TTSH Medical Digest Apr-Jun 2010

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Medicaldigest

* 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

TITLE OF EVENT / ORGANISING DATE & VENUE REGISTRATION FEES INTENDEDCOURSE TOPIC DEPARTMENT TIME PARTICIPANT

PUBLIC FORUMPublic Forum (English) -Cataract

Dept. ofOpthalmology

14 August 20101.30pm

Conference Room 1& 2, Level 1, TTSH

To register, please call6357-8266 or email:[email protected]

$5 NIL

Diary DatesPublic Forums and Continuing Medical Education (CME) Programmes @ TTSH

TITLE OF EVENT / ORGANISING DATE & TIME VENUE REGISTRATION FEES CMECOURSE TOPIC DEPARTMENT POINTS

CME PROGRAMMEGP Symposium:General Medicine

Dept. of GeneralMedicine

14 August 20101.30pm - 4.00pm

Theatrette, Level 1,TTSH

Please contact Ms DebraLee at 6357-7893 or email:[email protected]

Free 2 CME points will beawarded

Research MethodologyWorkshop

NHG Eye Institute 21 August 20108.00am - 12.30pm


Please contact MrsWasumathe Sukumar at6357-7687 or email:[email protected]

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Tendon Repair Workshop2010

Dept. of OrthopaedicSurgery

21 August 20109.00am - 1.00pm

Animal Lab, Level 1,TTSH

Please contact Ms NorlizahKassim at 6357-7597 oremail:[email protected]


GP Symposium:Diagnosis and Managementof Common Thyroid Disorders

Dept. of Endocrinology 21 August 20101.15pm - 4.00pm


Please contact Ms CynthiaLee at 6357-2373 or email:[email protected]


GP Symposium:Diabetes Mellitus

Dept. of Endocrinology 21 August 20101.30pm - 4.00pm


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GP Forum:Gastroenterology

Dept. ofGastroenterology

4 Sept 20101.30pm - 4.00pm


Please contact Chiang HanFong at 6357-7897 or email:[email protected]

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GP Workshop:Eye Examination in FamilyPractice

Dept. of Opthalmology 18 Sept 20101.30pm - 4.00pm

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TTSH and NHG staff:$10

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Apr.May.Jun. 2010

MICA (P) 031/04/2010

contents1 AN UPDATE ON ANTIDEPRESSANTS

5 SHORT NOTES FROM YOUR CLINICAL IMMUNOLOGY LABORATORY, PART 5

10 ATRIAL FIBRILLATION FOR THE NON-CARDIOLOGIST

14 RADIOLOGY QUIZ

16 ECG QUIZ

18 DIARY DATES

From The Editor

Dr Leong Khai PangEDITOR

Medical Digest

Most of us tried very hard to endear ourselves to the interviewers in thehigh-stake medical school selection exercise. I remember my pre-admission interview – I put on my best clothes and made my way to theCollege of Medicine Building. I did not prepare anything and simplyhoped for the best. I encountered a large interviewing team, none ofwhom I recognised then; the only panelist I now recall was the lateProfessor Wong Poi Kwong. The questions put to me were neither tootricky nor too difficult because it was a kinder world then.

Compared to 20 or 30 years ago, the game has now changed. Candidatesare coached on interview techniques and come prepared with a curriculumvitae listing impressive accomplishments. Candidates can find lists ofquestions they are likely to be asked in the interview on the Internet (forexample, the University of Colorado posts a good selection onhttp://www.colorado.edu/aac/PreMed_interviewquestions.pdf).

When asked the question, “Why do you want to be a doctor?”, someof us answered, “Because I want to help others.” Interviewers oftentease us by demanding why we cannot do the same as social workers,nurses or bus drivers. Actually, the best way to make a positive impactin the lives of a great number of people is to be a good politician. Othersmention individuals or events that inspired us. Some talk about theremuneration or respect that the profession commands.

I suppose that before we became doctors, we never truly know whatthe profession required of us. Now that we do, could we have answeredthe question in a better way? Perhaps we will respond this way – “I wantto 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 jobin which the intangible and spiritual rewards outweigh the material; Iwant 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 situationthat I am in, be it in a modern hospital or a rural outpost, in peacetimeor in conflict; I want to be part of the great tradition in which hard-earnedwisdom is passed from generation to generation, to the benefit of all; Iwant to make an original contribution to medical knowledge if given thechance; I want to find the golden mean between the demands of theprofession and of my family.”

If any potential student gives this response in the interview, he or sheshould be commended for having read Medical Digest!

Apr.May.Jun. 2010

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 wi thout wr i t ten

permission from the publisher.

We value your feedback.Please email your questions,

comments or suggestions to:[email protected]

Please also contact us for notification ofchange of postal address or

for requests of additional copies.

EDITORDr Leong Khai Pang

MEMBERSDr Jackie Tan

Dr Jaideepraj Rao

Dr Lee Cheng Chuan

Dr Khian Chong Yaw

Dr David Foo

Dr Gregory Kaw

Dr Nikol le Tan

Dr Ernest Kwek

Ms Lim Wan Peng

EDITORIALASSIST ANT

Ms Michelle Lee

DESIGNERMs Zaonah Yusof

Therapeutics Update

An Update on

Antidepressants

The mechanism of act ion ofantidepressants involves inhibiting thereuptake of monoamines (such asserotonin, noradrenal ine, anddopamine), blocking monoaminereceptors, or inhibiting the monoamineoxidase enzyme.3 Older classes ofantidepressants include monoamineoxidase inhibitors (MAOIs) and tricyclicantidepressants (TCAs). Medicationsin these two classes generally affecta wide range of neurotransmitter

systems and cause many undesirableside effects. Newer antidepressantsinclude the selective serotonin reuptakeinhibitors (SSRIs), serotonin andnoradrenaline reuptake inhibitors(SNRI), mirtazapine, and bupropion.These antidepressants usually targetsingle or dual neurotransmitters.

MONOAMINE OXIDASE INHIBITORSTraditional monoamine oxidaseinhibitors (MAOIs) are non-selective

and irreversible inhibitors of bothmonoamine oxidase A (MAO-A) and B(MAO-B) enzymes. By inhibiting bothMAO-A and MAO-B, they inhibit thefirst-pass metabolism of exogeneoustyramine, resulting in an accumulationof tyramine which may causehypertensive crisis.4 Patients takingMAOIs should be counselled abouttheir potential drug-drug and drug-food interactions. Patients takingMAOIs may experience hypertensivecrisis if they consume tyramine-richfoods, such as aged cheese, soyproducts or yeast extracts (such asMarmite). They are also oftenassociated with side effects such asorthostatic hypotension, headache,insomnia, weight gain, sexualdysfunction, edema, drowsiness andsedation.5

Newer MAOIs, such as moclobemide,is a reversible inhibitor of monoamineoxidase A, an enzyme that actsselectively on noradrenaline andserotonin. Unlike irreversible MAOIs,moclobemide is less likely to causehypertensive crisis with tyramine-richfood but caution should still beexercised when titrating dosesupwards.6 Common side effects ofmoclobemide include dizziness,insomnia and nausea. No dosageadjustment is required in renalimpairment but dosages should bereduced to half to a third in liverimpairment. Use of moclobemide withother medications that can increaseserotonin levels can lead to the

1:M E D I C A L D I G E S T

According to the World Health Organization (WHO), it is estimated that 5 to 10 per cent of the population at anygiven time is suffering from depression needing psychiatric or psychosocial intervention, but only 30 per cent ofthese received appropriate care.1 With advances in pharmacotherapy and a better knowledge of the biochemicalbasis of depression, many medications have been developed for the treatment of depression and prevention ofrelapses. The treatment of depression in patients with appropriate agents, at an appropriate dose over an appropriatelength of time, together with non-pharmacologic therapies, has been shown to be cost-effective.2 This article coversthe pharmacotherapy of depression in adults.

serotonin syndrome, which ispotentially life-threatening.

TRICYCLIC ANTIDEPRESSANTSTricyclic antidepressants (TCAs) areanother class of antidepressants thatwere developed at the same time asMAOIs. TCAs inhibit noradrenaline,serotonin, dopamine reuptake and hasinhibitory effects on the histamine,muscarinic, and alpha-1 receptors.5

TCAs have also been used for otherindicat ions such as migraineprophylaxis and neuropathic pain.Bothersome side effects such as drymouth, constipation, sedation can limitdose increases and affect patientcompliance. TCAs should be used withcaution in patients with urinaryr e t e n t i o n , b e n i g n p r o s t a t i chypertrophy, narrow angle glaucoma,xerostomia, visual disturbances,constipation or history of bowelobstruction as they may cause blurredvision, orthostatic hypotension, urinaryretention, dry mouth and constipation.In addition to all the above mentionedanticholinergic side effects that maybe particularly harmful in older adults,TCAs can also cause confusion andmemory impairment and hence shouldbe avoided in elderly patients wheneverpossible. TCAs can cause severecardiovascular side effects such astachyca rd ia and ven t r i cu la rarrhythmias. Hence it should be usedwith caution in patients with a historyof cardiovascular disease includingprevious myocardial infarction,t achyca rd i a , o r conduc t i onabnormalities and close monitoring isnecessary when increasing doses.Overdose of TCAs can lead tocomplete heart block, life-threateningbroadening of QRS interval orhypotension.

S E L E C T I V E S E R O T O N I NREUPTAKE INHIBITORSSelective serotonin reuptake inhibitors(SSRIs) are one of the current first-linetreatment options for depression. Theyexhibit better safety profile andtolerability than the older agents suchas TCAs and MAOIs. SSRIs inhibitneuronal uptake pump for serotonin,down-regulate serotonin receptors andincreases serotonin availability andduration of action. They have low

affinity for muscarinic, alpha-adrenergic and histamine receptorsand are less l ikely to causeanticholinergic and cardiovascularadverse e f fects than TCAs.Gastrointestinal discomfort such asnausea and diarrhea, and headachesare the most common side effects.Taking SSRIs after food can help tominimise nausea. Diarrhea andheadaches are usually transient andmay resolve after the first week of use.SSRIs may cause insomnia and areusually taken in the morning but thedose can be switched to bedtime ifthe patient experiences somnolenceafter taking the medication. SSRIs maycause sexual dysfunction such asdelayed orgasm or anorgasmia.Patients who experience this sideeffect may not develop tolerance tothis side effect and may require aswi tch to another c lass o fantidepressant (such as mirtazapineor bupropion) if they are bothered byit or if it affects their adherence totreatment. Other side effects includevivid dreams, weight gain, increasedrisk of bleeding, and syndrome ofinappropriate secretion of antidiuretichormone (SIADH).

All SSRIs have similar efficacy andside-effect profiles but they arestructurally different. Hence allergy,response to, or lack of response toone SSRI does not predict a similarreaction to another. All SSRIs aremetabolised in the liver. Fluvoxamine,paroxetine and citalopram aremetabolised to inactive metabolisedwhile sertaline and escitalopram aremetabolised to pharmacologically lessactive metabolites. Fluoxetine, on theother hand, is metabolised to an activecompound, norfluoxetine, which a longelimination half life. After a single dose,the half lives of fluoxetine andnorfluoxetine are 1.9 and 7 daysr e s p e c t i v e l y . W i t h c h r o n i cadministration, the half lives increasesto 5.7 days and 19.3 days respectively.These long half lives do not affect thetime expected to reach a therapeuticresponse, and could even be of benefitin non-compliant patients. However,this slow elimination can proveproblematic in the event of adverseeffects or drug interactions. For

example, when switching from an SSRIto a MAOI, a 5-week washout periodis required for fluoxetine compared toa 2-week washout period for the otherSSRIs. Fluoxetine is a potent inhibitorof CYP2D6, hence drugs metabolisedby CYP 2D6 (such as beta-blockers,TCA, antipsychotics, codeine, tramadoland dextromethorphan) should beused with caution when given togetherwith fluoxetine. Fluvoxamine is a stronginhibitor of CYP 1A2, 3A4 and 2C19and are more likely than other SSRIsto interact with other medications.Citalopram and escitalopram, on theother hand, has less CYP interactionsthan other SSRIs. Sertraline is the mostlikely to cause nausea among the classof SSRIs. It is also the most frequentlycited reason for discontinuation.Paroxetine can be slightly moresedating and has more anticholinergicactivity than the rest of the SSRIs. Thecontrolled release (CR) formulationtablets is designed to delay the releaseof drugs till after it leaves the stomachand hence may cause less nauseathan the immediate release tablets.About 80 percent of the paroxetinecontent of the tablets is released, whilethe remaining 20 percent is retainedwithin each tablet and the individualdose of paroxetine CR needs to beabout 25 percent higher than that ofthe immediate-release formulation toachieve equivalent dosing.

SELECTIVE SEROTONIN ANDNORADRENALINE REUPTAKEINHIBITORSSelective serotonin and noradrenalinereuptake inhibitors (SNRIs) weredeveloped based on the hypothesisthat antidepressants that act toincrease both serotonin andnoradrenaline signaling would providemore effective management of bothphysical and emotional symptoms ofdepression than the SSRIs.7 However,current evidence has not shown muchsignificant difference in efficacybetween the different classes ofantidepressants.8 SNRIs venlafaxineand duloxetine act on both serotoninand noradrenaline but do not affecthistamine or cholinergic receptors.

Venlafaxine inhibits serotonin reuptakeat lower doses (150mg daily or less).

2: M E D I C A L D I G E S T

3:

Hence its side effects are similar tothat of SSRIs which include nauseaand diarrhea. At higher doses, itseffects on noradrenaline are greaterand may cause increased bloodpressure. This increase in bloodpressure may be clinically significantin pat ients with uncontrol ledhypertension and the patient’s bloodpressure should be monitored closely.

Duloxetine does not appear to have adose- re l a t ed e f f ec t on t heneurotransmitters like venlafaxine. Iti nh ib i t s both se ro ton in andnoradrenaline reuptake across alldosage range. Common side effectsinclude nausea, constipation, drymouth, insomnia, and dizziness.Duloxetine also increases the risk ofelevation of serum transaminaselevels.9 There have been reports ofcases of hepatitis with abdominal pain,hepatomegaly and elevation oftransamine levels to more than 20 timesthe upper limit of normal with or withoutjaundice. Duloxetine should not beused in patients with a history of liverimpairment or substantial alcohol use.Patients taking duloxetine should alsobe counselled to monitor and reportfor any signs and symptoms of liverdysfunction such as jaundice, darkurine, pruritus or unexplained flu-likesymptoms. Both venlafaxine andduloxetine can also be used in thetreatment of neuropathic pain.

NEWER AGENTSMirtazapine is a noradrenergic andspecific serotonergic antidepressant(NaSSA). It increases noradrenergicand serotonergic activity throughblockade of the respective receptorsbut does not inhibit the reuptake ofserotonin or noradrenaline, nor doesit inhibit monoamine oxidase activity.The specific blockade of 5-HT2 and 5-HT3 receptors is postulated to reducethe likelihood of some serotonergicside effects such as restlessness,nausea and sexual dysfunction.10 Italso has substantial antihistaminergiceffect which causes sedation,increased appetite and weight gain.Interestingly, higher doses ofmirtazapine (greater than 30mg perday) cause less sedation than lowerdoses due to the greater noradrenergic

effect. Mirtazapine is available as anormal tablet formulation or an orallydisintegrating tablet (RemeronSolTab®). The SolTab formulation isdesigned to increase compliance inpatients who have difficulty swallowingconventional capsules or tablets. Itdisintegrates in the mouth withinseconds after administration, and itcan be subsequently swallowed withor without water.

The exact mechanism of action ofbupropion is unknown but it may berelated to inhibition of presynapticdopamine and noradrenaline reuptaketransporters. It does not affect thehistamine, cholinergic receptors oralpa-adrenergic receptors. Thisincreases its tolerability as it does nothave many of the side effects that otherantidepressants have. It should,however, be used with caution in

patients predisposed to seizures suchas those individuals with a history ofepilepsy, bulimia, or had recent heavyalcohol intake. The risk of seizures isestimated to be 0.1% for daily dosesless than 300mg but increases to 0.4%for doses up to 450mg daily. Otherside effects of bupropion includeconstipation, nausea, insomnia, lossof appetite and agitation. Nauseaappears to be slightly less of a problemfor bupropion than for SSRIs and theincidence of sexual dysfunction isp r o b a b l y t h e l e a s t o f a n yantidepressants.11 Bupropion has alsobeen shown to be effective in thesmoking cessation.12

Agomelatine (Valdoxan®) is the newestantidepressant to be registered inSingapore. It has a unique mechanismof action in that it is agonistic formelatonin MT1 and MT2 receptors butblocks serotonin receptors.13,14 It doesnot have an effect on monoamineuptake and does not have affinity foradrenergic, histamine, cholinergic,dopamine and benzodiazepinesreceptors. Agomelatine has beenshown to be non-inferior to sertralineand venlafaxine and it does not havethe common side effects (such asweight gain and sexual dysfunction) ofother antidepressants.15,16 Significants ide ef fects associated wi thagomelatine include dizziness,paraesthesia, blurred vision, insomniaand elevations in liver transaminases.The exact place in therapy foragomelatine is currently unclear but itmay be beneficial for patients whohave an intolerance for otherantidepressants or have marked sleepdisturbances, or both. It is contra-indicated in patients with any liverimpairment and liver function testsshould be monitored before startingtherapy, at 6-, 12-, and 24-weekintervals. It should not be used inpatients younger than 18 years old orabove 65 years old as efficacy has notbeen shown in these groups ofpatients.13

H O W T O P R E S C R I B EANTIDEPRESSANTSAll currently available antidepressantshave comparable efficacy. Whentreatment with antidepressants is

If the patientresponded to anantidepressant

previously, the sameantidepressant can be

used again. If therewas a lack of response

with thatantidepressant,

another agent from thesame class or from

another class can betried. If the patient has

never been on anantidepressant before

but an immediatefamily member has

been effectively treatedwith a particular

antidepressant, thatagent can be tried in

the patient.

If the patientresponded to anantidepressant

previously, the sameantidepressant can be

used again. If therewas a lack of response

with thatantidepressant,

another agent from thesame class or from

another class can betried. If the patient has

never been on anantidepressant before

but an immediatefamily member has

been effectively treatedwith a particular

antidepressant, thatagent can be tried in

the patient.

M E D I C A L D I G E S T

4:

indicated, clinicians should make theirinitial selection based on individualpatient characteristics, expected sideeffects, patient preference, and cost.Individual patient characteristicsi n c l u d e p r i o r r e s p o n s e t oantidepressant treatment, concurrentmedication use and co-morbidities.

If the patient responded to anantidepressant previously, the sameantidepressant can be used again. Ifthere was a lack of response with thatantidepressant, another agent fromthe same class or from another classcan be tried. If the patient has neverbeen on an antidepressant before butan immediate family member has beeneffectively treated with a particularantidepressant, that agent can be triedin the patient.

While making the selection, thepatient’s signs and symptoms andother concurrent medical issues shouldalso be considered. For example, in apatient who is complaining of loss ofappetite and weight loss, a trial ofmirtazapine may be considered.Antidepressants that cause sedationmay be used for treating insomnia anddepression in a patient who hasdifficulty sleeping. Bupropion iscontraindicated in an individual withse izures and agomelat ine iscontraindicated patients with liver

impairment. Venlafaxine should beused with caution in patients withuncontrolled hypertension and TCAsshould be used with caution in patientswith a history of heart disease.

Concurrent drug use or drug-druginteractions should be consideredbefore starting an antidepressant.Serotonin syndrome is a rare butpotentially fatal condition when two ormore medications that increaseserotonin levels in the body are usedconcurrently. Symptoms may includeanxiety, shivering, diaphoresis, tremor,and increased or decreased bloodpressure and pulse. This syndromemay occur when TCAs, MAOIs, SSRIs,SNRIs are used together or with othermedications such as pethidine,dextromethorphan, linezolid, andtramadol.

Convenience of dosing, costs andpatient’s preference should also betaken into account when selectingantidepressants. The prescription ofgener ic fo rms o f the o lderantidepressants and SSRIs maysubstantially reduce costs for thepatient.

It is also important to inform patientsthat the benefits of antidepressantsmay not be evident immediately.Pat ient may begin to not ice

improvements in physical symptomssuch as poor sleep, appetite, lack ofenergy within the first one to two weeksof treatment. Cognitive symptoms suchas gui l t , poor concentrat ion,hopelessness, sadness, and decreasedlibido may take three to four weeks ormore to show improvement. Fullbenefits of antidepressants may notbe noticeable till four to six weeks afterinitiating treatment.

All antidepressants start at low dosageand gradually increase every one totwo weeks as required. Starting at alow dose is important because sideeffects will occur first before thebeneficial effects and may affectpatient’s compliance to treatment.

References1. 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, placebo-

controlled, 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.

Ms Tan Keng Teng is a pharmacist inthe Pharmacy Department, Tan TockSeng Hospital


5

HOW MANY BLOOD TUBESSHOULD I SEND TO THELABORATORY?The right answer is: send enough bloodin the appropriate tubes.

As you know, most tests requirespecimens sent either in the yellowtop (containing coagulation-promotinggel) or purple top tubes (containingEDTA to stop clotting). As a generalrule, each category of test calls fora separate tube (even if the type oftube required is the same) becauseeach is performed in a separate partof the laboratory. For example, youare managing a patient with systemicvasculitis and you suspected that ahepatitis virus is involved. You orderedserum creatinine, AST, ALT, HBsAg,anti-HCV and ANCA. How many tubesdo you need to send? Well, youactually need three yellow-top tubesbecause serum creatinine, AST andALT go to Biochemistry, HBsAg andanti-HCV go to Microbiology andANCA go to Clinical Immunology.

It is unwise to send insufficient bloodbecause this will cause:a) Frustration of the laboratory staff

because they cannot do their joband they have to inform therequesting doctor that the testcannot be performed, and thencancel the charge for the test;

b) Blood to be drawn from the patientagain. Sometimes, th is isimpossible because the patienthas left the country. At the least,it causes some inconvenience; and

c) Delay in the processing ofimportant investigations.

On the other hand, we cannot condone

the collection of excessive tubes ofblood ‘just in case’. This is unfair tothe patient and wastes medicalequipment. Moreover, red cells willlyse when stored in these conditions,making the specimen unsuitable fortesting. In practice, the tubes areusually discarded anyway. Only twomammals suck blood from othermammals: vampires and humans. Andvampires only take what’s needed.

TELL ME SOMETHING ABOUT THEANTI-SCL-70 ANTIBODY.The anti-Scl-70 antibody is one thatdirected against the extractablenuclear antigens (ENA), just like theanti-double stranded antibody, anti-Ro, anti-La and anti-Sm. It is classicallya test for scleroderma. It is one of them o r e r e c e n t l y - d e s c r i b e dautoantibodies that has found its wayinto the service laboratory.

It was discovered about 30 years ago.The authors specifically set out to findan autoantibody in the serum ofscleroderma patients.1 The modernreader senses that the researcherswere working on the assumption thatthere ought to be a specif icautoantibody in any given connectivet issue disease, such as theassociations of mixed connectivetissue disease with anti-RNP and SLEwith anti-ds DNA. We now knowdifferently: to a certain degree, anyautoantibody can be found in anyautoimmune rheumatologic condition.To return to that paper, the authorsused sera from five sclerodermapatients (whose initials were GC, MC,JH, AT and LJ) that were known tocontain nuclear-reactive antibody.They precipitated a protein from the

purified and concentrated extract ofrat liver nuclei. Finally a protein of 70kilodaltons was identified as the targetof the antibody, hence the name anti-Scl-70.

In the original paper, Ouchterlonydiffusion was used to demonstrate thepresence of the antibody. Scl-70 wasidentified to be topoisomerase I in1986. Modern ELISA methods usepuri f ied or recombinant DNAtopoisomerase I as the substrate anti-Scl-70.

The sensitivity of anti-Scl-70 forsystemic sclerosis is around 20percent and the specificity is 100percent.2 For patients alreadydiagnosed with systemic sclerosis, thepresence of ant i-Scl-70 wasassociated with a greater likelihoodfor the development of diffusecutaneous involvement, radiographicpulmonary fibrosis, and abnormalitiesin pulmonary funct ion tests.

There’s a test for the CRESTsyndrome, a variant of scleroderma.It’s the anti-centromere pattern in theANA test.3 There is no need to orderthis test specially. Just ask for the ANAand state that you’re interested in thispattern. The laboratory will report ifthe pattern is present.

The classi f icat ion cr i ter ia forscleroderma do not include anylaboratory investigations. A patientis classified to have the diseasei f h e o r s h e h a s p r o x i m a lscleroderma, or, two of these three:sclerodactyly, digital pitting/loss ofsubstance and bilateral basilarpulmonary fibrosis.4

Laboratory UpdateShort Notes from yourClinical ImmunologyLaboratory, Part 5These short articles are culled from the email-circulated messages sent to our colleagues in TTSH between 2007and 2009. They reflect the issues faced by the users and the laboratory, and serve as a dialogue between the two.


6:

A new antibody associated withscleroderma was announced lately:the anti-platelet-derived growth factor(PDGF) receptor antibody was foundin 100% of 46 scleroderma patients.5

Unfortunately, this finding is notrepeatable so no useful test is likelyto result.6

C O E L I A C D I S E A S E A N DSEROLOGIC TESTSCoeliac disease is rather uncommonin Singapore. For example, a PubMedsearch of “celiac disease” and“Singapore” yielded no relevant hits.Coeliac disease is due to a geneticpredisposition to react to gluten,specifically in people with HLA DQ2and DQ8. Clinical features of celiacdisease 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 bedifficult to diagnose.7 The best proofthat a patient suffers from this is thedemonstration of villous atrophy in thesmall bowel and unequivocalimprovement with a gluten-free diet.

Gluten refers to the storage proteinsfound in wheat, rye and barley. Gliadinrefers to the alcohol-solublecomponent of these proteins. Gliadinis poorly digested and passes intactinto the gut epithelium. In coeliacs,these peptides initiate a self-

destructive immune response in theintestines. Transglutaminase has tworoles in celiac disease: it deamidatesg lu ten , mak ing i t a po ten timmunostimulatory agent and it alsoserves as a target autoantigen in theimmune response.8

Currently, the tests available in ourLaboratory for the serologic diagnosisof this disease are the anti-endomysial(anti-EmA) and anti-gliadin antibodies( b o t h u s i n g i n d i r e c timmunofluorescence). The anti-EmAis directed against transglutaminase.The anti-gliadin antibody is less specificand sensitive for diagnosing celiacdisease and is not recommended foradult patients. On the other hand, ithas a role in the diagnosis of patientsyounger than 18 months of age.9 Forthis reason, the CIL will continue tooffer this test.

The anti-tissue transglutaminase IgAantibody (anti-tTG) (using ELISA) isnow considered the best test forcoeliac disease. Current diagnosticalgorithms suggest screening patientswith anti-EmA or anti-tTG antibodies,and confirming with biopsy. The anti-EmA is occasionally present in coeliacpatients who do not have the anti-TTG. Patient with negative tests buthighly suspicious history and clinicalsigns should still undergo biopsy.

A point we should note is that IgAdeficiency is common in patients withcoeliac disease, up to 2 percent. If wefeel that a patient has celiac diseasebut the anti-tTG IgA antibody isnegative, we can ask for serum IgAlevel to confirm IgA deficiency andthen the anti-tTG IgG antibody,although it is less specific than the IgAantibody.

The anti-tissue transglutaminase IgAantibody is considered to be the mostsensitive and specific serologic testfor celiac disease. The definitive testis still a small bowel biopsy before andafter gluten avoidance.

In cases of strong clinical suspiciona n d n e g a t i v e a n t i - t i s s u etransglutaminase IgA, look for IgAdeficiency and order the anti-tissue


7:

transglutaminase IgG antibody.Occasionally, the anti-endomysialantibody is present patients who arenegat ive fo r the ant i - t i ssuetransglutaminase antibody. The anti-gliadin antibody is useful mainly inpaediatric patients.

REPLACING THE TPPA WITHSYPHILIS IgG IN THE DIAGNOSISOF SYPHILISSyphilis is almost always diagnosedserologically, not bacteriologically,because the organism is difficult toisolate and simply cannot be found inthe later disease stages.

In a previous article, we discussed twolaboratory diagnostic strategies forsyphilis, each employing a pair of tests.We said that our Laboratory offeredthe rapid plasma reagin (RPR) andTreponema pal l idum par t ic leagglutination (TPPA) for the diagnosisof syphilis. The other strategy is to useRPR and syphilis IgG.

TPPA is a treponemal test and RPR isa non-specific one. A positive TPPAtells us that the patient had beenexposed to Treponema pallidumresulting in the production of specificantibodies. RPR then lets us know theactivity of the infection. High titressuggest that the disease is untreated,while low titres or a negative testsuggest treated disease or lateuntreated disease (this is why thetreatment history is important).

The other diagnostic strategy usingsyphilis IgG and RPR yields virtuallythe same result.10 Since early 2008,CIL has stopped performing TPPA andhas been offering the syphilis IgG.Similar to the TPPA, the syphilis IgGis a specific test and will remain positivefor years after the initial infectionregardless of treatment.

How should we now screen forsyphilis? Interestingly, either RPR orsyphilis IgG may be ordered first, tobe followed by the other if the first ispositive. The advantages of orderingthe RPR first are the cheaper price andshorter turnaround time, but this testcan give a false-positive results, leadingto physician and patient anxiety! False

positives tend to occur in the agedand people with autoimmune diseases,v i r a l i n f ec t i ons and recen timmunization. If we ordered the syphilisIgG first, a positive test is almostcertainly due to true infection. We stillneed to order a RPR to demonstratethat the infection is active and is notmerely a serological scar.

We stress that the patient’s history isvery important in interpreting theabove. For example, a patient recentlytreated for syphilis may remain positiveto syphilis IgG and RPR. We shouldnot treat again if there is documentationof adequate therapy.

The syphilis IgG has replaced the TPPAas a specific test for exposure tosyphilis. In addition, it can also replaceRPR as a screening test especially ifyou are concerned about false-positives. When the syphilis IgG andRPR are both positive and the historyis consistent, we have to treat for activesyphilis.

IMPLICATIONS OF THE REVISED2006 SAPPORO CRITERIA ON THELABORATORY TESTING OF THEANTIPHOSPHOLIPID SYNDROMEThere has been a revision of the original1999 classification criteria of theantiphospholipid syndrome.11

Both criteria of 1999 and 2006 dividethe features into clinical and laboratory. The new laboratory requirements are:1. The level of anti-cardiolipin

antibodies (ACA), which may beIgG or IgM, considered to bepositive has been defined. To beconsidered positive, it should beabove 40 MPL or GPL, or abovethe 99th percent i le value.

2. There must be a relationshipbetween positive ACA or lupusanticoagulant and the clinical event(such as thrombosis andspontaneous abortion). In the newcriteria, the positive test must beperformed within 5 years of the event.

3. The anti-cardiolipin antibodies haveto be persistently positive.Previously, two positive tests 6weeks apart were needed. Now,the duration is increased to notless than 12 weeks.

Briefly, in the new 2006 classificationcriteria for APS, the cutoff levels forACA have been defined, the intervalbetween the clinical event and positivetest cannot be longer than five years,and the two positive tests must beseparated by a minimum of 12 weeks.

HOW LONG SHOULD I WAIT AFTERAN IgE-MEDIATED ALLERGICREACTION BEFORE ORDERING ASPECIFIC RAST TEST?The classical teaching is that we waitfour to six weeks after a Gell andCoombs type-1 or IgE-mediatedhypersensitivity reaction beforeassaying the specific IgE concentrationwith a RAST test or an epicutaneousskin test. The reasoning is that the IgEmay be consumed during the reaction,so if the test is performed too soon, itmay be falsely negative.

A recent report challenges thisconcept.12 Fifteen patients withanaphylaxis due to suxamethoniumwere recruited. The serum levels ofanti-suxamethonium IgE were studiedon the day of reaction, the next dayand at varying intervals after that. Serataken before the event were availablefor some patients.

This is an intriguing study. If thisunchanging specific IgE level is foundto hold true for more types of drugs,the classical teaching can be trashed.Meanwhile, wait a conservative fourto six weeks.

Though this single study indicatesotherwise, if there are no overridingreasons for not doing so, it is best towait a month or so before orderingRAST test after an IgE-mediatedreaction such as anaphylaxis,angioedema or urticaria. In this way,if the test is negative, we will not haveto wonder if it was a false negative.

WHAT ARE THE ANTI-RO ANDANTI-LA ANTIBODIES? I VE HEARDTHAT THE ANTI-RO ANTIBODY ISASSOCIATED WITH CONGENITALHEART BLOCK?These quest ions give me anopportunity to discuss yet another twoautoantibodies of great interest inRheumatology.


8:

The heyday of research in the serologyof SLE was the 1960’s and 70’s. Manynew autoantibodies were discoveredand their cellular targets identified. Overtime, the list of clinically usefulautoantibodies was whittled down andwe are left with a handful. Besides theantinuclear antibody (ANA) and anti-double-stranded DNA antibody, wehave the quartet of anti-Ro, anti-La,anti-Sm and anti-RNP (we haven’tfigured out what to do with anti-Ku andanti-ribosomal P). This is similar to thestatus of serum proteins, in whichdozens have been identified, but weare only interested in a few, such asa lbumin , α - l -an t i t r yps in andβ2-microglobulin.

Anti-Ro is present in about 40 percentof lupus patients and 50 percent ofSjögren’s syndrome patients while thenumbers for anti-La are 20 percent and30 percent respectively.

The anti-Ro and anti-La have been‘discovered’ a few times. This is whyanti-Ro is also called the anti-SSAantibody. The name ‘anti-Ro’ was firstused in 1969.13 The anti-La antibodyis also known as anti-SSB and anti-Ha.

A coup was achieved in 1981 whenthe molecular targets of anti-Ro andanti-La were identified.15 Similar to Smand RNP, Ro and La are small nuclearr ibonulceoproteins, which arecombinations of RNA and protein andare thought to be involved in theproduction of messenger RNA.Puzzlingly, the same group laterreported that the Ro antigen alsocontains the La antigen sometimes,but the La does not contain the Ro,which explains why anti-Ro and anti-La often go together, why anti-Rosometimes occur without anti-Labut anti-La is rarely found withoutanti-Ro .16

The anti-Ro antibody has been found toreact to a 52- as well as 60-kd protein.17

The kit that we use measures theantibody concentration against the 60-kd Ro antigen, the classical one thatis identical to SSA.

The anti-Ro antibody is associated with

photosensitivity, thrombocytopaenia,lymphocytopaenia , in terst i t ia lpneumonitis and nephritis in lupus. Ithad been suggested that anti-Laprotects against nephritis in lupuspatients.

Since the 1980’s, it was found thatmany cases of congenital heart blockin the infant was related to the presenceof anti-Ro antibody in the mother. Anexcellent prospective study of 100pregnant women (53 with SLE, 19 withundifferentiated connective tissuedisease, 25 with Sjögren’s syndrome,one with systemic sclerosis, one withmixed connective tissue disease andone with antiphospholipid syndrome)who are anti-Ro positive showed thatthe risk of having a child with heartblock was two percent.18

Thus, anti-Ro and anti-La targetmembers of the ribonucleoproteinfamily of unclear function. They maydenote different disease manifestationin lupus patients. A pregnant womanwith the anti-Ro antibody, regardlessof her type (or maybe even absence)of autoimmune disease, carries a twopercent risk of producing an infant withcongenital heart block.

THE AMERICAN COLLEGE OFRHEUMATOLOGY ISSUES APOSITION STATEMENT ON THEMETHODOLOGY OF ANTINUCLEARANTIBODY TESTINGThrough the years, we have stuck toimmunofluorescence (IF) as the methodof choice for detecting antinuclearantibody (ANA) because of a convictionthat it remains the best even thoughother more convenient techniques havebeen developed, In the positionstatement of February 2009, theAmerican College of Rheumatologystates “The immunofluorescenceantinuclear antibody (ANA) assay is thegold standard for ANA testing withgreater sensitivity than solid phaseassays”. I t is avai lable f romhttp://www.rheumatology.org/publications/position/ana_position_stmt.asp.

The human laryngeal cancer cell line(HEp2 cells) provides large nuclei thatare ideal for IF. The fluorescence mustbe read by the human eye. In the past

few years, other enzyme immunoassaymethods and a multiplex beads assayhave been developed.19,20 Manylaboratories, including some in thiscountry, have adopted them becausethey can be automated areconsequently easier to perform.

The reason for issuing the statementwas not stated in the website, but anarticle intimated that there were anumber of SLE patients who were ANA-positive by IF but negative by othermethods.21 This article cited a studythat showed that IF is more sensitivethan beads in detecting ANA in head-to-head comparison.22 Apparently,HEp2 nuclei contain 100 to 150autoantigens that cannot be totallycovered by the other tests. In 2005,the laboratory in Cedars–Sinai MedicalCenter in Los Angeles changed the testmethod for ANA. So many cases ofSLE were missed such that all 32rheumatologists petit ioned thelaboratory to revert to IF.23

The Clinical Immunology Laboratorywill continue to offer the time-provenindirect immunofluorescence on HEp2cells as the method for detecting ANA.This will not change in the foreseeablefuture.

DOES THE PRECISE LEVEL OFSPECIFIC IGE ANTIBODY MATTER?As you know, we use the enzymemethod ( f luorescent enzymeimmunoassay or FEIA) to detect IgEantibodies, with reagents and equipment(ImmunoCap) manufactured by Phadia(previously Pharmacia Diagnostics).

Though we report the preciseconcentration of the IgE, we also providethe result in terms of the classes (class 0to class 6). This semi-quantitative reportingis a relic from the past because exactconcentrations could not be determinedwith early versions of the RAST test. Thisis not surprising because the old detectionmethod consisted of measuring radiationwith a Geiger counter!

Here, we shall discuss whether aqualitative result is sufficient, or thequantitative finding adds value to thediagnosis. Specific IgE antibodies areuseful in the management of diseases


known to be mediated by suchantibodies, such as allergic rhinitis, insectvenom allergy and food allergy.

This question has been addressed infood allergy, though a definitiveconclusion has not been reached. Itwas first reported more than 10 yearsago that, in children below 18 yearswith atopic dermatitis who areinvestigated for food allergy, when thespecific IgE exceeds a certainthreshold, the food challenge is likelyto be positive.24 It is not clear if theyhad other symptoms of food allergy,or were investigated because theywere atopic. Anyway, the results offood challenge were recorded and thesera stored. The reactions were notonly exacerbation of the dermatitis,but could be any allergic reactionconsistent with food allergy such ashives or wheezing. Later, when theImmunoCap (or UniCap) systembecame available, the sera wereanalysed (which is why this study isconsidered retrospective). For egg,milk, peanut, and fish allergy, the

threshold levels were 6 kilounits ofallergen-specific IgE per liter (kUA/L),32 kUA/L, 15 kUA/L and 20 kUA/Lrespectively. The sensitivity andspecificity of IgE concentration for soyand wheat allergy were poor.

As a follow-up, a prospective study wasconducted by the same group ofresearchers. This study was plagued bya new problem: parents of children whoexperienced possible reactions to foodsand had positive IgEs often refused thefood challenge, resulting in the loss ofthe gold standard.25

This relationship between specific IgEand positive response to food challengehas not been demonstrated in differentdisease groups (that is, besides childrenwith atopic dermatisis) and themethodology to establish thesethresholds has been questioned.26

We take the conservative stand andsuggest that the IgE levels be read witha detailed understanding of the patient’shistory (and not replace history, clinical

examination and other tests). The doctormust decide if further tests, especially afood challenge, must follow. There is noshortcut: as for any other form ofinvestigation, the specific IgE must beinterpreted with full knowledge of theclinical context.

9:

References1. 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: 10514-

10522.2. 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; 2:410-

1.24. 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.

Dr Leong Khai Pang is a seniorconsultant in the Department ofRheumatology, Allergy and Immunology,Tan Tock Seng Hospital.


Review

INTRODUCTIONAtrial fibrillation (AF) is the most common arrhythmia in clinical practice, found in about 1% of the population, withincreasingly higher prevalence in older people.- In the past decade, there had been more than 1000 publications in theliterature exploring this unique and fascinating arrhythmia, clarifying certain management issues. However, the geneticbasis 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.

Atrial Fibrillation for the

non-Cardiologist

EPIDEMIOLOGYThe incidence and prevalence of AF areincreasing in developed and developingcountries.1 Most population-basedstudies had been conducted in eitherUnited States or Western Europe.2-4 Theyidentify a common trend: that with theageing populations and attendant rise incardiovascular risk factors, particularlyhypertension, the prevalence of AF willincrease many fold. According to theFramingham Heart Study, the lifetimerisk of AF in adults aged 40 was 26percent for men and 23 percent forwomen.5 In addition, the risk of strokealso mirrors the increase in age andprevalence of AF of the population.6

Therefore, it is predicted that the

economic burden of this arrhythmia willbe substantial as it will account for atleast a third of all hospital admissions forarrhythmia-related diagnoses. It istherefore a major cause of hospitalization,morbidity and mortality.7,8 Despite apaucity of data for non-Caucasianpopulations, including Singapore, it ispredicted that the rising disease burdenis global.

RISK FACTORSAF is associated not only with an olderage group and hypertension, but alsowith heart failure, coronary artery diseaseand cardiomyopathies. In addition,obes i t y , d i abe tes me l l i t us ,hyperlipidaemia, metabolic syndrome

and chronic kidney disease have alsobeen associated with AF.9-11

Meta-analyses of randomized controlledtrials have also demonstratedrelationship of AF to serious events indifferent vascular territories12 in additionto the two-fold increase in mortality13

and nearly five-fold increase in strokes.6

CLASSIFICATIONFor consistency and simplicity, AF isclassified into 3 categories:a) Paroxysmal AF refers to episodes

that terminate spontaneously andusually last less than 7 days;

b) Persistent AF refers to episodeslasting more than 7 days, which

Figure. A typical ECG showing atrial fibrillation. Note the irregularly spaced QRS complexes and absent P waves.


11:

may require either pharmacologicalor direct current cardioversion; and

c) Permanent AF implies failure ofcardioversion or cardioversion notattempted.14

Non-valvular AF implies that thearrhythmia is not associated withrheumatic mitral valve disease,prosthetic valve or mitral valve repair.

Lone AF applies to AF in the youngerage group with no evidence of anycardiopulmonary or systemic disease.

MANAGEMENTThe objectives of AF management arerate control, maintenance of sinus rhythmand prevention of thromboembolism.The strategies are not mutually exclusiveand individualized tailored therapies forpatients must be emphasized. Thedemographics , age, gender ,concomitant cardiovascular risk factorsand systemic diseases, socio-economicfactors and presence of symptoms arekey considerations in the decision-making process with the patient.

The reader can also refer to detailedmanagement guidelines issued byvarious academic societies.14-16

P R E V E N T I O N O FTHROMBOEMBOLISMThromboembolic phenomena in AF,especially strokes, lead to considerablemorbidity and mortality. The prevalenceof both stroke and AF is age dependent.The risk of thromboembolism in non-valvular AF is similar regardless whetherAF is paroxysmal, persistent orpermanent.17 In addition, strokes fromAF are usually more serious than strokesfrom other causes.18

Risk stratification for thromboembolismin AF is an extremely important aspectin the holistic management of thisarrhythmia. The most commonlyaccepted and widely used riskstratification tool is the CHADS score.19

CHADS is an acronym for: Congestiveheart failure, Hypertension, Age greaterthan 75 years, Diabetes mellitus andhistory of Stroke or transient ischaemicattack. The presence of each risk factoris scored 1 point except for ‘S’ which isaccredited 2 points. Therefore the

maximum CHADS score is 6. The riskof stroke increases with higher CHADSscore. The treatment is guided by theindividual’s risk profile according to thescore. For instance, if the CHADS scoreis 0, antiplatelet therapy could berecommended. If the CHADS scoreidentifies only one moderate risk factor,either aspirin or anticoagulation isrecommended. If the CHADS scoreinvolves any high-risk factor (such asprevious stroke of transient ischaemicattack) or more than one moderate riskfactor, anticoagulation is recommended.

N O N - P H A R M A C O L O G I C A LS T R A T E G Y F O R S T R O K EPREVENTIONThe major source of clinically significantemboli is assumed to originate from theleft atrial appendage.32 Mechanicaldevices to occlude the left atrialappendage had made this strategy apossible alternative for strokeprophylaxis, especially in high riskpatients where warfarin may becontraindicated.33 However, the level oftechnical expertise, various operatorlearning curves and higher proceduralcomplication rates may not make thisstrategy an attractive first line optionbased on risk-benefit ratio.

RATE VERSUS RHYTHMThe controversy between rate controland rhythm conversion persists up tilltoday. The main question is whetherleaving a patient in AF and maintainingadequate ventricular rate control ispreferable to the conversion andmaintenance of sinus rhythm either viaelectrical or pharmacological means.The AFFIRM and RACE trials weredesigned to address this issue.34,35 Inthe AFFIRM trial, the overall mortalitywas not significantly different betweenthe rate control and rhythm controlgroups. Conversely, in the rhythmcontrol group, there were morehospitalizations and deaths comparedto the rate control group. There wasno difference in the rate of strokebetween the 2 groups. Similarly, RACEalso demonstrated that rate controlwas not inferior to rhythm control forprevention of death and morbidity.However, in these and other smallertrials, younger patients, female patientsand those with paroxysmal AF were

not well represented. Therefore, whilstrate control with stroke prophylaxismay be the preferred strategy for themajority, there is a definite role inconversion and maintenance of sinusrhythm in a highly symptomaticpopulation group. These two studiesalso highlighted the considerableadverse effects of all anti-arrhythmicdrugs.

Because no anti-arrhythmic drugs areconsidered ‘safe’, comparative outcomestudies have been conducted within therate control group. Conventional anti-arrhythmics that were used in the rate-versus-rhythm trials include Class Ic andClass III (amiodarone, sotalol) drugs. TheCAST trial demonstrated increase inmortality when certain classes of anti-arrhythmics were used in the setting ofstructural and coronary artery disease.36

The recent publication of ATHENA raisedhopes in an amiodarone-equivalent drug,dronedarone.37 Dronedarone isstructurally similar to amiodarone but itlacks the iodine moiety, leading to fewerside effects. Dronedarone reduced thehospitalization rate in high-risk patientswith AF compared with placebo.However, it is a less effective anti-arrhythmic agent than amiodarone andis contraindicated in patients with NYHAClass IV functional status or acutedecompensated heart failure.38

Therefore, dronedarone trades safetyfor efficacy compared to amiodarone.

There is a non-pharmacologicalapproach to maintaining sinus rhythm.Radiofrequency ablation of AF hasbeen a hot topic of much interest. Aseminal paper published more than adecade ago demonstrated that the focifor AF arise from the pulmonary veins.39

Since then, much research workinvestigating a permanent cure for AFby radiofrequency ablation andelectrical isolation of pulmonary veinshas been published. Even in high-volume centres with experiencedoperators, success rates are higher inparoxysmal compared to persistent orpermanent AF. Current guidelinesrecommend ablation for AF as asecond-line therapy in patients whohave failed at least one anti-arrhythmicdrug.40


Rate control in AF is usually achievedwith beta-blockers, calcium channelblockers and agents acting on theatrioventricular node. There had been noclear indication of an ideal heart rate forpermanent AF, in which rate control isusually the preferred strategy. Mostauthorities recommend heart rate ofbetween 60 to 80 bpm at rest and 90 to110 bpm during exercise. The recentRACE II suggested that lenient ventricularrate control was equivalent to strictcontrol.41 The lenient strategy (restingheart rate <110 bpm) was non-inferior tothe strict approach (resting heart rate<80bpm and heart rate goal duringmoderate execvise <110 bpm) for acomposite primary end point thatincluded cardiovascular death, heartfailure hospitalization, stroke and othermajor events. The rate control strategyshould be individualized and mostpatients are able to achieve lenient ratecontrol. However, a stricter control isstrongly advocated if patients aresymptomatic, develop heart failure or

have elevated heart rates during exercise.

PREVENTING AFAngiotension converting enzymeinhibitors (ACEIs) and angiotensionreceptor blockers (ARBs) as well asstatins and fish oils have been found toprevent AF in several small experimentalstudies. These agents were postulatedto have impact on the electricalheterogeneity of the atria through anti-proliferative, anti-fibrotic and anti-inflammatory effects. However, recentpublications failed to show any benefitwith the ARBs.42,43

CONCLUSIONAF is the most arrhythmia in the hospitaland primary health care settings. Theincidence and prevalence of AF willincrease exponentially because of theageing population with the attendantco-morbidities. Recent advances inp h a r m a c o l o g i c a l a n d n o n -pharmacological treatments have madeit possible to reduce morbidity and

mortality of AF. The treatment of AFmust be individualized, especially thedecision whether to control ventricularrate albeit remaining in AF or to maintainsinus rhythm. The weight of opinion isthat rate control is appropriate in mostsituations except in a few circumstanceswhen maintenance of sinus rhythm isrecommended.44

Comments

Narrow therapeutic windowand has numerous drug andfood interactions. Deservingpatients even in clinical studiesare not prescribed warfarin23-25

or the International NormalisedRatios (INR) is not kept in thetherapeutic range of 2 to 3.26,27

Warfarin should be preferredto dual antiplatelet agentsbecause the latter carry asubstantial risk of bleeding andhave been shown to be inferiorto war fa r in fo r s t rokeprophylaxis in AF.

Dabigatran is potentially a veryattarctive alternative to warfarinin stroke prevention in AF inthe future.

These new agents are currentlybeing studied and trial resultsare expected in the near future.

Drug

Warfarin

Dualantiplateletagents

Directthrombininhibitors

Direct FactorXa inhibitors

Efficacy

Effective in reducing stroke in AFup to 68%.20

ACTIVE A showed 28% relativerisk reduction of stroke in theaspirin/clopidogrel combinationarm compared to aspirin alone.28

ACT IVE W showed tha taspirin/clopidogrel failed toprevent stroke, embolism,myocardial infarction and vasculardeath as well as warfarin.29

Ximelagatran showed favourableresults in the SPORTIF V study.30

RELY showed that the lower doseof dabigatran (110mg bd) led toa similar rate of stroke as warfarinand a significant reduction in thefrequency of major bleeding.Higher-dose dabigatran (150mgbd) had significant reduction instroke but similar risk of majorbleeding compared with warfarin.

–

Adverse effects

The consequences of sub- orsupra-therapeutic INR values hadbeen descr ibed . 2 1 Over -anticoagulation is associated withintracranial and extracranialhaemorrhage, and warfarin-induced intracranial bleed causesdeath in 75%.22

Risk of bleeding

Ximelagatran was withdrawn dueto its toxic effects on the liver.

–

Dr David Foo is a consultant andActing Head of the Department ofCardiology, Tan Tock Seng Hospital.

Table. Comparison of the agents to reduce risk of stroke in atrial fibrillation.


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1998; 82:2N-9N.

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RADIOLOGY Quiz

Question 1: What are the imaging findings?

Question 2: What is the diagnosis?

CASE PRESENTATIONAn 80-year-old Chinese lady presented with left buttock pain radiating to the left anterior knee and numbness over the left thigh of afew weeks’ duration. The pain was worse on walking, and partially relieved with rest. There was no weakness and she was able to walkwith a walking stick. There was no history of trauma, fever, back pain, urinary retention or bowel incontinence. She was suffering fromhyperlipidaemia, hypertension, and osteoarthritis of both knees. In the straight leg raising test, the hips flexed to 70-80 degrees bilaterallyassociated 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 preservationof the vertebral alignment and disc spaces. Magnetic resonance (MR) imaging of the spine was performed.


Figure 1 Figure 2

Figure 3 Figure 4

Question

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 tocompress 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 contrastat 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 COURSEThe patient subsequently underwent a decompression laminectomy. At surgery, there was a sequestered L3-4 disccompressing on the left L3 nerve root. This was confirmed on histology. Eighteen months post surgery, the patient is ableto walk independently.

Approximately 90 per cent of lumbarherniated discs occur at the L4-5 orL5-S1 levels. A sequestered disc is afree disc fragment that is no longer incontinuity with the parent disc material.A sequestered disc may lie adjacentto the disc of origin, or may migratecranially or caudally to a different discspace both in the midline and in thelateral recess, or in rare cases, evenpenetrate the dura. The most commonpath of disc migration is in theposterolateral direction to the anteriorepidural space, which most commonlyproduces a radiculopathy. Patientsusually present with back pain, mostoften in the lumbar region, with orwithout the presence of radiculopathy.

Complications of a sequestered discinclude compression on nerve root(s)causing pain and radiculopathy. Theimaging appearances of freefragments tend to look like the parentdisc on both computed tomography

(CT) and T1-weighted MR sequence,with low signal. However, in T2-weighted MR images the sequestereddisc is hyperintense in 80% of thecases and isointense in the remaining20%.

The periphery of the sequestered discenhances after administration ofintravenous gadolinium contrast, whilethe central portion displays low signalintensity. The peripheral contrastenhancement is due to thein f lammatory response w i thgranulation tissue and newly-formedvessels around the sequestered disc.Differential diagnoses of a sequestereddisc include epidural tumours (egneurofibroma and meningioma),epidural haematoma and epiduralabscess . These are usua l lydistinguishable with a combination ofMRI and clinical findings. MRI is nowreadily available and is the modalityof choice for the investigation of low

back pa in when p ro lapsedintervertebral disc, cord compressionor vertebral metastases are suspected.It is particularly useful in patients inwhom symptoms persist despite anunremarkable X-ray.

15:

Discussion

Dr Daniel Chee is an associate consultantin the Department of DiagnosticRadiology, Tan Tock Seng Hospital


Answer

ECG Quiz

Dr David Foo is a consultant andActing Head of the Department ofCardiology, Tan Tock Seng Hospital.


A 75-year-old man sustained a fracture of the neck of femur in a fall. He developed acute shortness of breath whilstwaiting for surgery. A 12-lead ECG was done. What should one suspect based on the ECG?

Question

The ECG shows sinus tachycardia, borderline right axis deviation, incompleteright bundle branch block and S1Q3T3. The ECG findings, coupled with a historyof prolonged immobilization and acute shortness of breath, should lead one tosuspect pulmonary embolism.

Answer

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TTSH Medical Digest Apr-Jun 2010