therefore, when descending inhibition is decreased, irrelevant nociceptive stimuli are more readily felt. Put another way, in patients with chronic pain syndromes descending inhibition may not be functioning adequately to prevent or mask irrelevant pain stimuli. When appropriate medication is used this normal descending inhibition is enhanced and pain is no longer troublesome.

The release of neurotransmitters (ligands) also requires a mechanism that involves voltage-sensitive calcium and sodium channels. Repetitive action potentials cause the calcium channels to open with the ensuing release of neurotransmitters into the synaptic cleft. The postsynaptic neurons are thus stimulated leading to molecular and structural changes (sprouting) which cause neuropathic pain. Drugs such as Pregabalin and Gabapentin bind to voltage-sensitive calcium channels and reduce calcium influx, which in turn diminishes pain. The concept of central pain sensitization now incorporates affective spectrum disorders and functional somatic syndromes. It seems that the more painful symptoms one has which are difficult to explain, the more likely the patient is suffering from a mood disorder. Dopamine may be involved in the regulation of cognition in the dorsolateral prefrontal cortex and could account for the cognitive deficits.⁵Because cingulate and prefrontal cortices are particularly implicated in pain modulation (inhibition and facilitation of pain), structural changes in these systems could contribute to the chronic pain associated with fibromyalgia.⁶

Many patients with fibromyalgia have an increased sensitivity to sensory stimuli that are not normally or previously painful (allodynia). In other words, minor sensory stimuli that ordinarily would not cause pain in most individuals induce disabling, sometimes severe pain in patients with fibromyalgia^.7 In normal individuals 4 kg/square cm²pressure (approximately the pressure needed to blanch the skin at the top of one’s thumb) causes patients with fibromyalgia to wince with pain or suddenly withdraw when the tender point is palpated. This indicates that pain occurs at a lower pain threshold in fibromyalgia sufferers when this pressure is applied.

The pain of fibromyalgia may be aggravated by emotional stress though the latter is difficult to quantify and evaluate. For instance, corticosteroid hormones are released in high amounts after stress yet fibromyalgia is associated in some patients with a decreased cortisol response to stress. Stress may therefore initiate, inhibit or perpetuate alterations in the corticotrophin-releasing hormone (CRH) neuron, with associated effects on the hypothalamic pituitary axis (HPA) and other neuroendocrine axes.⁸

There are many other possible explanations for fibromyalgia pain. One of the major neurotransmitters involved in nociception is substance P, found in high concentrations in the spinal cord, limbic system, hypothalamus, and nigrostriatal system. It is involved in the transmission of pain impulses from peripheral afferent receptors to the central nervous system. Nerve growth factor (NGF), a cytokine-like mediator may indirectly exert its effect through enhancing glutaminergic transmission and could account for sustained central sensitization in fibromyalgia. ^{9, 10} Another neuropeptide, calcitonin gene-related peptide, a potent vasodilator, present in non-myelinated afferent neurons, may also play a role in pain pathology.⁵

Levels of the neurotransmitter serotonin have been found to be low in some studies in fibromyalgia patients. Although serum levels of serotonin are lower than in some patients with rheumatoid arthritis and healthy controls, the variation is too broad and therefore measurement of serotonin has not proved useful tool in determining a diagnosis of fibromyalgia. ¹¹

Logically, pharmacologic agents used to treat pain in fibromyalgia would act by either increasing levels of inhibitory neurotransmitters or decreasing levels of excitatory neurotransmitter. In the United States of America (USA), Pregabalin was the first drug to be approved by the Food and Drug Administration (FDA) for the treatment of fibromyalgia and has been shown to improve pain, sleep and quality of life. It is ineffective against depression. The main inhibitory mediator in the brain, gamma amino butyric Acid (GABA), is formed from glutamate (excitatory) by the enzyme glutamate decarboxylase (GAD). It is particularly plentiful in the nigrostriatal pathways. About 20% of CNS neurons are GABAergic and it serves as a neurotransmitter at some 30% of all CNS synapses.¹² Pregabalin increases neuronal GABA levels by producing a dose-dependent increase in glutamate decarboxylase activity. In a meta-analysis of 21 clinical trials to estimate treatment differences vs. placebo, statistically significant improvement was observed with Duloxetine, Milnacipran 200 mg/day, Pregabalin 300 or 450 mg/day, and Tramadol plus Paracetamol. The meta-analysis showed a statistically increased risk of discontinuation because of adverse events related to Milnacipran and Pregabalin.¹³

Antidepressants may improve fibromyalgia symptoms by reducing pain, stabilizing mood and improving sleep, though the effect seems to be modest. If abnormal sleep, and hence subsequent tiredness, precedes the development of fibromyalgia the effect of antidepressants may be primarily associated with improved sleep. However, the efficacy of tricyclic antidepressants is difficult to quantify and their limited superiority over placebo lasts no more than a few months. A meta-analysis of ten randomized double-blinded, placebo-controlled studies revealed only poor to moderate evidence for a beneficial effect at low doses of Amitriptyline (25mg daily) over 6-8 weeks. Even when given in higher doses or prescribed for a longer duration, Amitriptyline did not make a great deal of difference. ¹⁴

The efficacy of Selective Serotonin Reuptake Inhibitors (SSRIs) is also inconclusive. More promising results have been demonstrated with Serotonin and Noradrenaline Reuptake Inhibitors (SNRIs) such as Duloxetine. Both serotonin (5-HT) and noradrenaline (NA) exert analgesic effects via descending pain pathways. Pain is a prominent feature of depression and vice versa and the alleviation of one modifies the other. ^{15, 16} The reduction in pain reduces fatigue and Duloxetine improves mood.

Other drugs used in this condition include Milnacipran and Cyclobenzaprine (a muscle relaxant structurally related to tricyclic antidepressants). Milnacipran and Cyclobenzaprine are not available in the United Kingdom (UK). Tramadol (a serotonin and noradrenaline reuptake inhibitor) is a weak mu-receptor opioid agonist used to control pain but its adverse effects are those of opiates in general, mainly nausea and dependence.

Although other adjunctive non-pharmacological treatments have been advocated the results are disappointing. Assessments of non-drug treatments are generally mediocre. Aerobic exercises benefit some patients, especially when combined with biofeedback, patient education and cognitive therapy. A whole gamut of treatments such as graded exercises, yoga, dietary advice, balneotherapy (heated pool bathing), homeopathy, massage, acupuncture, patient education, group therapy and cognitive behaviour therapy, have been suggested and tried, but few of them demonstrated clear-cut benefits in randomized controlled trials.Support groups may help some patients. ^{17, 18, 19}

Fibromyalgia is now considered to be, in part, a disorder of central pain processing. Central sensitization manifests as pain hypersensitivity, particularly allodynia, and hyperalgesia. It is believed that central sensitization occurs in part through the action of glutamate on the N-methyl-D-aspartate (NMDA) receptor, resulting in an increase in intracellular calcium and kinase activation, leading to hyperalgesia and allodynia.²⁰

Response to standard analgesics is erratic and more promising results have emerged with drugs such as the SNRIs Duloxetine and Milnacipran, the anticonvulsants Gabapentin and Pregabalin, either used alone or in combination, or with other agents such as Amitriptyline. There is only modest evidence to support SSRIs and Tramadol. Treatment needs to be holistic and multidisciplinary, focussing on both physical pain management and psychological dysfunction. The multidisciplinary approach, though difficult to measure, may help by imparting a sense of empathy and support for patients. Overall, most patients with fibromyalgia continue to have chronic pain and fatigue with symptoms persisting for many years, but it is not necessarily a progressive disorder and some patients may show moderate improvement.

Introduction:

There are approximately over 1.6 billion overweight people with a body mass index (BMI) greater than 25 kg/mAnnually, around 2.8 million deaths are attributed to overweight and obesity worldwide⁽¹⁾. Many overweight individuals underestimate their weight and despite acknowledging their overweightness, many are not motivated to losing weight⁽²⁾.Accurate measurement is important as it identifies patients with diagnoses which subsequently impact on their management. Self-reported weight is often used as a means of surveillance but has been shown to bias towards under reporting of body weight and BMI as well as over reporting on height⁽³⁾. Several estimation techniques has been devised to quantify anthropomorphic measurements when actual measurement cannot take place^(4),(5),(6), however, these methods are associated with significant errors for hospitalised patients⁽⁷⁾. There is no published study that questions the validity of visual estimation of obesity in daily clinical setting despite its relevance to the daily practice. We aim to investigate the accuracy of visual estimation compared to actual clinical measurements in the diagnosis of overweight and obesity.

Methods:

This is a case control study. Patients for this study were attending the endocrinology, cardiology and chest pain out-patient clinic in Cork University Hospital, Cork, Ireland. The questionnaire session was carried out at every endocrinology, cardiology and chest pain clinic for 5 consecutive weeks. A total of 100 patients were recruited allowing for a 10% margin of error at 95% confidence level in a sample population of 150 000. Ten doctors of varying grades were chosen randomly to visually score the subjects. Exclusion criteria included patients who were pregnant and who are wheelchair bound. Consent was obtained from patients prior to filling questionnaires. Ethical approval was received from the Clinical Research Ethics Committee of the Cork Teaching Hospitals.

In the waiting room, patients were asked to self- report their weight, height and waist circumference to the best of their estimate. Demographics and cardiovascular risk were obtained from medical charts and presented in Table 1. The questionnaires have a section that specifically tests patients’ awareness of abdominal obesity and patients were asked to choose between obesity and abdominal obesity, relying on their own knowledge of markers of cardiovascular risks. Clinical measurements were taken in the nurses’ assessment room. Weight was measured by using portable SECA scales (Seca 755 Mechanical Column Scale) and was measured to the nearest 0.1kilogram. All patients were measured on the same weighing scale to minimize instrumental bias. Patients were asked to remove their heavy outer garments and shoes and empty their pockets and to stand in the centre of the platform, so that weight is distributed evenly to both feet.

Height was measured by using a height rule attached to a fixed measuring rod (Seca 220 Telescopic Measuring Rod). Patients were asked to remove their shoes and are asked to stand with their back to the height rule. It was ensured that the back of the head, back, buttocks, calves and heels are touching the wall. Patients were asked to remain upright with their feet together. The top of the external auditory meatus is leveled with the inferior margin of the bony orbit. The patients were asked to look straight. Height is recorded to the resolution of the height rule (i.e. nearest millimeter).

Waist circumferences were measured using a myotape. Patients were asked to remove their outer garments and stand with their feet close together. The tape is placed horizontally at a level midway between the lower rib margin and iliac crest around the body. They were then asked to breathe normally and the reading of the measurement was taken at the end of gentle exhaling. This prevents patients from holding their breath. The measuring tape is held firmly, ensuring its horizontal position and loose enough that it allows placement of one finger between the tape and the subject's body. A single operator who has been trained to measure waist circumference as per the WHO guidelines is used repeatedly in order to reduce measurement bias⁽⁸⁾.

The doctors were asked to visually estimate the patients' weight, height, waist circumference and BMI. The estimation is recorded on a separate sheet. All doctors were blinded to the actual clinical measurements. The questionnaires were then collected at the end of the clinic and matched to individual patients. Data entry was performed in Microsoft Excel and exported for statistical analysis on SPSS version 16.

Findings

The study enrolled 100 patients. Demographic and cardiovascular risk details are shown in Table 1. Among these, 42 were obese, 35 were overweight and 23 patients had a normal BMI. The sample has a mean BMI of 29.9kg/m² (95% CI 28.7-31.1) with a mean waist circumference (WC) of 103.2cm (95% CI 100.7-107.2). The average male waist circumference is 105.8 cm while the average female waist circumference is 101.6cm. The mean measured weight was 84.6kg (95% CI 81.0-88.2) and the mean height measurement was 1.68m (95% CI 1.66-1.70).

Table 1: Cardiovascular risk factors

Patient’s perception and doctor’s estimation of anthropomorphic measurements were compared to actual measurements and is displayed in Table 2.

Table 2. Deviation from actual measurement values in both groups

In terms of patients own estimation of height, weight and waist circumference, 49% of patients under estimated their weight by up to 1.5kg, 35% reported accurately to 1.5 kg and 16% over reported weight. 67% of patients estimated height accurately, 18% of patients under-estimated, and 15% over-estimated. When asked to estimate their waist circumference, 68% of patients under estimated by up to 5cm, 30% over estimated and 2 patients estimated accurately to 5cm (Figure 1). We found that 70% of patients regarded obesity as the higher threat to health compared to abdominal obesity. There were no differences in patient’s self reported weight and doctor’s weight estimation (p= 0.236).

Figure 1. Graphical representation of patients estimated weight, height and waist circumference

We then analysed the doctor’s estimation of height, weight, waist circumference and BMI. For the purpose of interpreting the data on BMI, the estimates that is recorded by doctors that matches the patient’s real BMI by clinical measurement is considered accurate. Therefore, for patients who have a normal BMI, 69.5% were correctly estimated as normal and the rest (30.5%) were estimated as overweight. For those patients who are obese, 81% were estimated as obese and by the doctors as a group and the rest (19%) is estimated to be overweight. In patients who are overweight, 63% were correctly estimated as being overweight by doctors, 9% were estimated as being obese and the rest (28%) were mistakenly estimated as having a normal BMI. Accurate BMI estimation by doctors was achieved in 72% patients (Figure 2).

Figure 2. Doctors estimation of BMI compared to actual clinical measurement

Doctors were noted to underestimate the patients’ weight in 53 patients, over estimated in 26, while being accurate in their estimation in 21 patients. Estimation of waist circumference to the nearest 5 cm shows marked under estimation of waist circumference in 71% of patients, over reporting in 3% of patients and 26% accurate estimation. The majority of underestimation of waist circumference happens in the region of 10 to 15cm. For patients who are obese, doctors were able to estimate waist circumference correctly in 58% of obese individuals.

Discussion:

This is the first study demonstrating the relationship of visual estimation of a cardiovascular risk factor and comparing to actual clinical measurements. As obesity and abdominal obesity becomes an increasingly common phenomenon, our perception of the 'normal' body habitus may be distorted⁽⁹⁾.

It is observed that in the bigger hospitals out-patient departments, physicians and nurses are commonly affected by clinical workload and tend to spend a limited amount of time with patients in order to achieve a quicker turnaround time. Cleator et al looked at whether clinically significant obesity is well detected in three different outpatient department and whether they are managed appropriately once diagnosed⁽¹⁰⁾. In all the outpatient departments involving the specialties of rheumatology, cardiology and orthopedics, the actual cases of clinical obesity is higher than what is being diagnosed and the management of obesity was heterogeneous and minimal in terms of intervention. With the ever increasing obese patients attending hospitals, it is understandable that healthcare providers such as physicians, nurses, dietician and physiotherapist resort to relying on visual estimation.

In terms of patient’s own estimation of height, weight and waist circumference, we gained that patients were reasonably good at estimating their own height but tend to under estimate weight. This is probably due to the fact that these patients have not had a recent measurement of weight and their weight estimation is based on previous historical measurement from months to years back, which in the majority of people, is less than their current weight. This also explains why their height estimation is more accurate, as adult heights do not undergo significant changes and are relatively constant.

When attempting to obtain patient’s own estimation of waist circumference, we found that most patients are not at all aware of the method used to measure waist circumference. Some patients even mistaken waist circumference as being their trousers’ waist size. In those who were able to give estimation, a large proportion would under estimate.

The majority of patients think that general obesity is more predictive of cardiovascular outcome compared to abdominal obesity. This lack of awareness is reflective on clinician’s effort in addressing abdominal obesity as an important cardiovascular risk factor to patients during consultations. The lack of proper awareness campaign by healthcare providers along with the evolving markers of cardiovascular risk may further confuse the general public.

Recently, waist circumference, waist to hip ratio along with many serum biomarkers have been noted to correlate to adverse outcomes in obese individuals, independent of BMI. Waist circumference measurement is a relatively new tool compared to the measurement of BMI. This would explain the discrepancy between doctors’ estimation of BMI and waist circumference. Visual estimation is further compromise as many patients would be covered in items of clothing during consultations. In order to obtain a better estimation of waist circumference, the individual have to be observed from many angles, a task that may be impossible in a busy clinic.

Although BMI is a convenient method to quantify obesity, recent studies have shown that waist circumference is a stronger predictor of cardiovascular outcomes^{(11),(12),(13),(14)}.The importance of waist circumference in predicting health risk is thought to be due to the relationship between waist circumference and intra-abdominal fat^{(15),(16),(17),(18),(19),(20)}.We now know that the presence of intra-abdominal visceral fat is associated with a poorer outcome in that patients are prone to develop metabolic syndrome and insulin resistance⁽²¹⁾.We have yet to devise a more accurate measurement on visceral fat and at present limited to using waist circumference measurements.

Although doctors are generally good at BMI estimation, we found that in estimating overweight patients’ BMI, close to 30% were wrongly estimated as having normal BMI. Next to the obese, these groups of patients are likely to have metabolic abnormalities and increased cardiovascular risk. If actual measurement of BMI is not routinely done, we may neglect patients who would benefit from intervention. A simple, short counseling during the outpatient visit with emphasis on weight loss, the need to increase their daily activity levels and the morbidity related to being overweight may be all that is needed to improve the population health in general. Further intervention may include referrals to hospital or community dieticians and prescribed exercise programmes. These intervention tools already exist in the healthcare system and could be accessed readily.

The nature of our study design exposes it to several potential selection and measurement biases. Future studies should include patients of differing ages and socioeconomic background. Additionally, clinicians of differing appointments from various different specialties should be included to obtain a more applicable result. A measure of diagnostic efficacy should also be employed to further assess the value of clinical measurement and therapeutic intervention.

Conclusion:

The appropriateness of visual scoring of markers of obesity by doctors is flawed and limited to the obese individuals. True anthropometric measurements would avoid misdiagnosing overweight individuals as normals. We can conclude that patients’ own estimation of weight is unreliable and that they are unaware of the impact of high abdominal fat deposition on cardiovascular outcome. The latter should be addressed in consultations by both hospital physicians and general practitioners. Further emphasis and education in schools and awareness campaigns should also advocate this emerging cardiovascular risk factor.

INTRODUCTION

The widespread use of office-software in general practice makes the idea of simple, automatic computerised support an attractive one.  Different tools for different diseases have been tested with mixed results, and in 2009 a Cochrane review¹ concluded that “Point of care computer reminders generally achieve small to modest improvements in provider behavior. A minority of interventions showed larger effects, but no specific reminder or contextual features were significantly associated with effect magnitude”.  One year later another review² reached similar conclusion: “Computer reminders produced much smaller improvements than those generally expected from the implementation of computerised order entry and electronic medical record systems”.   Despite this, simple, non-expensive, automatic reminders are frequently part of GPs’ software, even if their real usefulness is seldom tested in real life.

Repeated hospitalisation for heart failure is an important problem for every National Health System; it is estimated that about half of all re-hospitalisation could be avoided³. Adherence to guidelines can reduce re-hospitalisation rate⁴, and pharmacotherapy according to treatment guidelines is associated with lower mortality in the community⁵. In 2004 a software commonly used in Italian primary care implemented a simple reminders’ system to help GPs to improve prescription of drugs recommended for heart failure. We evaluated if this could lead to a decrease in re-hospitalisation rate.

METHODS

In 2003, using Millewin ®, a software commonly used by Italian GPs, we showed that appropriate prescription could increase using a simple pop-up reminders⁶; a year later, using the Italian General Practitioners database ‘Health Search – CSD Patient database (HSD) (www.healthsearch.it), we observed a lower than expected prevalence of codified diagnosis of heart failure and of prescription of both beta-blockers and ACE-Inhibitors/ARBs (data on file). Therefore in 2004 Millewin® embedded a simple reminder system to help heart failure (HF) management. The first reminder aimed to identify patients with HF, but without codified diagnosis: in case of loop diuretic and/or digoxin prescription without codified HF diagnosis a pop-up told the GP that the patients could be affected by HF and invited the physician to verify this hypothesis and eventually to record the diagnosis. The second reminder appeared when a patient with codified HF diagnosis had no beta-blocker and/or ACE-inhibitor/ARB prescription: a pop-up invited the GP to prescribe the missing drug. This reminder system was already activated in the 2004 release of the software, but required voluntary activation in the successive releases. This is a common choice in real life, where positive choices in clinical practice by software-house neither are welcomed nor accepted by GPs. We had no possibility to know who decided to keep using the reminders.

We examined the 2004-2009 HF hospitalisations in Puglia, a Southern Italian Region with a population of over 4000000, and with high HF hospitalisation rate compared with the Italian mean⁷.  We compared the hospitalisations for patients cared for by GPs who used Millewin® in 2004 to those of the patients cared for by GPs who never used Millewin®. Data were provided by the local Health Authority, and were extracted from the administrative database. 

RESULTS

We identified 64591 patients (mean age 76 y, sd 12; 49.9% men) with one or more HF hospitalisation; 17810 had > 2 hospitalisations, and were analysed for the current study.

Figure 1 - Selection process leading to the identification of the patients with > 2 HF hospitalisations

The selection that led to this group is summarised in figure 1. There was no statistically significant difference between patients cared for GPs using or non using Millewin® software as far as age and gender are concerned. The re –hospitalisation rate according to the use or non-use of  Millewin® of patients’ GPs is summarised in table 1.

Table 1: Re-hospitalisation rate of patients cared by Millewin® users and non-users

MW = Millewin®, N.S = Not significant

The mean time before the first re-hospitalisation was 108.5 day +/- 103.3 for Millewin® non-users and 116.4 +/- 107.5 for users (p < 0.05).

DISCUSSION

Even if reasonable and clinically sound, the availability of computerised reminders aimed to help GPs to identify HF patients and to prescribe them with recommended drugs didn’t reduce re-hospitalisation rate. The first possibility to explain this result is that, after the first year, GPs didn’t re-activate the reminders’ system. Unfortunately we couldn’t verify this hypothesis, but it is known that the level of use of such a system may be low in usual care⁸; furthermore providers may agree with less than half of computer generated care suggestions from evidence-based CHF guidelines, most often because the suggestions are felt to be inapplicable to their patients or unlikely to be tolerated⁹.  Epidemiological studies have shown that heart failure with a normal ejection fraction is now a more common cause of hospital admission than systolic heart failure in many parts of the world^10-11. Despite being common, this type of heart failure is often not recognised, and evidence based treatment—apart from diuretics for symptoms—islacking¹². It is therefore possible that increasing ACE-I/ARBs and beta-blockers use in these patients doesn’t influence the prognosis and hospitalisation rate. Unfortunately administrative databases do not permit to distinguish the characteristic of HF. We must also consider that the use of appropriate drugs after HF hospitalisation could spontaneously increase in the last years; a survey in Italian primary care showed that 87% of HF patients used inhibitors of the renin-angiotensin system, and 33% beta-blockers¹³. A further relevant increase in ACE-I/ARBS is therefore unlikely, while a improvement is clearly needed for beta-blockers.   Could more complex and information-providing reminders be more useful? This is unlikely since adding symptom information to computer-generated care suggestions for patients with heart failure did not affect physician treatment decisions or improve patient outcomes¹⁴.  Furthermore, consultation with a cardiologist for starting beta-blocker treatment is judged mandatory by 57% of Italian GPs¹³, thus reducing the potential direct effect of reminders on prescription. Finally we must remember that part of the hospitalisation due to HF worsening can be due to non-cardiac disease, such as pneumonia, anemia, etc; all these cause cannot be affected by improved prescription of cardiovascular drugs.

Albeit simple and inexpensive, computerised reminders aren’t a neutral choice in professional software. Too many pop-ups may be disturbing and may lead to systematic skipping the reminders’ text. This can be a problem, since computerised reminders have proved to be useful for other important primary-care activity, such as preventive interventions¹⁵. In our opinion, at the moment, a computerised reminder-system should be proposed only as a part of a more complex strategy, such as long-term self or group audit and/or pay for performance initiative.

CONCLUSIONS

Availability of computerised automatic reminders aimed to improve detection of heart-failure patients and prescription of recommended drugs doesn’t decrease repeated hospitalisation; these tools should be probably tested in the context of a more complex strategy, such as a long-term audit.

Introduction

Majority of pancreatic tumours are of primary pancreatic origin. Nevertheless a multitude of extra pancreatic cancers can metastasize to the pancreas and may present a diagnostic and management dilemma. Our case demonstrates such a problem in a patient with a pancreatic lesion.

Case report

A 82 year old man was referred to our hospital with computed tomogram (CT) scan showing a hypodense lesion in the pancreas. He had an anterior resection done 5 years prior for a Duke’s B (pT3N0M0) colon cancer. He did not receive any post-operative chemotherapy or radiotherapy. Carcinoembryonic antigen (CEA) levels was normal. He underwent an MRI scan (Figure 1) of his abdomen which reported a 2.8cm ring enhancing lesion in the tail of pancreas. At endoscopic ultrasound (EUS) a 2 x 2 cm well circumscribed mass was demonstrated in the tail of the pancreas close to the splenic artery but, not involving the vessel. Fine needle aspiration (FNA) of the lesion demonstrated a poorly differentiated mucin secreting adenocarcinoma. Immuno-histochemical staining was strongly positive for CK 20 but, CK 7 was only weak focally positive (Figure 2) thus, suggesting metastasis to the pancreas from a colonic primary as opposed to a primary pancreatic malignancy.

The patient was given an option to undergo subtotal pancreatectomy or consider palliative chemotherapy. The patient chose neither and was discharged home with input from the Macmillan team.

Figure 1: MRI after gadolinium showing a ring-enhancing lesion in the tail of pancreas.

Figure 2: (a) Fine needle aspirate on liquid based cytology (x 400) shows irregular distribution of cells with nuclear palisading and pleomorphism. Immunocytochemistry performed on cytology smear shows (b) strong positivity for CK 20 (c) negative for CK7 and (d) focal positivity for CA19.9.

Discussion: 

The pancreas is an uncommon site of metastasis from other primary cancers.¹ Most of the space occupying lesions seen in the pancreas on imaging are of primary pancreatic origin.^{1, 2} Adsay, et al ² performed analyses on surgical and autopsy database in 2004 and found that amongst a total of 4955 adult autopsies and 973 pancreatic specimens at surgery; the prevalence of different metastatic tumours to the pancreas was only 1.6% of all examined autopsy cases and 3.9% of pancreatic resections.

A study from Japan found that the commonest primary malignancies to metastasize to the pancreas were from the stomach, lung and bile duct in that order.³ Other primary tumours that have been reported to metastasize to the pancreas include renal cell carcinoma, lung, breast, small bowel, colon, rectum and melanoma.^{4, 5} Several mechanisms for development of pancreatic metastases (particularly from colorectal cancer) have been described: transfer via the lymphatic system, metastases from peritoneal carcinomatosis, and/or transfer via the haematogenous system. ⁶   Direct invasion of the pancreas by the primary tumour was also noted to be a method of spread from bile duct and gastric malignancies.³ 

CT scan is often unhelpful in differentiating primary from secondary pancreatic lesions. Pancreatic metastasis can present as solid or cystic structures, hypodense or hyper dense lesions.^{7, 8} A series by Klein, et al in which the CT features of pancreatic tumours are described suggested that multiplicity of tumours and/or hypervascularity were characteristic of secondary pancreatic tumours.⁹ A recent study has suggested that Positron Emission Tomogram (PET) is a more sensitive investigative tool than CT in detecting metastatic colorectal cancer.¹⁰ Most patients (as in our unit) usually have EUS guided FNA or biopsy to arrive at a diagnosis.

The differential diagnosis of primary pancreatic cancer versus metastasis from other carcinomas may be difficult using common histopathological techniques.¹¹ Immuno-histochemical staining is often helpful in differentiating primary from secondary pancreatic tumours. Sometimes staining by a combination of different antibodies helps to reach a diagnosis. In a survey of 435 cases, the expression of CK 7 was positive in 92% of pancreatic cancers but in only 5% of colon cancers. On the other hand CK 20 was positive in 100% of colon cancers and in only 62% of pancreatic cancers.¹² Furthermore, CD X2 is frequently expressed in colorectal carcinoma but, rarely in pancreatic ductal adenocarcinoma.¹³

The choice between conservative chemotherapy and resection for solitary pancreatic metastasis from colorectal cancer is still undecided.  The natural history of untreated patients with pancreatic metastasis from cancer of the colon or rectum is unknown and thus it is impossible to compare the survival rate of resected and unresected patients treated with chemotherapy.¹⁴ Researchers from John Hopkins have reported only 4 colon metastasis to the pancreas (0.6%) among 650 pancreatico-duodenectomy procedures performed in their institution from 1990 to 1996.¹⁵ Experience from an Italian centre¹⁴ published that metastasis to the pancreas was the indication for surgery in a total of 18 out of 546 pancreatic resections (3.2%) performed over 27 years and colorectal cancer was the primary tumour in 50% of those cases. The median survival time was 16.5 months (range 8 – 105 months) with no peri-operative mortality being reported. In another study, all symptomatic (pain or jaundice) patients experienced complete relief of symptoms after surgery and no one experienced obstructive jaundice or abdominal pain until tumour recurrence.¹⁶

Oncologists may argue that chemotherapy can offer the same results as pancreatic resection but with less morbidity. Unfortunately, there is paucity of data in medical literature on comparisons of outcomes associated with surgical and chemotherapeutic treatment. We agree with Sperti et al ¹⁴ that resection of pancreatic metastasis from colorectal cancer is a palliative procedure with long-term survival being an exceptional event.

Conclusion:

Our case demonstrates that differential diagnoses for pancreatic masses should always include metastasis to the pancreas from other tumours particularly, when there is a history of previous or concurrent non-pancreatic malignancy. When disseminated malignancy is not present an aggressive surgical approach may offer successful palliation of symptoms and have a role in the multidisciplinary management of  metastatic malignancy.

Introduction

Assessment and evaluation are the foundations of learning; the former is concerned with how students perform and the latter, how successful the teaching was in reaching its objectives. Case based discussions (CBDs) are structured, non-judgmental reviews of decision-making and clinical reasoning¹. They are mapped directly to the surgical curriculum and “assess what doctors actually do in practice” ¹. Patient involvement is thought to enhance the effectiveness of the assessment process, as it incorporates key adult learning principles: it is meaningful, relevant to work, allows active involvement and involves three domains of learning²:

1. Clinical (knowledge, decisions, skills)
2. Professionalism (ethics, teamwork)
3. Communication (with patients, families and staff)

The ability of work based assessments to test performance is not well established. The purpose of this critical review is to assess if CBDs are effective as an assessment tool.

Validity of Assessment

Validity concerns the accuracy of an assessment, what this means in practical terms, and how to avoid drawing unwarranted conclusions or decisions from the results. Validity can be explored in five ways: face, content, concurrent, construct and criterion-related/predicative. 

CBDs have high face validity as they focus on the role doctors perform and are, in essence, an evolution of ‘bedside oral examinations’³. The key elements of this assessment are learnt in medical school; thus the purpose of a CBD is easy for both trainees and assessors to validate¹. In terms of content validity, CBDs are unique in assessing a student’s decision-making and which, is key to how doctors perform in practice. However, as only six CBDs are required a year, they are unlikely to be representative of the whole curriculum. Thus CBDs may have a limited content validity overall, especially if students focus on one type of condition for all assessments.

Determining the concurrent validity of CBDs is difficult as they assess the pinnacle of Miller’s triangle – what a trainee ‘does’ in clinical practice (figure1)⁴. CBDs are unique in this aspect, but there may be some overlap with other work based assessments particularly in task specific skills and knowledge. Simulation may give some concurrent validity to the assessment of judgment. The professional aspect of assessment can be validated by a 360 degree appraisal, as this requests feedback about a doctor’s professionalism from other healthcare professionals¹.

Figure 1: Miller’s triangle⁴

CBDs have high construct validity, as the assessment is consistent with practice and appropriate for the working environment. The clinical skills being assessed will improve with expertise and thus there should be ‘expert-novice’ differences on marking³. However the standard of assessment (i.e. the ‘pass mark’) increases with expertise – as students are always being assessed against a mark of competency for their level. A novice can therefore score the same ‘mark’ as an expert despite a difference in ability.

In terms of predictive validity performance-based assessments are simulations and examinees do not behave in the same way as they would in real life³. Thus, CBDs are an assessment of competence (‘shows how’) but not of true clinical performance and one perhaps could deduct that they don’t assess the attitude of the trainee which completes the cycle along with knowledge and skills (‘does’)⁴. CBDs permit inferences to be drawn concerning the skills of examinees that extend beyond the particular cases included in the assessment³. The quality of performance in one assessment can be a poor predictor of performance in another context. Both the limited number and lack of generalizability of these assessments have a negative influence on predictive validity³. 

Reliability of Assessment

Reliability can be defined as “the degree to which test scores are free from errors of measurement”. Feldt and Brennan describe the ‘essence’ of reliability as the “quantification of the consistency and inconsistency in examinee performance” ⁵. Moss states that less standardized forms of assessment, such as CBDs, present serious problems for reliability⁶. These types of assessment permit both students and assessors substantial latitude in interpreting and responding to situations, and are heavily reliant on assessor’s ability. Reliability of CBDs is influenced by the quality of the rater’s training, the uniformity of assessment, and the degree of standardization in examinee.

Rating scales are also known to hugely affect reliability – understanding of how to use these scales must be achieved by all trainee assessors in order to achieve marking consistency. In CBD assessments, trainees should be rated against a level of completion at the end of the current stage of training (i.e. core or higher training) ¹. While accurate ratings are critical to the success of any WBA, there may be latitude in the interpretation of these rating scales between different assessors. Assessors who have not received formal WBA training tend to score trainees more generously than trained assessors^7-8. Improved assessor training in the use of CBDs and spreading assessments throughout the student’s placement (i.e. a CBD every two months) may improve the reliability and effectiveness of the tool¹.

Practicality of Assessment

CBDs are a one-to-one assessment and are not efficient; they are labour intensive and only cover a limited amount of the curriculum per assessment. The time taken to complete CBDs has been thought to negatively impact on training opportunities⁷. Formalized assessment time could relieve the pressure of arranging ad hoc assessments and may improve the negative perceptions of students regarding CBDs.

The practical advantages of CBDs are that they allow assessments to occur within the workplace and they assess both judgment and professionalism – two subjects on the curriculum which are otherwise difficult to assess¹. CBDs can be very successful in promoting autonomy and self-directed learning, which improves the efficiency of this teaching method⁹. Moreover, CBDs can be immensely successful in improving the abilities of trainees and can change clinical practice – a feature than is not repeated by other forms of assessment⁸.

One method for ensuring the equality of assessments across all trainees is by providing clear information about what CBDs are, the format they take and the relevance they have to the curriculum. The information and guidance provided for the assessment should be clear, accurate and accessible to all trainees, assessors, and external assessors. This minimizes the potential for inconsistency of marking practice and perceived lack of fairness^7-10. However, the lack of standardization of this assessment mechanism combined with the variation in training and interpretation of the rating scales between assessors may result in inequality.

Formative Assessment

Formative assessments modify and enhance both learning and understanding by the provision of feedback¹¹. The primary function of the rating scale of a CBD is to inform the trainee and trainer about what needs to be learnt¹. Marks per see provide no learning improvement; students gain the most learning value from assessment that is provided without marks or grades¹². CBDs have feedback is built into the process and therefore it can given immediately and orally. Verbal feedback has a significantly greater effect on future performance than grades or marks as the assessor can check comprehension and encourage the student to act upon the advice given^1,11-12. It should be specific and related to need; detailed feedback should only occur to help the student work through misconceptions or other weaknesses in performance¹². Veloski, et al, suggests that systemic feedback delivered from a credible source can change clinical performance⁸.

For trainees to be able to improve, they must have the capacity to monitor the quality of their own work during their learning by undertaking self-assessment¹². Moreover, trainees must accept that their work can be improved and identify important aspects of their work that they wish to improve. Trainee’s learning can be improved by providing high quality feedback and the three main elements are crucial to this process are ¹²:

1. Helping students recognise their desired goal
2. Providing students with evidence about how well their work matches that goal
3. Explaining how to close the gap between current performance and desired goal

The challenge for an effective CBDis to have an open relationship between student and assessor where the trainee is able to give an honest account of their abilities and identify any areas of weakness. This relationship currently does not exists in most CBDs, as studies by Veloski, et al⁸and Norcini and Burch⁹ who revealed that only limited numbers of trainees anticipated changing their practice in response to feedback data. An unwillingness to engage in formal self-reflection by surgical trainees and reluctance to voice any weaknesses may impair their ability to develop and lead to resistance in the assessment process. Improved training of assessors and removing the scoring of the CBD form may allow more accurate and honest feedback to be given to improve the student’s future performance. An alternative method to improve performance is to ‘feed forward’ (as opposed to feedback) focusing on what students should concentrate on in future tasks¹⁰

Summative Assessment

Summative assessments are intended to identify how much the student has learnt. CBDs have a strong summative feel: a minimum number of assessments are required and a satisfactory standard must be reached to allow progression of a trainee to the next level of training¹. Summative assessment affects students in a number of different ways; it guides their judgment of what is important to learn, affects their motivation and self-perceptions of competence, structures their approaches to and timing of personal study, consolidates learning, and affects the development of enduring learning strategies and skills^12-13. Resnick and Resnick summarize this as “what is not assessed tends to disappear from the curriculum” ¹³. Accurate recording of CBDs is vital, as the assessment process is transient, and allows external validation and moderation.

Evaluation of any teaching is fundamental to ensure that the curriculum is reaching its objectives¹⁴. Student evaluation allows the curriculum to develop and can result in benefits to both students and patients. Kirkpatrick suggested four levels on which to focus evaluation¹⁴:

Level 1 – Learner’s reactions
Level 2a – Modification of attitudes and perceptions
Level 2b – Acquisition of knowledge and skills
Level 3 – Change in behaviour
Level 4a – Change in organizational practice
Level 4b – Benefits to patients

At present there is little opportunity within the Intercollegiate Surgical Curriculum Project (ISCP) for students to provide feedback. Thus a typical ‘evaluation cycle’ for course development (figure 2) cannot take place¹⁵. Given the widespread nature of subjects covered by CBDs, the variations in marking standards by assessors, and concerns with validity and reliability, an overall evaluation of the curriculum may not be possible. However, regular evaluation of the learning process can improve the curriculum and may lead to better student engagement with the assessment process¹⁴. Ideally the evaluation process should be reliable, valid and inexpensive¹⁵. A number of evaluation methods exist, but all should allow for ongoing monitoring review and further enquiries to be undertaken.

Figure 2: Evaluation cycle used to improve a teaching course¹⁵

Conclusion

CBDs, like all assessments, do have limitations, but we feel that they play a vital role in development of trainees. Unfortunately, Pereira and Dean suggest that trainees view CBDs with suspicion⁷. As a result, students do not engage fully with the assessment and evaluation process and CBDs are not being used to their full potential. The main problems with CBDs relate to the lack of formal assessor training in the use of the WBA and the lack of evaluation of the assessment process Adequate training of assessors will improve feedback and standardize the assessment process nationally. Evaluation of CBDs should improve the validity of the learning tool, enhancing the training curriculum and encouraging engagement of trainees.

If used appropriately, CBDs are valid, reliable and provide excellent feedback which is effective and efficient in changing practice. However, a combination of assessment modalities should be utilized to ensure that surgical trainees are facilitated in their development across the whole spectrum of the curriculum. 

Case Report

A 69 year old male with hypertension, body mass index 24 kg/m², neck circumference 16 inches, and moderate COPD, on home oxygen, presented to his pulmonary clinic appointment with worsening complaints of fatigue, leg cramps, and intermittent shortness of breath with chest discomfort.  A remote, questionable history of syncope five to ten years ago was elicited.  His vital signs were: temperature 98.8⁰F, blood pressure 119/76 mmHg, pulse 92/min and regular, and respirations 20/min.  Physical exam was significant for crowded oropharynx with a Mallampati score of four, distant breath sounds with a prolonged expiratory phase on lung exam with a normal cardiac exam.  Laboratory investigation showed normal complete blood counts, haemoglobin 15 g/dL, and normal chemistries.  Compared to his previous studies, a pulmonary function study showed stable parameters with a FEV1 1.47 L   (69%), FVC/FEV1 ratio 0.44 (62%), and a DLCO/alveolar volume ratio of 2.12 (49%).  A room air arterial blood gas revealed pH 7.41, PCO2 44 mmHg, and PO2 61 mmHg, with 92% oxygen saturation.  A six minute treadmill exercise test performed to assess the need for supplemental oxygen showed that he required supplemental oxygen at 1L/min via nasal cannula to eliminate hypoxemia during exercise.  His chest radiograph was significant for hyperinflation and prominence of interstitial markings.  A high resolution computed tomography of the chest demonstrated severe centrilobular and panacinar emphysema only.  A baseline electrocardiogram (EKG) showed normal sinus rhythm with an old anterior wall infarct (Figure 1).   Echocardiography of the heart revealed a normal left ventricle with an ejection fraction of 65%.  Right ventricular systolic function was normal although elevated mean pulmonary arterial pressure of 55 mmHg was noted.  A diagnostic polysomnogram performed for evaluation of daytime fatigue and snoring at night revealed mild OSA with an AHI of 6/hr. with sleep time spent with oxygen saturation below 90% (T-90%) of 19%.  The EKG showed normal sinus rhythm.  A full overnight polysomnogram for continuous positive airway pressure (CPAP) titration performed for treatment of sleep disordered breathing was sub-optimal,  however it demonstrated an apnoea–hypopnea index (AHI) of 28 during REM (rapid eye movement) sleep, and a T-90% of 93%.  The associated electrocardiogram showed Wenckebach second degree AV heart block during REM sleep usually near the nadir of oxygen desaturation.   On a repeat positive airway pressure titration study, therapy with Bilevel pressures (BPAP) of 18/14 cmH₂0 corrected the AHI and nocturnal hypoxemia to within normal limits during Non REM (NREM) and REM sleep.  His electrocardiogram remained in normal sinus rhythm .A twenty-four hour cardiac holter monitor revealed baseline sinus rhythm and confirmed the presence of second degree AV block of the Wenckebach type.  A one month cardiac event recording showed normal sinus rhythm with frequent episodes of second degree AV block.  These varied from Type I progressing to Type II with a 2:1 and 3:1 AV block, during sleep.  Progression to complete heart block was noted with the longest pause lasting 3.9 seconds during sleep.  The patient underwent an electrophysiology study with placement of a dual chamber pacemaker.  He was initiated on BIPAP therapy.  Subsequently, the patient was seen in clinic with improvements in his intermittent episodes of shortness of breath, fatigue, and daytime sleepiness.

Figure 1- Patient’s baseline EKG, normal sinus rhythm. Figure 2 -Progression to Mobitz Type II block 5:07 am. Figure 3 and 4- Sinus pauses, longest interval 11:07 pm 3.9 seconds (Figure 4).

Discussion

In healthy individuals, especially athletes, bradycardia, Mobitz I AV block, and sinus pauses up to 2 seconds are common during sleep and require no intervention⁵. Cardiac rhythm is controlled primarily by autonomic tone.  NREM sleep is accompanied by an increase in parasympathetic, and a decrease in sympathetic, tone. REM sleep is associated with decreased parasympathetic tone and variable sympathetic tone.  Bradyarrhythmias in patients with OSA are related to the apnoeic episodes and over 80% are found during REM sleep.   During these periods of low oxygen supply, increased vagal activity to the heart resulting in bradyarrhythmias may actually be cardioprotective by decreasing myocardial oxygen demand.  This may be important in patients with underlying coronary heart disease. 

Some studies have found that Mobitz I AV block may not be benign.  Shaw⁶ et al studied 147 patients with isolated chronic Mobitz I AV block.  They inserted pacemakers in 90 patients, 74 patients were symptomatic and 16 patients received a pacemaker for prophylaxis.  Outcome data included five-year survival, deterioration of conduction to higher degree AV block, and new onset of various forms of symptomatic bradycardia.  They concluded that survival was higher in the paced groups and that risk factors for poor outcomes in patients with Mobitz I included age greater than 45 years old, symptomatic bradycardia, organic heart disease, and the presence of a bundle branch block on EKG.

The Sleep Heart Health Study⁷ found a higher prevalence of first and second-degree heart block among subjects with sleep-disordered breathing (SDB) than in those without (1.8% vs. 0.3% and 2.2 vs. 0.9%, respectively). Gami et al⁸observed thatupon review of 112 Minnesota residents who hadundergone diagnostic polysomnography and subsequentlydied suddenly from a cardiac cause, sudden death occurred between the hours of  midnight and 6:00 AM in 46% of those with OSA, as compared with 21% of those without OSA.   In a study of twenty-three patients with moderate to severe OSA who were each implanted with an insertable loop recorder, about 50% were observed to have frequent episodes of bradycardia and long pauses (complete heart block or sinus arrest) during sleep⁹.  These events showed significant night-to-night intra individual variability and their incidence was under-estimated, only 13%, by conventional short-term EKG Holter recordings. 

Physiologic factors predisposing patients with OSA to arrhythmias include alterations in sympathetic and parasympathetic nervous system activity, acidosis, apnoea’s, and arousal^{2, 10, 11}.  Some patients with OSA may have an accentuation of the ‘Diving Reflex’.  This protective reflex consists of hypoxemia-induced sympathetic augmentation to muscles and vascular beds associated with increased cardiac vagal activity which results in increased brain perfusion, bradycardia and decreased cardiac oxygen demand.  In patients with cardiac ischemia, poor lung function (i.e. COPD), or both, it may be difficult to differentiate between these protective OSA-associated Bradyarrhythmias and those which may lead to sudden death.  It has been well established that patients with COPD are at higher risk for cardiovascular morbidity¹² and arrythmias¹³.  Fletcher¹⁴ and colleagues reported that the effects of oxygen supplementation on AHI, hypercapnea and supraventricular arrhythmias in patients with COPD and OSA were variable.  Out of twenty obese men with COPD studied, in most patients oxygen eliminated the bradycardia observed during obstructive apnoea’s and eliminated AV block in two patients.  In some patients supplemental oxygen worsened end-apnoea respiratory acidosis however this did not increase ventricular arrhythmias. 

CPAP therapy has been demonstrated to significantly reduce sleep–related Bradyarrhythmias, sinus pauses, and the increased risk for cardiac death ^{9, 15}.   Despite this, in certain situations placement of a pacemaker may be required.  These include persistent life-threatening arrhythmias present in patients with severe OSAS on CPAP, arrhythmias in patients who are non-compliant with CPAP, and in patients who may have persistent sympathovagal imbalance and hemodynamic fluctuations resulting in daytime bradyarrhythmias¹⁶.

Our case is interesting since it highlights the importance of recognizing the association between OSA, COPD, and life-threatening cardiac arrhythmias.  Primary care providers should note the possible association of OSA-associated bradyarrhythmias with life-threatening Type II bradyarrhythmias and pauses.  Since bradyarrhythmias related to OSA are relieved by CPAP, one option would be to treat with CPAP and observe for the elimination of these arrhythmias using a 24hour holter or event recorder¹⁷.  Compliance with CPAP is variable and if life-threatening bradycardia is present, placement of a permanent pacemaker may be preferred¹⁸. 

Our patient is unusual because most studies showing a correlation with the severity of OSA and magnitude of bradycardia have included overweight patients without COPD¹⁹. This patient’s electrocardiogram revealed a Type II AV block at 5am (Figure 2).  This is within the overnight time frame where patients with OSA have been observed to have an increased incidence of sudden death. Figures 3 and 4 show significant sinus pauses.   In selected cases where patients have significant co-morbidities (i.e. severe COPD with OSA), in addition to treatment with positive airway pressure, electrophysiological investigation with placement of a permanent pacemaker may be warranted.

Introduction:

Although one cell type may predominate, teratomas usually comprise of tissue from all three embryonic germ layers^1. Generally arising from the gonads, they may be found in extra-gonadal sites such as sacro-coccygeal region, mediastinum, neck and retroperitoneum.² Here we report a case of retroperitoneal teratoma in an adult with successful surgical treatment. Its clinical presentation, diagnosis and treatment are reviewed.

Case Report:

A woman aged 28 years presented with pain in the right hypochondrium of one year duration. There was no associated bowel or urinary symptom. Examination showed minimal fullness in the right hypochondrium. Routine blood tests and urinalysis were within normal limits. A plain abdominal radiograph showed calcification in the right side of the abdomen (Fig. 1). Ultrasonography demonstrated 13.6 x 8.1 cm soft tissue mass in the retro-peritoneum between liver and the right kidney. It was heterogeneous, well circumscribed with sharply defined borders, and had some calcification and cystic areas. CT abdomen revealed a hypo-dense lesion between liver and the right kidney. It had fatty attenuation with internal hyper-dense areas representing calcification. (Fig. 2). Provisional diagnosis of a retroperitoneal teratoma was made and an open exploration was performed with a right sub-costal incision. There was a large cystic mass behind the ascending colon, duodenum and the pancreas. It was located in the retroperitoneal compartment. There were dense, fibrous adhesions of the mass with aorta but entire cystic mass was excised successfully.

Post operatively this tumor mass measuring 5 x 5 cm was excised in vitro and found to be filled with yellowish creamy material containing hair, sebum and bony tissue. Microscopically it was confirmed to be a cystic teratoma with no malignancy. Stratified squamous epithelium with sebaceous and sweat glands, hair shafts, calcification, few bony spicules and bone marrow elements were all demonstrated. (Fig. 3). The post operative course was uneventful and she was well at the 2 months follow up.

Figure 1. Plain abdominal radiograph showing radio-opaque shadow (arrow heads) in the  right upper abdomen.

Figure 2: Computed Tomography showing an encapsulated mass that contains multiple tissue elements including fat and areas of calcification.

Figure 3: Microscopic examination of the tumor showing squamous epithelium (SE), hair shaft (HS), sebaceous glands (SBG) 

Discussion:

Teratomas are congenital tumours arising from pluri-potential embryonic cells and therefore have several recognizable somatic tissues³, Teratomas are usually localized to the ovaries, testis, anterior mediastinum or the retro-peritoneal area in descending order of frequency.⁴ Teratomas constitute less than 10% of all primary retroperitoneal tumours and hence are relatively uncommon⁵. Furthermore, retroperitoneal teratomas occur mainly in children and have been very rarely described in the adults. Half of these cases present in children less than 10 years of age and only a fifth of them present after 30 years of age. Retroperitoneal teratomas are often located near the upper pole of the kidney with preponderance on the left. The case described here is therefore unusual in that it was a primary retroperitoneal teratoma in an adult, on the right side and with adhesions to the aorta.

Retroperitoneal teratomas are seen in females twice as commonly than males.   Teratomas are usually benign if they are cystic and contain sebum or mature tissue. They are more likely to be malignant if they are solid and have immature embryonic tissue like fat, cartilage, fibrous and bony elements.⁶ In these regards our case is similar to other described cases as our patient is also female and as her teratoma was cystic, it  showed lack of malignancy.

Teratomas are usually asymptomatic as the retroperitoneal space is extensive enough to allow for their free growth. When compression of the surrounding structure occurs, patients may get compression symptoms.The diagnosis of a retroperitoneal teratoma cannot be made on clinical grounds alone. Ultrasound and computed tomography are important in its diagnosis and may show the presence of calcification, teeth or fat. Calcification on the rim of tumour or inside the tumour is seen in 53-62% of teratomas and although radiologically three quarters of patients with a benign teratoma may have calcification within it, a quarter of malignant cases may also demonstrate calcification.  Computed tomography is better than Ultrasonography in defining the extent and spread of teratoma to the surrounding organs.⁷

The prognosis is excellent for benign retroperitoneal teratoma if complete resection can be accomplished.

INTRODUCTION:

Even though it is commonly seen in Graves' disease, TPP is not related to the etiology, severity, and duration of thyrotoxicosis. ¹

The pathogenesis of hypokalaemic periodic paralysis in certain populations with thyrotoxicosis is unclear. Transcellular distribution of potassium is maintained by the Na+/K+–ATPase activity in the cell membrane, and it is mainly influenced by the action of insulin and beta-adrenergic catecholamines.² Hypokalemia in TPP results from an intracellular shift of potassium and not total body depletion. It has been shown that the Na+/K+–ATPase activity in platelets and muscles is significantly higher in patients with TPP.³ Hyperthyroidism may result in a hyperadrenergic state, which may lead to the activation of the Na+/K+–ATPase pump and result in cellular uptake of potassium.^{2, 4, 5} Thyroid hormones may also directly stimulate Na+/K+– ATPase activity and increase the number and sensitivity of beta receptors.^{2, 6} Patients with TPP have been found to have hyperinsulinemia during episodes of paralysis. This may explain the attacks after high-carbohydrate meals.⁷

CASE REPORT:

A 19 year old male patient presented to our emergency room with sudden onset weakness of lower limbs. He was not able to stand or walk. Power of 0/5 in both lower limbs and 3/5 in upper limbs was noticed on examination.  Routine investigations revealed to have severe hypokalemia with a serum potassium of 1.6 meq/l (normal range 3.5-5.0 meq/l), a serum phosphorus level of 3.4 mg/dl (normal range 3-4.5 mg/dl) and mild hypomagnesemia with serum magnesium level of 1.5mg/dl (normal range 1.8-3.0 mg/dl). ECG showed hypokalemic changes with prolonged PR interval, increased P-wave amplitude and widened QRS complexes. He was managed on intravenous as well oral potassium and history revealed weight loss, increased appetite and tremors from past 4 months. He had a multinodular goiter and radioactive iodine uptake scan (Iodine 131) showed a toxic nodule (Toxic nodule shows increased iodine uptake while the rest of the gland is suppressed) with no exophthalmos, sensory or cranial nerve deficits. Thyroid function tests revealed thyrotoxicosis with free T4 of 4.3ng/dl (normal range 0.8-1.8ng/dl), T3 of 279 ng/dl (normal range = 60 - 181 ng/dl) and a TSH level of <0.15milliunits/L (normal range = 0.3 - 4 milliunits/L). He was managed on intravenous  potassium & propanolol. The patient showed dramatic improvement of his symptoms. The patient was discharged home on carbamazole with the diagnosis of TPP secondary to toxic nodular goiter.

In this case there was a significant family history as one of  his elder brother had a sudden death (cause not known) and his mother was primary hypothyroid on levothyroxin replacement therapy.

DISCUSSION :

TPP is seen most commonly in Asian populations, with an incidence of approximately 2% in patients with thyrotoxicosis of any cause.^1,8,9,10 The attacks of paralysis have a well-marked seasonal incidence, usually occurring during the warmer months.¹ Pathogenesis of hypokalaemia has been explained by some authors to be due to an intracellular shift of body potassium, which is catecholamine mediated.^11,12 Shizume and his group studied total exchangeable potassium which revealed that patients with thyrotoxic periodic paralysis were not significantly different from controls when the value was related to lean body mass.¹¹ The paralytic symptoms and signs improve as the potassium returns from the intracellular space back into the extracellular space.¹³ The diurnal variation in potassium movement where there is nocturnal potassium influx into skeletal muscle would explain the tendency for thyrotoxic periodic paralysis to occur at night.¹⁴ Hypophosphataemia and hypomagnesaemia are also known to occur in association with thyrotoxic periodic paralysis.^{14,15,16,17,18} The correction of hypophosphataemia without phosphate administration supports the possibility of intracellular shift of phosphate.¹⁶ Electrocardiographic findings supportive of a diagnosis of TPP rather than sporadic or familial periodic paralysis are sinus tachycardia, elevated QRS voltage and first-degree AV block (sensitivity 97%, specificity 65%).²⁰ In addition to ST-segment depression, T-wave flattening or inversion and the presence of U waves are typical of hypokalaemia.

The management is to deal with the acute attack as well as treatment of the underlying condition to prevent future attacks. Rapid administration of oral or intravenous  potassium chloride can abort an attack and prevent cardiovascular and respiratory complications.⁴ A small dose of potassium is the treatment of choice for facilitating recovery and reducing rebound hyperkalaemia due to release of potassium and phosphate from the cells on recovery.^1,2,3 Rebound hyperkalaemia occurred in approximately 40% of patients with TPP, especially if they received >90 mmol of potassium chloride within the first 24 hours.⁴ Another mode of treatment is to give propranolol, a nonselective b-blocker, which prevents the intracellular shift of potassium and phosphate by blunting the hyperadrenergic stimulation of Na+/K+–ATPase.²⁰  Hence, initial therapy for stable TPP should include propranolol.^21,22,23  The definitive therapy for TPP includes treatment of hyperthyroidism with antithyroid medications, surgical thyroidectomy, or radioiodine therapy.

Introduction

Acute non-traumatic knee effusion is a common condition presenting to the Orthopaedic department which can be caused by a wide variety of diseases(Table 1). Septic arthritis is the most common and serious etiology. It can involve any joint; the knee is the most frequently affected. Accurate and swift diagnosis of septic arthritis in the acute setting is vital to prevent joint destruction, since cartilage loss occurs within hours of onset^1,2. Inpatient mortality due to septic arthritis has been reported as between 7-15%, despite improvement in antibiotic therapy^3,4. Crystal arthritis (Gout/Pseudogout) is the second most common differential diagnosis. It is often under-diagnosed and subsequently patients do not receive rheumatology referral for appropriate treatment and follow-up. In addition, some patients are misdiagnosed and treated as septic arthritis with inappropriate antibiotics. Untreated crystal-induced arthropathy has been shown to cause degenerative joint disease and disability leading to a considerable health economic burden.^6,7

When the patient is systemically unwell, it is common practice to start empirical antibiotic treatment after joint aspiration for the fear of septic arthritis. This aims to minimize the risk of joint destruction while awaiting gram stain microscopy and microbiological culture results. In a persistent painful swollen knee with negative gram stain and culture, antibiotic therapy can be continued with or without arthroscopic knee washout based on clinical suspicion of infection ⁸.

We have therefore undertaken a retrospective study to review our management of patients with non-traumatic hot swollen knees and in particular patients with crystal-induced arthritis. 

Materials and methods:

We performed a retrospective review of 180 patients presenting consecutively with acute non-traumatic knee effusion referred to the on-call Orthopaedic team in the hospital of study between November 2008 and November 2011. Sixty patients were included in the study (Table 2). There were 43 males and 17 females, with a mean age of 36 years (range, 23- 93 years).

Patient demographics, clinical presentation, co-morbidities, current medications and body temperature were recorded. The results of blood inflammatory markers (WBC, CRP), blood cultures, synovial fluid microscopy, culture and polarized microscopy were also collected. Subsequent treatment (e.g. antibiotics, surgical intervention), complications, and mortality rates were reviewed.

Results:

On presentation, a decreased range of movement was evident in all patients. Associated knee pain was reported by 55 patients (92%), and 24 patients (40%) had fever (temperature ≥ 37.5º). All joints were aspirated prior to starting antibiotics and samples were sent for gram stain microscopy, culture and antibiotic sensitivity, and polarized light microscopy.

Of the 60-patient cohort, 26 were admitted and started on intravenous antibiotics based on clinical suspicion of infection (Table 3). The median duration of inpatient admission was 4 days (range, 2 to 14 days). The median duration of antibiotic therapy was 6 days (range, 2 to 25 days). Eighteen patients were treated non-operatively by means of antibiotics and anti-inflammatory medications. Arthroscopic washout was performed in the remaining eight knees. In this group of patients, leucocyte count in the joint aspirate ranged from 0-3 leucocyte/mm³, blood leucocyte count ranged from 4-20 leucocyte/mm³, while mean CRP was 37.8 mg/l (range, 1-275 mg/l).

Review of laboratory results revealed that four patients had positive microscopic growth on gram stained films. Two samples showed staphylococcus aureus growth and two grew beta haemolytic streptococci. Eight patientshad crystals identified on polarized light microscopy of joint aspirate. Three showed monosodium urate (MSU) crystals while five had calcium pyrophosphate (CPP) crystals. They received antibiotic therapy for a mean duration of 10 days (range, 1-30 days). Two patients were taken to theatre for arthroscopic lavage. Only two patients received rheumatology referral.

Seven patients developed complications during their hospital stay. Four contracted diarrhoea; three of which had negative stool cultures but one was positive for clostridium difficile, developed toxic megacolon and died. One patient with known ischemic heart disease had a myocardial infarction and died. Two further patients acquiredurinary tract infections.

Discussion:

Acute monoarthritisof the knee joint can be a manifestation of infection, crystal deposits, osteoarthritis and a variety of systemic diseases. Arriving at a correct diagnosis is crucial for appropriate treatment ⁹. Septic arthritis, the most common etiology, develops as a result of haematogenous seeding, direct introduction, or extension from a contiguous focus of infection. Joint infectionis a medical emergency that can lead to significant morbidity and mortality. Mainstay of treatment comprises appropriate antimicrobial therapy and joint drainage ^10,11. Literature reveals the knee is the most commonly affected joint (55%) followed by shoulder (14%) in the septic joint population^12-13. 

The second most common differential diagnosis is crystal-induced monoarthritis. Gout and pseudogout are the two most common pathologies ¹⁴. They are debilitating illnesses in which recurrent episodes of pain and joint inflammation are caused by the formation of crystals within the joint space and deposition of crystals in soft tissue. Gout is caused by monosodium urate (MSU) crystals, while pseudogout is inflammation caused by calcium pyrophosphate (CPP) crystals, sometimes referred to as calcium pyrophosphate disease (CPPD) ^15,16. Misdiagnosis of crystals arthritis or delay in treatment can gradually lead to degenerative joint disease and disability in addition to renal damage and failure ⁵. The clinical picture of acute crystal-induced arthritis can sometimes be difficult to differentiate from acute septic arthritis. It is manifested by fever, malaise, raised peripheral WBC, CRP and other acute phase reactants. Synovial fluid aspirate can be turbid secondary to an increase in peripheral polymorphonuclear cells. Diagnosis can be challenging and therefore crystal identification on polarized microscopy is considered the gold standard ^{17, 18, 19}. Rest, ice and topical analgesia may be helpful but systemic non-steroidal anti-inflammatory medications are the treatment of choice for acute attacks provided there are no contraindications ²⁰.

In this study, all joints were aspirated and samples were sent for microscopy, culture and sensitivity, and polarized microscopy for crystals in-line with the British Society of Rheumatology and British Orthopaedic Association guidelines ⁸. Aspiration not only helps diagnosis but in addition reduces the pain caused by joint swelling. Twenty six patients were admitted, on clinical and biochemical suspicion of septic arthritis. They presented with acute phase response manifested by malaise, fever and raised inflammatory markers and were treated with antibiotic therapy and non steroidal anti-inflammatory medications while awaiting the results of microbiology and polarized light microscopy. Four of theses patients developed complications secondary to antibiotic therapy including death due to clostridium difficile infection and subsequent toxic megacolon.

Infection was confirmed to be underlying cause in four patients (6%) who showed positive microscopic growth on gram stained films. They underwent arthroscopic washout and continued antibiotic therapy according to the result of culture and sensitivity of their knee aspirate till their symptoms and blood markers were normal. Arthroscopic washout was required for four patients with negative microscopic growth due to persistant symptoms despite antibiotic treatment, as recommended by the British Society of Rheumatology and the British Orthopaedic Association ⁸. Two patients showed calcium pyrophosphate crystals on polarized microscopy and two had no bacterial growth or crystals.

We retrospectively reviewed laboratory results and found that eight patients (13%) were confirmed to have crystal arthritis as crystals (MSU/CPP) were identified in their knee aspirates by means of polarized microscopy. However, only two patients (25%) received this diagnosis whilst in hospital. In both cases, antibiotic therapy was discontinued and they were referred to a rheumatologist for appropriate treatment and follow up. The remaining six patients continued to receive antibiotics and two of them were taken to theatre for arthroscopic lavage on clinical suspicion of infection as symptoms did not improve significantly with medications. 

Our study shows that crystal-induced arthritis can easily be overlooked or misdiagnosed as septic arthritis. This results in patients having unnecessary antibiotic therapy, developing serious complications and undergoing surgical procedures, all of which can be avoided. Moreover, they were not referred to a rheumatologist.

Acute knee effusion is a common presentation to the Orthopaedic department and although we seem to be providing a good service for septic arthritis, patients with crystal arthropathy are still slipping through the net. Clinicians should always remember that crystal arthritis is almost as common as septic arthritis and will eventually lead to joint damage if not managed appropriately. It must be excluded as a cause of hot swollen joints by routine analysis of joint aspirate using polarized light microscopy. If crystal arthritis is proved to be the underlying pathology, patients must be treated accordingly and receive a prompt rheumatology referral for further management.