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Medical digest
MICA (P) 031/04/2010

Jul.Aug.Sep. 2010

NHG Eye Institute Ophthalmic Microsurgical Course

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contents
1 8 APPROACH TO SHOULDER PAIN INFLUENZA VACCINES

14 MORE THAN JUST A HEADACHE 18 RADIOLOGY QUIZ 20 ECG QUIZ 22 DIARY DATES

From The Editor

Jul.Aug.Sep. 2010

Doctors live cloistered lives. We transit from school to medical practice, conveniently bypassing the grimmer bits of life. We only have vicarious knowledge of the darker side of society from our patients. A few years ago, I saw a young man for a mild allergy problem. I asked him about his job and was surprised to learn that he wasnt working. He was living off the winnings of a football bet. I asked him about the amount he won, thinking that $10,000 or $100,000 wont last very long. One million dollars, he replied, But the trick was to collect the money from the bookie and leave safely. I treated a HIV-positive young man for cotrimoxazole allergy. He enlightened me on the finer points of selling illegal CDs. It brought financial security if one kept at it for two to three years. An old man who did not mind spending some time in prison for money would be employed as scapegoat should the shop be raided by the authorities. The way to convince 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. He was muscular and tattooed and wouldnt be out of place in Shinjuku Kabukicho. He woke up the next day and was fully alert by the third. He was extremely articulate in English. Before he went home (he was on bail 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 is the use of a long life? Doctors are privileged members of society. Our patients remind how fortunate we are everyday.

EDITOR
Dr Leong Khai Pang

MEMBERS
Dr Jackie Tan Dr Jaideepraj Rao Dr Lee Cheng Chuan Dr Chong Yaw Khian Dr David Foo Dr Gregory Kaw Dr Nikolle Tan Dr Ernest Kwek Ms Lim Wan Peng

EDITORIAL ASSIST ANT

Ms Michelle Lee

DESIGNE R
Ms Zaonah Yusof

We value your feedback. Please email your questions, comments or suggestions to: med_digest@ttsh.com.sg Please also contact us for notification of change of postal address or for requests of additional copies.

Dr Leong Khai Pang EDITOR Medical Digest

While every endeavour is made to ensure that information herein is accurate at the time of publication, Tan Tock Seng Hospital shall not be held liable for any inaccuracies. The opinions expressed in this publication do not necessarily reflect those of Tan Tock Seng Hospital. The contents of this publication may not be reproduced without written

permission from the publisher.

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Review

Approach to

Shoulder Pain
Shoulder pain is the third most common musculoskeletal complaint in the general population. Shoulder problems account for 5% of all general practitioner musculoskeletal visits. The peak incidence occurs in patients between 40 and 60 years of age. Patients usually present with pain during overhead activities, night pain, stiffness and/or weakness of the arm. They are often diagnosed as suffering from idiopathic frozen shoulder, and sometimes inappropriately treated with nonsteroidal 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 the common diagnosis of frozen shoulder. EXAMINATION OF THE SHOULDER To distinguish these conditions, a thorough examination of the shoulder is required, coupled with investigations on occasion. This includes locating the exact site of tenderness by careful palpation, testing the active and passive range of motion of the shoulder, determining the strength of the individual rotator cuff muscles, as well as the use of special provocative tests. This is a suggested examination scheme: a. Expose both shoulders and observe if there are asymmetry, bony abnormalities, swelling, erythema, wasting (especially of the supraspinatus, infraspinatus or deltoid). b. Palpate all bony landmarks, starting from the medial end of the clavicle and proceeding laterally. At the lateral end of the clavicle, examine the acromioclavicular joint. Move inferiorly to palpate the bicipital groove, lesser tuberosity, joint line and coracoid process. Proceed laterally to palpate the supraspinatus and infraspinatus muscles and greater tuberosity and

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then posteriorly to palpate the spine of the scapula. c. Put the joint through the range of motion in all planes. The patient is asked to raise the arms in the sagittal plane and then the coronal plane. External and internal rotation can be assessed both with the shoulders at 90-degree abduction as well as in the adducted position by the side of the body. Active internal rotation can also be tested by asking the patient to put his hand on his own back and try to touch the contralateral scapula (Apleys scratch test). He should be able to touch the medial border. Alternatively, count the highest

vertebra that he can reach with his index finger tip (for reference, the angle of the scapula is at T7). d. The power of the muscles is tested next. Shoulder flexion, extension, abduction, adduction, internal and external rotation are tested and graded 0 to 5. Supraspinatus strength is tested in abduction. External rotation is powered by the infraspinatus and teres minor. Int er nal rot at i on t est s t he subscapularis muscle. e. Special tests are performed as directed by the history, location of pain or indicators from the preceding examination. The table lists some of the most well known

manoeuvres. Unfortunately, goodquality sensitivity and specificity data are established only for very few of the tests.1 It is probably better to use tests together than in isolation. One study showed that the presence of three positive tests (supraspinatus weakness, weakness in external rotation and detection of impingement) were highly diagnostic of rotator cuff tears.2 Sometimes, a diagnostic hydrocortisone-and-lignocaine (H & L) injection into the suspected location of pathology can confirm the diagnosis and may even be therapeutic.

Table. Special tests of shoulder function and pathology.

Test Jobes test or empty can test

Purpose Test of supraspinatus strength, especially in the assessment of a tear

Method The shoulders are abducted to 90, the arms brought to the scapular plane (about 30'b0 to the coronal) and the thumbs point downwards. The patient resists the examiners attempt to adduct the shoulder (figure 1). Standing behind the seated patient, the examiner brings the patients elbow to 90 flexion and the shoulder to 20 abduction in the scapular plane. The examiner puts the shoulder into maximum external rotation minus 5 to allow for elastic recoil of the joint. The examiner keeps supporting the elbow but releases the arm and asks the patient to maintain the position. The arms are raised 190 and then gradually brought down.

What to look for Pain or weakness

External rotator lag sign3

Test for tears of the supraspinatus

The test is positive if a lag or angular drop occurs.

Drop-arm test

Test for supraspinatus tear

The patient is unable to control the gradual descent of the arm and it falls suddenly, suggesting a complete tear. The patient is unable to lift the palm or is weak against resistance

Gerbers lift-off test

Test of subscapularis strength

The patient is asked to place his hand on his back at the lumbar level, with the palm facing out. He is told to lift the palm off the back against resistance. This test is used if the patient is unable to internally rotate the shoulder. In this case, the hand is placed flat on the abdomen with the elbow forwards. The patient is asked to resist an external rotating force applied by the examiner (figure 2).

Belly press test

Test of subscapularis strength

The subscapularis is weak if the elbow drops and goes around the side of the body.

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Test Infraspinatus strength test

Purpose Test of infraspinatus strength

Method The patients shoulder is kept adducted while the elbow is brought to 90 flexion. The shoulder is now internally rotated 45. The examiner applies a medial or internal rotating force (figure 3). With the elbow extended, the shoulder is flexed forwards to 90 and internally rotated. The arm is then raised fully. With the elbow bent at a right angle, the shoulder is flexed forwards to 90'b0. Now, the shoulder is internally rotated (figure 4). The shoulder is adducted and the elbow flexed to 90. The patient is asked to supinate the forearm and to flex the elbow against resistance. The shoulder is flexed 90, with the elbow extended and the forearm supinated. The examiner applies downward pressure on the forearm.

What to look for Weakness indicates infraspinatus tear or tendinopathy.

Neers test

Subacromial impingement

Pain at the shoulder is suggestive of impingement.

Hawkins test

Subacromial impingement

Pain with this manoeuvre is suggestive of impingement.

Yergasons test

Biceps tendon pathology

Pain in the bicipital groove indicates tendinopathy.

Speeds test

Biceps tendon pathology

The test is positive if pain is experienced.

Apprehension test

Anterior shoulder instability

The examiner stands behind the patient. The patient shows With one hand to steady the shoulder, the apprehension on his examiner holds the patients forearm and face. pulls the arm upwards and backwards (figure 5). The shoulder is abducted 90 and the examiner internally rotates it and applies pressure along the axis of the humerus through the glenohumeral joint. The shoulder is adducted 10, flexed 90 with the thumb pointing downwards (figure 6). The elbow is extended. The patient is asked to resist the examiners downwards force. If the patient complains of pain, the test is repeated with the thumb pointing upwards. The test is positive if pain or clicking is detected.

Crank test

Labral tear or abnormality

OBriens test or active compression test

Labral tear or abnormality

The shoulder pain is more marked with the thumb pointing downwards than upwards. The test is also considered positive if a click is detected rather than pain. Pain at anterior shoulder as the movement is carried out.

Cross-body adduction test

Acromioclavicular joint disease

The arm is lifted to 90 and is brought across the body, with the hand aiming for the opposite shoulder.

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

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

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

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

Figure 3. The author is testing the patient s infraspinatus. With the shoulder abducted and the elbow flexed 90b0, the patient is asked to resist a medial or internal rotation force.

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

INVESTIGATIONS The standard X-rays of the shoulder are of the anteroposterior and Yscapular views (figure 7). They are useful in looking for subacromial spur or a hooked acromion, which may correlate with positive impingement tests. Sclerosis or osteophytes at the greater tuberosity often indicates degenerative rotator cuff tendons, and a partial or full-thickness tear must be

excluded if the patient does not respond to treatment. Superior subluxation of the humeral head usually represents chronic and large rotator cuff tears. Narrowing of the AC or glenohumeral joint, cyst or osteophyte formation indicates AC joint and glenohumeral joint arthritis, respectively. Calcific tendonitis can be easily diagnosed by the location of calcification in the subacromial space.

Although rare, tumours or metastases may be obvious at the humeral head or neck region. When the diagnosis is still uncertain, or when the need to confirm the diagnosis is essential before surgical treatment, diagnostic ultrasound or MRI is very useful. Diagnostic ultrasound scan is relatively

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shoulder is usually symptomatic in the overhead position. Some patients demonstrate a classic painful arc. Provocative tests such as Hawkins test (figure 4) and Neers test (table 1) are usually positive. Treatment includes scapula and rotator cuff strengthening exercises, and H&L injection into the subacromial space in selected patients. If these measures fail, patient will benefit from arthroscopic subacromial decompression or acromioplasty. Rotator cuff tears Most patients present with shoulder pain during activities, night pain and weakness. A tear can be caused by an acute traumatic event or, more commonly, repetitive overhead activities. Overuse-related rotator cuff tears typically occur after the age of forty years. Clinically, there is usually pain and weakness of the supraspinatus tendon in abduction. In massive and chronic tears, pseudoparalysis occurs, when the patient is unable to actively abduct but is able to hold the arm in the overhead position. There may be obvious wasting of the supraspinatus muscle on the scapula in chronic cases. Palpation of the space between the acromion and the greater tuberosity may reveal a gap in the supraspinatus tendon.4 An ultrasound or MRI is required to confirm the diagnosis (figure 9) and determine the size of the tear, as well as to look for atrophy and fatty infiltration of the supraspinatus muscle which if present, indicates longstanding tear and predict poor outcome even after surgical repair. Treatment depends on the age and functional demands of the patient, as well as the size and severity of the tear. Patients with partial-thickness rotator cuff tears may respond to NSAIDs and physical therapy consisting of gentle strengthening and stretching exercises. Should nonoperative treatment fails, arthroscopic decompression and debridement often relieve the symptoms. Symptomatic patients with full thickness tears will require surgical repair, which can be

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

Figure 8. The arrow indicates a subacromial spur.

cheap and is good for the diagnosis of impingement syndrome, rotator cuff tendonitis or tears, and biceps tendonitis or tears. However, its accuracy is highly dependent on the experience of the radiologist or technician. In addition, patients who have already developed severe pain or restriction of shoulder movements may not tolerate the various shoulder positions that are required for a complete ultrasound study. There is also limited ability to look for intraarticular pathology. MRI scan offers the most detailed evaluation of soft-tissue pathologies

of the shoulder and helps tremendously in arriving at a definitive diagnosis. It can also accurately detect intra-articular conditions such as labral tears and cartilage lesions. Unfortunately, its hefty cost is a major deterrent to many patients. COMMON SHOULDER CONDITIONS Subacromial impingement syndrome This is usually caused by a combination of curved or hooked acromion (figure 8) and intrinsic weakness and degeneration of the rotator cuff muscles. The affected

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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, Department of Diagnostic Imaging.

performed nowadays using a miniopen approach or even all-arthroscopic techniques. Acromioclavicular joint degeneration/osteoarthritis This condition is often underdiagnosed. The patient complains of pain at the acromioclavicular (AC) joint in overhead positions and when lying on the affected shoulder during sleep. Clinically, there is tenderness at the AC joint. Resisted cross adduction of

the arm accentuates the pain. A diagnostic H&L abolishes the pain rapidly, and may be therapeutic as well. X-rays may reveal mild degenerative changes or typical osteoarthritis changes (figure 10). Patients are advised to avoid overhead activities or lifting heavy loads that worsen the pain. If H & L fails to give a long-lasting pain relief, arthroscopic excision of the distal clavicle to unload the AC joint often gives a good outcome.

Biceps tendonitis or tears Pain and tenderness is usually localised to the proximal bicipital groove. Provocative tests include Speed test and Yergason test (see table 1), which basically stress the biceps tendon in resisted flexion of the e x t e n d e d e l b o w a n d f o re a r m supination, respectively. Ultrasound or MRI will reveal swelling of the tendon and fluids in the bicipital groove. Treatment includes rest, NSAIDS and steroid injection. For recalcitrant cases, arthroscopic biceps tenotomy or tenodesis is usually effective. Patient with a complete tear will develop a Popeye sign of the biceps muscle during elbow flexion. Treatment is conservative with minimal pain and little functional deficit expected after several weeks. Calcific tendonitis This is a relatively uncommon condition which affects predominantly the supraspinatus tendon. The diagnosis can be easily clinched on standard shoulder X-rays (figure 11). Treatment includes rest, NSAIDS and steroid injection. If the patient fails to respond, arthroscopic debridement and release of calcium often helps in the resolution of symptoms. Frozen shoulder or adhesive capsulitis Idiopathic adhesive capsulitis is a poorly understood disorder. It is a

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

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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 shows calcification of the right supraspinatus tendon at a more proximal location (arrow). The MRI image is provided courtesy of Dr Tham Seng Choe, Department of Diagnostic Imaging.

clinical diagnosis with the hallmark of the condition being global restriction of active AND passive range of motion. Risk factors include diabetes, thyroid disorders, female gender and middle age (4060 years). Patients with other primary shoulder conditions who present late may also develop secondary frozen shoulder. Treatment includes NSAIDs therapy and an early physiotherapy program focused on restoring range of motion. For patients who have severe restriction of movements, intra-articular steroid injection with or without hydrodilatation

often helps to accelerate the recovery process. Recalcitrant cases will benefit from manipulation under anaesthesia o r a r t h ro s c o p i c c a p s u l o t o m y. CONCLUSION Arriving at a precise diagnosis for complaints of shoulder pain is within the capability of all doctors. In difficult cases, radiology may help clinch the diagnosis. Many patients can be treated with activity modification and a course of physiotherapy. Surgery is indicated only if conservative treatment fails.

Dr Lee Keng Thiam is Consultant in the Department of Orthopaedic Surgery, Tan Tock Seng Hospital.

References 1. Hegedus EJ, Goode A, Campbell S, Morin A, Tamaddoni M, Moorman CT 3rd, Cook C. Physical examination tests of the shoulder: a systematic review 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; 5:30713. 4. Matsen FA 3rd. Rotator-cuff failure. N Engl J Med 2008; 358:2138-47.

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Pharmaceutical Update

Influenza

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

INFLUENZA A AND B Influenza A is categorized into subtypes based on the surface antigens on its envelope glycoproteins, hemagglutinin and neuraminidase. New influenza virus variants result from point mutations and recombination events during viral replication, resulting in antigenic shifts or drifts. Antigenic shifts are major antigenic changes that occur when a new subtype of influenza A appears. This new subtype has pandemiccausing potential if it is able to cause human disease, transmit from human to human and the population has little or no existing immunity. Antigenic drifts are minor antigenic changes associated with more localized outbreaks and seasonal epidemics. In circulation since 1977 are human influenza A (H1N1), A (H3N2) and influenza B viruses. Influenza A (H1N2), a possible product from genetic reassortment between human A (H3N2) and A (H1N1) viruses, has also been identified in some seasons. In April 2009, human infection with a novel influenza A (H1N1) virus was identified in North America, and has since spread globally. This novel virus is derived partly from influenza A viruses that circulate in swine and is antigenically distinct from human influenza A (H1N1) viruses, hence it is renamed influenza A ( H 1 N 1 ) 2 0 0 9 . H o w e v e r, b y September, pandemic influenza A (H1N1) 2009 infections had declined to sporadic levels in most countries. From Oct 2009 to Feb 2010, there had been 16 human cases of influenza A (H5N1) which was spread from poultry, but no evidence of sustained human-

to-human transmission to date. Two isolated influenza A (H9N2) infection cases had also been reported by Hong Kong in Oct and Dec 2009. Influenza B viruses undergo antigenic changes less rapidly than influenza A viruses. Currently circulating influenza B viruses are classified into two distinct genetic lineages - Yamagata and Victoria - but not further divided into subtypes. Influenza B viruses from both lineages have circulated in most recent influenza seasons. B/Victoria/2/87 lineage viruses predominated and were

antigenically close to B/Brisbane/60/2008 viruses. INFLUENZA VACCINE DESIGN Vaccination stimulates immunity to influenza viruses by induction of antibodies, mainly against hemagglutinin. Antibody against one influenza virus type or subtype confers limited or no protection against another type, subtype or antigenic variant of the same influenza virus. In view of the high mutation rates and continual evolution of influenza viruses, new vaccines are produced yearly to match

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the circulating viral strains. CDC and WHO through GISN collaborate in monitoring influenza disease activity, tracking influenza virus isolates and convening twice yearly in Febrary and September to recommend for components for the influenza vaccine. GISN is a global public health laboratory network coordinated by WHO, consisting of 131 National Influenza Centres in 102 countries. The network conducts public health activities such as warning and assessment of influenza viruses of concern. The vaccine composition is updated for each Northern (Nov Apr) and Southern hemispheric season (May Oct). Based on current analyses and recent epidemiological evidence, it is anticipated that A(H1N1) 2009, A(H3N2) and B viruses will co-circulate in the northern hemisphere in 2010 to 2011, with seasonal A(H1N1) unlikely circulating at significant levels, hence the latter has not been recommended for inclusion in the 2010-2011 vaccine. WHO recommends that vaccines should cover the following subtypes during the 2010 influenza season in the southern hemisphere: a) A/California/7/2009 (H1N1)-like virus b) A/Perth/16/2009 (H3N2)-like virus c) B/Brisbane/60/2008-like virus. Starting from the 2010 influenza season in the southern hemisphere, the trivalent influenza vaccine replaces the monovalent vaccine as it includes antigens from the 2009 pandemic H1N1 influenza A virus. WHAT ARE THE AVAILABLE INFLUENZA VACCINES? Current influenza vaccines include the intramuscular or deep-subcutaneously administered trivalent inactivated influenza vaccine (TIV) and the intranasal live attenuated influenza vaccine (LAIV). TIV can be used in any person aged 6 months, while LAIV may only be used in healthy, nonpregnant persons aged 2 to 49 years. Those with co-morbidities conferring a higher risk of influenza complications should be vaccinated only with TIV as the safety or effectiveness of LAIV has

not been established in these groups. LAIV uses a master attenuated, coldadapted donor virus to create reassortants with HA and NA antigens from currently circulating strains. Intranasal vaccine should not be administered to patients who are immunosuppressed or pregnant, suffering from chronic cardiovascular, pulmonary, metabolic diseases such as diabetes or renal insufficiency, or those with a history of severe egg hypersensitivity (such as anaphylaxis) or Guillain-Barre syndrome. Table 1 shows the comparison of TIV and LAIV. LAIV is not available in Singapore. Locally available inactivated trivalent influenza vaccines that are HSA-approved include Vaxigrip, Influvac, Fluvax, Fluarix, Fluad and Agrippal. Each 0.5ml prefilled syringe contains 15 micrograms hemagglutinin of strains matching those recommended for the influenza season in the respective hemisphere, such as: a) A/California/7/2009 (H1N1)-like

strain (A/California/7/2009 (NYMC X-179A) b) A/Perth/16/2009 (H3N2)-like strain (A/Wisconsin/15/2009 (NYMC X183) c) B/Brisbane/60/2008-like strain (B/Brisbane/60/2008). As inactivated vaccines take approximately 9 months to manufacture, they contain antigens from strains circulating in the previous year. The efficacy of the vaccine is determined by the closeness of fit between the strains in the vaccine and the viruses currently circulating. If the fit is close, protection of 50-80% can be expected.1 A Cochrane systematic review in 2007 that evaluated 15 trials of inactivated influenza vaccine found that it was 80% effective against laboratory-confirmed influenza when the vaccine matched the circulating strains, compared to 50% when it did not. The same review found the LAIV to be 62% effective at preventing laboratory-confirmed influenza, but noted the results as inconclusive due

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to conflicting results from a limited number of studies. WHO SHOULD BE VACCINATED? Influenza viruses can cause disease in any age group, but rates of infection are highest among children. Rates of serious illness and death are highest among persons aged 65 years, children aged <2 years, and persons of any age with comorbidities placing them at increased risk for influenza complications.2 More than 90% of the deaths occurred in patients above the age of 60 years. As influenza viruses undergo frequent antigenic change, we should be revaccinated annually against influenza viruses that are predicted to be prevalent based on the most recent viral surveillance data. Influenza vaccine can be administered to any person aged >6 months without contraindications. High-risk groups as highlighted below are encouraged to receive the vaccination, and are of priority for vaccination efforts when vaccine supply is limited.3 Nevertheless, starting in 2010, US Centres for Disease Control and Preventions (CDC) Advisory Committee on Immmunization Practices (ACIP) has expanded the recommendation for influenza vaccination to include all individuals 6 months or older. G ro u p s a t h i g h e r r i s k o f contracting influenza or developing complications Aged 6 months--4 years (59 months), 50 years and older Persons who have chronic diseases, including: - pulmonary (including asthma) - c a rd i o v a s c u l a r ( e x c e p t isolated hypertension) - renal - hepatic - neurologic condition that can compromise respiratory function and the handling of respiratory secretions, or increase risk of aspiration e.g. cognitive dysfunction, spinal cord injuries, seizure disorders, neuromuscular disorders) - hematological (including

hemoglobinopathies such as sickle cell disease) - metabolic disorders (including diabetes mellitus) Immunosuppressed individuals (including HIV infection especially if CD4 < 200 cells/'b5L, organ or hematopoietic stem cell t r a n s p l a n t a t i o n , immunosuppression caused by medications) Women who will be pregnant during the influenza season (ACIP also recommends vaccination for pregnant women regardless of the stage of pregnancy) Children/adolescents aged 6 months to 18 years receiving long-term aspirin therapy as they might be at risk of Reye's syndrome after influenza virus infection Residents of nursing homes and other long-term care facilities Health-care personnel Household contacts and caregivers of children aged <5 years and adults aged 50 years and older, and of persons with medical conditions that put them at higher risk for severe complications from influenza Asplenic individuals- influenza is a risk factor for secondary bacterial infections that can cause severe disease amone such patients. Vaccination should be offered as soon as the vaccine becomes available, ideally by October in the northern hemisphere and May in the southern hemisphere. Although influenza outbreaks occur almost exclusively during winter in temperate regions, they occur throughout the year in the tropical countries. For countries in equatorial regions, epidemiological findings will influence the decision to adopt the northern or southern vaccine by the national or regional authorities. Protection from the viruses contained in the vaccine starts about 2 to 3 weeks following the injection. Vaccination should be repeated annually even if the previous years vaccine contained one or more of the antigens found in the current vaccine as immunity

declines over the course of the year. CONTRAINDICATIONS/ PRECAUTIONS Egg allergy is a relative contraindication to the influenza vaccine as there could be residual egg protein due to the vaccine being prepared from viruses grown in eggs. The Food Allergy Management Guidelines issued by the Ministry of Health of Singapore states that Patients with egg allergy who need the influenza vaccine should be referred to a clinical facility experienced in the management of anaphylaxis.4 Vaccination should be avoided in persons with history of Guillain-Barre syndrome (GBS) or those who developed GBS within 6 weeks after a previous influenza immunization, unless benefit outweighs risk. Antiviral chemoprophylaxis may be considered in these patients. In cases of febrile illness or acute infection, vaccination should be postponed until symptoms have resolved. In immunocompromized patients, the antibody response may be lower. Appropriate medical treatment (including adrenaline) and supervision should be available in case of anaphylactic reactions. Intramuscular injection of TIV should be carried out cautiously in a patient with thrombocytopenia or coagulation disorder. The patient should be instructed about the risk of hematoma following the injection. Safety and efficacy of use in children <6 months of age have not been established. Vaccination may not fully protect against contracting influenza, hence vaccinated patients should be reminded to seek medical treatment if symptoms of influenza arise. We could still develop influenza if we are exposed to the virus immediately before or after vaccination. P R E G N A N C Y A N D BREASTFEEDING Changes in the immune system, heart, and lungs during pregnancy increase

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the risk of influenza complications in the mother and foetus, including premature labor and delivery. As there is currently still limited data with influenza vaccination in pregnant woman, influenza vaccine is listed as US FDA pregnancy category C and Australian Drug Evaluation Committee's (ADEC) Category B2. US FDA pregnancy category C means that studies in animals have revealed adverse effects on the foetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. ADEC Category B2 is used to designate drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Also, studies in animals are inadequate or may be lacking, but available data show no evidence of an increased occurrence of fetal damage. CDCs ACIP recommends that all pregnant or would be pregnant women be vaccinated to protect themselves and their infants who cannot yet be vaccinated. It is not known whether inactivated influenza vaccine is excreted in human milk. Thus, caution should be exercised when the vaccine is administered to a nursing woman. According to Thomson Lactation Rating, the subvirioninactivated vaccine poses minimal risk to the infant during breastfeeding. From the literature, infants and young children are at high risk for influenza complications; hence vaccination with the inactivated influenza virus vaccine is recommended for nursing women unless contraindicated (CDC, 2009). DOSAGE/POSOLOGY Influenza seasons vary in their timing and duration year to year. Hence, the optimal time to be vaccinated lies between October and November prior to exposure to influenza. The vaccine is administered via intramuscular or deep subcutaneous injection. It should be well shaken, and brought to room temperature before use. For most of the available single-dose

TIVs, the recommended dosages (1 dose per season) are: Adults and children older than 36 months: 0.5ml intramuscularly in the deltoid muscle using a '5f1 inch needle. Children from 6 months to 35 months: 0.25ml (push the plunger stopper to the edge of the mark of the syringe to eliminate half the volume and inject the remaining half). Children of 6 months through 2 years of age should be vaccinated in the anterolateral aspect of the thigh, using a 7/8 to 1 inch needle. The ACIP recommends that infants and children aged '5f9 years not previously vaccinated should receive two doses of H1N1 influenza vaccine at least 4 weeks apart. They should preferably receive their first dose in September so that both doses can be administered prior to onset of influenza activity. The vaccine should be stored at 2-8 degree Celsius, protected from light. PHARMACOKINETICS Protective antibody titres are expected to be attained about 2 weeks after vaccination. Protective antibody titres can be sustained for approximately '5f6 months. In elderly, the antibody titres may fall '5f4 months after vaccination. DRUG-DRUG INTERACTIONS The influenza vaccine can be given at the same time as other vaccines on separate limbs. However, the side effects may be intensified. Immunological response may decrease during concurrent immunosuppressant treatment, such as corticosteroids, cytotoxic drugs or radiotherapy. ADVERSE EFFECTS The inactivated vaccines are generally well tolerated. The most common side effect reported was mild arm soreness. Others ('5f2%) include headache, low-grade fever, chills, myalgia, arthralgia, malaise (which may start within 6-12 hours), upper respiratory symptoms (such as nasopharyngitis), and local reactions such as redness,

swelling, pain, bruising, induration at the site of injection. These reactions usually disappear within 1-2 days without treatment. From post-marketing surveillance, rare side effects include allergic reactions including anaphylaxis, shock, angioedema, skin reactions, vasculitis with transient renal impairment, neuralgia, paraesthesia, febrile fits, neuromuscular disorders that may result in stiff neck, confusion, numbness, pain and weakness of limbs, loss of balance, gradual loss of reflexes, paralysis of part or all of the body (encephalomyelitis, neuritis, Guillain-Barre Syndrome). A slightly increased risk of GuillainBarre syndrome has been associated with the influenza vaccine during certain influenza seasons. A study undertaken by Nachamkin et al in 2008 found that inoculation of the 1976 swine flu vaccine, as well as the 19911992 and 2004-2005 influenza vaccines, into mice prompted production of antibodies to antiganglioside (anti-GM1), which are linked to the development of GBS.5 However, more research would be required to investigate how influenza vaccine components elicit antiganglioside effects. Continual surveillance for adverse events of influenza vaccine is practised worldwide via the US Vaccine Adverse Event Report System (VAERS). Initial data found no substantial differences in the safety profiles of pandemic H1N1 and seasonal influenza vaccines. As certain rare adverse events may only show up when a significant number of people have received the vaccine, hence the need for constant vigilance and prompt reporting of any vaccinerelated adverse event. Healthcare professionals may also report locally any vaccine adverse event via CMIS (Critical Medical Information Store) which is linked to HSAs website. On August 5, 2010, ACIP published a statement linking Fluvax'ae and Fluvax Jr'ae (produced by CSL Biotherapies) use during the 2010 influenza season to an increased risk

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Factor Route of administration Type of vaccine

LAIV Intranasal spray Live virus

TIV Intramuscular injection Noninfectious virus (i.e., inactivated) Three (two influenza A, one influenza B) Annually Annually* Persons aged 6 months and older 4 weeks

No. of included virus strains

Three (two influenza A, one influenza B) Annually Annually* Persons aged 249 yrs

Vaccine virus strains updated Frequency of administration Approved age

Interval between 2 doses recommended for children aged 6 mos and older -- 8 yrs who are receiving influenza vaccine for the first time Can be administered to persons with medical risk factors for influenza-related complications Can be administered to children with asthma or children aged 2--4 yrs with wheezing in the past year Can be administered to family members or close contacts of immunosuppressed persons not requiring a protected environment Can be administered to family members or close contacts of immunosuppressed persons requiring a protected environment (e.g., hematopoietic stem cell transplant recipient) Can be administered to family members or close contacts of persons at high risk but not severely immunosuppressed Can be simultaneously administered with other vaccines If not simultaneously administered, can be administered within 4 wks of another live vaccine If not simultaneously administered, can be administered within 4 wks of an inactivated vaccine

4 weeks

No

Yes

No

Yes

Yes

Yes

No

Yes

Yes

Yes

Yes Space 4 wks apart

Yes** Yes

Yes

Yes

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 in their 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-term aspirin therapy (at risk for developing Reye syndrome after wild-type influenza infection); persons who have any condition (e.g., cognitive dysfunction, spinal cord injuries, seizure disorders, or other neuromuscular disorders) that can compromise respiratory function or the handling of respiratory secretions or that can increase the risk for aspiration; pregnant women; and residents of nursing homes and other chronic-care facilities 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 rubella vaccine 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

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of febrile seizures in children aged 6 months through 4 years, and Fluvax'ae and Afluria'ae to a higher frequency of reported fever in children aged 5 years through 8 years compared to previous seasons. The rate of febrile seizures following Fluvax'ae or Fluvax Jr'ae was estimated to be approximately 1 per 100 doses administered among children aged 6 months through 4 years. In view of this, ACIP recommends that these brands of vaccines should be avoided in children aged 6 months to 8 years in the 2010-11 influenza season unless no alternatives exist and the benefits outweigh the risks.6 OTHER RECENT DEVELOPMENTS The US FDA approved rapid tests for detecting the 2009 H1N1 influenza virus on June 21, 2010. For example, the 3M Rapid Detection Flu A+B Test takes less than 15 minutes to perform. It detects and distinguishes between influenza A and B. Acceptable specimens are nasopharyngeal swab/aspirate, nasal wash/aspirate. In contrast, reverse transcription polymerase chain reaction (RT-PCR) takes 2 to 4 hours and viral culture 3 to 10 days. According to the CDC, sensitivity is of rapid diagnostic tests is approximately 50-70% compared with viral culture or RT-PCR and specificity is approximately 90-95%.7 The CDC no longer endorses mandatory influenza vaccination for h e a l t h c a re w o r k e r s , a n d n o w

recommends surgical facemasks instead of the N-95 respirators for healthcare workers during contact with influenza patients. This follows the recommendation previously made by the Association of Professionals in Infection Control, the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America.8 On August 10, 2010, WHO had declared the H1N1 influenza pandemic officially over, and the outbreak had entered the postpandemic period. Nonetheless, the WHO Director-General Dr Margaret Chan cautioned that the 2009 H1N1 influenza virus has not disappeared and still poses a risk for serious illness, especially for young children, pregnant women, and persons with respiratory or chronic illnesses. CONCLUSIONS The experience of handling the recent influenza epidemics have led to improvements in policies, vaccines, medications and diagnostics. However, influenza is a constantly evolving disease and medical practitioners and policy-makers have to keep abreast of new developments. FURTHER READING http://www.medscape.com/ resource/influenza http://www.cdc.gov/flu/ professionals/ http://www.who.int/csr/disease/ influenza/en/

http://www.hsa.gov.sg/publish/ hsaportal/en/for_consumers/influen za_a_h1n1/h1n1_vaccines/about_hs a_regulatory.html Hibberd PL, Jun 2010, Seasonal influenza vaccination in adults; Thorner AR, Feb 2010, Pandemic H1N1 influenza (swine influenza) vaccine. UpToDate 2010. Available at: www.uptodate.com Influenza Virus Vaccine. In: DRUGDEX System. Thomson Healthcare. Available at: h t t p : / / w w w. t h o m s o n h c . c o m Vaxigrip Influenza Vaccine Product Information Influvac Influenza Vaccine Product Information

Ms Serene Tan is a Pharmacist in the Department of Pharmacy, Tan Tock Seng Hospital.

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. Management of food allergy. AMS-MOH Clinical Practice Guidelines 2/2010. Available at 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-Barr'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.

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Case Report

More than just

a headache
Case Presentation A 25-year-old woman was admitted to our hospital with acute onset of left-sided headache associated with vomiting but without aura, photophobia or neurological deficits. She had recurrent headaches for the past 2 years that had been diagnosed as migraine. She did not report palpitations or diaphoresis. Clinical examination was unremarkable except for 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 was confirmed to be pregnant. Her blood pressure remained severely elevated at 200/110 mmHg. The 24 hour urinary vanillyl 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 with phaeochromocytoma (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 3 weeks later. The computerised tomography (CT) scan of the abdomen showed a 38x36x29 mm heterogeneous enhancing mass arising from the right adrenal gland. Following adequate control of her blood pressure, laparoscopic right adrenalectomy was performed. Histopathology was consistent with adrenal phaeochromocytoma with no overt malignant features. Her blood pressure normalised post-operatively and anti-hypertensive medications were discontinued. The 24-hour urinary catecholamines and metanephrines were normal 3 months later.

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

Reference range 11.015.00 g/dl 35.045.0% 034.3 mmol/day 3109 noml/day 89473 nmol/day 600-1900 nmol/day 59413 nmol/day 0.633.08 mg/L/h 97.3834 pmol/L

Table 1. Investigations supporting the diagnosis of phaeochromocytoma.

DISCUSSION Phaeochromocytomas are rare catecholamine secreting tumors arising from the chromaffin cells of the adrenal medulla or sympathetic ganglia (paraganglioma). The prevalence of phaeochromocytoma in patients with hypertension is 0.10.6% in the general outpatient setting.1-2 Its incidence in pregnancy is not known. There have been at least 200 cases reported in pregnancy and the prevalence is estimated at 1 in 54 000. 3-4 It is important to suspect and diagnose these tumors because: Undiagnosed tumors have been associated with significant maternal and fetal mortality (up to 48% and

54.4% respectively in one early report);5 Hypertension is potentially curable with resection of the tumor; The cardiovascular complications are potentially lethal; At least 10% of these tumors are malignant; and A hereditary basis may be found in up to 24% of patients and detection of phaeochromocytoma in the proband may result in early diagnosis in other affected family members.6-8

The most common clinical presenting features of phaeochromocytoma include headaches, palpitations,

diaphoresis and hypertension. Other symptoms such as nausea, flushing and anxiety are non-specific and can be easily overlooked especially in a pregnant woman. Frequent headaches in our patient had been misdiagnosed as migraine. Phaeochromocytoma should be suspected in patients with paroxysmal signs and symptoms, in those with treatment-resistant or labile hypertension and in those who demonstrate a paradoxical blood pressure response during surgery and anaesthesia. In our patient, an additional clue was an elevated haemoglobin level and haematocrit, both of which have been observed in patients with phaeochromocytomas.

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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

angiotensin-aldosterone system is activated as a physiological response to pregnancy. Early diagnosis and treatment has been shown to reduce morbidity and mortality for the mother and the foetus.4, 9, 10 In pregnancy, paroxysms can be precipitated by stress, increasing intra-abdominal pressure, medications such as metoclopramide, foetal movements and vaginal delivery. The ensuing hypertensive crisis can be detrimental to both mother and fetus. Adverse pregnancy outcomes include spontaneous abortion (as in our patient), intrauterine growth restriction and foetal death. Catecholamine production generally remains unchanged during pregnancy. The initial and essential step in diagnosing phaeochromocytoma is biochemical confirmation of excessive catecholamine production. The most sensitive tests are measurements of plasma free metanephrines or urinary fractionated metanephrines (normetanephrines and metanephrines) mainly because production of Om e t h y l a t e d m e t a b o l i t e s f ro m phaeochromocytomas is continuous and independent of the highly variable release of catecholamines (table 2).11-12 It is important to remember that foods and drugs such as tricyclic antidepressants, clonidine, methyldopa, prochlorperazine, decongestants and alcohol can i n c re a s e m e a s u re d l e v e l s o f catecholamines and metanephrines, giving rise to false positive results. The magnitude of increase is much greater in patients with phaeochromocytoma compared with false positives. The clonidine suppression test can also help to differentiate true positive from false positive results. This test, however, has not been validated in pregnancy. Following biochemical confirmation, the next step is localization of the tumor. This can be done by ultrasound, CT scan or magnetic resonance imaging (MRI) of the abdomen (mass with bright signal on T2-weighted image). Ultrasound scans are safe but

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

In our patient the haemoglobin and haematocrit normalized following volume expansion prior to surgery. Raised plasma renin activity and

aldosterone levels have been observed in patients with phaeochromocytoma secondary to the norepinephrineinduced renin release contributing to the hypertension. Moreover, the rennin-

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

less reliable. CT scan and MRI have similar sensitivities (90-100%) and specificities (70-80%). MRI is the preferred modality during pregnancy as it is free from ionizing radiation. Functional imaging with 1 2 3 Imetaiodobenzylguanidie (MIBG) is indicated mainly for those with extraadrenal or large (>5cm) adrenal tumors because of increased risk of malignant disease or in those with suspected multi-focal disease. It should be avoided during pregnancy. Familial phaeochromocytomas such as von Hippel Lindau syndrome, multiple endocrine neoplasia type 2, neurofibromatosis type I and familial paraganglioma occur rarely. Genetic testing should be considered in those with a positive family history, those who are young (<50 years of age), those with bilateral phaeochromocytomas or multifocal extra-adrenal disease or those with associated tumors.13 Definitive treatment requires surgical resection of the tumor. The optimal timing for surgery is during the late first trimester or early second trimester. When diagnosed in the late second or third trimester phaeochromocytoma is best managed medically until close to term when combined caesarean section followed by tumor resection can be performed. Vaginal delivery should be avoided as it may trigger a hypertensive crisis. The laparoscopic approach is now the preferred technique for tumors which are smaller

than 6cm as it is associated with lower postoperative morbidity and shorter hospital stay compared to conventional laparotomy. The complication rate of laparoscopic adrenalectomy is less than 8% and operative mortality rate is less than 1% in experienced centres.13 Appropriate pre-operative medical management to control hypertension is essential to prevent catecholamine-induced complications during surgery including hypertensive crises, cardiac arrhythmias, pulmonary oedema and cardiac ischaemia. Blood pressure should be normalised 2 weeks before surgery. Alpha-blockade with drugs such as phenoxybenzamine, prazosin and doxazosin is started followed several days later by beta-blockers to minimise reflex tachycardia. Amongst the alphablocking agents, phenoxybenzamine is the most common drug used during pregnancy. Phenoxybenzamine has been shown to cross the placenta and neonatal hypotension has been reported in newborns of mothers treated with the drug prior to delivery.1417 Prazosin has been used to treat maternal hypertension although one r a n d o m i s e d c o n t ro l l e d s t u d y comparing nifedipine and prazosin as a second line agent to treat severe early hypertension in pregnancy noted that there were more intra-uterine deaths in the prazosin group.16 There have been no reports on the use of doxazosin in pregnancy. Beta-blockers may be added if tachyarrhythmia is present but it should not be started before alpha-blockade as the

unopposed alpha-adrenoceptor stimulation can precipitate a hypertensive crisis. Intravenous phentolamine (by bolus or continuous infusion) is the agent of choice to control hypertension intraoperatively. Labetalol (alpha- and beta-adrenergic antagonist) has been used for preoperative adrenergic blockade, however it has a fixed alpha- to betaadrenergic blocking effect (1:7) which may result in paradoxical hypertensive crisis. Anaesthetic agents which can trigger hypertensive crisis such as fentanyl, ketamine, halothane and desflurane should be avoided. Following successful surgical resection, blood pressure normalises although hypertension may persist in nearly 50% of patients.17 Recurrent disease of 17% has been reported in those with extraadrenal disease and with familial disease.18 All patients should undergo yearly surveillance for at least 10 years after surgery. For those with familial phaeochromocytoma or extra-adrenal disease, follow-up should be indefinite because of the higher risk of recurrent disease. SUMMARY Early diagnosis of phaeochromocytoma requires a high index of suspicion. Patients with the typical triad of headache, sweating and palpitations in the presence of resistant or labile hypertension should be evaluated for phaeochromocytoma. The most sensitive tests are measurements of plasma free

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metanephrines or urinary fractionated metanephrines. MRI is the preferred imaging modality for radiological localisation of the tumor during pregnancy. Alpha-adrenergic blockade using phenoxybenzamine should be used for pre-operative management of hypertension. Neonates born to mothers receiving phenoxybenzamine prior to delivery should be closely monitored for hypotension. In pregnancy, depending on the gestation at which diagnosis is made, the optimal timing for surgery is during the late first or second trimester. When pregnancy is more advanced, medical management followed by combined caesarean section and tumor resection c l o s e r t o t e r m i s p re f e r re d . Multidisciplinary care involving the endocrinologist, obstetric physician, anaesthesiologist, obstetrician and surgeon is essential for an optimal outcome.

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

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; 54:72837. 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

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RADIOLOGY Quiz
CLINICAL HISTORY A 51-year-old Malay man was admitted for abdominal pain and vomiting. He also gives a history of chronic epigastric pain and chronic diarrhea for the past ten years.

Figure 1

Figure 2

Figure 3

Question
Question 1: What are the abnormalities on these contrast-enhanced CT images? Question 2: What is the most likely diagnosis?

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

Answer 2:
Zollinger-Ellison syndrome.

Discussion
Zollinger-Ellison syndrome (ZES) is caused by a nonbeta islet cell, gastrinsecreting tumour of the pancreas which stimulates the acid-secreting cells of the stomach, resulting in gastrointestinal mucosal ulceration. Pancreatic endocrine tumours along with hyperparathyroidism and pituitary tumors constitute the autosomal dominant condition Multiple Endocrine Neoplasm (MEN) Type 1. The diagnosis of ZES is based on a combination of the clinical presentation, gastrin radioimmunoassay findings, gastric acid secretory testing, and the findings on diagnostic imaging. The role of current imaging studies is to evaluate the tumour, assess for metastases and to detect contraindications to resection surgery. Imaging is also utilised in the monitoring of patients following resection of tumours. The imaging findings include hypertrophy of the gastric mucosa secondary to the hypergastrinemia. Gastrointestinal mucosal ulceration may also be seen due to the large amount of acid secretion. The primary tumour is most frequently seen in the pancreas or the duodenum. The tumours are usually small and subcentimeter in size. They can be multiple in 20-40% of cases and the majority (two-thirds) of them are malignant. These tumours are usually hypervascular with early arterial enhancement and may occasionally calcify. Metastases to the liver can also be detected as they are also usually hypervascular and are best seen on arterial phases of the study. The study of choice for the initial evaluation of patients with ZES is however somatostatin-receptor scintigraphy (SRS) due to the higher sensitivity compared to other forms of imaging. The primary lesion and metastases all show uptake of the radioisotope (octreotide) and present as hot spots. The patient was diagnosed to have ZES as, in addition to the hypervascular pancreatic lesion, his serum gastrin level was markedly elevated. He was also found to have hypercalcemia and an elevated parathyroid hormone level. Ultrasound investigations revealed a left parathyroid nodule which was confirmed as a parathyroid adenoma on excision. Given the clinical and radiological findings, the patient was diagnosed to have MEN 1 Syndrome. The pancreatic lesion was followed up with subsequent MR studies and was stable.

Dr Lim Wei Yang is a registrar in the Department of Diagnostic Radiology, Tan Tock Seng Hospital.

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

Figure 1

Figure 2

Answer
Figure 1 shows a 12-lead ECG demonstrating complete heart block. Figure 2 demonstrates 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 pacemaker leads therefore enters the persistent left SVC to the coronary sinus and exits out into the right atrium. From the right atrium, both leads are then manipulated into the right ventricle and right atrial appendage.

Dr David Foo is a consultant and Acting Head of the Department of Cardiology, Tan Tock Seng Hospital.