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contents1 APPROACH TO SHOULDER PAIN

8 INFLUENZA VACCINES

14 MORE THAN JUST A HEADACHE

18 RADIOLOGY QUIZ

20 ECG QUIZ

22 DIARY DATES

From The Editor

Dr Leong Khai PangEDITOR

Medical Digest

Doctors live cloistered lives. We transit from school to medical practice,conveniently bypassing the grimmer bits of life. We only have vicariousknowledge of the darker side of society from our patients.

A few years ago, I saw a young man for a mild allergy problem. I askedhim about his job and was surprised to learn that he wasn’t working. Hewas living off the winnings of a football bet. I asked him about the amounthe won, thinking that $10,000 or $100,000 won’t last very long. “Onemillion dollars,” he replied, “But the trick was to collect the money fromthe bookie and leave safely.”

I treated a HIV-positive young man for cotrimoxazole allergy. Heenlightened me on the finer points of selling illegal CDs. It broughtfinancial security if one kept at it for two to three years. An old man whodid not mind spending some time in prison for money would be employedas scapegoat should the shop be raided by the authorities. The way toconvince the police he was the boss is to teach him two main things:where the light switches are and which keys open the locks and doors.

Recently, an unconscious man was admitted with aspiration pneumonia.He smoked meth crystal and probably overdosed on another drug. Hewas muscular and tattooed and wouldn’t be out of place in ShinjukuKabukicho. He woke up the next day and was fully alert by the third. Hewas extremely articulate in English. Before he went home (he was onbail and had ten days of freedom before he had to report to the police),I wished him long life and happiness. He asked, existentially, “What isthe use of a long life?”

Doctors are privileged members of society. Our patients remind howfortunate we are everyday.

Jul.Aug.Sep. 2010

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EDITORDr Leong Khai Pang

MEMBERSDr Jackie Tan

Dr Jaideepraj Rao

Dr Lee Cheng Chuan

Dr Chong Yaw Khian

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

Review

Approach to

Shoulder Pain

EXAMINATION OF THE SHOULDERTo distinguish these conditions, athorough examination of the shoulderis required, coupled with investigationson occasion. This includes locatingthe exact site of tenderness by carefulpalpation, testing the active andpassive range of motion of theshoulder, determining the strength ofthe individual rotator cuff muscles, aswell as the use of special provocativetests. This is a suggested examinationscheme:a. Expose both shoulders and

observe if there are asymmetry,bony abnormalities, swelling,erythema, wasting (especially ofthe supraspinatus, infraspinatus ordeltoid).

b. Palpate all bony landmarks, startingfrom the medial end of the clavicleand proceeding laterally. At thelateral end of the clavicle, examinethe acromioclavicular joint. Moveinferiorly to palpate the bicipitalgroove, lesser tuberosity, joint lineand coracoid process. Proceedl a t e r a l l y t o p a l p a t e t h esupraspinatus and infraspinatusmuscles and greater tuberosity and

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

Shoulder pain is the third most common musculoskeletal complaint in the general population. Shoulder problemsaccount for 5% of all general practitioner musculoskeletal visits. The peak incidence occurs in patients between40 and 60 years of age.

Patients usually present with pain during overhead activities, night pain, stiffness and/or weakness of the arm. Theyare often diagnosed as suffering from idiopathic frozen shoulder, and sometimes inappropriately treated with non-steroidal anti-inflammatory drugs (NSAIDs) for prolonged periods, or even with steroids for symptomatic relief.In truth, many such patients are suffering from one of the conditions below:• Subacromial impingement syndrome and rotator cuff tendonitis• Partial or full-thickness rotator cuff tears• Acromioclavicular (AC) joint arthritis• Biceps tendonitis or tears• Calcific tendonitis (uncommon)• Glenohumeral osteoarthritis (uncommon).

As the disease progresses, many of these patients begin to develop reduced range of shoulder motion; hence thecommon diagnosis of frozen shoulder.

then posteriorly to palpate thespine of the scapula.

c. Put the joint through the range ofmotion in all planes. The patient isasked to raise the arms in thesagittal plane and then the coronalplane. External and internal rotationcan be assessed both with theshoulders at 90-degree abductionas well as in the adducted positionby the side of the body. Activeinternal rotation can also be testedby asking the patient to put hishand on his own back and try totouch the contralateral scapula(Apley’s scratch test). He shouldbe able to touch the medial border.Alternatively, count the highest

vertebra that he can reach with hisindex finger tip (for reference, theangle of the scapula is at T7).

d. The power of the muscles is testednext. Shoulder flexion, extension,abduction, adduction, internal andexternal rotation are tested andgraded 0 to 5. Supraspinatusstrength is tested in abduction.External rotation is powered by theinfraspinatus and teres minor.Internal rotat ion tests thesubscapularis muscle.

e. Special tests are performed asdirected by the history, location ofpain or indicators from thepreceding examination. The tablelists some of the most well known

manoeuvres. Unfortunately, good-quality sensitivity and specificitydata are established only for veryfew of the tests.1 It is probablybetter to use tests together thanin isolation. One study showed thatthe presence of three positive tests(suprasp ina tus weakness ,weakness in external rotation anddetection of impingement) werehighly diagnostic of rotator cufftears.2

S o m e t i m e s , a d i a g n o s t i chydrocortisone-and-lignocaine (H & L)injection into the suspected locationof pathology can confirm the diagnosisand may even be therapeutic.

Test Purpose Method What to look for

The subscapularis isweak if the elbow dropsand goes around theside of the body.

Jobe’s test orempty can test

Test of supraspinatusstrength, especially inthe assessment of a tear

The shoulders are abducted to 90°, thearms brought to the scapular plane (about30°'b0 to the coronal) and the thumbspoint downwards. The patient resists theexaminer’s attempt to adduct the shoulder(figure 1).

Pain or weakness

External rotatorlag sign3

Test for tears of thesupraspinatus

Standing behind the seated patient, theexaminer brings the patient’s elbow to 90°flexion and the shoulder to 20° abductionin the scapular plane. The examiner putsthe shoulder into maximum external rotationminus 5° to allow for elastic recoil of thejoint. The examiner keeps supporting theelbow but releases the arm and asks thepatient to maintain the position.

The test is positive if a lagor angular drop occurs.

Drop-arm test Test forsupraspinatus tear

The arms are raised 190° and then graduallybrought down.

The patient is unable tocontrol the gradual descentof the arm and it fallssuddenly, suggesting acomplete tear.

Gerber’s lift-offtest

Test ofsubscapularisstrength

The patient is asked to place his hand onhis back at the lumbar level, with the palmfacing out. He is told to lift the palm off theback against resistance.

The patient is unable tolift the palm or is weakagainst resistance

Belly press test Test ofsubscapularisstrength

This test is used if the patient is unable tointernally rotate the shoulder. In this case,the hand is placed flat on the abdomen withthe elbow forwards. The patient is asked toresist an external rotating force applied bythe examiner (figure 2).

Table. Special tests of shoulder function and pathology.

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

3:

Test Purpose Method What to look for

The patient showsapprehension on hisface.

Neer’s test Subacromialimpingement

With the elbow extended, the shoulder isflexed forwards to 90° and internallyrotated. The arm is then raised fully.

Pain at the shoulder issuggestive of impingement.

Hawkin’s test Subacromialimpingement

With the elbow bent at a right angle, theshoulder is flexed forwards to 90°'b0. Now,the shoulder is internally rotated (figure 4).

Pain with this manoeuvre issuggestive of impingement.

Yergason’stest

Biceps tendonpathology

The shoulder is adducted and the elbowflexed to 90°. The patient is asked tosupinate the forearm and to flex the elbowagainst resistance.

Pain in the bicipital grooveindicates tendinopathy.

Speed’s test Biceps tendonpathology

The shoulder is flexed 90°, with the elbowextended and the forearm supinated. Theexaminer applies downward pressure onthe forearm.

The test is positive if painis experienced.

Apprehensiontest

Anterior shoulderinstability

The examiner stands behind the patient.With one hand to steady the shoulder, theexaminer holds the patient’s forearm andpulls the arm upwards and backwards (figure5).

The test is positive ifpain or clicking isdetected.

Crank test Labral tear orabnormality

The shoulder is abducted 90° and theexaminer internally rotates it and appliespressure along the axis of the humerusthrough the glenohumeral joint.

The shoulder pain ismore marked withthe thumb pointingdownwards thanupwards. The test isalso consideredpositive if a click isdetected rather thanpain.

O’Brien’s testor activecompressiontest

Labral tear orabnormality

The shoulder is adducted 10°, flexed 90°with the thumb pointing downwards (figure6). The elbow is extended. The patient isasked to resist the examiner’s downwardsforce. If the patient complains of pain, thetest is repeated with the thumb pointingupwards.

Pain at anteriorshoulder as themovement is carriedout.

Cross-bodyadduction test

Acromioclavicular jointdisease

The arm is lifted to 90° and is brought acrossthe body, with the hand aiming for theopposite shoulder.

Weakness indicatesinfraspinatus tear ortendinopathy.

Infraspinatusstrength test

Test of infraspinatusstrength

The patient’s shoulder is kept adductedwhile the elbow is brought to 90° flexion.The shoulder is now internally rotated 45°.The examiner applies a medial or internalrotating force (figure 3).

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

4:

Figure 1. The author is testing the power of the patient s rightsupraspinatus with Jobe s test or empty can test.

Figure 2. This belly-press test determines if subscapularis strength iscompromised. The patient s hand is placed flat on the abdomen andis told to resist external rotation. The test is positive if the elbow movesbackwards and goes around the side.

Figure 3. The author is testing the patient s infraspinatus. With theshoulder abducted and the elbow flexed 90¡’b0, the patient is askedto resist a medial or internal rotation force.

Figure 4. Hawkin s test for shoulder impingement attempts to elicitpain by internally rotating the shoulder that is extended to 90¡’b0.

Figure 5. Apprehension test: the examiner steadies the patient s shoulderwith one hand and uses the other to apply an external rotating andabducting force. A positive test is a look of apprehension on the patient sface.

Figure 6. The author is using O Brien s test to detect a labral lesion. Ifthe patient complains of pain, the test is repeated with the thumbpointing upwards. The test is positive if pain is present, especially sowith the thumb in the downward orientation.

INVESTIGATIONSThe standard X-rays of the shoulderare of the anteroposterior and Y-scapular views (figure 7). They areuseful in looking for subacromial spuror a hooked acromion, which maycorrelate with positive impingementtests. Sclerosis or osteophytes at thegreater tuberosity often indicatesdegenerative rotator cuff tendons, anda partial or full-thickness tear must be

excluded if the patient does notrespond to treatment. Superiorsubluxation of the humeral head usuallyrepresents chronic and large rotatorcuff tears. Narrowing of the AC orglenohumeral joint, cyst or osteophyteformation indicates AC joint andg lenohumera l jo in t a r th r i t i s ,respectively. Calcific tendonitis can beeasily diagnosed by the location ofcalcification in the subacromial space.

Although rare, tumours or metastasesmay be obvious at the humeral heador neck region.

When the diagnosis is still uncertain,or when the need to confirm thediagnosis is essential before surgicaltreatment, diagnostic ultrasound orMRI is very useful.

Diagnostic ultrasound scan is relatively


cheap and is good for the diagnosisof impingement syndrome, rotator cufftendonitis or tears, and bicepstendonitis or tears. However, itsaccuracy is highly dependent on theexperience of the radiologist ortechnician. In addition, patients whohave already developed severe painor restriction of shoulder movementsmay not tolerate the various shoulderpositions that are required for acomplete ultrasound study. There isalso limited ability to look for intra-articular pathology.

MRI scan offers the most detailedevaluation of soft-tissue pathologies

o f the shou lde r and he lpstremendously in arriving at a definitivediagnosis. It can also accurately detectintra-articular conditions such as labraltears and car t i lage les ions.Unfortunately, its hefty cost is a majordeterrent to many patients.

C O M M O N S H O U L D E RCONDITIONSS u b a c ro m i a l i m p i n g e m e n tsyndromeThis is usual ly caused by acombination of curved or hookedacromion (figure 8) and intrinsicweakness and degeneration of therotator cuff muscles. The affected

shoulder is usually symptomatic in theoverhead position. Some patientsdemonstrate a classic painful arc.Provocative tests such as Hawkin’stest (figure 4) and Neer’s test (table 1)are usually positive. Treatment includesscapula and rotator cuff strengtheningexercises, and H&L injection into thesubacromial space in selectedpatients. If these measures fail, patientwil l benefit from arthroscopicsubacromial decompression oracromioplasty.

Rotator cuff tearsMost patients present with shoulderpain during activities, night pain andweakness. A tear can be caused byan acute traumatic event or, morecommonly, repetitive overheadactivities. Overuse-related rotator cufftears typically occur after the age offorty years.

Clinically, there is usually pain andweakness of the supraspinatus tendonin abduction. In massive and chronictears, pseudoparalysis occurs, whenthe patient is unable to actively abductbut is able to hold the arm in theoverhead position. There may beobvious wasting of the supraspinatusmuscle on the scapula in chroniccases. Palpation of the space betweenthe acromion and the greater tuberositymay reveal a gap in the supraspinatustendon.4

An ultrasound or MRI is required toconfirm the diagnosis (figure 9) anddetermine the size of the tear, as wellas to look for atrophy and fattyinfiltration of the supraspinatus musclewhich if present, indicates long-standing tear and predict pooroutcome even after surgical repair.Treatment depends on the age andfunctional demands of the patient, aswell as the size and severity of thetear. Patients with partial-thicknessrotator cuff tears may respond toNSAIDs and physical therapyconsisting of gentle strengthening andstretching exercises. Should non-operative treatment fails, arthroscopicdecompression and debridement oftenrelieve the symptoms. Symptomaticpatients with full thickness tears willrequire surgical repair, which can be

5

Figure 7. Normal radiographs of the right shoulder, AP (left) and Y-scapular (right) views.

Figure 8. The arrow indicates a subacromial spur.


performed nowadays using a mini-open approach or even all-arthroscopictechniques.

A c r o m i o c l a v i c u l a r j o i n tdegenera t ion/os teoar thr i t i sThis condition is often under-diagnosed. The patient complains ofpain at the acromioclavicular (AC) jointin overhead positions and when lyingon the affected shoulder during sleep.Clinically, there is tenderness at theAC joint. Resisted cross adduction of

the arm accentuates the pain. Adiagnostic H&L abolishes the painrapidly, and may be therapeutic aswel l . X-rays may reveal mi lddegenerative changes or typicalosteoarthritis changes (figure 10).Patients are advised to avoid overheadactivities or lifting heavy loads thatworsen the pain. If H & L fails to givea long-lasting pain relief, arthroscopicexcision of the distal clavicle to unloadthe AC joint often gives a goodoutcome.

Biceps tendonitis or tearsPain and tenderness is usuallylocalised to the proximal bicipitalgroove. Provocative tests includeSpeed test and Yergason test (seetable 1), which basically stress thebiceps tendon in resisted flexion of theextended elbow and forearmsupination, respectively. Ultrasound orMRI will reveal swelling of the tendonand fluids in the bicipital groove.Treatment includes rest, NSAIDS andsteroid injection. For recalcitrant cases,arthroscopic biceps tenotomy ortenodesis is usually effective. Patientwith a complete tear will develop a“Popeye” sign of the biceps muscleduring elbow flexion. Treatment isconservative with minimal pain andlittle functional deficit expected afterseveral weeks.

Calcific tendonitisThis is a relatively uncommon conditionwhich affects predominantly thesupraspinatus tendon. The diagnosiscan be easily clinched on standardshoulder X-rays (figure 11). Treatmentincludes rest, NSAIDS and steroidinjection. If the patient fails to respond,arthroscopic debridement and releaseof calcium often helps in the resolutionof symptoms.

Frozen shoulder or adhesivecapsulitisIdiopathic adhesive capsulitis is apoorly understood disorder. It is a

6:

Figure 9. On the left, an MRI image showing a tear of the supraspinatus tendon just before its insertion into the greater tubercle of the humerus.On the right, an ultrasound image of a tear of the subscapularis muscle. The MRI image is provided courtesy of Dr Tham Seng Choe, Departmentof Diagnostic Imaging.

Figure 10. An MRI image showing osteoarthritic changes in the right acromioclavicular joint(arrow).


7:

clinical diagnosis with the hallmark ofthe condition being global restrictionof active AND passive range of motion.Risk factors include diabetes, thyroiddisorders, female gender and middleage (40–60 years). Patients with otherprimary shoulder conditions whopresent late may also developsecondary frozen shoulder. Treatmentincludes NSAIDs therapy and an earlyphysiotherapy program focused onrestoring range of motion. For patientswho have severe restriction ofmovements, intra-articular steroidinjection with or without hydrodilatation

often helps to accelerate the recoveryprocess. Recalcitrant cases will benefitfrom manipulation under anaesthesiaor arthroscopic capsulotomy.

CONCLUSIONArriving at a precise diagnosis forcomplaints of shoulder pain is withinthe capability of all doctors. In difficultcases, radiology may help clinch thediagnosis. Many patients can betreated with activity modification anda course of physiotherapy. Surgery isindicated only if conservative treatmentfails.

Figure 11. The radiograph on the left shows calcification of the left supraspinatus tendon (arrow). The MRI image on the right of a different patient showscalcification of the right supraspinatus tendon at a more proximal location (arrow). The MRI image is provided courtesy of Dr Tham Seng Choe, Departmentof Diagnostic Imaging.

References1. Hegedus EJ, Goode A, Campbell S, Morin A, Tamaddoni M, Moorman CT 3rd, Cook C. Physical examination tests of the shoulder: a systematicreview with meta-analysis of individual tests. Br J Sports Med 2008; 42:80-92.2. Murrell GAC, Walton JR. Diagnosis of rotator cuff tears. Lancet 2001; 357:769-70.3. Hertel R, Ballmer FT, Lombert SM, Gerber C. Lag signs in the diagnosis of rotator cuff rupture. J Shoulder Elbow Surg. 1995; 5:307–13.4. Matsen FA 3rd. Rotator-cuff failure. N Engl J Med 2008; 358:2138-47.

Dr Lee Keng Thiam is Consultant in theDepartment of Orthopaedic Surgery, TanTock Seng Hospital.


8:

Pharmaceutical Update

InfluenzaVaccinesInfluenza, an acute respiratory condition, occurs seasonally in outbreaks or in epidemics. It is mainly caused by twoinfluenza viruses which circulate among humans - types A and B. H1N1 influenza virus (first termed swine flu) andavian influenza (bird flu) are influenza A subtypes. Depending on the individual’s susceptibility, variable degree of flusymptoms could result, ranging from mild cough and fatigue to respiratory failure and death. Management of influenzaincludes prevention through vaccination, chemoprophylaxis and treatment with antiviral medication such as oseltamivir,zanamivir, amantadine and rimantadine.

INFLUENZA A AND BInfluenza A is categorized into subtypesbased on the surface antigens on itsenvelope glycoproteins, hemagglutininand neuraminidase. New influenza virusvariants result from point mutationsand recombination events during viralreplication, resulting in antigenic shiftsor drifts. Antigenic shifts are majorantigenic changes that occur when anew subtype of influenza A appears.This new subtype has pandemic-causing potential if it is able to causehuman disease, transmit from humanto human and the population has littleor no existing immunity. Antigenic driftsare minor antigenic changes associatedwith more localized outbreaks andseasonal epidemics.

In circulation since 1977 are humaninfluenza A (H1N1), A (H3N2) andinfluenza B viruses. Influenza A (H1N2),a possible product from geneticreassortment between human A (H3N2)and A (H1N1) viruses, has also beenidentified in some seasons. In April2009, human infection with a novelinfluenza A (H1N1) virus was identifiedin North America, and has since spreadglobally. This novel virus is derivedpartly from influenza A viruses thatcirculate in swine and is antigenicallydistinct from human influenza A (H1N1)viruses, hence it is renamed influenzaA (H1N1) 2009. However, bySeptember, pandemic influenza A(H1N1) 2009 infections had declinedto sporadic levels in most countries.From Oct 2009 to Feb 2010, there hadbeen 16 human cases of influenza A(H5N1) which was spread from poultry,but no evidence of sustained human-

to-human transmission to date. Twoisolated influenza A (H9N2) infectioncases had also been reported by HongKong in Oct and Dec 2009.

Influenza B viruses undergo antigenicchanges less rapidly than influenza Aviruses. Currently circulating influenzaB viruses are classified into two distinctgenetic lineages - Yamagata andVictoria - but not further divided intosubtypes. Influenza B viruses from bothlineages have circulated in most recentinfluenza seasons. B/Victoria/2/87lineage viruses predominated and were

a n t i g e n i c a l l y c l o s e t oB /B r i sbane /60 /2008 v i r uses .

INFLUENZA VACCINE DESIGNVaccination stimulates immunity toinfluenza viruses by induction ofa n t i b o d i e s , m a i n l y a g a i n s themagglutinin. Antibody against oneinfluenza virus type or subtype conferslimited or no protection against anothertype, subtype or antigenic variant ofthe same influenza virus. In view of thehigh mutation rates and continualevolution of influenza viruses, newvaccines are produced yearly to match


9:

the circulating viral strains. CDC andWHO through GISN collaborate inmonitoring influenza disease activity,tracking influenza virus isolates andconvening twice yearly in Febrary andSeptember to recommend forcomponents for the influenza vaccine.GISN is a global public healthlaboratory network coordinated byWHO, consisting of 131 NationalInfluenza Centres in 102 countries. Thenetwork conducts public healthactivities such as warning andassessment of influenza viruses ofconcern. The vaccine composition isupdated for each Northern (Nov – Apr)and Southern hemispheric season(May – Oct).

Based on current analyses and recentepidemiological evidence, it isanticipated that A(H1N1) 2009,A(H3N2) and B viruses will co-circulatein the northern hemisphere in 2010 to2011, with seasonal A(H1N1) unlikelycirculating at significant levels, hencethe latter has not been recommendedfor inclusion in the 2010-2011 vaccine.WHO recommends that vaccinesshould cover the following subtypesduring the 2010 influenza season inthe southern hemisphere:a) A/California/7/2009 (H1N1)-like

virusb) A/Perth/16/2009 (H3N2)-like virusc) B/Brisbane/60/2008-like virus.

Starting from the 2010 influenzaseason in the southern hemisphere,the trivalent influenza vaccine replacesthe monovalent vaccine as it includesantigens from the 2009 pandemicH1N1 influenza A virus.

WHAT ARE THE AVAILABLEINFLUENZA VACCINES?Current influenza vaccines include theintramuscular or deep-subcutaneouslyadministered trivalent inactivatedinfluenza vaccine (TIV) and theintranasal live attenuated influenzavaccine (LAIV). TIV can be used in anyperson aged ≥6 months, while LAIVmay only be used in healthy, non-pregnant persons aged 2 to 49 years.Those with co-morbidities conferringa higher risk of influenza complicationsshould be vaccinated only with TIV asthe safety or effectiveness of LAIV has

not been established in these groups.LAIV uses a master attenuated, cold-adapted donor virus to createreassortants with HA and NA antigensfrom currently circulating strains.Intranasal vaccine should not beadministered to patients who areimmunosuppressed or pregnant,suffering from chronic cardiovascular,pulmonary, metabolic diseases suchas diabetes or renal insufficiency, orthose with a history of severe egghypersensitivity (such as anaphylaxis)or Guillain-Barre syndrome.

Table 1 shows the comparison of TIVand LAIV. LAIV is not available inSingapore. Local ly avai lableinactivated trivalent influenza vaccinesthat are HSA-approved includeVaxigrip®, Influvac®, Fluvax®,Fluarix®, Fluad® and Agrippal®. Each0.5ml prefilled syringe contains 15micrograms hemagglutinin of strainsmatching those recommended for theinfluenza season in the respectivehemisphere, such as:a) A/California/7/2009 (H1N1)-like

strain (A/California/7/2009 (NYMCX-179A)

b) A/Perth/16/2009 (H3N2)-like strain(A/Wisconsin/15/2009 (NYMC X-183)

c) B/Brisbane/60/2008-like strain(B/Brisbane/60/2008).

As inact ivated vaccines takeapprox imate ly 9 months tomanufacture, they contain antigensfrom strains circulating in the previousyear. The efficacy of the vaccine isdetermined by the closeness of fitbetween the strains in the vaccine andthe viruses currently circulating. If thefit is close, protection of 50-80% canbe expected.1 A Cochrane systematicreview in 2007 that evaluated 15 trialsof inactivated influenza vaccine foundthat it was 80% effective againstlaboratory-confirmed influenza whenthe vaccine matched the circulatingstrains, compared to 50% when it didnot. The same review found the LAIVto be 62% effective at preventinglaboratory-confirmed influenza, butnoted the results as inconclusive due


to conflicting results from a limitednumber of studies.

WHO SHOULD BE VACCINATED?Influenza viruses can cause diseasein any age group, but rates of infectionare highest among children. Rates ofserious illness and death are highestamong persons aged ≥65 years,children aged <2 years, and personsof any age with comorbidities placingthem at increased risk for influenzacomplications.2 More than 90% of thedeaths occurred in patients above theage of 60 years.

As influenza viruses undergo frequentantigenic change, we should be re-vaccinated annually against influenzaviruses that are predicted to beprevalent based on the most recentviral surveillance data. Influenzavaccine can be administered to anyperson aged >6 months withoutcontraindications. High-risk groups ashighlighted below are encouraged toreceive the vaccination, and are ofpriority for vaccination efforts whenvaccine supply is limited.3 Nevertheless,starting in 2010, US Centres forDisease Control and Prevention’s(CDC) Advisory Committee onImmmunization Practices (ACIP) hasexpanded the recommendation forinfluenza vaccination to include allindividuals 6 months or older.

Groups at h igher r isk ofcon t rac t i ng i n f l uenza o rdeve lop ing compl icat ions•Aged 6 months--4 years (59months), 50 years and older

•Persons who have chronicdiseases, including:- pulmonary (including asthma)- cardiovascular (except

iso lated hypertens ion)- renal- hepatic- neurologic condition that can

compromise respiratoryfunction and the handling ofrespiratory secretions, orincrease risk of aspiration e.g.cognitive dysfunction, spinalcord in ju r ies , se izuredisorders, neuromusculardisorders)

- hematological (including

hemoglobinopathies such assickle cell disease)

- metabolic disorders (includingdiabetes mellitus)

• Immunosuppressed individuals(including HIV infection especiallyif CD4 < 200 cells/μ'b5L, organor hematopoietic stem cellt r a n s p l a n t a t i o n ,immunosuppression caused bymedications)

•Women who will be pregnantduring the influenza season (ACIPalso recommends vaccination forpregnant women regardless ofthe stage of pregnancy)

•Children/adolescents aged 6months to 18 years receivinglong-term aspirin therapy as theymight be at risk of Reye'ssyndrome after influenza virusinfection

•Residents of nursing homes andother long-term care facilities

•Health-care personnel•Household contacts andcaregivers of children aged <5years and adults aged 50 yearsand older, and of persons withmedical conditions that put themat higher r isk for severecomplications from influenza

•Asplenic individuals- influenza isa risk factor for secondarybacterial infections that cancause severe disease amonesuch patients.

Vaccination should be offered as soonas the vaccine becomes available,ideally by October in the northernhemisphere and May in the southernhemisphere. Although influenzaoutbreaks occur almost exclusivelyduring winter in temperate regions,they occur throughout the year in thetropical countries. For countries inequatorial regions, epidemiologicalfindings will influence the decision toadopt the northern or southern vaccineby the national or regional authorities.

Protection from the viruses containedin the vaccine starts about 2 to 3 weeksfollowing the injection. Vaccinationshould be repeated annually even ifthe previous year’s vaccine containedone or more of the antigens found inthe current vaccine as immunity

declines over the course of the year.

C O N T R A I N D I C A T I O N S /PRECAUTIONSEgg allergy is a relative contraindicationto the influenza vaccine as there couldbe residual egg protein due to thevaccine being prepared from virusesgrown in eggs. The Food AllergyManagement Guidelines issued by theMinistry of Health of Singapore statesthat “Patients with egg allergy who needthe influenza vaccine should be referredto a clinical facility experienced in themanagement of anaphylaxis”.4

Vaccination should be avoided inpersons with history of Guillain-Barresyndrome (GBS) or those whodeveloped GBS within 6 weeks after aprevious influenza immunization, unlessbenefit outweighs risk. Antiviralchemoprophylaxis may be consideredin these patients.

In cases of febrile illness or acuteinfection, vaccination should bepostponed until symptoms haveresolved. In immunocompromizedpatients, the antibody response may belower.

Appropriate medical treatment (includingadrenaline) and supervision should beavailable in case of anaphylacticreactions.

Intramuscular injection of TIV should becarried out cautiously in a patient withthrombocytopenia or coagulationdisorder. The patient should beinstructed about the risk of hematomafollowing the injection.

Safety and efficacy of use in children <6months of age have not been established.

Vaccination may not fully protect againstcontracting influenza, hence vaccinatedpatients should be reminded to seekmedical treatment if symptoms ofinfluenza arise. We could still developinfluenza if we are exposed to the virusimmediately before or after vaccination.

P R E G N A N C Y A N DBREASTFEEDINGChanges in the immune system, heart,and lungs during pregnancy increase


11:

the risk of influenza complications inthe mother and foetus, includingpremature labor and delivery. As thereis currently still limited data withinfluenza vaccination in pregnantwoman, influenza vaccine is listed asUS FDA pregnancy category C andAustralian Drug Evaluation Committee's(ADEC) Category B2. US FDApregnancy category C means thatstudies in animals have revealedadverse effects on the foetus(teratogenic or embryocidal or other)and there are no controlled studies inwomen or studies in women andanimals are not available. ADECCategory B2 is used to designate drugswhich have been taken by only a limitednumber of pregnant women andwomen of childbearing age, withoutan increase in the frequency ofmalformation or other direct or indirectharmful effects on the human fetushaving been observed. Also, studiesin animals are inadequate or may belacking, but available data show noevidence of an increased occurrenceof fetal damage. CDC’s ACIPrecommends that all pregnant or wouldbe pregnant women be vaccinated toprotect themselves and their infantswho cannot yet be vaccinated.

It is not known whether inactivatedinfluenza vaccine is excreted in humanmilk. Thus, caution should be exercisedwhen the vaccine is administered to anursing woman. According to ThomsonLactation Rating, the subvirion-inactivated vaccine poses minimal riskto the infant during breastfeeding. Fromthe literature, infants and young childrenare at high r isk for inf luenzacomplications; hence vaccination withthe inactivated influenza virus vaccineis recommended for nursing womenunless contraindicated (CDC, 2009).

DOSAGE/POSOLOGYInfluenza seasons vary in their timingand duration year to year. Hence, theoptimal time to be vaccinated liesbetween October and November priorto exposure to influenza. The vaccineis administered via intramuscular ordeep subcutaneous injection. It shouldbe well shaken, and brought to roomtemperature before use.For most of the available single-dose

TIVs, the recommended dosages (1dose per season) are:• Adults and children older than 36

months: 0.5ml intramuscularly inthe deltoid muscle using a ≥'5f1inch needle.

• Children from 6 months to 35months: 0.25ml (push the plungerstopper to the edge of the mark ofthe syringe to eliminate half thevolume and inject the remaininghalf). Children of 6 months through2 years of age should be vaccinatedin the anterolateral aspect of thethigh, using a 7/8 to 1 inch needle.

• The ACIP recommends that infantsand children aged ≤'5f9 years notpreviously vaccinated shouldreceive two doses of H1N1influenza vaccine at least 4 weeksapart. They should preferablyreceive their first dose in Septemberso that both doses can beadministered prior to onset ofinfluenza activity.

The vaccine should be stored at 2-8degree Celsius, protected from light.

PHARMACOKINETICSProtective antibody titres are expectedto be attained about 2 weeks aftervaccination. Protective antibody titrescan be sustained for approximately≥'5f6 months. In elderly, the antibodytitres may fall ≤'5f4 months aftervaccination.

DRUG-DRUG INTERACTIONSThe influenza vaccine can be given atthe same time as other vaccines onseparate limbs. However, the sideeffects may be intensified.

Immunological response may decreaseduring concurrent immunosuppressanttreatment, such as corticosteroids,cytotoxic drugs or radiotherapy.

ADVERSE EFFECTSThe inactivated vaccines are generallywell tolerated. The most common sideeffect reported was mild arm soreness.Others (≥'5f2%) include headache,low-grade fever, chills, myalgia,arthralgia, malaise (which may startwithin 6-12 hours), upper respiratorysymptoms (such as nasopharyngitis),and local reactions such as redness,

swelling, pain, bruising, induration atthe site of injection. These reactionsusually disappear within 1-2 dayswithout treatment.

From post-marketing surveillance, rareside effects include allergic reactionsincluding anaphylaxis, shock,angioedema, skin reactions, vasculitiswith transient renal impairment,neuralgia, paraesthesia, febrile fits,neuromuscular disorders that mayresult in stiff neck, confusion,numbness, pain and weakness oflimbs, loss of balance, gradual loss ofreflexes, paralysis of part or all of thebody (encephalomyelitis, neuritis,Guillain-Barre Syndrome).

A slightly increased risk of Guillain-Barre syndrome has been associatedwith the influenza vaccine duringcertain influenza seasons. A studyundertaken by Nachamkin et al in 2008found that inoculation of the 1976swine flu vaccine, as well as the 1991-1992 and 2004-2005 influenzavaccines, into mice promptedproduct ion o f ant ibod ies toantiganglioside (anti-GM1), which arelinked to the development of GBS.5

However, more research would berequired to investigate how influenzav a c c i n e c o m p o n e n t s e l i c i tantiganglioside effects.

Continual surveillance for adverseevents of influenza vaccine is practisedworldwide via the US Vaccine AdverseEvent Report System (VAERS). Initialdata found no substantial differencesin the safety profiles of pandemic H1N1and seasonal influenza vaccines. Ascertain rare adverse events may onlyshow up when a significant number ofpeople have received the vaccine,hence the need for constant vigilanceand prompt reporting of any vaccine-related adverse event. Healthcareprofessionals may also report locallyany vaccine adverse event via CMIS(Critical Medical Information Store)which is linked to HSA’s website.

On August 5, 2010, ACIP published astatement linking Fluvax®'ae andFluvax Jr®'ae (produced by CSLBiotherapies) use during the 2010influenza season to an increased risk


Factor

TABLE 1. Live, attenuated influenza vaccine (LAIV) compared with inactivated influenza vaccine (TIV) for seasonal influenza

* Children aged 6 months--8 years who have never received influenza vaccine before should receive 2 doses. Those who only receive 1 dose intheir first year of vaccination should receive 2 doses in the following year, spaced 4 weeks apart.

† Persons at higher risk for complications of influenza infection because of underlying medical conditions should not receive LAIV. They include:adults and children with chronic disorders of the pulmonary or cardiovascular systems; adults and children with chronic metabolic diseases(including diabetes mellitus), renal dysfunction, hemoglobinopathies, or immunnosuppression; children and adolescents receiving long-termaspirin therapy (at risk for developing Reye syndrome after wild-type influenza infection); persons who have any condition (e.g., cognitivedysfunction, spinal cord injuries, seizure disorders, or other neuromuscular disorders) that can compromise respiratory function or the handlingof respiratory secretions or that can increase the risk for aspiration; pregnant women; and residents of nursing homes and other chronic-carefacilities that house persons with chronic medical conditions.

§ Clinicians and immunization programs should screen for possible reactive airways diseases when considering use of LAIV for children aged 2--4 years and should avoid use of this vaccine in children with asthma or a recent wheezing episode.

¶ LAIV coadministration has been evaluated systematically only among children aged 12--15 months who received measles, mumps, and rubellavaccine or varicella vaccine.

** TIV coadministration has been evaluated systematically only among adults who received pneumococcal polysaccharide or zoster vaccine.Source: Prevention &Control of Seasonal Influenza with Vaccines - Recommendations of the Advisory Committee on Immunization Practices (ACIP)2009. MMWR 2009 Jul 24; Early Release:1-52. Available at: http://www.cdc.gov/flu/professionals/acip/composition0910.htm

Route of administration

Type of vaccine

No. of included virus strains

Vaccine virus strains updated

Frequency of administration

Approved age

Interval between 2 doses recommended for childrenaged 6 mos and older -- 8 yrs who arereceiving influenza vaccine for the first time

Can be administered to persons with medical risk factorsfor influenza-related complications†

Can be administered to children with asthma or childrenaged 2--4 yrs with wheezing in the past year§

Can be administered to family members or close contactsof immunosuppressed persons not requiring a protectedenvironment

Can be administered to family members or close contactsof immunosuppressed personsrequiring a protected environment (e.g., hematopoieticstem cell transplant recipient)

Can be administered to family members or close contactsof persons at high risk but notseverely immunosuppressed

Can be simultaneously administered with other vaccines

If not simultaneously administered, can be administeredwithin 4 wks of another live vaccine

If not simultaneously administered, can be administeredwithin 4 wks of an inactivated vaccine

Intranasal spray

Live virus

Three (two influenza A, oneinfluenza B)

Annually

Annually*

Persons aged 2–49 yrs†

4 weeks

No

No

Yes

No

Yes

Yes¶

Space 4 wks apart

Yes

Intramuscular injection

Noninfectious virus (i.e.,inactivated)

Three (two influenza A, oneinfluenza B)

Annually

Annually*

Persons aged 6 months andolder

4 weeks

Yes

Yes

Yes

Yes

Yes

Yes**

Yes

Yes

LAIV TIV


13:

of febrile seizures in children aged 6months through 4 years, andFluvax®'ae and Afluria®'ae to a higherfrequency of reported fever in childrenaged 5 years through 8 years comparedto previous seasons. The rate of febrileseizures following Fluvax®'ae or FluvaxJr®'ae was est imated to beapproximately 1 per 100 dosesadministered among children aged 6months through 4 years. In view of this,ACIP recommends that these brandsof vaccines should be avoided inchildren aged 6 months to 8 years inthe 2010-11 influenza season unlessno alternatives exist and the benefitsoutweigh the risks.6

OTHER RECENT DEVELOPMENTSThe US FDA approved rapid tests fordetecting the 2009 H1N1 influenza viruson June 21, 2010. For example, the3M™ Rapid Detection Flu A+B Testtakes less than 15 minutes to perform.It detects and distinguishes betweeninfluenza A and B. Acceptablespecimens are nasopharyngealswab/aspirate, nasal wash/aspirate. Incontrast, reverse transcriptionpolymerase chain reaction (RT-PCR)takes 2 to 4 hours and viral culture 3to 10 days. According to the CDC,sensitivity is of rapid diagnostic testsis approximately 50-70% comparedwith viral culture or RT-PCR andspecificity is approximately 90-95%.7

The CDC no longer endorsesmandatory influenza vaccination forhealthcare workers, and now

recommends surgical facemasksinstead of the N-95 respirators forhealthcare workers during contact withinfluenza patients. This follows therecommendation previously made bythe Association of Professionals inInfection Control, the InfectiousDiseases Society of America and theSociety for Healthcare Epidemiologyof America.8

On August 10, 2010, WHO haddeclared the H1N1 influenza pandemicofficially over, and the outbreak hadentered the postpandemic period.Nonetheless, the WHO Director-GeneralDr Margaret Chan cautioned that the2009 H1N1 influenza virus has notdisappeared and still poses a risk forserious illness, especially for youngchildren, pregnant women, and personswith respiratory or chronic illnesses.

CONCLUSIONSThe experience of handling the recentinfluenza epidemics have led toimprovements in policies, vaccines,medications and diagnostics. However,influenza is a constantly evolvingdisease and medical practitioners andpolicy-makers have to keep abreast ofnew developments.

FURTHER READING• h t tp : / /www.medscape .com/

resource/influenza• h t t p : / / w w w . c d c . g o v / f l u /

professionals/• http://www.who.int/csr/disease/

influenza/en/

• http://www.hsa.gov.sg/publish/hsaportal/en/for_consumers/influenza_a_h1n1/h1n1_vaccines/about_hsa_regulatory.html

• Hibberd PL, Jun 2010, Seasonalinfluenza vaccination in adults;Thorner AR, Feb 2010, PandemicH1N1 influenza (‘swine influenza’)vaccine. UpToDate 2010. Availableat: www.uptodate.com

• Inf luenza Virus Vaccine. In:DRUGDEX® System. ThomsonH e a l t h c a re . Av a i l a b l e a t :h t t p : / / w w w. t h o m s o n h c . c o m

• Vaxigrip® Influenza Vaccine ProductInformation

• Influvac® Influenza Vaccine ProductInformation

References

1. Beran J VT, Wertzova V, et al. Efficacy of inactivated split-virus influenza vaccine against culture-confirmed influenza in healthy adults: a prospective, randomized,

placebo-controlled trial. J Infect Dis 2009; 200: 1861. Jefferson TO, Di Pietrantonj, Rivetti D C, et al: Vaccines for preventing influenza in healthy adults. Cochrane Database

Syst Rev 2007; CD001269.

2. Sprenger MG, Mulder PG, Beyer WE: Impact of influenza on mortality in relation to age and underlying disease, 1967-1989. Int J Epidemiol 1993; 22:334.

3. Barclay L. ACIP Updates Guidelines for Prevention and Control of Influenza With Vaccines, adapted from: MMWR Morb Mortal Wkly Rep. July 29, 2010;59 (Early

Release);1-62. Available at: http://www.medscape.com/viewarticle/726213?src=mp&spon=30&uac=144214PT. Assessed August 13, 2010.

4. M a n a g e m e n t o f f o o d a l l e r g y . A M S - M O H C l i n i c a l P r a c t i c e G u i d e l i n e s 2 / 2 0 1 0 . A v a i l a b l e a t

http://www.moh.gov.sg/mohcorp/uploadedFiles/Publications/Guidelines/Clinical_Practice_Guidelines/Management%20of%20Food%20Allergy_Final%28A5%29.pdf

5. Nachamkin I, Shadomy SV, Moran AP, Cox N, Fitzgerald C, Ung H, et al. Anti-ganglioside antibody induction by swine (A/NJ/1976/H1N1) and other influenza vaccines:

insights into vaccine-associated Guillain-Barré'e9 syndrome. J Infect Dis. Jul 15 2008; 198:226-33.

6. ACIP Recommendation for Use of CSL Influenza Vaccine. Media statement. Available at: http://www.cdc.gov/media/pressrel/2010/s100806.htm Assessed August 13,

2010.

7. Press release: new CDC test to detect human infections with the 2009 H1N1 influenza virus authorized for use by FDA. June 22, 2010. Available at:

http://www.cdc.gov/media/pressrel/2010/r100622.htm Accessed August 12, 2010.

8. CDC. Updated guidance: prevention strategies for seasonal influenza in healthcare settings. Federal Register June 22, 2010;75. Available at:

http://edocket.access.gpo.gov/2010/2010-15015.htm Accessed August 12, 2010.

Ms Serene Tan is a Pharmacist in theDepartment of Pharmacy, Tan Tock SengHospital.


DISCUSSIONPhaeochromocytomas are rarecatecholamine secreting tumors arisingfrom the chromaffin cells of the adrenalmedulla or sympathetic ganglia(paraganglioma). The prevalence ofphaeochromocytoma in patients withhypertension is 0.1–0.6% in the generaloutpatient setting.1-2 Its incidence inpregnancy is not known. There havebeen at least 200 cases reported inpregnancy and the prevalence isestimated at 1 in 54 000.3-4 It isimportant to suspect and diagnosethese tumors because:• Undiagnosed tumors have been

associated with significant maternaland fetal mortality (up to 48% and

54.4% respectively in one earlyreport);5

• Hypertension is potentially curablewith resection of the tumor;

• The cardiovascular complicationsare potentially lethal;

• At least 10% of these tumors aremalignant; and

• A hereditary basis may be found inup to 24% of patients and detectionof phaeochromocytoma in theproband may result in earlydiagnosis in other affected familymembers.6-8

The most common clinical presentingfeatures of phaeochromocytomainclude headaches, palpitations,

diaphoresis and hypertension. Othersymptoms such as nausea, flushingand anxiety are non-specific and canbe easily overlooked especially in apregnant woman. Frequent headachesin our patient had been misdiagnosedas migraine. Phaeochromocytomashould be suspected in patients withparoxysmal signs and symptoms, inthose with treatment-resistant or labilehypertension and in those whodemonstrate a paradoxical bloodpressure response during surgery andanaesthesia. In our patient, anadditional clue was an elevatedhaemoglobin level and haematocrit,both of which have been observed inpatients with phaeochromocytomas.

Case Report

More than just

a headacheCase PresentationA 25-year-old woman was admitted to our hospital with acute onset of left-sided headache associated with vomitingbut without aura, photophobia or neurological deficits. She had recurrent headaches for the past 2 years that had beendiagnosed as migraine. She did not report palpitations or diaphoresis. Clinical examination was unremarkable exceptfor an elevated blood pressure of 180/110 mmHg. She was treated for migraine and hypertension with ibuprofen,metoclopramide and atenolol. When seen in the outpatient clinic 4 weeks later, she reported a missed period and wasconfirmed to be pregnant. Her blood pressure remained severely elevated at 200/110 mmHg. The 24 hour urinaryvanillyl mandelic acid was elevated at 77.7 umol/day. On account of her pregnancy and suspected phaeochromocytoma,atenolol was stopped and substituted with long-acting nifedipine. Further investigations were consistent withphaeochromocytoma (table 1). She was started on phenoxybenzamine followed later by atenolol. At 8 weeks’ gestation,ultrasound scan failed to detect any fetal heart activity. This was followed by spontaneous complete miscarriage 3weeks later. The computerised tomography (CT) scan of the abdomen showed a 38x36x29 mm heterogeneous enhancingmass arising from the right adrenal gland. Following adequate control of her blood pressure, laparoscopic rightadrenalectomy was performed. Histopathology was consistent with adrenal phaeochromocytoma with no overt malignantfeatures. Her blood pressure normalised post-operatively and anti-hypertensive medications were discontinued. The24-hour urinary catecholamines and metanephrines were normal 3 months later.

Reference range

11.0–15.00 g/dl

35.0–45.0%

0–34.3 mmol/day

3–109 noml/day

89–473 nmol/day

600-1900 nmol/day

59–413 nmol/day

0.63–3.08 mg/L/h

97.3–834 pmol/L

Test

Haemoglobin

Haematocrit

24-hour urinary vanillyl mandelic acid

24-hour urinary norepinephrine

24-hour urinary metanephrines

24-hour urinary normetanephrines

24-hour urinary free cortisol

Plasma renin activity

Serum aldosterone

Preoperative

16.6 g/dL

48.8%

77.7 mmol/day

157 noml/day

9577 nmol/day

22 253 nmol/day

216 nmol/day

11.75 mg/L/h

1119.2 pmol/L

Postoperative

12.1 g/dL

35.4%

Not done

10 nmol/day

229 nmol/day

1344 nmol/day

Not done

Not done

Not done

Table 1. Investigations supporting the diagnosis of phaeochromocytoma.


In our patient the haemoglobin andhaematocrit normalized followingvolume expansion prior to surgery.

Raised plasma renin activity and

aldosterone levels have been observedin patients with phaeochromocytomasecondary to the norepinephrine-induced renin release contributing tothe hypertension. Moreover, the rennin-

angiotensin-aldosterone system isactivated as a physiological responseto pregnancy.

Early diagnosis and treatment has beenshown to reduce morbidity andmortality for the mother and thefoetus.4, 9, 10 In pregnancy, paroxysmscan be precipitated by stress,increasing intra-abdominal pressure,medications such as metoclopramide,foetal movements and vaginal delivery.The ensuing hypertensive crisis canbe detrimental to both mother andfetus. Adverse pregnancy outcomesinclude spontaneous abortion (as inour patient), intrauterine growthrestriction and foetal death.

Catecholamine production generallyremains unchanged during pregnancy.The initial and essential step indiagnosing phaeochromocytoma isbiochemical confirmation of excessivecatecholamine production. The mostsensitive tests are measurements ofplasma free metanephrines or urinaryf r a c t i o n a t e d m e t a n e p h r i n e s(normetanephrines and metanephrines)mainly because production of O-methy lated metabol i tes f romphaeochromocytomas is continuousand independent of the highlyvariable release of catecholamines(table 2).11-12

It is important to remember that foodsand drugs such as t r icyc l ica n t i d e p re s s a n t s , c l o n i d i n e ,methyldopa, prochlorperazine,decongestants and alcohol canincrease measured leve ls ofcatecholamines and metanephrines,giving rise to false positive results. Themagnitude of increase is much greaterin patients with phaeochromocytomacompared with false positives. Theclonidine suppression test can alsohelp to differentiate true positive fromfalse positive results. This test, however,has not been validated in pregnancy.

Following biochemical confirmation,the next step is localization of thetumor. This can be done by ultrasound,CT scan or magnetic resonanceimaging (MRI) of the abdomen (masswith bright signal on T2-weightedimage). Ultrasound scans are safe but

15:

Test

Plasma free metanephrines

Plasma catecholamines

Urinary catecholamines

Urinary fractionated metanephrines

Urinary total metanephrines

Urinary vanillyl mandelic acid

Sensitivity (%)

99

84

86

97

77

64

Specificity (%)

89

81

88

69

93

95

Table 2. Sensitivity and specificity of biochemical tests for diagnosis of phaeochromocytoma.


less reliable. CT scan and MRI havesimilar sensitivities (90-100%) andspecificities (70-80%). MRI is thepreferred modality during pregnancyas it is free from ionizing radiation.Funct ional imaging with 1 2 3 I-metaiodobenzylguanidie (MIBG) isindicated mainly for those with extra-adrenal or large (>5cm) adrenal tumorsbecause of increased risk of malignantdisease or in those with suspectedmulti-focal disease. It should beavoided during pregnancy.

Familial phaeochromocytomas suchas von Hippel Lindau syndrome,multiple endocrine neoplasia type 2,neurofibromatosis type I and familialparaganglioma occur rarely. Genetictesting should be considered in thosewith a positive family history, thosewho are young (<50 years of age),t h o s e w i t h b i l a t e r a lphaeochromocytomas or multifocalextra-adrenal disease or those withassociated tumors.13

Definitive treatment requires surgicalresection of the tumor. The optimaltiming for surgery is during the latefirst trimester or early second trimester.When diagnosed in the late second orthird trimester phaeochromocytoma isbest managed medically until close toterm when combined caesareansection followed by tumor resectioncan be performed. Vaginal deliveryshould be avoided as it may trigger ahypertensive crisis. The laparoscopicapproach is now the preferredtechnique for tumors which are smaller

than 6cm as it is associated with lowerpostoperative morbidity and shorterhospital stay compared to conventionallaparotomy. The complication rate oflaparoscopic adrenalectomy is lessthan 8% and operative mortality rateis less than 1% in experiencedcentres.13 Appropriate pre-operativemedical management to controlhypertension is essential to preventcatecholamine-induced complicationsduring surgery including hypertensivecrises, cardiac arrhythmias, pulmonaryoedema and cardiac ischaemia. Bloodpressure should be normalised 2weeks before surgery. Alpha-blockadew i t h d r u g s s u c h a sphenoxybenzamine, prazosin anddoxazosin is started followed severaldays later by beta-blockers to minimisereflex tachycardia. Amongst the alpha-blocking agents, phenoxybenzamineis the most common drug used duringpregnancy. Phenoxybenzamine hasbeen shown to cross the placenta andneonatal hypotension has beenreported in newborns of motherstreated with the drug prior to delivery.14-

17 Prazosin has been used to treatmaternal hypertension although onerandomised contro l led studycomparing nifedipine and prazosin asa second line agent to treat severeearly hypertension in pregnancy notedthat there were more intra-uterinedeaths in the prazosin group.16 Therehave been no reports on the use ofdoxazosin in pregnancy. Beta-blockersmay be added if tachyarrhythmia ispresent but it should not be startedbefore alpha-blockade as the

unopposed alpha-adrenoceptorst imulat ion can precipitate ahypertensive crisis. Intravenousphentolamine (by bolus or continuousinfusion) is the agent of choice tocontrol hypertension intraoperatively.Labetalol (alpha- and beta-adrenergicantagonist) has been used forpreoperative adrenergic blockade,however it has a fixed alpha- to beta-adrenergic blocking effect (1:7) whichmay result in paradoxical hypertensivecrisis. Anaesthetic agents which cantrigger hypertensive crisis such asfentanyl, ketamine, halothane anddesflurane should be avoided.

Following successful surgical resection,blood pressure normalises althoughhypertension may persist in nearly 50%of patients.17 Recurrent disease of 17%has been reported in those with extra-adrenal disease and with familialdisease.18 All patients should undergoyearly surveillance for at least 10 yearsafter surgery. For those with familialphaeochromocytoma or extra-adrenaldisease, follow-up should be indefinitebecause of the higher risk of recurrentdisease.

SUMMARYE a r l y d i a g n o s i s o fphaeochromocytoma requires a highindex of suspicion. Patients with thetypical triad of headache, sweatingand palpitations in the presence ofresistant or labile hypertension shouldbe evaluated for phaeochromocytoma.The most sensit ive tests aremeasurements of plasma free

Figure. AP (left) and transverse CT images of the right adrenal mass (arrowheads).


17:

References

1. Omura M, Saito J, Yamaguchi K et al. Prospective study on the prevalence of secondary hypertension among hypertensive patients visiting a general outpatient clinic in

Japan. Hypertens Res 2004; 27-193-202.

2. Sinclair AM, Isles CG, Brown I et al. Secondary hypertension in a blood pressure clinic. Arch intern Med 1987; 147:1289-93.

3. Grodski S, Jung C, Kertes P et al. Paheochromocytoma in Pregnancy. Internal Medicine Journal 2006; 36:604-4.

4. Lindsay JR, Nieman LK. Adrenal Disorders in Pregnancy. Endocrinol Metab Clin N America 2006; 35:1-20.

5. Schenker JG, Chowers I. Pheochromocytoma and pregnancy. Review of 89 cases. Obstet Gynecol Surv 1971; 26:739-47.

6. Neumann HP, Bausch B, McWhinney SR, et al. Germ-line mutations in non-syndromic pheochromocytoma. N Engl J Med 2002; 346:1459-66.

7. Bryant J, Farmer J, Kessler LJ et al. Pheochromocytoma: the expanding genetic differential diagnosis. J Natl Cancer Inst 2003; 95: 1196-204.

8. Bauters C, Vantyghem MC, LeteurtreE, et al. Hereditary phaeochromocytoma and paragangliomas: s study of five susceptibility genes. J Med Genet 2003; 40:e75.

9. Stenstrom G, Swolin K. Pheochromocytoma in pregnancy. Experience of tretment with phenoxybenzamine in three patients. Acta Obstet Gynecol Scand 1985; 64:357-61.

10. Ahlawart SK, Jain S, Kumari S, Varma S et al. Pheochromocytoma associated with pregnancy: case report and review of the literature. Obstet Gynecol Surv 1999; 54:728-

37.

11. Lenders JW, Pacak K, Walther MM et al. Biochemical diagnosis of pheochromocytoma: which test is best? JAMA 2002; 287:1427-34.

12. Sawka AM, Jaeschke R, Singh RJ et al. A comparison of biochemical tests for pheochromocytoma: measurement of fractionated plasma metanephrines compared with

the combination of 24-hour urinary metanephrines and catecholamines. J Clin Endocrinol Metab 2003; 88:553-8.

13. Lenders JWM, Eisenhofer G, Mannelli M et al. Phaemochromocytoma. Lancet 2005; 366:665-75.

14. Santeiro ML, Stromquist C, Wyble L. Phenoxybenzamine placental transfer during the third trimester. Ann Pharmacother 1996; 30:1249-50.

15. Aplin SC, Yee KF, Cole MJ. Neonatal Effects of Long-term Phennoxybenzamine Therapy. Anesthesiology 2004; 100:1608-10.

16. Hall DR, Odendaal HJ, Steyn DW et al. Nifedipine or prazosin as a second agent to control early severe hypertension in pregnancy: a randomized controlled trial. BJOG

2000; 107:759-65.

17. Plouin PF, Chatellier G, Fofol I et al. Tumour recurrence and hypertension persistence after successful pheochromocytoma operation. Hypertension1997; 29:1133-9.

18. Amar L, Servais A, Gimenez-Roqueplo AP et al. Year of diagnosis, features at presentation and risk of recurrence in patients with pheochromocytoma or secreting paraganglioma.

J Clin Endocrinol Metab 2005; 90:2110-1

metanephrines or urinary fractionatedmetanephrines. MRI is the preferredimaging modality for radiologicallocalisation of the tumor duringpregnancy. Alpha-adrenergic blockadeusing phenoxybenzamine should beused for pre-operative management ofhypertension. Neonates born tomothers receiving phenoxybenzamineprior to delivery should be closelymonitored for hypotension. Inpregnancy, depending on the gestationat which diagnosis is made, the optimaltiming for surgery is during the late firstor second trimester. When pregnancyi s more advanced , med ica lmanagement followed by combinedcaesarean section and tumor resectionc loser to term is pre fer red.Multidisciplinary care involving theendocrinologist, obstetric physician,anaesthesiologist, obstetrician andsurgeon is essential for an optimaloutcome.

Dr Julie George (left) is a consultant in the Department of General Medicine, Tan TockSeng Hospital. Dr Jackie Tan Yu Ling (right) is a senior consultant and Head of theDepartment of General Medicine, Tan Tock Seng Hospital.


RADIOLOGY Quiz

Question 1: What are the abnormalities on these contrast-enhanced CT images?

Question 2: What is the most likely diagnosis?

CLINICAL HISTORYA 51-year-old Malay man was admitted for abdominal pain and vomiting. He also gives a history of chronic epigastricpain and chronic diarrhea for the past ten years.


Figure 1 Figure 2

Figure 3

Question

Answer 1:There are thickened gastric rugae (figure 1) and mucosal folds in the duodenum and jejunum (figure 2) as well as anenhancing lesion at the tail of the pancreas (figure 3).

Answer 2:Zollinger-Ellison syndrome.

Zollinger-Ellison syndrome (ZES) iscaused by a non–beta islet cell, gastrin-secreting tumour of the pancreas whichstimulates the acid-secreting cells oft h e s t o m a c h , r e s u l t i n g i ngastrointestinal mucosal ulceration.

Pancreatic endocrine tumours alongwith hyperparathyroidism and pituitarytumors constitute the autosomaldominant condition Multiple EndocrineNeoplasm (MEN) Type 1.

The diagnosis of ZES is based on acombina t ion o f the c l i n ica lp r e s e n t a t i o n , g a s t r i nradioimmunoassay findings, gastricacid secretory testing, and the findingson diagnostic imaging. The role ofcurrent imaging studies is to evaluatethe tumour, assess for metastases andto detect contraindications to resectionsurgery. Imaging is also utilised in themonitoring of patients followingresection of tumours.

The imaging f indings includehypertrophy of the gastric mucosasecondary to the hypergastrinemia.Gastrointestinal mucosal ulcerationmay also be seen due to the largeamount of acid secretion.

The primary tumour is most frequentlyseen in the pancreas or the duodenum.The tumours are usually small andsubcentimeter in size. They can bemultiple in 20-40% of cases and themajority (two-thirds) of them aremalignant. These tumours are usuallyhypervascular with early arterialenhancement and may occasionallycalcify.

Metastases to the liver can also bedetected as they are also usuallyhypervascular and are best seen onarterial phases of the study.

The study of choice for the initialevaluation of patients with ZES ishowever somatostatin-receptorscintigraphy (SRS) due to the highersensitivity compared to other forms ofimaging. The primary lesion andmetastases all show uptake of theradioisotope (octreotide) and presentas hot spots.

The patient was diagnosed to haveZES as, in addition to the hypervascularpancreatic lesion, his serum gastrinlevel was markedly elevated. He wasalso found to have hypercalcemia andan elevated parathyroid hormone level.

Ultrasound investigations revealed aleft parathyroid nodule which wasconfirmed as a parathyroid adenomaon excision. Given the clinical andradiological findings, the patient wasdiagnosed to have MEN 1 Syndrome.The pancreatic lesion was followed upwith subsequent MR studies and wasstable.

19:

Discussion

Dr Lim Wei Yang is a registrar in theDepartment of Diagnostic Radiology, TanTock Seng Hospital.


Answer

ECG Quiz

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

Figure 2

Figure 1


A 60-year-old has a pacemaker implanted for the problem found in the following ECG (figure 1). A chest x-ray post implantis shown (figure 2). What are the ECG and chest x-ray diagnoses?

Question

Figure 1 shows a 12-lead ECG demonstrating complete heart block. Figure 2demonstrates the presence of a persistent left-sided superior vena cava (SVC).This structure usually disappears after birth or becomes rudimentary. However,on rare occasions it persists and drains into the coronary sinus. The pacemakerleads therefore enters the persistent left SVC to the coronary sinus and exits outinto the right atrium. From the right atrium, both leads are then manipulated intothe right ventricle and right atrial appendage.

Answer

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TTSH Medical Digest Jul-Sept 2010

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