Diary Dates Public Forums and Continuing Medical Education (CME) Programmes @ TTSH TITLE OF EVENT / COURSE TOPIC
DATE & TIME
CME PROGRAMME GP Symposium: General Medicine
Dept. of General Medicine
14 August 2010 1.30pm - 4.00pm
Research Methodology Workshop
NHG Eye Institute
Tendon Repair Workshop 2010
Dept. of Orthopaedic Surgery
Please contact Ms Debra Lee at 6357-7893 or email: firstname.lastname@example.org
2 CME points will be awarded
21 August 2010 Theatrette, Level 1, 8.00am - 12.30pm TTSH
Please contact Mrs Wasumathe Sukumar at 6357-7687 or email: wasumathe_sukumar@nhg. com.sg
CME points will be awarded
21 August 2010 9.00am - 1.00pm
Animal Lab, Level 1, TTSH
Please contact Ms Norlizah Kassim at 6357-7597 or email:norlizah_khaidura_ email@example.com
2 CME points will be awarded
GP Symposium: Dept. of Endocrinology Diagnosis and Management of Common Thyroid Disorders
21 August 2010 1.15pm - 4.00pm
Theatrette, Level 1, TTSH
Please contact Ms Cynthia Lee at 6357-2373 or email: firstname.lastname@example.org
2 CME points will be awarded
GP Symposium: Diabetes Mellitus
Dept. of Endocrinology
21 August 2010 1.30pm - 4.00pm
Theatrette, Level 1, TTSH
Please contact Ms Cynthia Lee at 6357-2373 or email: email@example.com
GP Forum: Gastroenterology
Dept. of Gastroenterology
4 Sept 2010 1.30pm - 4.00pm
Theatrette, Level 1, TTSH
Please contact Chiang Han Free Fong at 6357-7897 or email: firstname.lastname@example.org
GP Workshop: Eye Examination in Family Practice
Dept. of Opthalmology
18 Sept 2010 1.30pm - 4.00pm
TTSH Eye Centre, Level 1
Please contact Lalitha 6357-7648 or email: email@example.com
TITLE OF EVENT / COURSE TOPIC
DATE & TIME
Theatrette, Level 1, TTSH
2 CME points will be awarded
MICA (P) 031/04/2010
CME points will be awarded
TTSH and NHG staff: 2 CME points will be $10 awarded
PUBLIC FORUM Public Forum (English) Cataract
Dept. of Opthalmology
14 August 2010 1.30pm
Conference Room 1 & 2, Level 1, TTSH
To register, please call 6357-8266 or email: firstname.lastname@example.org
* Pre-registration is required for all Public Forums and CME Programmes. **Please keep a lookout for the latest event updates on our website at www.ttsh.com.sg
Important T TSH contact numbers CENTRAL APPOINTMENT Tel : 6357 7000 Tel : 6357 8000 (for private appointments only) NHG PARTNERS Direct Access Hotline: 9666 6698 ARTIFICIAL LIMB CENTRE • Prosthetic-Orthotic Services Tel : 6259 4026 • Podiatry Services Tel : 6259 2678 HEALTH ENRICHMENT CENTRE • Health Screening & Assessment Tel: 6357 2233 / 35
LASIK CENTRE Tel : 6357 8000 (General Appointments) Tel : 6357 2255 (Laser Hotline)
SMOKING CESSATION SERVICES Tel : 6357 8010
MOBILE DIABETIC PHOTOGRAPHY SERVICE FOR GPs Tel: 9665 1034
THERAPY SERVICES • Physiotherapy Tel : 6357 8307 • DBC neck and back care Tel : 6357 8309 • Occupational Therapy Tel : 6357 8338 • Speech and Language Therapy Tel : 6357 8324 / 27
ONCOLOGY SERVICES THE CANCER INSTITUTE @TAN TOCK SENG HOSPITAL • Medical Oncology Tel : 6357 2390 • Radiation Oncology Tel : 6357 1080
TRAVELLERS’ HEALTH & VACCINATION CENTRE TEL : 6357 2222
AN UPDATE ON ANTIDEPRESSANTS
SHORT NOTES FROM YOUR CLINICAL IMMUNOLOGY LABORATORY, PART 5
10 ATRIAL FIBRILLATION FOR THE NON-CARDIOLOGIST 14 RADIOLOGY QUIZ
REHABILITATION CENTRE Tel : 6450 6181
16 ECG QUIZ 18 DIARY DATES
Tan Tock Seng Hospital 11 Jalan Tan Tock Seng Singapore 308433 Tel: 6256 6011 Fax: 6252 7282 Website: www.ttsh.com.sg HP-CCS-ED JUN-10-6K
F rom The Editor
EDITOR Dr Leong Khai Pang
MEMBERS Dr Jackie Tan Dr Jaideepraj Rao Dr Lee Cheng Chuan Dr Khian Chong Yaw Dr David Foo
Most of us tried very hard to endear ourselves to the interviewers in the high-stake medical school selection exercise. I remember my preadmission interview – I put on my best clothes and made my way to the College of Medicine Building. I did not prepare anything and simply hoped for the best. I encountered a large interviewing team, none of whom I recognised then; the only panelist I now recall was the late Professor Wong Poi Kwong. The questions put to me were neither too tricky nor too difficult because it was a kinder world then. Compared to 20 or 30 years ago, the game has now changed. Candidates are coached on interview techniques and come prepared with a curriculum vitae listing impressive accomplishments. Candidates can find lists of questions they are likely to be asked in the interview on the Internet (for example, the University of Colorado posts a good selection on http://www.colorado.edu/aac/PreMed_interviewquestions.pdf).
Dr Gregory Kaw Dr Nikolle Tan Dr Ernest Kwek Ms Lim Wan Peng
EDITORIAL ASSIST ANT Ms Michelle Lee
DESIGNER Ms Zaonah Yusof
We value your feedback. Please email your questions, comments or suggestions to: email@example.com Please also contact us for notification of change of postal address or for requests of additional copies.
When asked the question, “Why do you want to be a doctor?”, some of us answered, “Because I want to help others.” Interviewers often tease us by demanding why we cannot do the same as social workers, nurses or bus drivers. Actually, the best way to make a positive impact in the lives of a great number of people is to be a good politician. Others mention individuals or events that inspired us. Some talk about the remuneration or respect that the profession commands. I suppose that before we became doctors, we never truly know what the profession required of us. Now that we do, could we have answered the question in a better way? Perhaps we will respond this way – “I want to be in a profession that will challenge me to the limits of my abilities; I want to give all that I have, intellectually and physically; I want a job in which the intangible and spiritual rewards outweigh the material; I want to experience life at its rawest, deepest and most tender levels; I want to possess a set of skills that will find good use in any situation that I am in, be it in a modern hospital or a rural outpost, in peacetime or in conflict; I want to be part of the great tradition in which hard-earned wisdom is passed from generation to generation, to the benefit of all; I want to make an original contribution to medical knowledge if given the chance; I want to find the golden mean between the demands of the profession and of my family.” If any potential student gives this response in the interview, he or she should be commended for having read Medical Digest!
While every endeavour is made to ensure that information herein is accurate at the time of publication, Tan Tock Seng Hospital shall not be held liable for any inaccuracies. The opinions expressed in this publication do not necessarily reflect those of Tan Tock Seng Hospital. The contents of this publication may not be reproduced
permission from the publisher.
Dr Leong Khai Pang EDITOR Medical Digest
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An Update on
Antidepressants According to the World Health Organization (WHO), it is estimated that 5 to 10 per cent of the population at any given time is suffering from depression needing psychiatric or psychosocial intervention, but only 30 per cent of these received appropriate care.1 With advances in pharmacotherapy and a better knowledge of the biochemical basis of depression, many medications have been developed for the treatment of depression and prevention of relapses. The treatment of depression in patients with appropriate agents, at an appropriate dose over an appropriate length of time, together with non-pharmacologic therapies, has been shown to be cost-effective.2 This article covers the pharmacotherapy of depression in adults.
and irreversible inhibitors of both monoamine oxidase A (MAO-A) and B (MAO-B) enzymes. By inhibiting both MAO-A and MAO-B, they inhibit the first-pass metabolism of exogeneous tyramine, resulting in an accumulation of tyramine which may cause hypertensive crisis.4 Patients taking MAOIs should be counselled about their potential drug-drug and drugfood interactions. Patients taking MAOIs may experience hypertensive crisis if they consume tyramine-rich foods, such as aged cheese, soy products or yeast extracts (such as Marmite). They are also often associated with side effects such as orthostatic hypotension, headache, insomnia, weight gain, sexual dysfunction, edema, drowsiness and sedation.5
The mechanism of action of antidepressants involves inhibiting the reuptake of monoamines (such as serotonin, noradrenaline, and dopamine), blocking monoamine receptors, or inhibiting the monoamine oxidase enzyme.3 Older classes of antidepressants include monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs). Medications in these two classes generally affect a wide range of neurotransmitter
systems and cause many undesirable side effects. Newer antidepressants include the selective serotonin reuptake inhibitors (SSRIs), serotonin and noradrenaline reuptake inhibitors (SNRI), mirtazapine, and bupropion. These antidepressants usually target single or dual neurotransmitters. MONOAMINE OXIDASE INHIBITORS Traditional monoamine oxidase inhibitors (MAOIs) are non-selective
Newer MAOIs, such as moclobemide, is a reversible inhibitor of monoamine oxidase A, an enzyme that acts selectively on noradrenaline and serotonin. Unlike irreversible MAOIs, moclobemide is less likely to cause hypertensive crisis with tyramine-rich food but caution should still be exercised when titrating doses upwards.6 Common side effects of moclobemide include dizziness, insomnia and nausea. No dosage adjustment is required in renal impairment but dosages should be reduced to half to a third in liver impairment. Use of moclobemide with other medications that can increase serotonin levels can lead to the
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serotonin syndrome, which is potentially life-threatening. TRICYCLIC ANTIDEPRESSANTS Tricyclic antidepressants (TCAs) are another class of antidepressants that were developed at the same time as MAOIs. TCAs inhibit noradrenaline, serotonin, dopamine reuptake and has inhibitory effects on the histamine, muscarinic, and alpha-1 receptors.5 TCAs have also been used for other indications such as migraine prophylaxis and neuropathic pain. Bothersome side effects such as dry mouth, constipation, sedation can limit dose increases and affect patient compliance. TCAs should be used with caution in patients with urinary retention, benign prostatic hypertrophy, narrow angle glaucoma, xerostomia, visual disturbances, constipation or history of bowel obstruction as they may cause blurred vision, orthostatic hypotension, urinary retention, dry mouth and constipation. In addition to all the above mentioned anticholinergic side effects that may be particularly harmful in older adults, TCAs can also cause confusion and memory impairment and hence should be avoided in elderly patients whenever possible. TCAs can cause severe cardiovascular side effects such as tachycardia and ventricular arrhythmias. Hence it should be used with caution in patients with a history of cardiovascular disease including previous myocardial infarction, tachycardia, or conduction abnormalities and close monitoring is necessary when increasing doses. Overdose of TCAs can lead to complete heart block, life-threatening broadening of QRS interval or hypotension. SELECTIVE SEROTONIN REUPTAKE INHIBITORS Selective serotonin reuptake inhibitors (SSRIs) are one of the current first-line treatment options for depression. They exhibit better safety profile and tolerability than the older agents such as TCAs and MAOIs. SSRIs inhibit neuronal uptake pump for serotonin, down-regulate serotonin receptors and increases serotonin availability and duration of action. They have low
affinity for muscarinic, alphaadrenergic and histamine receptors and are less likely to cause anticholinergic and cardiovascular adverse effects than TCAs. Gastrointestinal discomfort such as nausea and diarrhea, and headaches are the most common side effects. Taking SSRIs after food can help to minimise nausea. Diarrhea and headaches are usually transient and may resolve after the first week of use. SSRIs may cause insomnia and are usually taken in the morning but the dose can be switched to bedtime if the patient experiences somnolence after taking the medication. SSRIs may cause sexual dysfunction such as delayed orgasm or anorgasmia. Patients who experience this side effect may not develop tolerance to this side effect and may require a switch to another class of antidepressant (such as mirtazapine or bupropion) if they are bothered by it or if it affects their adherence to treatment. Other side effects include vivid dreams, weight gain, increased risk of bleeding, and syndrome of inappropriate secretion of antidiuretic hormone (SIADH). All SSRIs have similar efficacy and side-effect profiles but they are structurally different. Hence allergy, response to, or lack of response to one SSRI does not predict a similar reaction to another. All SSRIs are metabolised in the liver. Fluvoxamine, paroxetine and citalopram are metabolised to inactive metabolised while sertaline and escitalopram are metabolised to pharmacologically less active metabolites. Fluoxetine, on the other hand, is metabolised to an active compound, norfluoxetine, which a long elimination half life. After a single dose, the half lives of fluoxetine and norfluoxetine are 1.9 and 7 days respectively. With chronic administration, the half lives increases to 5.7 days and 19.3 days respectively. These long half lives do not affect the time expected to reach a therapeutic response, and could even be of benefit in non-compliant patients. However, this slow elimination can prove problematic in the event of adverse effects or drug interactions. For
example, when switching from an SSRI to a MAOI, a 5-week washout period is required for fluoxetine compared to a 2-week washout period for the other SSRIs. Fluoxetine is a potent inhibitor of CYP2D6, hence drugs metabolised by CYP 2D6 (such as beta-blockers, TCA, antipsychotics, codeine, tramadol and dextromethorphan) should be used with caution when given together with fluoxetine. Fluvoxamine is a strong inhibitor of CYP 1A2, 3A4 and 2C19 and are more likely than other SSRIs to interact with other medications. Citalopram and escitalopram, on the other hand, has less CYP interactions than other SSRIs. Sertraline is the most likely to cause nausea among the class of SSRIs. It is also the most frequently cited reason for discontinuation. Paroxetine can be slightly more sedating and has more anticholinergic activity than the rest of the SSRIs. The controlled release (CR) formulation tablets is designed to delay the release of drugs till after it leaves the stomach and hence may cause less nausea than the immediate release tablets. About 80 percent of the paroxetine content of the tablets is released, while the remaining 20 percent is retained within each tablet and the individual dose of paroxetine CR needs to be about 25 percent higher than that of the immediate-release formulation to achieve equivalent dosing. SELECTIVE SEROTONIN AND NORADRENALINE REUPTAKE INHIBITORS Selective serotonin and noradrenaline reuptake inhibitors (SNRIs) were developed based on the hypothesis that antidepressants that act to increase both serotonin and noradrenaline signaling would provide more effective management of both physical and emotional symptoms of depression than the SSRIs.7 However, current evidence has not shown much significant difference in efficacy between the different classes of antidepressants.8 SNRIs venlafaxine and duloxetine act on both serotonin and noradrenaline but do not affect histamine or cholinergic receptors. Venlafaxine inhibits serotonin reuptake at lower doses (150mg daily or less).
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Hence its side effects are similar to that of SSRIs which include nausea and diarrhea. At higher doses, its effects on noradrenaline are greater and may cause increased blood pressure. This increase in blood pressure may be clinically significant in patients with uncontrolled hypertension and the patientâ€™s blood pressure should be monitored closely. Duloxetine does not appear to have a dose-related effect on the neurotransmitters like venlafaxine. It inhibits both serotonin and noradrenaline reuptake across all dosage range. Common side effects include nausea, constipation, dry mouth, insomnia, and dizziness. Duloxetine also increases the risk of elevation of serum transaminase levels.9 There have been reports of cases of hepatitis with abdominal pain, hepatomegaly and elevation of transamine levels to more than 20 times the upper limit of normal with or without jaundice. Duloxetine should not be used in patients with a history of liver impairment or substantial alcohol use. Patients taking duloxetine should also be counselled to monitor and report for any signs and symptoms of liver dysfunction such as jaundice, dark urine, pruritus or unexplained flu-like symptoms. Both venlafaxine and duloxetine can also be used in the treatment of neuropathic pain. NEWER AGENTS Mirtazapine is a noradrenergic and specific serotonergic antidepressant (NaSSA). It increases noradrenergic and serotonergic activity through blockade of the respective receptors but does not inhibit the reuptake of serotonin or noradrenaline, nor does it inhibit monoamine oxidase activity. The specific blockade of 5-HT2 and 5HT3 receptors is postulated to reduce the likelihood of some serotonergic side effects such as restlessness, nausea and sexual dysfunction.10 It also has substantial antihistaminergic effect which causes sedation, increased appetite and weight gain. Interestingly, higher doses of mirtazapine (greater than 30mg per day) cause less sedation than lower doses due to the greater noradrenergic
If the patient responded to an antidepressant previously, the same antidepressant can be used again. If there was a lack of response with that antidepressant, another agent from the same class or from another class can be tried. If the patient has never been on an antidepressant before but an immediate family member has been effectively treated with a particular antidepressant, that agent can be tried in the patient.
effect. Mirtazapine is available as a normal tablet formulation or an orally disintegrating tablet (Remeron SolTabÂŽ). The SolTab formulation is designed to increase compliance in patients who have difficulty swallowing conventional capsules or tablets. It disintegrates in the mouth within seconds after administration, and it can be subsequently swallowed with or without water. The exact mechanism of action of bupropion is unknown but it may be related to inhibition of presynaptic dopamine and noradrenaline reuptake transporters. It does not affect the histamine, cholinergic receptors or alpa-adrenergic receptors. This increases its tolerability as it does not have many of the side effects that other antidepressants have. It should, however, be used with caution in
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patients predisposed to seizures such as those individuals with a history of epilepsy, bulimia, or had recent heavy alcohol intake. The risk of seizures is estimated to be 0.1% for daily doses less than 300mg but increases to 0.4% for doses up to 450mg daily. Other side effects of bupropion include constipation, nausea, insomnia, loss of appetite and agitation. Nausea appears to be slightly less of a problem for bupropion than for SSRIs and the incidence of sexual dysfunction is probably the least of any antidepressants.11 Bupropion has also been shown to be effective in the smoking cessation.12 Agomelatine (ValdoxanÂŽ) is the newest antidepressant to be registered in Singapore. It has a unique mechanism of action in that it is agonistic for melatonin MT1 and MT2 receptors but blocks serotonin receptors.13,14 It does not have an effect on monoamine uptake and does not have affinity for adrenergic, histamine, cholinergic, dopamine and benzodiazepines receptors. Agomelatine has been shown to be non-inferior to sertraline and venlafaxine and it does not have the common side effects (such as weight gain and sexual dysfunction) of other antidepressants.15,16 Significant side effects associated with agomelatine include dizziness, paraesthesia, blurred vision, insomnia and elevations in liver transaminases. The exact place in therapy for agomelatine is currently unclear but it may be beneficial for patients who have an intolerance for other antidepressants or have marked sleep disturbances, or both. It is contraindicated in patients with any liver impairment and liver function tests should be monitored before starting therapy, at 6-, 12-, and 24-week intervals. It should not be used in patients younger than 18 years old or above 65 years old as efficacy has not been shown in these groups of patients.13 HOW TO PRESCRIBE ANTIDEPRESSANTS All currently available antidepressants have comparable efficacy. When treatment with antidepressants is
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indicated, clinicians should make their initial selection based on individual patient characteristics, expected side effects, patient preference, and cost. Individual patient characteristics include prior response to antidepressant treatment, concurrent medication use and co-morbidities. If the patient responded to an antidepressant previously, the same antidepressant can be used again. If there was a lack of response with that antidepressant, another agent from the same class or from another class can be tried. If the patient has never been on an antidepressant before but an immediate family member has been effectively treated with a particular antidepressant, that agent can be tried in the patient. While making the selection, the patient’s signs and symptoms and other concurrent medical issues should also be considered. For example, in a patient who is complaining of loss of appetite and weight loss, a trial of mirtazapine may be considered. Antidepressants that cause sedation may be used for treating insomnia and depression in a patient who has difficulty sleeping. Bupropion is contraindicated in an individual with seizures and agomelatine is contraindicated patients with liver
impairment. Venlafaxine should be used with caution in patients with uncontrolled hypertension and TCAs should be used with caution in patients with a history of heart disease. Concurrent drug use or drug-drug interactions should be considered before starting an antidepressant. Serotonin syndrome is a rare but potentially fatal condition when two or more medications that increase serotonin levels in the body are used concurrently. Symptoms may include anxiety, shivering, diaphoresis, tremor, and increased or decreased blood pressure and pulse. This syndrome may occur when TCAs, MAOIs, SSRIs, SNRIs are used together or with other medications such as pethidine, dextromethorphan, linezolid, and tramadol.
improvements in physical symptoms such as poor sleep, appetite, lack of energy within the first one to two weeks of treatment. Cognitive symptoms such as guilt, poor concentration, hopelessness, sadness, and decreased libido may take three to four weeks or more to show improvement. Full benefits of antidepressants may not be noticeable till four to six weeks after initiating treatment. All antidepressants start at low dosage and gradually increase every one to two weeks as required. Starting at a low dose is important because side effects will occur first before the beneficial effects and may affect patient’s compliance to treatment.
Convenience of dosing, costs and patient’s preference should also be taken into account when selecting antidepressants. The prescription of generic forms of the older antidepressants and SSRIs may substantially reduce costs for the patient. It is also important to inform patients that the benefits of antidepressants may not be evident immediately. Patient may begin to notice
Ms Tan Keng Teng is a pharmacist in the Pharmacy Department, Tan Tock Seng Hospital
References 1. World Health Organization. Mental Health and Substance Abuse- Facts and Figures. Available from: http://www.searo.who.int/en/section1174/section1199/section1567_6741.htm Accessed 4 May 2010. 2. Davidson JRT, Meltzer-Brody SE The underrecognition and undertreatment of depression: What is the breadth and depth of the problem? J Clin Psychiatry 1999; 60 Suppl 7:4-9; discussion 10-1. 3. Papakostas GI. Initial treatment approaches for patients with major depressive disorder. J Clin Psychiatry 2009; 70:e18. 4. Yamada M, Yasuhara H. Clinical pharmacology of MAO inhibitors: safety and future. Neurotoxicology 2004; 25:215-21. 5. Martinez M, Marangell LB, Martinez JM. Chapter 26: Psychopharmacology, Textbook of Clinical Psychiatry, 5th edition. Edited by Hales RE, Yudofsky SC, Gabbard GO. American Psychiatric Publishing, Inc. Arlington, VA, 2008. 6. Bonnet U. Moclobemide: Therapeutic use and clinical studies. CNS Drug Rev 2003; 9: 87-140. 7. Frampton JE, Plosker GL. Duloxetine: A review of its use in the treatment of major depressive disorder. CNS Drug 2007; 21:581-609. 8. Hansen RA, Gartlehner G, Lohr KN, et al. Efficacy and safety of second-generation antidepressants in the treatment of major depressive disorder. Ann Intern Med 2005; 143:415-26. 9. Cymbalta PIL Available online from Health Science Authority Website: http://eservice.hsa.gov.sg/prism/common/enquirepublic/SearchDRBProduct.do?action=getProductDetails. Accessed 18 May 2010. 10. Croom KF, Perry CM, and Plosker GL. Mirtazapine: A review of its use in major depression and other psychiatric disorders. CNS Drugs. 2009; 23(5): 427-452. 11. Foley KF, DeSanty KP, Kast RE. Bupropion: pharmacology and therapeutic applications. Expert Rev Neurother 2006; 6:1249-65. 12. Tønnesen P, Tonstad S, Hjalmarson A, Lebargy F, Van Spiegel PI, Hider A, Sweet R, Townsend J. A multicentre, randomized, double-blind, placebocontrolled, 1-year study of bupropion SR for smoking cessation. J Intern Med 2003; 254:184-92. 13. Valdoxan PIL. Available online from Health Science Authority Website: http://eservice.hsa.gov.sg/prism/common/enquirepublic/SearchDRBProduct.do?action=getProductDetails. Accessed 18 May 2010. 14. McAllister-Williams RH, Baldwin DS, Haddad PM, Bazire S. The use of antidepressants in clinical practice: focus on agomelatine. Hum Psychopharmacol 2010; 25:95-102. 15. Kasper S. Effect of agomelatine on rest-activity cycle in patients with major depressive disorder compared to sertraline. International Journal of Neuropsychopharmacology 2008; 11 (Supplement 1): 193. 16. Lemoine P, Guilleminault C, Alvarez E. Improvement in subjective sleep in major depressive disorder with a novel antidepressant, agomelatine: randomized, double-blind comparison with venlafaxine. J Clin Psychiatry 2007; 68:1723-1732.
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Short Notes from your
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Clinical Immunology Laboratory, Part 5 These short articles are culled from the email-circulated messages sent to our colleagues in TTSH between 2007 and 2009. They reflect the issues faced by the users and the laboratory, and serve as a dialogue between the two.
HOW MANY BLOOD TUBES SHOULD I SEND TO THE LABORATORY? The right answer is: send enough blood in the appropriate tubes. As you know, most tests require specimens sent either in the yellow top (containing coagulation-promoting gel) or purple top tubes (containing EDTA to stop clotting). As a general rule, each category of test calls for a separate tube (even if the type of tube required is the same) because each is performed in a separate part of the laboratory. For example, you are managing a patient with systemic vasculitis and you suspected that a hepatitis virus is involved. You ordered serum creatinine, AST, ALT, HBsAg, anti-HCV and ANCA. How many tubes do you need to send? Well, you actually need three yellow-top tubes because serum creatinine, AST and ALT go to Biochemistry, HBsAg and anti-HCV go to Microbiology and ANCA go to Clinical Immunology. It is unwise to send insufficient blood because this will cause: a) Frustration of the laboratory staff because they cannot do their job and they have to inform the requesting doctor that the test cannot be performed, and then cancel the charge for the test; b) Blood to be drawn from the patient again. Sometimes, this is impossible because the patient has left the country. At the least, it causes some inconvenience; and c) Delay in the processing of important investigations. On the other hand, we cannot condone
the collection of excessive tubes of blood ‘just in case’. This is unfair to the patient and wastes medical equipment. Moreover, red cells will lyse when stored in these conditions, making the specimen unsuitable for testing. In practice, the tubes are usually discarded anyway. Only two mammals suck blood from other mammals: vampires and humans. And vampires only take what’s needed. TELL ME SOMETHING ABOUT THE ANTI-SCL-70 ANTIBODY. The anti-Scl-70 antibody is one that directed against the extractable nuclear antigens (ENA), just like the anti-double stranded antibody, antiRo, anti-La and anti-Sm. It is classically a test for scleroderma. It is one of the more recently-described autoantibodies that has found its way into the service laboratory. It was discovered about 30 years ago. The authors specifically set out to find an autoantibody in the serum of scleroderma patients.1 The modern reader senses that the researchers were working on the assumption that there ought to be a specific autoantibody in any given connective tissue disease, such as the associations of mixed connective tissue disease with anti-RNP and SLE with anti-ds DNA. We now know differently: to a certain degree, any autoantibody can be found in any autoimmune rheumatologic condition. To return to that paper, the authors used sera from five scleroderma patients (whose initials were GC, MC, JH, AT and LJ) that were known to contain nuclear-reactive antibody. They precipitated a protein from the
purified and concentrated extract of rat liver nuclei. Finally a protein of 70 kilodaltons was identified as the target of the antibody, hence the name antiScl-70. In the original paper, Ouchterlony diffusion was used to demonstrate the presence of the antibody. Scl-70 was identified to be topoisomerase I in 1986. Modern ELISA methods use purified or recombinant DNA topoisomerase I as the substrate antiScl-70. The sensitivity of anti-Scl-70 for systemic sclerosis is around 20 percent and the specificity is 100 percent. 2 For patients already diagnosed with systemic sclerosis, the presence of anti-Scl-70 was associated with a greater likelihood for the development of diffuse cutaneous involvement, radiographic pulmonary fibrosis, and abnormalities in pulmonary function tests. There’s a test for the CREST syndrome, a variant of scleroderma. It’s the anti-centromere pattern in the ANA test.3 There is no need to order this test specially. Just ask for the ANA and state that you’re interested in this pattern. The laboratory will report if the pattern is present. The classification criteria for scleroderma do not include any laboratory investigations. A patient is classified to have the disease if he or she has proximal scleroderma, or, two of these three: sclerodactyly, digital pitting/loss of substance and bilateral basilar pulmonary fibrosis. 4
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destructive immune response in the intestines. Transglutaminase has two roles in celiac disease: it deamidates gluten, making it a potent immunostimulatory agent and it also serves as a target autoantigen in the immune response.8 Currently, the tests available in our Laboratory for the serologic diagnosis of this disease are the anti-endomysial (anti-EmA) and anti-gliadin antibodies (both using indirect immunofluorescence). The anti-EmA is directed against transglutaminase. The anti-gliadin antibody is less specific and sensitive for diagnosing celiac disease and is not recommended for adult patients. On the other hand, it has a role in the diagnosis of patients younger than 18 months of age.9 For this reason, the CIL will continue to offer this test. The anti-tissue transglutaminase IgA antibody (anti-tTG) (using ELISA) is now considered the best test for coeliac disease. Current diagnostic algorithms suggest screening patients with anti-EmA or anti-tTG antibodies, and confirming with biopsy. The antiEmA is occasionally present in coeliac patients who do not have the antiTTG. Patient with negative tests but highly suspicious history and clinical signs should still undergo biopsy.
A new antibody associated with scleroderma was announced lately: the anti-platelet-derived growth factor (PDGF) receptor antibody was found in 100% of 46 scleroderma patients.5 Unfortunately, this finding is not repeatable so no useful test is likely to result.6 COELIAC DISEASE AND SEROLOGIC TESTS Coeliac disease is rather uncommon in Singapore. For example, a PubMed search of “celiac disease” and “Singapore” yielded no relevant hits. Coeliac disease is due to a genetic predisposition to react to gluten, specifically in people with HLA DQ2 and DQ8. Clinical features of celiac disease can be grouped into three:
asymptomatic, gastrointestinal (diarrhea, fatigue, borborygmus, abdominal pain, weight loss, abdominal distension and flatulence) and atypical (anaemia, osteoporosis, short stature, infertility and neurologic). Therefore, coeliac disease can be difficult to diagnose.7 The best proof that a patient suffers from this is the demonstration of villous atrophy in the small bowel and unequivocal improvement with a gluten-free diet. Gluten refers to the storage proteins found in wheat, rye and barley. Gliadin refers to the alcohol-soluble component of these proteins. Gliadin is poorly digested and passes intact into the gut epithelium. In coeliacs, these peptides initiate a self-
A point we should note is that IgA deficiency is common in patients with coeliac disease, up to 2 percent. If we feel that a patient has celiac disease but the anti-tTG IgA antibody is negative, we can ask for serum IgA level to confirm IgA deficiency and then the anti-tTG IgG antibody, although it is less specific than the IgA antibody. The anti-tissue transglutaminase IgA antibody is considered to be the most sensitive and specific serologic test for celiac disease. The definitive test is still a small bowel biopsy before and after gluten avoidance. In cases of strong clinical suspicion and negative anti-tissue transglutaminase IgA, look for IgA deficiency and order the anti-tissue
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transglutaminase IgG antibody. Occasionally, the anti-endomysial antibody is present patients who are negative for the anti-tissue transglutaminase antibody. The antigliadin antibody is useful mainly in paediatric patients. REPLACING THE TPPA WITH SYPHILIS IgG IN THE DIAGNOSIS OF SYPHILIS Syphilis is almost always diagnosed serologically, not bacteriologically, because the organism is difficult to isolate and simply cannot be found in the later disease stages. In a previous article, we discussed two laboratory diagnostic strategies for syphilis, each employing a pair of tests. We said that our Laboratory offered the rapid plasma reagin (RPR) and Treponema pallidum particle agglutination (TPPA) for the diagnosis of syphilis. The other strategy is to use RPR and syphilis IgG. TPPA is a treponemal test and RPR is a non-specific one. A positive TPPA tells us that the patient had been exposed to Treponema pallidum resulting in the production of specific antibodies. RPR then lets us know the activity of the infection. High titres suggest that the disease is untreated, while low titres or a negative test suggest treated disease or late untreated disease (this is why the treatment history is important). The other diagnostic strategy using syphilis IgG and RPR yields virtually the same result.10 Since early 2008, CIL has stopped performing TPPA and has been offering the syphilis IgG. Similar to the TPPA, the syphilis IgG is a specific test and will remain positive for years after the initial infection regardless of treatment. How should we now screen for syphilis? Interestingly, either RPR or syphilis IgG may be ordered first, to be followed by the other if the first is positive. The advantages of ordering the RPR first are the cheaper price and shorter turnaround time, but this test can give a false-positive results, leading to physician and patient anxiety! False
positives tend to occur in the aged and people with autoimmune diseases, viral infections and recent immunization. If we ordered the syphilis IgG first, a positive test is almost certainly due to true infection. We still need to order a RPR to demonstrate that the infection is active and is not merely a serological scar. We stress that the patientâ€™s history is very important in interpreting the above. For example, a patient recently treated for syphilis may remain positive to syphilis IgG and RPR. We should not treat again if there is documentation of adequate therapy. The syphilis IgG has replaced the TPPA as a specific test for exposure to syphilis. In addition, it can also replace RPR as a screening test especially if you are concerned about falsepositives. When the syphilis IgG and RPR are both positive and the history is consistent, we have to treat for active syphilis. IMPLICATIONS OF THE REVISED 2006 SAPPORO CRITERIA ON THE LABORATORY TESTING OF THE ANTIPHOSPHOLIPID SYNDROME There has been a revision of the original 1999 classification criteria of the antiphospholipid syndrome.11 Both criteria of 1999 and 2006 divide the features into clinical and laboratory. The new laboratory requirements are: 1. The level of anti-cardiolipin antibodies (ACA), which may be IgG or IgM, considered to be positive has been defined. To be considered positive, it should be above 40 MPL or GPL, or above the 99th percentile value. 2. There must be a relationship between positive ACA or lupus anticoagulant and the clinical event (such as thrombosis and spontaneous abortion). In the new criteria, the positive test must be performed within 5 years of the event. 3. The anti-cardiolipin antibodies have to be persistently positive. Previously, two positive tests 6 weeks apart were needed. Now, the duration is increased to not less than 12 weeks.
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Briefly, in the new 2006 classification criteria for APS, the cutoff levels for ACA have been defined, the interval between the clinical event and positive test cannot be longer than five years, and the two positive tests must be separated by a minimum of 12 weeks. HOW LONG SHOULD I WAIT AFTER AN IgE-MEDIATED ALLERGIC REACTION BEFORE ORDERING A SPECIFIC RAST TEST? The classical teaching is that we wait four to six weeks after a Gell and Coombs type-1 or IgE-mediated hypersensitivity reaction before assaying the specific IgE concentration with a RAST test or an epicutaneous skin test. The reasoning is that the IgE may be consumed during the reaction, so if the test is performed too soon, it may be falsely negative. A recent report challenges this concept. 12 Fifteen patients with anaphylaxis due to suxamethonium were recruited. The serum levels of anti-suxamethonium IgE were studied on the day of reaction, the next day and at varying intervals after that. Sera taken before the event were available for some patients. This is an intriguing study. If this unchanging specific IgE level is found to hold true for more types of drugs, the classical teaching can be trashed. Meanwhile, wait a conservative four to six weeks. Though this single study indicates otherwise, if there are no overriding reasons for not doing so, it is best to wait a month or so before ordering RAST test after an IgE-mediated reaction such as anaphylaxis, angioedema or urticaria. In this way, if the test is negative, we will not have to wonder if it was a false negative. WHAT ARE THE ANTI-RO AND ANTI-LA ANTIBODIES? I VE HEARD THAT THE ANTI-RO ANTIBODY IS ASSOCIATED WITH CONGENITAL HEART BLOCK? These questions give me an opportunity to discuss yet another two autoantibodies of great interest in Rheumatology.
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The heyday of research in the serology of SLE was the 1960’s and 70’s. Many new autoantibodies were discovered and their cellular targets identified. Over time, the list of clinically useful autoantibodies was whittled down and we are left with a handful. Besides the antinuclear antibody (ANA) and antidouble-stranded DNA antibody, we have the quartet of anti-Ro, anti-La, anti-Sm and anti-RNP (we haven’t figured out what to do with anti-Ku and anti-ribosomal P). This is similar to the status of serum proteins, in which dozens have been identified, but we are only interested in a few, such as albumin, α-l-antitrypsin and β2-microglobulin. Anti-Ro is present in about 40 percent of lupus patients and 50 percent of Sjögren’s syndrome patients while the numbers for anti-La are 20 percent and 30 percent respectively. The anti-Ro and anti-La have been ‘discovered’ a few times. This is why anti-Ro is also called the anti-SSA antibody. The name ‘anti-Ro’ was first used in 1969.13 The anti-La antibody is also known as anti-SSB and antiHa. A coup was achieved in 1981 when the molecular targets of anti-Ro and anti-La were identified.15 Similar to Sm and RNP, Ro and La are small nuclear ribonulceoproteins, which are combinations of RNA and protein and are thought to be involved in the production of messenger RNA. Puzzlingly, the same group later reported that the Ro antigen also contains the La antigen sometimes, but the La does not contain the Ro, which explains why anti-Ro and antiLa often go together, why anti-Ro sometimes occur without anti-La but anti-La is rarely found without anti-Ro .16 The anti-Ro antibody has been found to react to a 52- as well as 60-kd protein.17 The kit that we use measures the antibody concentration against the 60kd Ro antigen, the classical one that is identical to SSA. The anti-Ro antibody is associated with
photosensitivity, thrombocytopaenia, lymphocytopaenia, interstitial pneumonitis and nephritis in lupus. It had been suggested that anti-La protects against nephritis in lupus patients. Since the 1980’s, it was found that many cases of congenital heart block in the infant was related to the presence of anti-Ro antibody in the mother. An excellent prospective study of 100 pregnant women (53 with SLE, 19 with undifferentiated connective tissue disease, 25 with Sjögren’s syndrome, one with systemic sclerosis, one with mixed connective tissue disease and one with antiphospholipid syndrome) who are anti-Ro positive showed that the risk of having a child with heart block was two percent.18 Thus, anti-Ro and anti-La target members of the ribonucleoprotein family of unclear function. They may denote different disease manifestation in lupus patients. A pregnant woman with the anti-Ro antibody, regardless of her type (or maybe even absence) of autoimmune disease, carries a two percent risk of producing an infant with congenital heart block. THE AMERICAN COLLEGE OF RHEUMATOLOGY ISSUES A POSITION STATEMENT ON THE METHODOLOGY OF ANTINUCLEAR ANTIBODY TESTING Through the years, we have stuck to immunofluorescence (IF) as the method of choice for detecting antinuclear antibody (ANA) because of a conviction that it remains the best even though other more convenient techniques have been developed, In the position statement of February 2009, the American College of Rheumatology states “The immunofluorescence antinuclear antibody (ANA) assay is the gold standard for ANA testing with greater sensitivity than solid phase assays”. It is available from http://www.rheumatology.org/publica tions/position/ana_position_stmt.asp. The human laryngeal cancer cell line (HEp2 cells) provides large nuclei that are ideal for IF. The fluorescence must be read by the human eye. In the past
few years, other enzyme immunoassay methods and a multiplex beads assay have been developed. 19,20 Many laboratories, including some in this country, have adopted them because they can be automated are consequently easier to perform. The reason for issuing the statement was not stated in the website, but an article intimated that there were a number of SLE patients who were ANApositive by IF but negative by other methods.21 This article cited a study that showed that IF is more sensitive than beads in detecting ANA in headto-head comparison. 22 Apparently, HEp2 nuclei contain 100 to 150 autoantigens that cannot be totally covered by the other tests. In 2005, the laboratory in Cedars–Sinai Medical Center in Los Angeles changed the test method for ANA. So many cases of SLE were missed such that all 32 rheumatologists petitioned the laboratory to revert to IF.23 The Clinical Immunology Laboratory will continue to offer the time-proven indirect immunofluorescence on HEp2 cells as the method for detecting ANA. This will not change in the foreseeable future. DOES THE PRECISE LEVEL OF SPECIFIC IGE ANTIBODY MATTER? As you know, we use the enzyme method (fluorescent enzyme immunoassay or FEIA) to detect IgE antibodies, with reagents and equipment (ImmunoCap) manufactured by Phadia (previously Pharmacia Diagnostics). Though we report the precise concentration of the IgE, we also provide the result in terms of the classes (class 0 to class 6). This semi-quantitative reporting is a relic from the past because exact concentrations could not be determined with early versions of the RAST test. This is not surprising because the old detection method consisted of measuring radiation with a Geiger counter! Here, we shall discuss whether a qualitative result is sufficient, or the quantitative finding adds value to the diagnosis. Specific IgE antibodies are useful in the management of diseases
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known to be mediated by such antibodies, such as allergic rhinitis, insect venom allergy and food allergy. This question has been addressed in food allergy, though a definitive conclusion has not been reached. It was first reported more than 10 years ago that, in children below 18 years with atopic dermatitis who are investigated for food allergy, when the specific IgE exceeds a certain threshold, the food challenge is likely to be positive.24 It is not clear if they had other symptoms of food allergy, or were investigated because they were atopic. Anyway, the results of food challenge were recorded and the sera stored. The reactions were not only exacerbation of the dermatitis, but could be any allergic reaction consistent with food allergy such as hives or wheezing. Later, when the ImmunoCap (or UniCap) system became available, the sera were analysed (which is why this study is considered retrospective). For egg, milk, peanut, and fish allergy, the
threshold levels were 6 kilounits of allergen-specific IgE per liter (kUA/L), 32 kUA/L, 15 kUA/L and 20 kUA/L respectively. The sensitivity and specificity of IgE concentration for soy and wheat allergy were poor.
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examination and other tests). The doctor must decide if further tests, especially a food challenge, must follow. There is no shortcut: as for any other form of investigation, the specific IgE must be interpreted with full knowledge of the clinical context.
As a follow-up, a prospective study was conducted by the same group of researchers. This study was plagued by a new problem: parents of children who experienced possible reactions to foods and had positive IgEs often refused the food challenge, resulting in the loss of the gold standard.25 This relationship between specific IgE and positive response to food challenge has not been demonstrated in different disease groups (that is, besides children with atopic dermatisis) and the methodology to establish these thresholds has been questioned.26 We take the conservative stand and suggest that the IgE levels be read with a detailed understanding of the patient’s history (and not replace history, clinical
Dr Leong Khai Pang is a senior consultant in the Department of Rheumatology, Allergy and Immunology, Tan Tock Seng Hospital.
References 1. Douvas AS, Achten M, Tan EM. Identification of a nuclear protein (Scl-70) as a unique target of human antinuclear antibodies in scleroderma. J Biol Chem 1979; 20: 1051410522. 2. Reveille JD, Solomon DH; American College of Rheumatology Ad Hoc Committee of Immunologic Testing Guidelines. Evidence-based guidelines for the use of immunologic tests: anticentromere, Scl-70, and nucleolar antibodies. Arthritis Care Res 2003; 49:399-402. 3. Fritzler MJ, Kinsella TD. The CREST syndrome: a distinct serologic entity with anticentromere antibodies. Am J Med 1980; 69:520-6. 4. No authors listed. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum 1980; 23:581-90. 5. Baroni SS, Santillo M, Bevilacqua F, Luchetti M, Spadoni T, Mancini M, Fraticelli P, Sambo P, Funaro A, Kazlauskas A, Avvedimento EV, Gabrielli A. Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis. N Engl J Med 2006; 354:2667-76. 6. Dragun D, Distler JH, Riemekasten G, Distler O. Stimulatory autoantibodies to platelet-derived growth factor receptors in systemic sclerosis: what functional autoimmunity could learn from receptor biology. Arthritis Rheum 2009; 60:907-11. 7. Green PHR, Cellier C. Celiac disease. New Engl J Med 2007; 357:1731-43. 8. Dieterich W, et al. Identification of tissue transglutaminase as the autoantigen of celiac disease. Nat Med 1997; 3:797-801. 9. Sugai E, et al. Accuracy of testing for antibodies to synthetic gliadin-related peptides in celiac disease. Clin Gastroenterol Hepatol 2006; 4:1112-7. 10. Reisner BS, et al. Use of the Treponema pallidum-specific Captia syphilis IgG assay in conjunction with the rapid plasma reagin to test for syphilis. J Clin Microbiol 1997; 35:1141-3. 11. Miyakis S, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4:295–306. 12. Guttormsen AB, et al. No consumption of IgE antibody in serum during allergic drug anaphylaxis. Allergy 2007; 62:1326-30. 13. Feltkamp TEW, et al. The first international standard for antibodies to double stranded DNA. Ann Rheum Dis 1988; 47:740-6. 14. Clark G, et al. Characterization of a soluble cytoplasmic antigen reactive with sera from patients with systemic lupus erythmatosus. J Immunol 1969; 102:117-22. 15. Lerner MR, et al. Two novel classes of small ribonucleoproteins detected by antibodies associated with lupus erythematosus. Science 1981; 211:400-2. 16. Hendrick JP, et al. Ro small cytoplasmic ribonucleoproteins are a subclass of La ribonucleoproteins: further characterization of the Ro and La small ribonucleoproteins from uninfected mammalian cells. Mol Cell Biol 1981; 1:1138-49. 17. Scofield RH, et al. Fine specificity of the autoimmune response to the Ro/SSA and La/SSB ribonucleoproteins. Arthritis Rheum 1999; 42:199-209. 18. Brucato A, et al. Risk of congenital complete heart block in newborns of mothers with anti-Ro/SSA antibodies detected by counterimmunoelectrophoresis. Arthritis Rheum 2001; 44:1832-5. 19. Shovman O, et al. Multiplexed AtheNA multi-lyte immunoassay for ANA screening in autoimmune diseases. Autoimmunity 2005;38: 105–109. 20. Ló'97pez-Hoyos M, et al. Performance of antinuclear antibody connective tissue disease screen. Ann NY Acad Sci 2007; 1109:322–9. 21. Satoh M, et al. Clinical interpretation of antinuclear antibody tests in systemic rheumatic diseases. Mod Rheumatol. 2009 Mar 10. [Epub ahead of print]. 22. Bonilla E, et al. Immunofluorescence microscopy is superior to fluorescent beads for detection of antinuclear antibody reactivity in systemic lupus erythematosus patients. Clin Immunol 2007; 124:18-21. 23. Wallace DJ. New methods for antinuclear antibody testing: does it cut costs and corners without jeopardizing clinical reliability? Nat Clin Pract Rheumatol 2006; 2:4101. 24. Sampson HA, Ho DG. Relationship between food-specific IgE concentrations and the risk of positive food challenges in children and adolescents. J Allergy Clin Immunol 1997; 100:444-51. 25. Sampson HA. Utility of food-specific IgE concentrations in predicting symptomatic food allergy. J Allergy Clin Immunol 2001;107:891-6. 26. Sopo SM, Radzik D, Calvani M. The predictive value of specific immunoglobulin E levels for the first diagnosis of cow’s milk allergy. A critical analysis of pediatric literature. Pediatr Allergy Immunol 2007; 18:575–82.
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Atrial Fibrillation for the
non-Cardiologist INTRODUCTION Atrial fibrillation (AF) is the most common arrhythmia in clinical practice, found in about 1% of the population, with increasingly higher prevalence in older people. In the past decade, there had been more than 1000 publications in the literature exploring this unique and fascinating arrhythmia, clarifying certain management issues. However, the genetic basis and mechanisms remain poorly understood. The immense burden of the problem in the ageing global population, coupled with new developments in therapy, makes this arrhythmia both fascinating and challenging to treat. EPIDEMIOLOGY The incidence and prevalence of AF are increasing in developed and developing countries.1 Most population-based studies had been conducted in either United States or Western Europe.2-4 They identify a common trend: that with the ageing populations and attendant rise in cardiovascular risk factors, particularly hypertension, the prevalence of AF will increase many fold. According to the Framingham Heart Study, the lifetime risk of AF in adults aged 40 was 26 percent for men and 23 percent for women.5 In addition, the risk of stroke also mirrors the increase in age and prevalence of AF of the population.6 Therefore, it is predicted that the
economic burden of this arrhythmia will be substantial as it will account for at least a third of all hospital admissions for arrhythmia-related diagnoses. It is therefore a major cause of hospitalization, morbidity and mortality.7,8 Despite a paucity of data for non-Caucasian populations, including Singapore, it is predicted that the rising disease burden is global. RISK FACTORS AF is associated not only with an older age group and hypertension, but also with heart failure, coronary artery disease and cardiomyopathies. In addition, obesity, diabetes mellitus, hyperlipidaemia, metabolic syndrome
and chronic kidney disease have also been associated with AF.9-11 Meta-analyses of randomized controlled trials have also demonstrated relationship of AF to serious events in different vascular territories12 in addition to the two-fold increase in mortality13 and nearly five-fold increase in strokes.6 CLASSIFICATION For consistency and simplicity, AF is classified into 3 categories: a) Paroxysmal AF refers to episodes that terminate spontaneously and usually last less than 7 days; b) Persistent AF refers to episodes lasting more than 7 days, which
Figure. A typical ECG showing atrial fibrillation. Note the irregularly spaced QRS complexes and absent P waves.
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may require either pharmacological or direct current cardioversion; and c) Permanent AF implies failure of cardioversion or cardioversion not attempted.14 Non-valvular AF implies that the arrhythmia is not associated with rheumatic mitral valve disease, prosthetic valve or mitral valve repair. Lone AF applies to AF in the younger age group with no evidence of any cardiopulmonary or systemic disease. MANAGEMENT The objectives of AF management are rate control, maintenance of sinus rhythm and prevention of thromboembolism. The strategies are not mutually exclusive and individualized tailored therapies for patients must be emphasized. The demographics, age, gender, concomitant cardiovascular risk factors and systemic diseases, socio-economic factors and presence of symptoms are key considerations in the decisionmaking process with the patient. The reader can also refer to detailed management guidelines issued by various academic societies.14-16 P R E V E N T I O N O F THROMBOEMBOLISM Thromboembolic phenomena in AF, especially strokes, lead to considerable morbidity and mortality. The prevalence of both stroke and AF is age dependent. The risk of thromboembolism in nonvalvular AF is similar regardless whether AF is paroxysmal, persistent or permanent.17 In addition, strokes from AF are usually more serious than strokes from other causes.18 Risk stratification for thromboembolism in AF is an extremely important aspect in the holistic management of this arrhythmia. The most commonly accepted and widely used risk stratification tool is the CHADS score.19 CHADS is an acronym for: Congestive heart failure, Hypertension, Age greater than 75 years, Diabetes mellitus and history of Stroke or transient ischaemic attack. The presence of each risk factor is scored 1 point except for ‘S’ which is accredited 2 points. Therefore the
maximum CHADS score is 6. The risk of stroke increases with higher CHADS score. The treatment is guided by the individual’s risk profile according to the score. For instance, if the CHADS score is 0, antiplatelet therapy could be recommended. If the CHADS score identifies only one moderate risk factor, either aspirin or anticoagulation is recommended. If the CHADS score involves any high-risk factor (such as previous stroke of transient ischaemic attack) or more than one moderate risk factor, anticoagulation is recommended. NON-PHARMACOLOGICAL STRATEGY FOR STROKE PREVENTION The major source of clinically significant emboli is assumed to originate from the left atrial appendage.32 Mechanical devices to occlude the left atrial appendage had made this strategy a possible alternative for stroke prophylaxis, especially in high risk patients where warfarin may be contraindicated.33 However, the level of technical expertise, various operator learning curves and higher procedural complication rates may not make this strategy an attractive first line option based on risk-benefit ratio. RATE VERSUS RHYTHM The controversy between rate control and rhythm conversion persists up till today. The main question is whether leaving a patient in AF and maintaining adequate ventricular rate control is preferable to the conversion and maintenance of sinus rhythm either via electrical or pharmacological means. The AFFIRM and RACE trials were designed to address this issue.34,35 In the AFFIRM trial, the overall mortality was not significantly different between the rate control and rhythm control groups. Conversely, in the rhythm control group, there were more hospitalizations and deaths compared to the rate control group. There was no difference in the rate of stroke between the 2 groups. Similarly, RACE also demonstrated that rate control was not inferior to rhythm control for prevention of death and morbidity. However, in these and other smaller trials, younger patients, female patients and those with paroxysmal AF were
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not well represented. Therefore, whilst rate control with stroke prophylaxis may be the preferred strategy for the majority, there is a definite role in conversion and maintenance of sinus rhythm in a highly symptomatic population group. These two studies also highlighted the considerable adverse effects of all anti-arrhythmic drugs. Because no anti-arrhythmic drugs are considered ‘safe’, comparative outcome studies have been conducted within the rate control group. Conventional antiarrhythmics that were used in the rateversus-rhythm trials include Class Ic and Class III (amiodarone, sotalol) drugs. The CAST trial demonstrated increase in mortality when certain classes of antiarrhythmics were used in the setting of structural and coronary artery disease.36 The recent publication of ATHENA raised hopes in an amiodarone-equivalent drug, dronedarone. 3 7 Dronedarone is structurally similar to amiodarone but it lacks the iodine moiety, leading to fewer side effects. Dronedarone reduced the hospitalization rate in high-risk patients with AF compared with placebo. However, it is a less effective antiarrhythmic agent than amiodarone and is contraindicated in patients with NYHA Class IV functional status or acute decompensated heart failure. 3 8 Therefore, dronedarone trades safety for efficacy compared to amiodarone. There is a non-pharmacological approach to maintaining sinus rhythm. Radiofrequency ablation of AF has been a hot topic of much interest. A seminal paper published more than a decade ago demonstrated that the foci for AF arise from the pulmonary veins.39 Since then, much research work investigating a permanent cure for AF by radiofrequency ablation and electrical isolation of pulmonary veins has been published. Even in highvolume centres with experienced operators, success rates are higher in paroxysmal compared to persistent or permanent AF. Current guidelines recommend ablation for AF as a second-line therapy in patients who have failed at least one anti-arrhythmic drug.40
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Effective in reducing stroke in AF up to 68%.20
The consequences of sub- or supra-therapeutic INR values had been described.21 Overanticoagulation is associated with intracranial and extracranial haemorrhage, and warfarininduced intracranial bleed causes death in 75%.22
Narrow therapeutic window and has numerous drug and food interactions. Deserving patients even in clinical studies are not prescribed warfarin23-25 or the International Normalised Ratios (INR) is not kept in the therapeutic range of 2 to 3.26,27
Dual antiplatelet agents
ACTIVE A showed 28% relative risk reduction of stroke in the aspirin/clopidogrel combination arm compared to aspirin alone.28 ACTIVE W showed that aspirin/clopidogrel failed to prevent stroke, embolism, myocardial infarction and vascular death as well as warfarin. 29
Risk of bleeding
Warfarin should be preferred to dual antiplatelet agents because the latter carry a substantial risk of bleeding and have been shown to be inferior to warfarin for stroke prophylaxis in AF.
Ximelagatran showed favourable results in the SPORTIF V study.30 RELY showed that the lower dose of dabigatran (110mg bd) led to a similar rate of stroke as warfarin and a significant reduction in the frequency of major bleeding. Higher-dose dabigatran (150mg bd) had significant reduction in stroke but similar risk of major bleeding compared with warfarin.
Ximelagatran was withdrawn due to its toxic effects on the liver.
Dabigatran is potentially a very attarctive alternative to warfarin in stroke prevention in AF in the future.
These new agents are currently being studied and trial results are expected in the near future.
Direct thrombin inhibitors
Direct Factor Xa inhibitors
Table. Comparison of the agents to reduce risk of stroke in atrial fibrillation.
Rate control in AF is usually achieved with beta-blockers, calcium channel blockers and agents acting on the atrioventricular node. There had been no clear indication of an ideal heart rate for permanent AF, in which rate control is usually the preferred strategy. Most authorities recommend heart rate of between 60 to 80 bpm at rest and 90 to 110 bpm during exercise. The recent RACE II suggested that lenient ventricular rate control was equivalent to strict control.41 The lenient strategy (resting heart rate <110 bpm) was non-inferior to the strict approach (resting heart rate <80bpm and heart rate goal during moderate execvise <110 bpm) for a composite primary end point that included cardiovascular death, heart failure hospitalization, stroke and other major events. The rate control strategy should be individualized and most patients are able to achieve lenient rate control. However, a stricter control is strongly advocated if patients are symptomatic, develop heart failure or
have elevated heart rates during exercise. PREVENTING AF Angiotension converting enzyme inhibitors (ACEIs) and angiotension receptor blockers (ARBs) as well as statins and fish oils have been found to prevent AF in several small experimental studies. These agents were postulated to have impact on the electrical heterogeneity of the atria through antiproliferative, anti-fibrotic and antiinflammatory effects. However, recent publications failed to show any benefit with the ARBs.42,43 CONCLUSION AF is the most arrhythmia in the hospital and primary health care settings. The incidence and prevalence of AF will increase exponentially because of the ageing population with the attendant co-morbidities. Recent advances in pharmacological and nonpharmacological treatments have made it possible to reduce morbidity and
mortality of AF. The treatment of AF must be individualized, especially the decision whether to control ventricular rate albeit remaining in AF or to maintain sinus rhythm. The weight of opinion is that rate control is appropriate in most situations except in a few circumstances when maintenance of sinus rhythm is recommended.44
Dr David Foo is a consultant and Acting Head of the Department of Cardiology, Tan Tock Seng Hospital.
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References 1. Kannel WB, Wolf PA, Benjamin EJ, Levy D. Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: population-based estimates. Am J Cardiol 1998; 82:2N-9N. 2. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001; 285:2370-5. 3. Heeringa J, van der Kuip DA, Hofman A, et al. Prevalence, incidence and lifetime risk of atrial fibrillation: the Rotterdam study. Eur Heart J 2006; 27:949-53. 4. Miyasaka Y, Barnes ME, Gersh BJ, et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation 2006; 114:119-25. 5. Lloyd-Jones DM, Wang TJ, Leip EP, et al. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation 2004; 110:1042-6. 6. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991; 22:983-8. 7. Friberg J, Buch P, Scharling H, Gadsbphioll N, Jensen GB. Rising rates of hospital admissions for atrial fibrillation. Epidemiology 2003; 14:666-72. 8. Mitra R, Leatham EW. Admissions with atrial fibrillation: disease patterns and outcomes in a District General Hospital. QJM 2005; 98:153-4. 9. Tsang TS, Miyasaka Y, Barnes ME, Gersh BJ. Epidemiological profile of atrial fibrillation: a contemporary perspective. Prog Cardiovasc Dis 2005; 48:1-8. 10. Iguchi Y, Kimura K, Kobayashi K, et al. Relation of atrial fibrillation to glomerular filtration rate. Am J Cardiol 2008; 102:1056-9. 11. Wanahita N, Messerli FH, Bangalore S, Gami AS, Somers VK, Steinberg JS. Atrial fibrillation and obesity--results of a meta-analysis. Am Heart J 2008;155:310-5. 12. Taylor FC, Cohen H, Ebrahim S. Systematic review of long term anticoagulation or antiplatelet treatment in patients with non-rheumatic atrial fibrillation. BMJ 2001; 322:321-6. 13. Benjamin EJ, Wolf PA, D'Agostino RB, Silbershatz H, Kannel WB, Levy D. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 1998; 98:946-52. 14. Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation--executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation). J Am Coll Cardiol 2006; 48:854-906. 15. National Collaborating Centre for Chronic Conditions. Atrial fibrillation. National clinical guideline for management in primary and secondary care. London: Royal College of Physicians, 2006. Available from http://www.nice.org.uk/nicemedia/live/10982/30055/30055.pdf 16. Snow V, Weiss KB, LeFevre M, McNamara R, Bass E, Green LA, Michl K, Owens DK, Susman J, Allen DI, Mottur-Pilson C; AAFP Panel on Atrial Fibrillation; ACP Panel on Atrial Fibrillation. Management of newly detected atrial fibrillation: a clinical practice guideline from the American Academy of Family Physicians and the American College of Physicians. Ann Intern Med 2003; 139:1009-17. 17. Hart RG, Pearce LA, Rothbart RM, McAnulty JH, Asinger RW, Halperin JL. Stroke with intermittent atrial fibrillation: incidence and predictors during aspirin therapy. Stroke Prevention in Atrial Fibrillation Investigators. J Am Coll Cardiol 2000; 35:183-7. 18. Savelieva I, Bajpai A, Camm AJ. Stroke in atrial fibrillation: update on pathophysiology, new antithrombotic therapies, and evolution of procedures and devices. Ann Med 2007; 39:371-91. 19. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. 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Albers GW, Diener HC, Frison L, et al. Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: a randomized trial. JAMA 2005; 293:6908. 31. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361:1139-51. 32. Manning WJ, Silverman DI, Gordon SP, Krumholz HM, Douglas PS. Cardioversion from atrial fibrillation without prolonged anticoagulation with use of transesophageal echocardiography to exclude the presence of atrial thrombi. N Engl J Med 1993; 328:750-5. 33. Holmes DR, Reddy VY, Turi ZG, et al. Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial. Lancet 2009; 374:534-42. 34. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002;347:1825-33. 35. Van Gelder IC, Hagens VE, Bosker HA, et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 2002; 347:1834-40. 36. Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991; 324:781-8. 37. Hohnloser SH, Crijns HJ, van Eickels M, et al. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med 2009; 360:668-78. 38. Singh D, Cingolani E, Diamond GA, Kaul S. Dronedarone for atrial fibrillation have we expanded the antiarrhythmic armamentarium? J Am Coll Cardiol 2010; 55:156976. 39. Haissaguerre M, Jais P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 1998;339:659-66. 40. Calkins H, Brugada J, Packer DL, et al. 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RADIOLOGY Quiz CASE PRESENTATION An 80-year-old Chinese lady presented with left buttock pain radiating to the left anterior knee and numbness over the left thigh of a few weeksâ€™ duration. The pain was worse on walking, and partially relieved with rest. There was no weakness and she was able to walk with a walking stick. There was no history of trauma, fever, back pain, urinary retention or bowel incontinence. She was suffering from hyperlipidaemia, hypertension, and osteoarthritis of both knees. In the straight leg raising test, the hips flexed to 70-80 degrees bilaterally associated with pain shooting down the left thigh. There was decreased sensation over the left L3 dermatome. Reflexes were intact. Laboratory findings revealled no significant abnormality. X-ray of the lumbar spine showed mild lumbar spondylosis with preservation of the vertebral alignment and disc spaces. Magnetic resonance (MR) imaging of the spine was performed.
Question Question 1: What are the imaging findings? Question 2: What is the diagnosis?
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Answer Answer 1: Fig. 1 - This shows a sagittal T2 weighted image with fat saturation. There is intermediate signal intensity mass in the central canal posterior to L3 vertebra. It is of higher signal intensity than the adjacent L3-4 disc. Fig. 2 - This shows a sagittal T1 weighted image with fat saturation after administration of intravenous gadolinium contrast. The mass now shows thin continuous rim enhancement. Fig. 3 - This shows an axial T2 weighted image with fat saturation at the level of the L3 vertebra. The mass is seen to compress on the left L3 nerve root within the spinal canal. Fig. 4 - This shows an axial T1 weighted image with fat saturation after administration of intravenous gadolinium contrast at the level of the L3 vertebra. The peripheral enhancement of the mass is again demonstrated. Answer 2: L3-4 sequestered disc that has migrated cranially compressing on the left L3 nerve root. CLINICAL COURSE The patient subsequently underwent a decompression laminectomy. At surgery, there was a sequestered L3-4 disc compressing on the left L3 nerve root. This was confirmed on histology. Eighteen months post surgery, the patient is able to walk independently.
Discussion Approximately 90 per cent of lumbar herniated discs occur at the L4-5 or L5-S1 levels. A sequestered disc is a free disc fragment that is no longer in continuity with the parent disc material. A sequestered disc may lie adjacent to the disc of origin, or may migrate cranially or caudally to a different disc space both in the midline and in the lateral recess, or in rare cases, even penetrate the dura. The most common path of disc migration is in the posterolateral direction to the anterior epidural space, which most commonly produces a radiculopathy. Patients usually present with back pain, most often in the lumbar region, with or without the presence of radiculopathy. Complications of a sequestered disc include compression on nerve root(s) causing pain and radiculopathy. The imaging appearances of free fragments tend to look like the parent disc on both computed tomography
(CT) and T1-weighted MR sequence, with low signal. However, in T2weighted MR images the sequestered disc is hyperintense in 80% of the cases and isointense in the remaining 20%.
back pain when prolapsed intervertebral disc, cord compression or vertebral metastases are suspected. It is particularly useful in patients in whom symptoms persist despite an unremarkable X-ray.
The periphery of the sequestered disc enhances after administration of intravenous gadolinium contrast, while the central portion displays low signal intensity. The peripheral contrast enhancement is due to the inflammatory response with granulation tissue and newly-formed vessels around the sequestered disc. Differential diagnoses of a sequestered disc include epidural tumours (eg neurofibroma and meningioma), epidural haematoma and epidural abscess. These are usually distinguishable with a combination of MRI and clinical findings. MRI is now readily available and is the modality of choice for the investigation of low
Dr Daniel Chee is an associate consultant in the Department of Diagnostic Radiology, Tan Tock Seng Hospital
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ECG Quiz Question A 75-year-old man sustained a fracture of the neck of femur in a fall. He developed acute shortness of breath whilst waiting for surgery. A 12-lead ECG was done. What should one suspect based on the ECG?
Answer The ECG shows sinus tachycardia, borderline right axis deviation, incomplete right bundle branch block and S1Q3T3. The ECG findings, coupled with a history of prolonged immobilization and acute shortness of breath, should lead one to suspect pulmonary embolism.
Dr David Foo is a consultant and Acting Head of the Department of Cardiology, Tan Tock Seng Hospital.