Consult 001 2007 by Virtual Medical Centre

Volume no. 1 2007 May â&#x20AC;&#x201C; July 2007 Virtual Medical centre

consult Quarterly Publication RRP $12.95

the Australian Medical Magazine for specialists and GPs

MAGAzine

PAIN Sydney patients implanted with new pain device

CANCER New treatments for prostate cancer Day surgery TURP

CARDIAC Getting Physical with CVD Cognitive function & CABG

ALLERGY Adverse drug reactions

NEURO Stimulating news for people with Parkinsons Role of pregnancy registers in epilepsy

EDUCATION Continuing medical education

Help him go the distance

(celecoxib)

Relieving pain, empowering lives.

Before prescribing, please review full Product Information available from Pfizer Australia Pty Ltd. MINIMUM PRODUCT INFORMATION. CELEBREX® 100 mg and 200 mg Capsules. Use: Symptomatic treatment of osteoarthritis and rheumatoid arthritis. Treatment of primary dysmenorrhoea in adults. Contraindications: Hypersensitivity to ingredients; allergic-type reactions to sulphonamides; in conjunction with NSAIDs; aspirin/NSAID sensitive asthma, urticarial/allergic reactions to aspirin or NSAIDs; peri-operatively in CABG surgery*; patients with unstable or significant established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease*. Precautions: Patients with known cardiovascular disease or risk factors, especially high risk cardiovascular patients, with significant and multiple risk factors*; history of GI ulcer disease or GI bleeding; severe hepatic impairment or renal disease; asthma; fluid retention; hypertension, heart failure; pregnancy and lactation, children < 18 years, concomitant use with ACE inhibitors or angiotensin receptor antagonists and thiazide diuretics (increased risk of renal impairment)*. Discontinue at first appearance of skin rash, mucosal lesions or any sign of hypersensitivity*. Adverse Reactions: Dyspepsia, diarrhoea, abdominal pain, peripheral oedema, rash, aggravated epilepsy*, aseptic meningitis*, very rarely serious skin reactions (exfoliative dermatitis, StevensJohnson syndrome, toxic epidermal necrolysis)*. Dosage: Use lowest effective dose for shortest duration possible. Review long-term patients regularly (e.g. 3 monthly) .* Osteoarthritis: 200mg od or in divided doses*. Rheumatoid arthritis: 200 mg daily in two divided doses; up to 400 mg daily short term only*. Primary dysmenorrhoea (maximum 5 days)*: Day 1: 400mg od or 200mg bd. Day 2 onwards: 200mg od. An additional 200mg dose may be taken on any day if required. Presentation: Oral capsules 100mg and 200mg. Based on TGA approved PI dated 4 April 2006. Minimum PI prepared 10 April 2006. PBS dispensed price: $29.91 (100mg x 60; 200mg x 30). *Please note changes in Product Information. 1. Celebrex Approved Product Information. Pfizer Australia Pty Ltd, ABN 50 008 422 348, 38-42 Wharf Road, West Ryde NSW 2114 www.pfizer.com.au Medical information 1800 675 229. Celebrex® is a registered trademark of Pharmacia. Pharmacia is a wholly-owned subsidiary of Pfizer Inc. 03/07 PFI0874/CJB.

PBS Information: Restricted Beneﬁt. Symptomatic treatment of osteoarthritis and rheumatoid arthritis. Note: Celebrex is not subsidised for the treatment of acute pain, soft tissue injury or arthrosis without an inﬂammatory component.

1-3

Get

tive

pantoprazole �

Before prescribing, please review Approved Product Information. Full PI available from Altana Pharma Pty Ltd, ABN 71095 610 870, 2-4 Lyonpark Road, North Ryde NSW 2113. SOMAC� (pantoprazole) INDICATIONS: Duodenal and gastric ulcers; gastro-oesophageal reflux disease (GORD), including symptomatic GORD and reflux oesophagitis; gastrointestinal lesions refractory to H2 blockers; Zollinger-Ellison Syndrome; maintenance of healed reflux oesophagitis; eradication of H. pylori in peptic ulcer (combination therapy); prevention of gastroduodenal lesions and dyspeptic symptoms associated with non-selective NSAIDs in increased risk patients with a need for continuous NSAID treatment. CONTRAINDICATIONS: Hypersensitivity to ingredients; cirrhosis; severe liver disease. Combination therapy: Hypersensitivity to antibiotics; moderate to severe hepatic or renal dysfunction; atazanavir therapy#. PRECAUTIONS: If suspected gastric ulcer or reflux oesophagitis, exclude malignancy; rare cases of Vitamin B12 deficiency reported; monitoring for long-term use; investigation if non-responsive symptomatic GORD; pregnancy; lactation; children; monitoring for patients on coumarin anticoagulants; drugs with pH dependent bioavailability, including atazanavir#. ADVERSE EVENTS: Most commonly reported: Fatigue, asthenia, sweating, headache, diarrhoea, severe eructation, constipation, flatulence, dry mouth, upper abdominal pain, metallic taste; psychiatric disorders#; others, see full PI. DOSAGE AND ADMINISTRATION: Monotherapy: 20-40 mg once daily depending on indication (may be increased for Zollinger-Ellison Syndrome or reflux oesophagitis), see full PI. Combination therapy: 40 mg twice daily. Reduced initial dose with mild liver disease. #Please note changes in Product Information. Price: 20mg (30): Restricted Benefit - PBS/RPBS: fully dispensed $22.89; 40mg (30): Restricted Benefit - PBS/RPBS: fully dispensed $38.27. 1. van Zyl J et al. Digestion 2004; 70: 61-69. 2. Metz DC et al. Aliment Pharmacol Ther 2003; 17: 155-164. 3. Richter JE et al. Aliment Pharmacol Ther 2004; 20: 567-575. Altana Pharma 1800 675 957. �Registered Trademark 03/07 ALTSO0057

PBS Information: Restricted Benefit. Gastro-oesophageal reflux disease; initial treatment of peptic ulcer; Zollinger-Ellison syndrome; scleroderma oesophagus.

Helping chronic pain sufferers focus on life, not their pain

72-hour efficacy1 PlEASE REvIEw FUll APPROvED PRODUCT INFORMATION BEFORE PRESCRIBING, AvAIlABlE FROM JANSSEN-CIlAG UPON REqUEST

DUROGESIC® (fentanyl) Minimum Product Information. Description: DUROGESIC® is a matrix transdermal system (patch) delivering 12, 25, 50, 75 & 100 micrograms/hour fentanyl to the systemic circulation. Indications: DUROGESIC is indicated in the management of chronic pain requiring opioid analgesia. Dosage: Individualise dosage. Opioid-naïve patients with chronic pain: initial dose should not exceed 25 micrograms/hour. The dose may subsequently be titrated upwards or downwards in increments of either 12 or 25 micrograms/hour every 3 days as needed to achieve the lowest appropriate dose of DUROGESIC. DUROGESIC is not recommended in opioid-naïve patients with non-cancer pain - see full PI. Opioid-tolerant patients: see full PI for initial dose; increase in increments of either 12 or 25 micrograms/hour every 3 days as needed. Contraindications: Patients with known hypersensitivity to fentanyl or the adhesive; management of acute or post operative pain; management of mild or intermittent pain; doses exceeding 25 micrograms/hour at the initiation of opioid therapy. Precautions: Not recommended in opioid-naïve patients; patches should not be cut or divided; hypoventilation; chronic pulmonary disease; head injuries, brain tumour, increased intracranial pressure; hypotension, bradycardia; impaired immunity; fever, direct external heat sources; alcohol, CNS depressants; elderly; hepatic, renal impairment; prolonged use; pregnancy, during childbirth, breast-feeding; children <12 years; proper disposal of used patches. Interactions: CNS depressants including opioids, sedatives, hypnotics, general anaesthetics, phenothiazines, tranquillisers, skeletal muscle relaxants; monoamine oxidase inhibitors (MAOIs); ritonavir; other CYP 3A4 inhibitors (e.g. ketoconazole, itraconazole, troleandomycin, erythromycin, diltiazem and cimetidine). Others see full PI. Adverse Reactions: Nausea, vomiting, constipation, dry mouth, anorexia, diarrhoea; somnolence, dizziness, headache, hallucinations, depression, syncope; sweating, pruritus, application site reaction; hypoventilation, hiccups, dyspnoea. Tolerance, physical and psychological dependence can develop on repeated use. Others see full PI. Presentation: Patches: 12, 25, 50, 75 & 100 micrograms/hour. PBS Dispensed Price: 12µg: $44.74, 25µg: $54.12, 50µg: $92.91, 75µg: $126.01, 100µg: $153.31. Prepared December 2006. Reference: 1. Product Information for DUROGESIC. DUROGESIC is a trademark of Janssen-Cilag ABN 47 000 129 975. 1-5 Khartoum Rd, North Ryde NSw 2113. Ph: (612) 8875 3333, Fax: (612) 8875 3300. H&T JAN0023/P

PBS INFORMATION: Restricted Benefit. DUROGESIC is PBS listed for chronic severe disabling pain, not responding to non-narcotic analgesics.

POWERFUL CHOLESTEROL REDUCTION THROUGH DUAL INHIBITION

Indicated for patients inadequately controlled with statin or ezetimibe alone or patients already treated with statin and ezetimibe.

Please reVIeW Product InformatIon before PrescrIbIng. aPProVed Product InformatIon Is aVaIlable from mercK sHarP & doHme. Indications: as adjunctive therapy to diet in patients with primary hypercholesterolaemia or mixed hyperlipidaemia where use of a combination product is appropriate. Patients with homozygous familial hypercholesterolaemia. Precautions: myopathy/ rhabdomyolysis, particularly if co-administered with itraconazole, ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, nefazodone, cyclosporin, danazol, niacin (q1g/day), amiodarone, verapamil, diltiazem; liver enzymes; high alcohol use; hepatic insufficiency; co-administration with fibrates; monitor prothrombin time if used with coumarin derivatives. Contraindications: hypersensitivity; active liver disease; unexplained persistent elevations of serum transaminases; myopathy secondary to other lipid-lowering agents; pregnancy; lactation. Pregnancy: Category D. Adverse events: dizziness; headache; arthralgia; myalgia; asthenia; abdominal pain; diarrhoea; fatigue; influenza-like illness; muscle cramp; elevations of ALT and/or AST. Adverse events reported rarely include: thrombocytopaenia; cholelithiasis, cholecystitis, hepatitis; arthralgia, myopathy, rhabdomyolysis; hypersensitivity reactions; anaphylaxis, angiodoema; pancreatitis; nausea; increased CPK; elevations of liver transaminases; GI upsets. Dosage: Primary hypercholesterolaemia: usual starting dose 10/40mg/day, in the evening, with or without food. Dosage adjustment after 2 weeks if required. HoFH: 10/40mg/day or 10/80mg/day in the evening. Overdosage: symptomatic and supportive measures should be employed. Price: VyTorIn 10/40mg: $131.23; VyTorIn 10/80mg: $158.12. VyTorIn 10/10mg is not available in Australia. VyTorIn 10/20mg is not PBS listed. Reference: 1. Approved Product Information for VyTorIn. 速VyTorIn is a registered trademark of MSP Singapore Company, LLC. Merck Sharp & Dohme (Australia) Pty Limited. 54-68 Ferndell St South Granville nSW 2142. 03-08-VyT-07-MSP-2128-J. H&T MSD0112/P

PBS Information: Authority required. Refer to PBS Schedule for full authority requirement information.

11 Gibbon Road, Baulkham Hills NSW 2153, Australia

why should I choose Sleepcare? BOC Sleepcare is different

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Make the right choice before you buy with our six week trial period– try any of our masks and machines at home for six weeks for just $250.

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Get your $250 back when you buy your mask and machine from us during your trial period – you can then call us any time to arrange after sales service, warranties or support.

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Victoria Boronia Melbourne City Moorabbin Preston Hoppers Crossing Sunbury

Freedom for your UC patients Colazide® is an azo-bonded prodrug activated by colonic bacteria for delivery of mesalazine to the

99%

colon where needed.1

of 5-ASA delivered directly to the entire colon1

Colazide® (balsalazide sodium) INDICATION Treatment of mild–to–moderate ulcerative colitis and maintenance of remission, in patients who are intolerant to sulphasalazine. CONTRAINDICATIONS Hypersensitivity to mesalazine, salicylates; severe hepatic, mod-severe renal impairment; tendency to bleeding; concomitant anticoagulants; active peptic ulcer, pregnancy (last weeks). PRECAUTIONS Asthma; mild–moderate hepatic, renal impairment; blood dyscrasias; lactation; children < 18 years. ADVERSE REACTIONS Headache; GI upset; others, see full PI. INTERACTIONS Agents secreted by renal tubule, narrow therapeutic range e.g. methotrexate; digoxin; oral antibiotics. DOSAGE AND ADMINISTRATION Treatment: 3 capsules orally 3 times/day until remission or max 12 weeks; maintenance treatment: 2 capsules orally twice daily; adjust according to response (additional benefit shown with 8 caps daily). REFER TO PRODUCT INFORMATION BEFORE PRESCRIBING The full disclosure Product Information is available on request from Pharmatel Fresenius Kabi Pty Ltd 6/6–18 Bridge Road Hornsby NSW 2077 Phone: 02 9472 2222 Fax: 02 9472 2255 www.pfk.com.au ® Registered Trademark. REFERENCES 1. Colazide® Product Information.

PBS Information: Authority required. Please refer to PBS schedule for full information.

greetings from the

medical director

he May, June, July 2007 issue of Consult Magazine is a celebration of the outstanding contributions of the Virtual Medical Centre Editorial Advisory Board (EAB) over the last 12 months. Over 1000 specialists nationally from 18 disease specialty areas belong to the EAB. The diversity of topics and opinions written and published in Consult Magazine and also on the www.virtualmedicalcentre.com by the EAB are guaranteed to stimulate medical discussion amongst you, the exclusive medical membership of Virtual Medical Centre. If you are a medical practitioner and would like to be a medical member and receive a complimentary subscription to Consult Magazine, please send your details to info@ virtualmedicalcentre.com or fax 08 9388 0611.

consult

Dr Andrew Dean Medical Director Virtual Medical Centre

Magazine

contents

We acknowledge the important contribution of the Medical Directors: Dr Andrew Dean, Dr Peter Bremner, Dr Nick de Felice, Professor Graeme Hankey, Dr Clay Golledge, Dr Roger Goucke, Dr Andrew McQuillan Dr Brendan McQuillan, Dr Donald Ormonde, Dr Rob Will

PAIN

6 Sydney Patients Among First to Be Implanted With New Pain Device

CANCER

7 New Treatments for Prostate Cancer - How Do I Choose? Assoc Prof Phillip Stricker 11 Day Surgery TURP Dr Neil S.I. Gordon

CARDIAC

NEURO

13 Getting Physical with Cardiovascular Disease Dr Andrew Maiorana

26 Stimulating News for People with Parkinson’s Professor Robert Iansek

15 Cognitive Function and CABG Dr Pamela Bradshaw

28 The Burden of Epilepsy and the Role of Pregnancy Registers Professor FJE Vajda

ALLERGY 19 Adverse Drug reactions

Gary A Unglick & Assoc Prof. John W Quin

EDUCATION 32 Continuing Medical Education Professor Roderick Underwood

Published by Virtual Cancer Centre.com PTY LTD trading as Virtual Medical Centre.com (ABN: 120 975 935 87) Medical Director: Dr Andrew Dean Managing Director: Wayne Hughes General Manager: Thomas Maher Marketing Manager: Janine Hoffman Production Coordinator: Katharina Kotte Art Director: Barry Epstein Editor: Jaci Moore (Aspermont Ltd), Medical Editor: Elizabeth Tysoe SUB Editor: Jen deVos National Advertising Sales: Tracy Pitts Circulation: 12,000 copies Head office: Virtual Medical Centre, PO 1048, Subiaco, Western Australia 6904. Ph: Perth (08) 9388 0344 Fax: (08) 9388 0611; SYDNEY OFFICE: Level 4, 201 Miller Street North Sydney Ph: Sydney (02)9025 3590 Fax: (02) 9025 3535 Email: consult@virtualmedicalcentre.com, advertising@virtualmedicalcentre.com Website: www.virtualmedicalcentre.com COPYRIGHT WARNING: All editorial copy and some advertisements in this magazine are subject to copyright and cannot be reproduced in any form without the written permission of the Production Coordinator. Offenders will be prosecuted. DISCLAIMER: Virtual Cancer Centre.com PTY LTD (ABN: 120 975 935 87), (‘the publisher’), and each of its directors, employees and related entities do not make any warranty whatsoever as to the accuracy or reliability of any information, estimates, opinions, conclusions or recommendations contained in this publication and, to the maximum extent permitted by law, the publisher disclaims all liability and responsibility for any direct or indirect loss or damage which may be suffered by any person or entity through relying on anything contained in, or omitted from, this publication whether as a result of negligence on the part of the publisher or not.

Aspermont Limited Information for Industry

Production Management: Aspermont Limited (ABN: 66 000 375 048)

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PA I N

pain

Sydney patients among first to be implanted with new pain device An Eon Rechargeable Neurostimulation System with TGA approval is giving physicians in Australia a new tool to combat chronic pain from areas such as failed back surgery syndrome. Patients at the Royal North Shore Hospital in Sydney have been the first recipients.

dvanced Neuromodulation Systems (ANS), the neuromodulation business of St. Jude Medical, Inc. (NYSE:STJ), has announced Australian Therapeutic Goods Administration (TGA) regulatory approval for its Eon Rechargeable Neurostimulation System. In Australia, the Eon system is fully reimbursable via the private health system. Patients at the Pain Management Research Institute, Royal North Shore Hospital in Sydney, were among the first to receive the Eon system. Pain Medicine Specialist Professor

Michael Cousins, M.D., who performed one of the first surgeries, said: “Eon was easy to implant and the patients continue to gain substantial pain relief. With its rechargeable battery, Eon is a good option for patients who require high-power stimulation settings and need to use an existing system for a large percentage of the day.” Eon delivers spinal cord stimulation (SCS) therapy to treat chronic, intractable pain of the trunk and limbs, including pain associated with failed back surgery syndrome. Similar to a cardiac pacemaker, this ‘pacemaker for pain’ uses mild electrical pulses from leads selectively placed near the spinal cord to interrupt pain signals to the brain. Eon contains the highest-capacity rechargeable battery available, which is designed to last a minimum of seven years at high-power settings. This allows patients to go longer between battery replacement surgeries. The rechargeable technology is easy for patients to understand and use – they simply recharge the device periodically, similar to recharging a mobile phone. Eon can power up to 16 independent electrodes, which allow clinicians more programming options to better manage the patient’s pain. “Approval of the Eon system provides physicians in Australia with a new tool to combat chronic pain,” said Chris Chavez, President of ANS. “The full power of the Eon system is realised when coupled with the advanced clinician programming features of Rapid Programmer 3.0, such as Dynamic MultiStim and Active Balancing. Eon and this programming platform work together as an integrated system to provide clinicians greater speed, precision and effectiveness in addressing complex pain.” Chronic pain is a largely under-treated and misunderstood disease that affects

millions of people worldwide. The World Health Organization, in conjunction with the International Association for the Study of Pain (IASP), reports that “One in five people suffer from moderate to severe chronic pain, and one in three is unable or less able to maintain an independent lifestyle due to pain.” Spinal cord stimulators like Eon often allow patients to greatly reduce their need for potent and potentially addictive pain medication. Eon was approved by the US Food and Drug Administration in 2005. Approximately 25,000 patients in more than 25 countries around the world use ANS neurostimulation CM devices to manage chronic pain.

may – july 2007 | Consult Magazine

New Treatments for Prostate Cancer: How Do I Choose?

The many new treatments now available for localised prostate cancer make it more difficult to choose the best treatment. Assoc Prof Phillip Stricker M.B., B.S. (NSW) (Hons), FRACS Conjoint Associate Professor UNSW; Chairman Department of Urology; Urological Surgeon; Uro-oncologist; Prostate Cancer Specialist; Editorial Advisory Board member; Virtual Cancer Centre

he many new treatments now available for localised prostate cancer make it more difficult to choose the best treatment. Options include radical prostatectomy in all its various forms, including nervesparing, non-nerve-sparing and non-nervesparing with sural nerve graft and roboticassisted laparoscopic surgery. It also includes conformal external beam radiotherapy, brachytherapy with seeds, high dose rate brachytherapy through wires, high intensity focused ultrasound, active surveillance (watchful waiting) and hormone therapy. With every individual it is important to discuss all these options, including their cure rates, the side effects of each treatment, the institution and surgeonâ&#x20AC;&#x2122;s particular expertise and the individual factors that may influence the choice of therapy.

New Options (1) Surgery The newer forms of therapy for surgery include careful nerve-sparing prostate cancer surgery, robotic and laparoscopic surgery and sural nerve grafting.

Nerve-sparing surgery aims to protect the erection nerves, minimising the side effects of surgery. What is most critical is that one selects the right cancer to perform this surgery on, otherwise one will tend to leave cancer behind. This tends to occur if the cancer has eaten into the nerve tissue. Certain factors relating to the tumour give one an indication as to whether it is suitable or not for nerve-sparing surgery. These factors are: the clinical stage, the number of biopsies positive on that side and the presence or absence of perineural invasion. The technique of nerve-sparing surgery has increasingly become more and more refined and an experienced nerve-sparing surgeon can more confidently now say that one can preserve nerves in patients with the right type of tumour. Potency rates, now as high as 80% or 90%, can be achieved in young patients who are potent and have very early stage tumours having nerve-sparing surgery. Robotic-assisted surgery and laparoscopic surgery achieve the same as open surgery, with smaller incisions. By having smaller incisions, this increases the speed of recovery and return to working activities, compared to

HIFU using the Ablatherm machine.

Consult Magazine | may â&#x20AC;&#x201C; july 2007

most series where open surgery is performed. The robotic-assisted surgery in particular, gives excellent magnification and dexterity, although one does lose the ability to feel and touch the tissues. In very experienced robotic units, the more important measures of outcome include cancer cure (negative margins), urinary control (continence) and return of erections (potency) appear to be equal to the best open surgical units in the world, but only after considerable experience. Certain factors make robotic surgery more difficult, e.g. very large prostate, middle lobes of prostate, extreme obesity, advanced cancers which need wide lymph node dissection, and extensive cancer at the base of the prostate. Extensive abdominal adhesions from previous surgery may also make this surgery more difficult. Robotic and laparoscopic surgery would appear to be a good option in those patients wishing to speed up their post-operative recovery and minimise blood loss, but patients should understand that this is relatively new technology and, as with any new technology, experience is required to gain the excellent outcomes of a very experienced surgeon with a track record of low positive margins, high continence results and high potency results. Many of the patients after robotic radical prostatectomy can go home in 48 hours and get back to work in two weeks. Sural nerve grafts have now been used for almost five years in very selected cases. In some more extensive cancers, to ensure that the cancer is completely removed, it is safer to remove a nerve on one side than it is to preserve it. In these patients, a nerve from the leg (the sural nerve) can be used to bridge the gap. Although initial results were very encouraging, more recent results are not as encouraging as we originally thought. Dr Peter Scardino, one of the pioneers of this technique, who has done the most cases, is slightly less enthusiastic than he originally was. A recent development has made this technique a little less attractive, as it is now known that not

CANCER

cancer

CANCER

all of the nerves have to be removed to clear the cancer, even when cancer is outside of the shell of the prostate; this leaves one with the opportunity to remove the cancer, yet still preserve the vast majority of the nerve, minimising the need for any grafting. Only certain people would be suitable for a sural nerve graft; these are younger patients who are potent and who require one of their nerves to be removed to ensure a high likelihood of clearing the cancer. As the results are less than encouraging, they must accept a relatively experimental procedure, which has never been properly trialled, and also accept the possibility of some side effects from the site of the grafting of the nerve (the leg). (2) Brachytherapy Brachytherapy using radioactive seeds is a therapy which is an option for patients with localised and early, low-grade prostate cancer. It is only suitable for those with very early stage and Gleason scores less than seven and a PSA less than 10. The rapid strand system, where the seeds are linked together, can help place seeds on the outside edge of the prostate to ensure the tumour is covered. The technique to do this involves making a volume assessment of the prostate, constructing a template and preparing a plan to place the seeds correctly. Ultimately, the procedure places the radioactive seeds in the predetermined position. This therapy, in its modern mode, has now been around for 20 years and in Australia for 10 years. It gives an excellent outcome if one chooses the right tumour and particularly if patients with severe urinary obstruction are excluded. Recent information suggests that patients even with PSAs up to 15 can be included and a limited number of patients with Gleason 3+4=7 can be included. Sexual side effects are the least in this group. Prostates larger than 40cc are unsuitable, in general. It tends to be used more in a slightly older age group (over 60), as results have not been going as long as surgical results. High dose rate brachytherapy is a more invasive new treatment where very high doses of radiotherapy can be placed accurately into the prostate by wires. This therapy is always combined with external beam radiotherapy and is appropriate for more advanced cancers where the PSA is greater than 10, the Gleason score is greater than seven and the

Robotic Prostate Surgery.

clinical stage is greater than, or equal to, T2B. These cancers, generally, are more difficult to cure with surgery and high dose rate brachytherapy may be more appropriate. It is particularly useful where there is extensive cancer at the apex or where local conditions, e.g. severe obesity, make surgery impossible. As with all radiotherapy procedures, this tends to be used more in the over-60 age group, as treatment options are limited if this therapy fails, whereas the reverse is not true with surgery. Furthermore, all radiotherapy procedures have a small risk of increasing second malignancies in adjacent organs after 15-20 years. (3) High Intensity Focused Ultrasound (HIFU) HIFU is an emerging new therapy which uses intense heat applied through the rectum to destroy the prostate and the contained prostate cancer. Two devices are currently available: the Ablatherm and the Sonoblate, but most published results have used the more established ablatherm machine. It is generally suitable for patients with tumours which are not too extensive, where the PSA is less than 20 and they are clinically contained. Follow-up is limited to only five years at this stage and therefore it tends to be used on older patients, those generally over 65 years of age. It is unknown whether surgery can follow this therapy, but radiotherapy certainly can follow this treatment. The treatment itself is repeatable. Side effects do occur in the first three months, including prolonged retention and infection. However, long-term side effects are low, although impotence rates are still relatively high, depending on the extent of the treatment. It is unsuitable for patients who have very large prostates or lots of calcification in their prostate. It is extremely useful in the older patient who is unsuitable for surgery or radiotherapy or who refuses surgery or radiotherapy and particularly suits a patient who has had a previous transurethral resection of prostate (TURP). Furthermore, it is one of the only therapies that can be used after radiotherapy has failed. It is therefore one of the new, emerging, minimally invasive treatments, albeit with short follow-up, which can treat lower risk tumours in older patients who are unsuitable for, or refuse, surgery or radiotherapeutic options. (4) Active Surveillance An increasing number of patients with Gleason 6 tumours, especially in the older age group, are having their tumours monitored. It has been shown that many tumours that are Gleason 6 do not require treatment, and patients die with their tumour rather than of their tumour. These tumours can be safely watched, using six-monthly PSAs and yearly or second-yearly biopsies, to ensure that they do not progress. Even younger patients, with

low-risk tumours are initially monitoring their tumour, due to personal circumstances or with the understanding that not all these tumours need to be treated. (5) Conformal Radiotherapy With increasing experience, radiotherapy can be focused on the prostate more accurately. This requires experienced units in this technique. Ever newer technologies of conformal radiotherapy are emerging internationally using a technique called a Cyber-knife or tomography. These are not yet available in Australia but have the promise of being able to deliver very accurate radiotherapy while minimising side effects. Conformal radiotherapy allows one to deliver very high doses of radiotherapy, which is necessary to eradicate tumours where PSAs are higher than 10 with minimal side effects, which can decrease the side effects to the bowel. As with all radiotherapy procedures, it tends to be used in the 60-year-old age group, as treatment options are limited if it fails. (6) Other Treatment Hormone therapy or cryotherapy are other options. Cryotherapy has generally not taken off in this country. Results are very inconsistent and side effect profile can be high in inexperienced hands. Hormone therapy is often used in older patients, perhaps over 75 years, where life expectancy is limited. Hormone therapy is generally reserved for more advanced and incurable cancer.

Cure Rates Special tables or nomograms (known as Kattan Tables) have now been developed, which help predict the likely cure rates of many of these different therapies. More information on these tables can be found at www.nomograms@mskcc.org. Individual institutions maintaining results should also give results to patients.

Side Effects Radical prostatectomy side effects have considerably improved over the last 10 years. Incontinence is down to very low figures (about 2%) and erectile dysfunction is much less common in selected patients. Nervesparing techniques in very experienced hands can now give a more rapid return of erections and a higher chance of recovery particularly in younger patients. Early post-operative use of medications and/or injection appears to speed up the recovery of erections. Erections can, however, take up to 12-18 months to return. Erection recovery after robotic surgery appears to be similar to open surgery but only after considerable experience in the robotic technique. Brachytherapy side effects are mainly

may â&#x20AC;&#x201C; july 2007 | Consult Magazine

urinary frequency and urgency. Patients who have a very large prostate or a lot of urinary symptoms before brachytherapy are more likely to suffer a complete urinary blockage (retention). Brachytherapy using seeds appears to have the lowest side effects on sexual function. HIFU initially causes difficulty in passing urine with frequency and burning and some risk of infection and temporary incontinence, but by three months most of these symptoms have disappeared. Sexual side effects depend on the extent of the treatment and can vary from 20-80%. Hormone therapy side effects include hot flushes, mood swings, decreased libido, decreased erections, weight gain, lethargy, breast tenderness and bone loss. All these can be addressed if they become a problem. In particular, bone loss can now be prevented by the use of bisphosphonate therapy.

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Freedom for your UC patients

Factors To Consider When Deciding What Treatment One Needs In general there are five factors to consider when deciding on a treatment. These include: 1. Tumour factors; 2. Prostate factors; 3. Local factors; 4. Patient factors; and 5. Institutional factors. 1) Tumour Factors There are seven tumour factors that will dictate the type of treatment which is best for an individual cancer: the clinical stage, the PSA level, the Gleason score, the position of the cancer, the extent of the cancer, the presence of perineural invasion, and the likelihood of disease penetrating through the capsule. For example, nerve-sparing prostatectomy should only be considered in those patients where the cancer is almost certainly confined to the prostate, is not too extensive and of a low clinical stage. On the other hand, brachytherapy seed treatment should only be considered where the PSA is less than 10, the Gleason score is less than seven and the clinical stage is less than T2B. High dose rate brachytherapy, in combination with external beam radiotherapy, should be considered where surgery is highly unlikely to cure the cancer such as in patients with very extensive cancer, with a high clinical stage and a PSA between 10 and 30, or where there is a high likelihood of disease penetrating through the capsule – particularly if it is located at the apex, which is difficult to cure surgically. Robotic surgery is more complex when extensive nodal dissection is required with more advanced cancer, or where there is a lot of cancer at the base. Hormone therapy should be considered where there is extensive local cancer unlikely to be cured such as a T4 tumour or where the PSA is greater than 50. HIFU is best with lower stage and grade tumours. Active surveillance should be considered in less aggressive microscopic tumours where, for example, only one of many biopsies are involved with a microscopic focus of low-grade tumour with a low PSA. (2) Prostate Factors The size and shape of the prostate as well as urinary symptoms may influence decisions. Urinary symptoms include obstruction, irritation and prostatitis. For example, a very large prostate may not be suitable for seed therapy or high dose rate brachytherapy or HIFU or robotic surgery. Furthermore, a patient with severe urinary obstruction may not be suitable for any radiotherapy treatment. If a patient has severe bladder irritation, it may be wise to avoid radical prostatectomy because these patients often become incontinent after surgery. Prostatitis may, for example, suggest that one shouldn’t have seed therapy. Heavy calcification makes HIFU and seed treatment inappropriate. Large middle lobes of the prostate make seed and robotic surgery difficult.

Consult Magazine | may – july 2007

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(3) Local Factors Factors that may influence therapy include previous surgery, previous radiotherapy and the pelvis anatomy such as its shape, the presence of a previous injury or general obesity. Where previous surgery has occurred, such as bowel surgery, this may make further surgery more difficult. Where previous radiotherapy has occurred, clearly no further radiotherapy is possible. When a patient is extremely obese, it may be better and safer to have a non-surgical treatment. If a patient has had a fractured pelvis, he may be wise to avoid surgery, as this would lead to incontinence. Abdominal adhesions from previous abdominal operation make robotic and laparoscopic surgery very difficult. HIFU and radiotherapy should not be used when colitis of the rectum is present. (4) Patient Factors The patient factors can broadly be grouped into sexual, urinary, bowel, general health, the type of person and other factors. Sexual The patient’s current sexual status as well as his personal situation in life, i.e. his relationship and the importance he places on sexual potency are clearly major factors in making a decision. His preparedness to use sexual aids is also an important factor. For example, a man who has recently married a younger partner and wishes to choose the treatment with the lowest chance of sexual side effects would select seed therapy, or careful nerve-sparing technique, assuming he has the appropriate tumour. Urinary The patient’s current status with regard to urinary and irritative symptoms as well as his fear of incontinence may have a bearing on his treatment. For example, if a patient has a particular fear of incontinence then he should not consider surgery. Bowel The patient’s current bowel status with regard to previous treatment, the presence of underlying bowel problems such as ulcerative colitis or Crohn’s disease or irritable bowel symptoms may have a major bearing. If he is particularly fearful of long-term bowel side effects such as faecal incontinence, for example, he should not consider radiotherapeutic options. General Health The age of the patient and his life expectancy, the presence of longevity in the family, as well as other health problems, the various medications he takes such as Warfarin and the presence of obesity will have an influence on the therapy. For example, if the patient has a life expectancy of less than 10 years and has

a slow-growing tumour, he may be better to consider active surveillance. Type of Person The type of person the patient is will largely dictate his ultimate choice. Whether he is the worrying type or the accepting type; whether he is a person who needs to make a joint decision with the doctor or he leaves the decision to the doctor; whether he “wants it out” or has a fear of surgery; whether he is a pragmatic type or has unrealistic expectations of his life expectancy; or whether he is a more conservative or punter type. Finally, there is the natural therapy type. He may also be the technology lover type. Each different type of patient will bias the decision to one therapy or another. For example, the conservative type will always go for a surgical solution whilst the natural therapy type will go more for active surveillance therapy. The worrier will never accept active surveillance whilst the fear of surgery type will always go for a less invasive therapy. The lover of new technology will tend to try robotic surgery or HIFU. Other Factors Other factors which may influence patients’ treatment choices include geographical location, the particular person’s personal experience with cancer with a friend or family, the family history and the pattern of the cancer, cultural factors, finances or work commitments. For example, a son with a strong family history where the father has died of prostate cancer at a young age will tend to choose early and aggressive treatment. A person who runs his own business may choose quicker treatments (e.g. seeds, HIFU or robotic surgery) to get back to work quicker. (5) Institutional Factors The availability of technologies and the local expertise will influence the choice of radical prostatectomy. For example, if robotic surgery or HIFU are not available locally and travel is difficult, this may influence choice.

Ideal Cases Every treatment method has an “ideal patient”. Here are some examples: Nerve-sparing radical prostatectomy is “ideal” for a younger, conservative type patient with normal erections, possibly experiencing urinary obstruction, who has a low volume but high-grade tumour. Radical prostatectomy with a sural nerve graft is “ideal” for a younger patient who has good erections, is anxious to preserve his potency and is prepared to “take a punt” on a successful result. He could have a cancer of high volume and high grade and still be suitable for this methodology.

Radical prostatectomy without nervesparing is “ideal” for a conservative patient of any age who has greater than 10 years life expectancy, poorer erections, is less concerned about his future potency and “wants it out”. He may have urinary obstruction and a higher grade, higher volume tumour. Conformal external beam radiotherapy is “ideal” for patients who are aged 70 and over with health preconditions that make surgery inadvisable, or who are obese or averse to surgery, and who have a life expectancy of greater than 10 years. Brachytherapy with seeds is “ideal” for middle aged to older patients who have a fear of surgery and who are sexually potent and anxious to retain their sexual potency. They should have a low volume, low stage cancer in a small prostate, with no urinary obstruction. Obesity is not a problem for this therapy. High dose rate brachytherapy is “ideal” for patients of any age without urinary obstruction, who prefer not to have surgery, or who have medical conditions that make surgery inadvisable. They may have an extensive tumour that is high volume and high stage, and they may be obese. Hormone therapy is “ideal” for patients who have an incurable tumour (i.e. that has a high PSA and has spread beyond the prostate), or are over 70, or have other health problems that limit treatment options, or who have a life expectancy of less than 10 years. Note that hormone therapy is often administered as a pre-treatment to radiotherapy or brachytherapy with seeds. Active surveillance (or “watchful waiting”) is “ideal” for a patient with a low-grade, low stage tumour. It particularly suits older patients for whom retention of sexual potency is very important, who prefer “natural therapies”, or have a fear of surgery, or are prepared to take the risk, or gamble, that the tumour will not progress. Robotic surgery is “ideal” for patients with localised prostate cancer (low to intermediate grade) where the prostate is not too large and has no large middle lobe. Patients wanting to get back to work quicker and are attracted to new technologies are ideal particularly when potency is not the dominant factor. Naturally they need access to an institution that provides this technology. HIFU is “ideal” in older patients with lessextensive cancers who are prepared to accept less trusted new technology. They should have a small prostate even with a previous TURP operation. Ideally PSA should be less than 20. It is also suitable for some younger patients after previously failed radical treatment, but only where the radiation did not damage the CM rectum.

may – july 2007 | Consult Magazine

Transurethral resection of prostate (TURP) using electrocautery has long been regarded as the gold standard for the surgical management of bladder outlet obstruction. Dr Neil S.I. Gordon MB, BS (Melb.), FRCS (Glasg.), FRCSEd., FRACS, FICS. Urologist, Cairns Urology and Cairns Day Surgery; 98 Spence Street, P.O.Box 7787, Cairns, Queensland, Australia; Editorial Advisory Board member, Virtual Cancer Centre

Introduction Transurethral resection of prostate (TURP) using electrocautery has long been regarded as the gold standard for the surgical management of bladder outlet obstruction1. It has long been regarded as the standard by which all others should be compared. Over the years there has been considerable reduction in the post-operative length of stay as an inpatient in hospital and in recent years, a number of papers have been published on TURP in the day surgery setting2,3. In recent years, a number of procedures4,5,6,7,8 including transurethral electrovaporisation (TUVP), Holmium laser enucleation (HoLEP), transurethral microwave thermotherapy (TUMT), transurethral needle ablation (TUNA), high intensity focused ultrasound (HIFU) and most recently, photoselective vaporisation of prostate (PVP) using the Greenlight laser have been compared with TURP and a number of cost comparisons carried out. Many of these procedures have been claimed to be less costly than the conventional procedure but the only cost savings have been in reduced length of stay. The length of stay relates to the individual surgeon’s routine, the amount of post-operative bleeding and the experience of the nursing care given. Nowadays, a considerable number of surgical procedures are carried out in day surgery hospitals because of the understanding of the post-operative courses of the procedures and the adequacy of provision for post-operative analgesia and the greater education, awareness, availability and access to advice. The hoteltype of services such as a bed, regular meals, bathing, toileting and entertainment: books, television, radio, internet are readily available at home during the recovery period.

Patients and methods All the patients considered for DSTURP were private referrals from their General Practitioners with symptoms of bladder

outlet obstruction (BOO), failed medical management (pharmaceutical) or acute urinary retention (AUR) on a background of BOO and failed trial of micturition (TOM). All patients were seen in consulting rooms prior to being admitted for the procedure. They were all assessed by history and examination including using the AUA symptom score and urine was analysed using the Bayer Clinitek 50 urinalysis machine. Urine was only sent for microscopy and culture if indicated by showing positive to two out of three of nitrites, leucocytes and blood. The patients underwent full blood examination, urea, electrolytes, creatinine estimations and prostate specific antigen (PSA). All patients also underwent ultrasound evaluation of the upper urinary tract and non-catheterised patients had pre- and postmicturition volume estimations. The patients whose post-micturition volume was estimated at greater than or equal to 200ml preoperatively were informed that they would be discharged home with a catheter in place for three to four weeks on free drainage to enable to assist the bladder to regain tone. Those patients were then subsequently admitted to day surgery for removal of catheter and postmicturition ultrasound estimated residual urine (ROC PMUERU). Patients on aspirin had the medication continued throughout the operative period and the author has not experienced any adverse consequences of this protocol in the last 15 years. Patients on anticoagulants (coumarin derivatives) had the medication ceased pre-operatively and re-commenced three to five days post-operatively. The criteria for proceeding to day surgery were based on the patients’ general medical conditions and fitness for general anaesthesia. All patients were assessed by their Anaesthetist pre-operatively. Informed procedural and financial consent was obtained after a full discussion of the procedure and its likely post-operative

Consult Magazine | may – july 2007

sequelae. The patient was provided with a brochure covering the discussion including post-operative advice on self-care in the immediate post-discharge period. The patients fasted for six hours prior to the anticipated time of surgery. There was no premedication given and most procedures were carried out under general anaesthesia. All patients were given one dose of prophylactic antibiotics (Gentamicin 240mg IV stat) via an infusion of Hartmann’s solution. The decision to remove the catheter was based on the degree of mental alertness, adequacy of analgesia and fluid intake and the colour of the effluent drainage. The patients who underwent spinal anaesthesia were required to be able to weight bear and walk unassisted. This was usually removed two to three hours post-operatively and the intravenous Hartmann’s solution stopped (one to two litres infused) and the patients encouraged to consume fluid orally. They were then monitored in Stage 2 recovery where they were allowed to get dressed and sit in recliner chairs and given solid food in the form of sandwiches. Monitoring of fluid balance was then continued. Postmicturition volumes were measured using the Bard Bladder Scan 2500.

Results The results are shown in Table 1. Preoperatively, it had been elected to discharge those patients (44) with greater than 200ml residual home with a catheter in place on free drainage to regain bladder tone. All were successful in micturating after the four weeks. Of the remaining 215, some 64 (30%) patients required re-catheterisation. Six of those catheters were removed the same day. The patients micturated successfully and were discharged without catheter. In 26 patients, the catheter then remained in place and the patient was discharged home overnight. The patients were then readmitted the following

CANCER

Day Surgery TURP

cancer

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morning for removal of catheter and PMUERU carried out, as had been the case in the routine catheter removal. Catheter reinsertion was not required for those patients. Five patients’ catheters were removed within 72 hours and the remaining 27 (12.6% of those in whom we had hoped to send home catheter-free) patients were deemed to have relatively hypotonic bladders and were discharged home with the catheter on free drainage for four weeks. All micturated successfully upon removal of the catheter. There have been four repeat procedures in addition to 11 (4.2%) bladder neck incisions for post-operative bladder neck stenosis (BNS) and 23 (8.8%) visual urethrotomies for post-operative urethral stricture (US). In all cases, there was a significant amount of inflammation reported by the Pathologist in the specimen which may have contributed. No patients developed any complications requiring admission to hospital and no patients required blood transfusion or developed sepsis. There were no cases of clot retention.

Discussion While there have been a number of papers11,12 produced to attest to the efficacy of alternative surgical treatments in the treatment of BOO, none of the work has been carried out in a free-standing day surgery. The key factor related to the length of stay after any non-radical prostatectomy is the post-operative duration of catheterisation, which is determined by the amount and duration of post-operative bleeding deemed acceptable for catheter removal. Therefore meticulous haemostasis is mandatory in order to achieve earlier catheter removal. DSTURP performed in the conventional manner has significant advantages. The cost of set-up including building works for alternative procedures as well as the costs per case are significantly higher when compared with DSTURP. All the newer modalities which have been reported to cost less per case than conventional TURP have done so based only on a shorter length of stay however, when the conventional procedure can be carried out as a day case with a documented length of mean stay 10.6 hours there does not appear to be an advantage to the more expensive newer procedures. A significant number of patients are electing to have surgical procedures carried out as selffunding and uninsured. The ability to carry out surgical procedures safely and effectively in the day surgery setting makes that a reality for those who choose to be managed that way. By having procedures done in this manner, it reduces the waiting time for the procedure,

Table 1: Results of patients undergoing DSTURP

Number of patients

259

Age (years)

69 (48-87)

AUA Score

22 (3-35)

G.A.

205

S.A.

Resection Weight (g)

14 (3-80)

Blood Loss Estimated (ml)

80 (10-200)

Length of Catheterisation (hours)

2.9

Post-Micturition Residual (ml)

Re-insertion of catheter

64 (30%)

Patients discharged electively with catheter

44 (17%)

Average length of stay at day surgery (hours)

10.6

which is usually one to two weeks after the initial consultation. It also takes the “pressure” off the public waiting list, which can require patients to be transported to the state capital for their procedures for a period of up to four weeks, often with the requirement that a “carer” accompany the patient.

References 1. Gordon NSI, Hadlow G, Knight E and Mohan P. Transurethral Resection of the Prostate: still the gold standard. AustNZJSurg 1997; 67: 354. 2. Gordon NSI. Catheter-free same day surgery transurethral resection of the prostate. J. Urol 1998; 160: 1709-1712. 3. Chander J, Vanitha V, Lal P and Ramteke VK. Transurethral resection of the prostate as catheter-free day-care surgery. BJU Int 2003; 92: 422-425. 4. Kaplan SA, Laor E, Fatal M and Te AE. Transurethral resection of the prostate versus transurethral electrovaporisation of the prostate: a blinded, prospective comparative study with 1 year follow up. JUrol 1998; 159: 154. 5. Montorsi F, Naspro R, Salonia A et al. Holmium laser enucleation versus transurethral resection of the prostate: results from a 2-center, prospective, randomised trial in patients with obstructive benign prostatic hyperplasia. JUrol 2004; 172: 1926-9. 6. Gilling PJ, Kennet KM, Fraundorfer MR. Holmium laser resection v transurethral resection of the prostate: results of a randomised trial with 2 years follow up. J Endourol 2000; 14: 757. 7. Hoffman RM, Macdonald R, Monga

M et al. Transurethral microwave thermotherapy vs transurethral resection for treating benign prostatic hyperplasia: a systematic review. BJU Int 2004; 94: 1031-6. 8. Wagrell L, Schelin S, Nordling J et al. Three-year follow up of feedback microwave thermotherapy versus TURP for clinical BPH: a prospective randomized multicenter study. Urology 2004; 64: 698702. 9. Gordon NSI. The tide is stemmed. A method of catheter traction for the control of venous haemorrhage following transurethral resection of the prostate. AustNZJSurg 1987; 57: 475 10. Klimberg IW, Locke DR, Leonard E, Madore R, Klimberg SR. Outpatient transurethral resection of the prostate at a urological ambulatory center. JUrol 1994; 151: 1547-9. 11. Bouchier-Hayes DM, Anderson P, Van Appledorn S, et al. A randomised trial comparing Greenlight® laser treatment and trans-urethral resection of the prostate (TURP) in patients. BJU 2005; 95 Supp 5: 15-16. 12. Kumar SM. Photoselective vaporisation of the prostate: a volume reduction analysis in patients with lower urinary tract symptoms secondary to benign prostatic hyperplasia and carcinoma of the prostate. JUrol 2005; 173: 511-13. 13. McLoughlin MG, Kinahan TJ. Transurethral resection of the prostate in the outpatient setting. JUrol 1990; 143: CM 951-2.

may – july 2007 | Consult Magazine

Getting Physical with Cardiovascular Disease

It’s not so long ago that standard medical advice given to patients with cardiovascular disease (CVD) was “take it easy, don’t exert yourself ”. How times have changed. Dr Andrew Maiorana, PhD, is the Senior Exercise Physiologist with the Cardiac Transplant Unit at Royal Perth Hospital. He was a member of the Executive Working Group responsible for writing the National Heart Foundation of Australia physical activity recommendation for people with CVD. Editorial Advisory Board member, Virtual Cardiac Centre

t’s not so long ago that standard medical advice given to patients with cardiovascular disease (CVD) was “take it easy, don’t exert yourself ”. How times have changed. The overwhelming evidence from a growing body of research is that the benefits of being physically active for those with stable CVD* far outweigh the risks. In fact, patients who take up regular endurance activity after an initial cardiac event have a 31% lower risk of experiencing a subsequent fatal cardiac event than their inactive counterparts1. This is the clear message of the recently released National Heart Foundation of Australia physical activity recommendations for people with cardiovascular disease2 and a companion position statement appearing in the Medical Journal of Australia3 http://www. heartfoundation.com.au/index.cfm?page=42. These recommendations have been formulated with the purpose of providing general practitioners and physicians with evidence-based guidelines about appropriate physical activity prescription for people with stable CVD. Insufficient physical activity is second only to smoking as the most important modifiable risk factor contributing to CVD, the leading cause of death in Australia. Yet despite large-scale public health campaigns, over half the adult Australian population are not sufficiently active to derive health benefits4. The problem is likely to be even more dire for those with existing CVD, in part due to the continuation of a lifestyle, that in all likelihood, contributed to the pathogenesis of the disease, but also as a result of ongoing misconceptions about the perceived risks of physical exertion in this group. The challenge facing all health professionals who are endeavouring to promote physical activity, especially to the historically sedentary, is to provide both a compelling case for the benefits of being active

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Consult Magazine | may – july 2007

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cardiac

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and to convince prospective “converts” to activity that the amount of activity required to attain these benefits is achievable. With respect to health benefits, in addition to improved prognosis, regular physical activity favourably alters important risk factors for atherosclerosis including elevated blood pressure, raised triglyceride concentrations, low high-density lipoprotein cholesterol (HDL-C), insulin resistance and glucose intolerance and obesity. Physical activity also results in less angina, possibly as a result of improved coronary endothelial function and resultant vasodilator capacity5 and evidence is emerging for physical activity as a treatment for depression in patients following acute myocardial infarction6. So how much physical activity should people with CVD be aiming for – is it achievable? The recommendations advise that people with clinically stable CVD should aim for similar minimum activity levels to the general population. That is, to accumulate 30 minutes or more of moderate intensity physical activity on most, if not all days of the week. Importantly, this doesn’t need to be done all at once; three bouts of 10 minutes of activity in a day confers a similar benefit to a continuous bout of 30 minutes. The activity doesn’t need to be strenuous either; a walk that is associated with a moderate increase in breathing, but still allows conversation, is a

Advocate physical activity for those with CVD.

good guide. To be prudent, people with CVD, especially those who have previously been sedentary, should build up gradually to these levels. A good practical approach is to start with shorter bouts of light activity, increasing the duration of the activity in the first instance and then increasing the intensity gradually to more moderate levels as fitness starts to improve. The dose and rate of progression for physical activity may need to be modulated for patients with more advanced disease, significant functional limitations and the elderly. Furthermore, specific considerations may need to be taken when advising physical activity for people with non-cardiac CVD including stroke, peripheral vascular disease and diabetes. These issues are all addressed in greater detail in the National Heart Foundation recommendations. It is relevant to note that the evidence supporting the health benefits of physical activity for people with CVD comes predominantly from studies of formal endurance exercise such as walking, cycling and swimming. Therefore, it is not clear whether regular manual vocational and domestic tasks contribute to a reduced risk of secondary events in established CVD. Many manual tasks involve relatively short periods (<10 minutes) of continuous activity, interspersed with rest, so they may not result in the same physiological stimulus as more structured activities. Consequently, although non-exercise activities should be encouraged, provided they don’t induce symptoms, there is insufficient evidence to support the premise that manual work alone is sufficient to reduce cardiovascular risk in those with existing disease. Similarly, resistance exercise (lifting weights) may not directly improve cardiovascular risk. However, resistance exercise is effective in developing and maintaining muscular strength and endurance, outcomes that will assist people with CVD in undertaking many commonly encountered tasks of daily living. Cardiovascular responses to resistance exercise are no greater than to comparable intensities of endurance physical activity7, and resistance exercise should be encouraged as part of a comprehensive physical activity program to complement the benefits of endurance physical activity, preferably under the supervision of an exercise professional in the first instance. In the early stages after a cardiovascular event, patients may benefit from attending formal exercise classes under the supervision of a qualified exercise specialist as part of a cardiac rehabilitation program. Outpatient cardiac rehabilitation is provided at many hospitals as well as in community settings. Alternatively, people with chronic diseases

(including stable CVD) can utilise new Medicare item numbers to receive rebates for specialist exercise advice and prescription from an exercise physiologist when they are referred by their GP as part of a general practice management plan or team care plan. Medicine is a constantly evolving science and traditionally held beliefs are consistently being superseded by evidence-based practice. Physical activity in CVD is a classic case-inpoint. So rather than “take it easy”, the new catch cry for cardiovascular disease should be “let’s get physical … in a moderate way!” *Well compensated, clinically stable; receiving appropriate pharmacotherapy, without evidence of new or progressive signs or symptoms indicative of clinical deterioration.

References 1. Jolliffe JA, Rees K, Taylor RS, et al. Exercisebased rehabilitation for coronary heart disease. Cochrane Database Systematic Review, 2001; 1 (CD001800). 2. Briffa T, Maiorana A, Allan R, et al. On behalf of the Executive Working Group and National Forum Participants. National Heart Foundation of Australia physical activity recommendations for people with cardiovascular disease. Sydney (Australia): National Heart Foundation of Australia; September 2005. 3. Briffa TG, Maiorana A, Sheerin NJ, et al. Physical activity for people with cardiovascular disease: recommendations of the National Heart Foundation of Australia. MJA 2006; 184: 71-5. 4. Australian Institute of Health and Welfare (AIHW). Heart, stroke and vascular diseases – Australian facts 2004 (Cardiovascular Diseases Series No. 22). AIHW and National Heart Foundation of Australia, 2004. 5. Hambrecht R, Walter C, Mobius-Winkler, S. Percutaneous coronary angioplasty compared with exercise training in patients with stable coronary artery disease; a randomised trial. Circulation 2004; 109: 1371-8. 6. Blumenthal JA, Babyak MA, Carney RM, et al. Exercise, depression, and mortality after myocardial infarction in the ENRICHED Trial. Med Sci Sports Exerc 2004; 36: 74655. 7. McKelvie RS, McCartney N, Tomlinson C, et al. Comparison of hemodynamic responses to cycling and resistance exercise in congestive heart failure secondary to ischemic cardiomyopathy. Am J Cardiol CM 1995; 76: 977-9.0

may – july 2007 | Consult Magazine

Memory loss, poor concentration and “fuzzy thinking” are common complaints after coronary artery bypass graft (CABG) surgery, with estimates of cognitive dysfunction as high as 75%. Dr Pamela Bradshaw, PhD; Adjunct Research Fellow, School of Population Health, University of Western Australia; Editorial Advisory Board member, Virtual Cardiac Centre

emory loss, poor concentration and “fuzzy thinking” are common complaints after coronary artery bypass graft (CABG) surgery, with estimates of cognitive dysfunction as high as 75%. Symptoms are likely to resolve within a year of surgery for the majority of patients, but for some there may be ongoing cognitive decline.

Possible Causes of Neurocognitive Dysfunction Short-term cognitive dysfunction after general anaesthesia for non-cardiac surgery such as hip and knee replacement has been noted, especially among the elderly. The longer term deficits after CABG have been attributed to the use of mechanical cardio-pulmonary bypass (CPB). CPB is associated with known effects that are implicated in cognitive dysfunction. These include the generation of micro-emboli during cannulation and clamping/unclamping of the aorta, cerebral hypoperfusion and systemic inflammatory response. None has been shown convincingly to be causally linked to the extent or persistence of cognitive dysfunction.

Measurement issues Although there is a range of widely-used and validated tests for the assessment of all major cognitive domains, the measurement of cognitive dysfunction after CABG is complicated by the lack of a standard assessment protocol and of an agreed measure of “cognitive dysfunction”. In addition, practice effects may accompany the serial administration of tests, and comorbidities such as pre-surgery anxiety and post-surgery depression can influence results. Despite this, there is general agreement that measurable changes in cognitive function can be identified in patients in the short and long-term after CABG.

Consult Magazine | may – july 2007

CARDIAC

cardiac Cognitive Function and CABG Surgery

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CARDIAC

summary of off-pump surgery, but little other Australian-based information about cognitive function and CABG surgery is available to the consumer, though studies are in progress. The Mayo Clinic provides more detailed online patient information8 , which includes information on the risk factors for decline in memory and other impairment of cognitive functions (older age, hypertension, pulmonary disease and excessive alcohol consumption) and the reassurance that effects are not usually persistent. Probably the most important statement is: “Bypass surgery does not cause dementia, but it may worsen any pre-existing mental decline, including early dementia.” The families of patients with existing mental decline or dementia to whom CABG surgery is recommended should be urged to discuss this issue with the surgeon or cardiologist before surgery.

References

The Research Neurocognitive changes after CABG surgery have been reported for decades. While the incidence of stroke and post-operative delirium were the focus of earlier studies, more subtle changes were also recognised, and consensus on the measurement of cognitive dysfunction was sought in the mid-1990s1. A longitudinal study from Duke University Medical Centre2 published in 2001 reported the incidence of cognitive decline as 53% at discharge, 24% at six months and 42% at five years, highlighting the long-term nature of the problem. Like most studies on the topic, the study group was small (n=261) and there was no control group against which results could be compared. The publication of these findings coincided with the increase in the use of “off-pump” CABG, with surgery performed on the beating heart. It was anticipated that side effects of CPB use, including neurocognitive complications, would be reduced.

On-Pump versus Off-Pump CABG Several studies of cognitive function among patients having off-pump versus on-pump CABG, some of which were randomised controlled trials, were performed. The largest RCT (n=281), from the Netherlands, found minimal benefits for off-pump surgery at three months, and no difference at 12 months3. In addition, when the normal fluctuations in cognitive function found in

non-surgical controls were taken into account, the incidence of cognitive dysfunction among patients after CABG was over-estimated4. One of the few prospective studies to include non-surgical controls with and without coronary artery disease, found that patients with heart disease had poorer cognitive scores than those with no heart disease. After surgery there was no difference in outcomes for patients who had off-pump versus on-pump CABG, though this was not a randomised study5. There is some support for the position that CABG surgery adds insult to pre-existing injury. MRI studies show the prevalence of silent ischaemic cerebral disease amongst patients with coronary artery disease is likely to be underestimated6 and that the degree of pre-operative cerebral disease may indicate the likelihood of postoperative cognitive decline for patients who have otherwise uncomplicated surgery7. Patients with impaired cognitive function early after CABG are more likely to suffer persistent decline. An independent positive effect of off-pump CABG on the preservation of long-term cognitive function has not yet been demonstrated.

What Should Patients Know About Cognitive Function and CABG Surgery? The Royal Australasian College of Surgeons makes fleeting reference to an incidence of 70% for “confusion” in its online consumer

1. Murkin J, Newman S, Stump D, Blumenthal A. Statement of consensus on assessment of neurobehavioral outcomes after cardiac surgery. Ann Thorac Surg 1995; 59: 128995 2. Newman M, Kirchner J, Phillips-Bute B, et al. Longitudinal assessment of neurocognitive function after coronaryartery bypass surgery. N Engl J Med 2001; 344: 395-402 3. van Dijk D, Jansen E, Hijman R, et al. Cognitive outcome after off-pump and onpump coronary artery bypass graft surgery: a randomized trial. JAMA 2002; 287: 140512 4. van Dijk D, Diephuis JC, Nierich AP, Keizer AM, Kalkman CJ. Beating heart versus conventional cardiopulmonary bypass: the octopus experience: a randomized comparison of 281 patients undergoing coronary artery bypass surgery with or without cardiopulmonary bypass. Semin Cardiothorac Vasc Anesth. 2006; 10: 16770. 5. Selnes O, Grega M, Borowicz L Jr, Royall R, McKhann G, Baumgartner W. Cognitive changes with coronary artery disease: a prospective study of coronary artery bypass graft patients and non-surgical controls. Ann Thorac Surg 2003; 75: 1377-84 6. Goto T, Baba T, Honma T, et al. Magnetic resonance imaging findings and postoperative neurologic dysfunction in elderly patients undergoing coronary artery bypass grafting. Ann Thorac Surg 2001; 72: 137-42 7. Lund C, Sundet K, Tennoe B, et al. Cerebral ischemic injury and cognitive impairment after off-pump and on-pump coronary artery bypass grafting surgery. Ann Thorac Surg 2005; 80: 2126-31 8. http://w w w.mayoclinic.com/health/ CM coronary-bypass-surgery/HB00022

may – july 2007 | Consult Magazine

Adverse Drug Reactions

Adverse events following medical therapies are common. Studies have shown that between 5% and 30% of all patients receiving medical therapies develop an adverse event. Gary A Unglick MBBS (hons); Advanced Trainee Registrar Clinical Immunology Sydney South West Area Health Services Assoc Prof. John W Quin, MBBS (hons) BSc (hons) PhD FRACP FRCPA; Director Clinical Immunology Sydney South West Area Health Services; Assoc Professor Medicine UNSW; Editorial Advisory Board member, Virtual Allergy Centre

Introduction, Classification and Definitions Adverse events following medical therapies are common. Studies have shown that between 5% and 30% of all patients receiving medical therapies develop an adverse event1,2,3,4,5. In many cases, little effort is spent in determining the underlying mechanism for these adverse events and hence no reliable information can be given to prevent a recurrence. This article will review what is known about adverse drug events and outline a scheme for investigating them and predicting the likelihood of a recurrence. Adverse drug reaction (ADR) is a term used to describe the unwanted, negative consequences of drug therapy. Drug hypersensitivity is used to describe any immune mediated ADR while drug allergy is restricted specifically to a reaction mediated by IgE antibodies. There are many ways of classifying ADRs but most classification schemes incorporate the divisions outlined in Table 1. In terms of aetiology, ADRs can be classified into immunologic and non-immunologic aetiologies. The majority (75-80%) are type A (see Table 1) and are caused by non-immunologic effects7. Immune mediated reactions account for 5-10% of all ADRs and are generally classified according to the Gell and Coombs Hypersensitivity reactions (see Table 2). Pseudoallergic or anaphylactoid reactions are the result of direct mast cell activation and degranulation by drugs such as opiates, vancomycin and radiocontrast media. These reactions may be clinically indistinguishable from Type I hypersensitivity, but do not involve drug specific IgE. In addition, there are other specific drug hypersensitivity syndromes caused by non-IgE immune mechanism (see Table 3). More recently, an alternative way of viewing immune activation by drug therapy has been proposed based on the aetiology of immune activation. Three hypotheses are proposed:

Table 1 Classification of Adverse Drug reactions

Type

Name /Mechanism

Examples

Type A

Pharmacologically predicted

Bleeding and anticoagulants, extrapyramidal effects and phenothiazines, some may be useful, e.g. peripheral vasodilatation and nicotinic acid (vitamin B2) in Raynaud’s

Type B

Idiosyncratic and Unpredictable (Includes drug allergy)

Haemolytic anaemia in a patient with glucose 6 phosphate dehydrogenase deficiency after primaquine therapy

Type C

Arising from Chronic use Obesity and glucocorticoids

Type D

Delayed Toxicity

Teratogenic or carcinogenic effects

Type E

Drug-drug interactions

Quinidine and digoxin

Type F

Failure of therapy

Unfortunately many drugs

a) The Hapten Hypothesis – the parent drug or a reactive metabolite binds to an endogenous protein and generates a foreign protein that leads to an immune mediated adverse reaction8. b) The PI hypothesis – this is proposed by WJ Pichler and proposes that some drugs may bind reversibly to the MHC or possibly the T cell receptor, eliciting immune reactions9. This theory may explain the appearance of drug hypersensitivity without prior sensitisation. c) The Danger Hypothesis – this theory proposes that cell damage (endogenous stimuli) produced by reactive metabolites of a drug result in upregulation of costimulatory molecules that drive the immune response. This theory may explain why some infections (HIV, chronic hepatitis C and EBV) are associated with increased risk of ADRs with the pathogen providing an exogenous stimuli6,10.

Host Factors Influencing ADRs Adverse reactions are known to be more common in older persons and in females but more recently the importance of HLA type has become obvious, with defined HLAs posing a risk of ADRs with particular drugs (see Table

Consult Magazine | may – july 2007

4). The value of this knowledge is that the risk of an ADR with certain drugs can be reduced if you avoid giving the drug to patients with a high risk HLA.

Drug Factors Influencing ADRs While adverse events have been reported with most medical therapies, certain classes of drugs have a high incidence of adverse events. These are the nonsteroidal anti-inflammatory drugs (NSAIDS), antimicrobials, anticonvulsants, anaesthetic agents and neuromuscular blocking drugs2,16. Recent published adverse events include the risk of cardiovascular disease with selective cox2 inhibitors, myopathy with statins, angioedema with ACE inhibitors and angiotensin II antagonists, and lipid changes with antiretrovirals. There is convincing evidence that drugs associated with a high incidence of drug hypersensitivity are converted to reactive metabolites by the normal processes of drug metabolism and stimulate an immune mediated response in sensitive individuals8,17,18,19. In general, reactive metabolites are either electrophiles (i.e. electron deficient) and react with biological nucleophiles, such as glutathione, or nucleophilic groups on

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Immune Reaction

Mechanism

Clinical manifestations

Timing of reactions

Type I (IgE mediated)

Drug-IgE complex binding to mast cells with release of histamine and other mediators

Urticaria, angioedema, bronchospasm, inflammatory pruritus, anaphylaxis

Minutes to hours after drug exposure

Type II (Cytotoxic)

Specific IgG or IgM antibodies directed at drug-hapten coated cells

Haemolytic anaemia, neutropenia, thrombocytopenia

Variable

Type III (immune complex)

Tissue deposition of drug antibody complexes with complement activation and inflammation

Serum sickness, fever, rash, arthralgias, lymphadenopathy, urticaria, glomerulonephritis, vasculitis

1-3 weeks after drug exposure

Major Histocompatibility complex presentation of drug molecules to T cells with cytokine and inflammatory mediator release

Allergic contact 2-7 days after dermatitis, cutaneous drug maculopapular drug rash exposure Blistering diseases (e.g. Stevens-Johnson Syndrome) and neutrophilic drug eruptions (e.g. acute generalised exanthematous pustulosis â&#x20AC;&#x201C; AGEP)

Type IV (delayed cell mediated)

proteins, such as sulphydryl or amino groups; or free radicals19. Certain metabolic or enzyme pathways involved in drug bioactivation are known to be associated with a higher risk of ADRs, for example metabolism involving acyl glucuronides, reactive electrophils such as epoxides, arene oxidases, quinones, nitros compounds, free radicals and others (examples are shown in Fig 1). It has been suggested that screening using in vitro assays for the presence of these known reactive metabolites in drugs under development may reduce the incidence of ADRs19. The route of administration also influences the likelihood of an adverse event and its severity. Drugs applied topically are more likely to sensitise a patient to allergic reactions than parenteral and least often with the oral route. Intravenous administration gives rise to more severe reactions1.

Diagnosis: Clinical History Evaluation of an adverse drug reaction must begin with a precise and detailed history, including clinical symptoms and their timing and duration in relation to drug exposure. The most serious clinical manifestation is anaphylaxis with hypotension, bronchospasm, angioedema, urticaria and cardiovascular collapse. These reactions occur within a

short time of taking the drug (usually less than three hours) and are caused by Type I hypersensitivity or anaphylactoid mechanisms. The drugs more commonly associated with these reactions are antibiotics, radiocontrast media, anaesthetic drugs, enzymes, cisplatin, insulin and latex. Tryptase enzyme levels are a valuable marker of mast cell degranulation. Serum concentrations peak one hour after anaphylactic reactions but may be detected up to five hours later20. Unfortunately, serum tryptase levels are not available as a stat test in Australia and it may take days to weeks before the result is available. A negative tryptase does not rule out an anaphylactic event. Dermatological reactions are the commonest side effect of many drugs. Table 5 summarises the common skin manifestations and their mechanisms. Other clinical manifestations are summarised in Table 6. The value of clinical history in differentiating drug allergy from other forms of adverse drug reactions has been demonstrated with penicillin allergy. Two studies21,22 involving 638 and 319 patients who were referred to an allergy clinic for possible penicillin allergy were divided into three groups based on clinical history. The likelihood of a positive skin test to penicillin in the groups with a history suggestive of drug allergy was 72.2% and 14.1%, while in a second group with only

Consult Magazine | may â&#x20AC;&#x201C; july 2007

ALLERGY

Table 2 Gell and Coombs Classification of Drug Hypersensitivity reactions8

a vague history of drug allergy, the incidence of positive skin tests was 14.1% and 6.7% and in the third group with an unconvincing history of drug allergy only 0.9% and 0% were positive on skin testing. This area is, however, is controversial with other studies such as that by Macy et al23 providing conflicting data and some experts therefore recommend that all patients with any history of penicillin allergy should be skin tested prior to administration of penicillin. This recommendation is further strengthened by data that show that one quarter to one third of penicillin related deaths were history positive24.

Laboratory Investigations Tests to determine possible immune mediated mechanisms of ADR are listed in Table 7. The diagnosis of drug allergy or hypersensitivity can be difficult and may require the input of a clinical immunologist. The benefits of making an accurate diagnosis of an ADR include: 1. Dangerous re-administration of drugs can be avoided; and 2. Incorrect diagnosis and drug exclusion with resulting expense, use of less efficacious second-line drugs and generation of antibiotic resistance can be avoided. Testing in drug allergy clinics allows alternative drugs to be identified if required and if no alternative is available, desensitisation can be performed with tolerance maintained only for the course of therapy.

Therapy The most important therapeutic decision for all suspected adverse drug reactions is to discontinue the suspected drug. In patients with poly-pharmacy, the decisions to stop the drugs must be weighed up between the need for the drug and its likelihood of causing the observed clinical manifestations. In suspected systemic Type I or anaphylactoid reactions, the drug of choice is adrenaline. It may be given intramuscularly without delay, as early administration leads to better outcomes25. Intravenous adrenaline may be used in cases of severe hypotension, but this usually only occurs in advanced cases. Adjuvants would be bronchodilators and systemic corticosteroids but administration of these should not delay the administration of adrenaline if required. Care should be taken with IV Phenergen to prevent thrombophlebitis and its use is not recommended if the patient can take an oral non-sedating histamine such as cetirizine, due to the additional hypotensive action of Phenergan. For other immune mediated hypersensitivity reactions (II to IV), systemic corticosteroids can be used, in Type III reactions plasmapheresis to remove

ALLERGY

options for investigating ADRs are likely to expand rapidly due to future research in this important area.

Table 3 Specific Drug Hypersensitivity Syndromes caused by Non-IgE Immune Mechanisms (Author modified from ref 7).

Causative Drug

Syndrome

Postulated Mechanism

Hydralazine Procainamide

Lupus-like syndrome

Induced autoantibodies and immune complexes

Carbamazepine Phenytoin

Anticonvulsant hypersensitivity syndrome

Unknown

Sulphonamides Anticonvulsants

Stevens-Johnson Syndrome, toxic epidermal necrolysis

Fas/Fas ligand induced apoptosis

ACE inhibitors

Angioedema

Altered Bradykinin levels

References

Table 4 Host Factors known to predispose to adverse drug reactions Factor

At Risk Group

Drug(s)

Reference

Age

Older

Many

1, 4, 5

Sex

Female

Many

1, 4, 5

HLA

HLA-DQw2

Aspirin

HLA-B7, D22, D23

Insulin

HLA-B*5701

Abacavir

HLA-B*1502

Carbamazepine

HLA-B*5802

Allopurinol

HLA-DR9

Penicillin

Slow acetylators

Sulphonamides

Drug Metabolism

Hydralazine Anti TB drugs Infection

HIV

Cotrimoxazole

EBV

Ampicillin

6, 15

Table 5 Cutaneous Reactions to Drugs (author modified from ref 1 and 8)

Manifestation

Mechanism of drug reaction

Examples

Exanthematous or morbilliform eruption originating on the trunk

Type III or IV

Antibiotics, anticonvulsants

Urticaria

Type I or direct mast cell stimulation

Most drugs

Purpura-vasculitis

Type III, Type IV

Allopurinol

Photodermatitis

Type IV

Griseofulvin, sulphonamides

Stevens-Johnson Syndrome

Fas/Fas ligand induced apoptosis

Allopurinol, sulphonamides, anticonvulsants

Contact dermatitis

Type IV

Antibiotics

See page 25 for Table 6 and 7.

autoantibodies or immune complexes may be helpful.

Conclusions A better understanding of the mechanisms underlying an ADR is important in drug development and in-patient care. Avoiding drugs metabolised by certain metabolic or enzymatic pathways may avoid the creation of reactive metabolites responsible for many drug hypersensitivity reactions. In-

patient care practitioners should consider tailoring medical therapies to individuals by considering pharmacogenetic factors such as age, sex, HLA type, renal and hepatic function in deciding drug therapy and drug doses. In the event of an ADR occurring, it is important to attempt to determine the underlying mechanism in order to avoid a repeat incidence in the future. A scheme summarising this process is outlined in Figure 2. It must be emphasised that

1. Vervloet D, Durham S. Adverse reactions to drugs. BMJ 1998; 316: 1511-1514. 2. Huic M, Mucolic V, Vrhovac B, Francetic I, Bakran I, Giljanovic S. Adverse drug reactions resulting in hospital admission. Int J Clin Pharmacol Ther 1994; 32(12): 675-682. 3. Davies EC, Green CF, Mottram DR, Pirmohamed M. Adverse drug reactions in hospital inpatients: a pilot study. J Clin Pharm Ther 2006; 31(4): 335-341. 4. Gurwitz JH, Field TS, Harrold LR, Rothschild J, Debellis K, Seger AC, Cadoret C, Fish LS, Garber L, Kelleher M, Bates DW. Incidence and preventability of adverse events among older persons in the ambulatory setting. JAMA 2003; 289(9): 1107-1116. 5. Rodriguez Velasco JG, Torres Valdos JE, Montero Mora P, Juarez Morales DT, Rodriguez E, Almeida Arvizu VM. Reactions to drugs: a review of literature. Rev Alerg Mex 2006; 53(2): 73-75. 6. Coopman SE, Johnson RA, Platt R, Stern RS. Cutaneous diseases and drug reactions in HIV infection. N Engl J Med 1993; 328(23): 1670-1674. 7. Riedl MA, Casillas MD. Adverse drug reactions: types and treatment options. Am Fam Physician 2003; 68: 1781-1790. 8. Naisbitt DJ, Williams DP, Pirmohamed M, Kitteringham NR, Park BK. Reactive metabolites and their role in drug reactions. Curr Opin Allergy Clin Immunol 2001; 1:317-325. 9. Pichler WJ. Pharamacological interaction of drugs with antigen-specific immune receptors: the p-I concept. Curr Opin Allergy Clin Immunol 2002; 2: 301-305. 10. Matzinger P. An innate sense of danger. Semin immunol 1998; 10: 399-415. 11. Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte C, Maxwell D, James I, Christiansen FT. Association between presence of HLA-B* 5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet 2002; 359(9308): 727-732. 12. Hung SI, Chung WH, Jee SH, Chen WC, Chang YT, Lee WR, Hu SL, Wu MT, Chen GS, Wong TW, Hsiao PF, Chen WH, Shih HY, Fang WH, Wei CY, Lou YH, Huang YL, Lin JJ, Chen YT. Genetic susceptibility to carbamezepine-induced cutaneous drug reactions. Pharmacogenet Genomics 2006; 16(4): 297-306. 13. Hung SI, Chung WH, Liou LB, Chu CC,

may â&#x20AC;&#x201C; july 2007 | Consult Magazine

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Table 6 Clinical Manifestations of Immune Mediated Drug Hypersensitivity1

Manifestation

Clinical Features

Examples of Drugs

Anaphylaxis

Urticaria or angioedema, rhinitis, asthma, abdominal pain

Penicillin, neuromuscular blocking drugs

Pulmonary

Asthma Interstitial pneumonitis

Aspirin, NSAIDS, Beta blockers Amiodarone, nitrofurantoin Chemotherapeutic agents

Cardiac

Eosinophilic myocarditis

Methyldopa

Hepatic

Hepatitis

Halothane, chlorpromazine, carbamazepine

Haematological

Haemolytic anaemia Thrombocytopenia Neutropenia Aplastic anaemia

Penicillin Frusemide, thiazides Penicillin NSAIDS, sulphonamides

Renal

Interstitial nephritis

Cimetidine

Table 7 Laboratory Investigations for Immune Mediated Adverse Drug Reactions

Immune Reaction Laboratory Test

Drugs that can be tested

Type I

Serum Tryptase

All drugs

Specific IgE assays (previously RAST) Drug to be tested must be specified when ordering â&#x20AC;&#x201C; list likely to expand in near future.

Penicillin G + V Ampicillin/amoxycillin Cephalexin Latex/Chlorhexidine Muscle relaxants Thiopentone

Skin Testing

Penicillin and beta lactams Anaesthetic agents Muscle relaxants Insulin Sex hormones

Oral or iv challenge

Most drugs

Type II

Direct or indirect Coombs Platelet antibodies Tissue Biopsy

Suspected haemolytic anaemia Drug-induced thrombocytopenia

Type III

Complement levels Immune complexes Cryoglobulins Autoantibodies Tissue biopsy

Type IV

Tissue biopsy Patch Testing Lymphocyte Proliferation assays

Lin M, Huang HP, Lin YL, Lan JL, Yang LC, Hong HS, Chen MJ, Lai PC, Wu MS, Chu CY, Wang KH, Chen CH, Fann CS, Wu JY, Chen YT. HLA_B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci USA 2005; 102(17): 6237. 14. Yang J, Qiao HL, Zhang YW, Jia LJ, Tian X, Gao N. HLA-DRB genotype and specific IgE responses in patients with allergies to penicillins. Chin Med J (Engl) 2006; 119(6): 458-466.

15. Carr A, Cooper DA. Pathogenesis and management of HIV-associated drug hypersensitivity. AIDS Clin Rev 1996; 96: 65-97. 16. Zanocchi M, Tibaldi V, Amati D, Fracisetti F, Martinelli E, Gonella M, Cerrato F, Ponte E, Luppino A, Bardelli B, Canade A, Gariglio F, Moiraghi C, Molaschi M. Adverse drug reactions as a cause of visits to emergency department: incidence, features and outcomes. Recenti Prog Med 2006; 97(7-8): 381-388.

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17. Nassar A-E F, Lopez-Anaya A. Strategies for dealing with reactive intermediates in drug discovery and development. Curr Opin Drug Discov & Devel 2004; 7(1): 126-136. 18. Amacher DE. Reactive intermediates and the pathogenesis of adverse drug reactions: the toxicology perspective. Curr Drug Metab 2006; 7(3): 219-229. 19. Uetrecht J. Screening for the potential of a drug candidate to cause idiosyncratic drug reactions. DDT 2003; 8(18): 832-837. 20. Komericki P, Arab E, Grims R, Kranke B, Aberer W. Tryptase as severity marker in drug provocation tests. Int Arch Allergy Immunol 2006; 140: 164-169. 21. Kalogeromitros, Dimitrios; Rigopoulos, Dimitrios; Gregoriou, Stamatios; Papaioannou, Dimitrios; Mousatou,Vassiliki; Katsarou-Katsari, Alexandra. Penicillin hypersensitivity: value of clinical history and skin testing in daily practice. Allergy Asthma Proc. 2004 May-Jun; 25(3):157-60. 22. Stember, Rishon H. Prevalence of Skin Test Reactivity in Patients with Convincing, Vague, and Unacceptable Histories of Penicillin Allergy. Allergy and Asthma proceedings. 2005, JanuaryFebruary; (6):59-64. 23. Macy E, Richter PK, Falkoff R. Skin Testing with penicilloate and penilloate prepared by an improved method: amoxicillin oral challenges in patients with negative skin test responses to penicillin reagents. J Allergy Clin Immunol 1997; 100: 586-591 24. Idsoe O, Guthe T, Willcox RR, de Weck AL. Nature and extent of penicillin sidereactions, with particular reference to fatalities from anaphylactic shock. Bull World Health Organ 1968; 38(2): 159-188. 25. McLean-Tooke APC, Bethune CA, Fay AC, Spickett GP. Adrenaline in the treatment of anaphylaxis: what is the evidence? BMJ 2003; 327:1332-1335. CM

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Stimulating News for People with Parkinson’s

In younger people with advanced Parkinson’s symptoms an alternate approach has been the use of deep brain stimulation (DBS) of the subthalamic nucleus. Professor Robert Iansek PhD, FRACP, Director, Geriatric Research Unit and Geriatric Neurology Service, Kingston Centre; Editorial Advisory Board member, Virtual Neuro Centre

arkinson’s is a degenerative neurological condition characterised by neuronal inclusions of an abnormal protein, alpha syneuclein. The condition starts six to seven years prior to the development of any motor symptoms but inevitably continues to invade more and more neurons causing an accumulation of symptoms over a person’s life span. The process of protein inclusion starts in the dorsal nucleus of the vagus nerve and the olfactory bulb1, 2 . It then slowly spreads up the brainstem to eventually involve the basal ganglia. It is at that stage that Parkinson’s symptoms appear (hypokinesia, tremor, rigidity and postural disturbance). However non-Parkinson’s symptoms are common but not recognisable in the early stages. Some of these symptoms include anosmia, constipation, cardiac abnormalities and REM associated sleep disturbance3. As the accumulation of abnormal proteins continues Lewy bodies develop in some neurons, which form the conventional basis of pathological diagnosis. The development of motor symptoms heralds a gradual decline in functional capacity for the individual resulting in the use of symptomatic treatment. Currently no cure exists and the pathological process cannot be retarded. Treatment enables better use of endogenous dopamine (L-dopa therapy) or the use of artificial dopamine (dopamine agonists). Unfortunately, although dopamine agonists (especially agonists with a long half-life) are better agents to provide more stable control of motor symptoms, they are generally much less potent than L-dopa and as such most people become dependant on L-dopa for long-term management. The progression of the pathological process leads to increasing loss of substantia nigra neurons and it is this gradual attrition which leads to the development of a shortening

of the duration of action of each dose of Ldopa, as it heralds the reduced capacity of remaining neurons to store dopamine and to provide a long duration response. Eventually the motor response will only be of one to two hours duration as this represents the half-life of L-dopa in the blood and represents the total delivery time to the brain. In addition to the shortened duration of response dyskinesia develops and the window of benefit between immobility and dyskinesia can reach only 2–5mg of L-dopa after five to 15 years of treatment (depending on the age of onset). The reason for the development of the narrow window is unclear, but may be related to the pulsatile effect of L-dopa on the striatal neurons. Certainly long half-life (greater than 60 hours) dopamine agonists (cabergoline) which minimise the use of L-dopa are quite effective in eliminating or reducing dyskinesia. Approaches to manage advanced Parkinson’s symptoms include the use of liquid L-dopa, apomorphine subcutaneous infusion and concentrated L-dopa pumped into the duodenum. In younger people with advanced Parkinson’s symptoms an alternate approach has been the use of deep brain stimulation (DBS) of the subthalamic nucleus. The mechanism of action of DBS is unclear but may relate to the reduction of neuronal resting membrane potential of adjacent neural tissues so that action potentials cannot be generated and as such it acts much like a lesion procedure, except that it is reversible. The benefits of DBS are the same as L-dopa except that the benefit is provided constantly, 24 hours a day. Consequently, DBS leads to a reduction of Ldopa usage and in some fortunate individuals L-dopa can be eliminated completely. The amount of L-dopa reduction cannot be predicted prior to surgery and appears to be an individual response in regard to the

placement of the electrode, the local anatomy of the person and the amount of current that can be used without causing side effects. The mechanism of reversal of hypokinesia by subthalamic DBS is unknown and quite remarkable. It suggests that hypokinesia is in fact a positive phenomenon which can be reversed anatomically downstream from the main pathology. An alternate suggestion is that only part of the basal ganglia functions at any one time and that inactivation of the disturbed outflow enables intact components to perform the function normally. The decision to proceed to DBS surgery has no evidence base as no comparison has taken place of best medical management compared to DBS outcomes. The decision has to also include the costs of the procedure ($A40,000– 60,000) as well as the side effects which can be quite high (5–10% major morbidity and 15–20% minor morbidity)4. A recent report on subthalamic DBS has partly addressed this issue of the best approach to manage advanced Parkinson’s motor fluctuations5. This randomised controlled trial across multiple centres in Germany and Austria compared best medical management (undefined) with subthalamic DBS. Centres enrolled subjects in pairs and then randomised each subject to either treatment modality. End points were changes in the quality of life scale (PDQ39) and the unified Parkinson’s disease rating scale motor component (UPDRS III) at six months post intervention. Out of 196 subjects, 178 were randomised but only 120 subjects were available for final analysis (60 pairs). A significant difference was found in favour of surgery in 50 pairs for PDQ39 and in 55 pairs for UPDRS III. A 4% death rate and 13% serious morbidity occurred in the surgery group compared to 1% death rate and 4% serious morbidity in the non-surgical group. Continues on page 32.

may – july 2007 | Consult Magazine

NEURO

neuro

The Burden of Epilepsy.

The Role of Pregnancy Registers In the Australian Pregnancy Register, enrolments are continuing to rise, indicating acceptance of the need for prospective data. Professor FJE Vajda, MD, FRCP, FRACP, Professor of Clinical Neuropharmacology, Monash University and Medical Centre, Melbourne and Department of Medicine, St Vincentâ&#x20AC;&#x2122;s Hospital, University of Melbourne; Director, Australian Register of Pregnancy for Women with Epilepsy and Allied Conditions; Editorial Advisory Board member, Virtual Neuro Centre

Introduction Epilepsy is one of the most common neurological disorders and one of the most complex. It is best regarded as a series of disorders, called epilepsy syndromes. Knowledge of epidemiology is incomplete. In developed countries the estimated incidence is 40â&#x20AC;&#x201C;70 per 100,000 persons per year but higher in less developed countries. Prevalence is approximately four to 10 per 1000. Over 70% of patients will enter remission on treatment with the first drug. There is a significantly higher risk of SUDEP (sudden unexplained death) in people with epilepsy than in the general population. Seizures are detrimental for the brain, and should be ablated early in the course of the condition. All seizures, not only status, should be taken seriously, as anoxia, injury, more seizures and metabolic complications may supervene.

The Burden The burdens of epilepsy comprise many problems including the risk of seizures and resultant injuries, restrictions on driving and alcohol, and risk of sleep deprivation. Employment discrimination has not been totally overcome, but it is vigorously fought by the medical profession and epilepsy associations. Both established and newly introduced epilepsy drugs produce side effects. Some are quite specific to each drug. Reproductive side effects alone involve hormones, a polycystic ovary syndrome comprising anovulation, hirsutism, insulin resistance and obesity, which may occur in women on valproate therapy, but also independently. Significance of this may be overstated. Bone disorders and

osteomalacia are ascribed due to an effect on Vitamin D, by the so-called enzyme inducing drugs, phenytoin, carbamazepine and barbiturates. Sex hormones are affected by enzyme inducers, but conversely, hormones hasten the elimination of lamotrigine making it less effective. Sperm motility and viscosity are claimed to be reduced by conventional antiepileptic drugs1, 2 . As half the population of people with treated epilepsy are women, many of them of child-bearing age, the greatest burden of epilepsy may relate to whether their child would inherit epilepsy and whether it would be normal, physically and mentally. The inheritance of epilepsy is complex, but certainly not an inevitable event. It is influenced by the type of epilepsy, and the presence of the disorder in one or both parents, and the frequency with which it is present in near relatives. Counselling is available and should be utilised to obtain an estimate, which may be quite favourable for a normal outcome. The question of drug-related malformations poses an ethical dilemma. We cannot experiment with drugs in pregnancy. It is difficult to get prospective data, and the value of retrospective data is questionable. Retrospective data on malformations suggests that multiple drug therapy is an added risk. Treated women have worse outcomes than untreated women with epilepsy. Seizures themselves may pose a hazard, but comparative figures are difficult to obtain. All studies have different designs and generally small numbers. None of the new antiepileptics have been systematically studied for their effects on babies. No specific drug has yet been linked to a single defect.

may â&#x20AC;&#x201C; july 2007 | Consult Magazine

INTRODUCING

ON-LINE CME ü RACGP approved QA&CPD Category 1 ü ALearning Activity (30 points) ü 740 topics multi-media ü Comprehensive online programs medical specialist ü Leading presenters available from ü Conveniently your surgery/home through the programs at ü Work your own rate

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These unique online and multi-media based CME programs allow you to select from 740 different topics according to your personal level of interest. You are able to participate in self-directed learning from the convenience of your surgery and/or home, and attract 30 CPD points. To access the CME program you need to be a registered member of Virtual Medical Centre. Go to www.virtualmedicalcentre.com and click “Join Now”. Once your membership is confirmed, you are free to start your CME activity. Prof. Roderic Underwood Director of Education & Research

Email: info@virtualmedicalcentre.com

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NEURO

In terms of physical malformations, it has been suspected since 1979 that valproate was significantly more hazardous than other drugs, but prospective studies are lacking, although high-dose valproate has been confirmed to be hazardous. Cognitive studies to date have been largely retrospective. For studying cognitive effects a child must be a few years old, before testing their intelligence. The optimal way to advance our knowledge is to collect information, according to defined protocols. Hence the establishment of pregnancy registers3,4,5,6. After ethical committee approval and written patient consent4, telephone interviews are done and access to patients’ medical records is obtained. The format is of an observational study. Care by family doctor is not interfered with7,8. Registers aim to evaluate the incidence of adverse foetal outcomes resulting from pregnancies exposed to antiepileptic drugs, and to determine if certain drugs, or combinations thereof, are associated with a higher incidence or specific adverse outcomes. Attempts are made to determine the influence of seizures, epilepsy syndromes, genetic background and environmental factors, as well as the comparative efficacy of antiepileptic drugs on seizure protection in pregnancy, based on self-reporting or additional drug requirements. Recruitment into the Australian Pregnancy Register is organised by letters and pamphlets to neurologists, obstetricians, specialists, lay groups and maternity hospitals. Support by the Epilepsy Society of Australia is crucial. State enrolments since 1999 have been highest in Victoria, New South Wales and Queensland, followed by Western Australia, South Australia, the Australian Capital Territory and Tasmania, according to population size. Around 5000 patients are required to assess exposure to each drug as monotherapy, hence collaborative links with the international register, EURAP, have been established.

Trends Results after 75 months from the Australian Pregnancy Register, comprising 903 outcomes, indicate that there were 803 live normal births, including 14 sets of twins, and two babies from two twin sets, and 33 live births with defects, with 12 defects detected at 12 months after delivery. There were 45 miscarriages, the majority occurring spontaneously. Thus the outcome of a normal baby can be anticipated in over 90% of mothers with epilepsy. If miscarriages were regarded as a separate category, 95% of the babies appear to be free of physical defects, 45 defects in 903 outcomes. These figures give a favourable and optimistic outlook for each woman with epilepsy9.

The other major, specific finding reported was an unacceptably high level of malformation risk associated with high doses of valproate at doses above 1100mg per day. Doses below that level were not linked to a statistically significant difference between drugs, but they all contributed to malformations in excess of untreated controls8. The register addressed the control of seizures. Although lamotrigine may be safer for the baby than valproate, an analysis was made on how drugs in monotherapy with valproate, lamotrigine and carbamazepine affected seizure control. Foetal losses had been recorded, associated with major seizures, thus control is important. Analysis was based on reported seizure activity, and alterations in drug regimens. For all types of seizures – convulsive, non-convulsive and auras – valproate was significantly more effective than lamotrigine, even though patients were not crossed over nor were randomised at the beginning of pregnancy. Thus the results are not as conclusive as a full clinical trial.

Overview How do we advise our patients? We give them the information available, explaining that a balance must be maintained between risks of seizures to both mother and baby, and safety of the child. High-dose VPA poses an unacceptable risk but VPA is more effective than LTG. Older drugs, phenytoin and carbamazepine as well as lamotrigine, have a comparable incidence of malformation rates, lower than valproate, but the first two mentioned are recommended for generalised epilepsy syndromes. We advise against hastily discarding VPA, because of risk that seizures may occur. We advise against changing medication once pregnancy has occurred. Anticipate pregnancy, and discuss options early, to establish optimal control before pregnancy occurs. We recommend pre-conception folic acid, 5mg twice daily, based on studies in pregnant women, without epilepsy. In the Australian Pregnancy Register, enrolments are continuing to rise, indicating acceptance of the need for prospective data. Prescribing patterns are changing, with a fall in doses and numbers of valproate related prescriptions. Doses of lamotrigine have risen, but this paralleled an increase in reported malformations: a causal relationship is possible and has been reported. The impression of lamotrigine being less effective than valproate has been confirmed in a limited series8. The role of untreated controls and of foetal cognitive challenge are under investigation10, 11, 12 .

Consult Magazine | may – july 2007

References: 1. Tomson T, Perucca E and Battion D. Navigating toward Fetal and Maternal Health. Epilepsia 2004; 45(10): 1171-75. 2. Sabers A, Buchholt J, Uldall P, and Hansen EL. Lamotrigine plasma levels reduced by oral contraceptives. Epilepsy Research 2001; 47: 151-154. 3. Tomson T, Battino D, Bonizzoni E, Craig J, Lindhout D, Perucca E, Sabers A, and Vajda F . Drug Registries. EURAP: An international Registry of Antiepileptic Drugs and Pregnancy Epilepsia 2004; 45: 1463. 4. Vajda FJ, Lander CM, Hitchcock A, Graham J, O’Brien TJ and Eadie MJ. Foetal malformations and seizure control: 52 months data of the Australian Pregnancy Registry. European J. Neurology 2006; 13: 645-654. 5. Holmes LB, Wyszynski MD, Leberman E. The AED (Antiepileptic Drug) Pregnancy Registry. Arch Neurol 2004; (61): 6723678. 6. Morrow JJ and Craig JJ. Antiepileptic drugs in pregnancy: current safety and other issues. Expert Opin Pharmacother 2003; 4(4): 445-456. 7. Vajda FJE, O’Brien TJ, Graham J, Hitchcock A, Lander CM, Eadie MJ. The pregnancies in women with epilepsy. J Royal College of Physicians of Edinburgh 2006; 36: 201207. 8. Vajda FJE, O’Brien TJ, Hitchcock A, Graham J, Lander CM, Eadie MJ. Critical relationship between sodium valproate dose and human teratogenicity: results of the Australian register of antiepileptic drugs in pregnancy. J Clin Neuroscience 2004; 11(8): 854-858. 9. Vajda FJ, Lander CM, Hitchcock A, Graham J, O’Brien TJ and Edie MJ. Update and trends from the Australian Pregnancy Register: 75 months data. Annual Scientific Meeting, Epilepsy Society of Australia, Melbourne 4-9. October 2006-10-16. 10. Craig J, Perucca E, Sabers A, Tomson T, Vajda F, Battino D, Bonizzoni E, and Lindhout D. Seizure control and treatment in pregnancy: Observations from the EURAP Epilepsy Pregnancy Registry. Neurology 2006; 66(3): 354-360. 11. Meador KJ, Baker GA, Finnell RH et al. In utero antiepileptic drug exposure. Neurology 2006; 67: 407-41. 12. Vajda F, O’Brien T, Graham J, Hitchcock A, Lander C and Eadie M. The value of an untreated internal control group in the Pregnancy-Antiepileptic Drug Register. Submitted for publication. J Clinical Neuroscience, September 2006, revised CM October 2006.

E D U C AT I O N

education

Continuing Medical Education

The Virtual Medical Centre Review Program and its benefits explained. Professor Roderick Underwood, BA MA PhD, Director of Education and Research, Virtual Medical Centre

n a recent article, Hiramanek1 argued that self-directed learning for Continuing Medical Education is the most effective approach for improving physician performance and patient care outcomes1. So, what is self-directed learning? One definition provided by Hiramanek states that self-directed learning “is a process in which a learner assumes primary responsibility for planning, implementing and evaluating the learning process”. Hiramanek argues that the challenge for Continuing Medical Education providers is to facilitate self-directed learning while taking General Practitioners’ views and preferences into consideration. In developing the Virtual Medical Centre Review Program, Hiramanek’s challenge was borne in mind. GPs participating in the VMC Review Program are able to select a topic from the 740 different entries in the data base. That is, GPs are able to select a topic according to their own perceived learning needs. In addition to the topic content, GPs are provided with a comprehensive reading

list which they will pursue, again according to their self-assessed learning needs. The VMC Review Program provides GPs with the opportunity to familiarise themselves with the latest research findings according to their level of personal interest. The patient audit requirements of the Review Program encourage GPs to reflect upon the nature of care they have provided patients. Reflective learning is an integral component of self-directed learning. The learning process is integrated through the development of a hypothetical case study reflecting best practice as it is understood today. I believe the VMC Review Program can be seen to have risen to the challenge set by Hiramanek by providing GPs with a unique opportunity to participate in a Continuing Medical Education program focused on selfdirected learning.

If you would like to participate in the complimentary VMC Review Program which attracts RACGP-approved 30 Category 1, QA&CPD points, please visit www.virtualmedicalcentre.com and click on the CME button on the top left side of the screen.

Reference: 1. Hiramanek, N. Self directed learning and continuing medical education. Australian Family Physician 2005 Oct; 34(10): 879-80.

Parkinson’s Potential from page 26

Although this report is welcome, unfortunately its design and implementation left a number of questions unanswered which made the interpretation of the results difficult. It was not blinded. Best medical management was not defined. The pair analysis did not average outcomes across the groups which may have given a different outcome. Although quality of life is important, it is a consequence of better motor control and the one factor which is the primary determinant of that entity is L-dopa reduction and elimination. In this regard surgery in this report fell short as no subjects eliminated medication post surgery. Medical management was better in 25% of patient pairs. Unfortunately for the individual patient contemplating surgery the decision is still difficult. Is the risk of surgery, with a combined death and major morbidity of 17%, worth the 24% improvement in quality of life (the primary outcome measure)? The real decision should balance the probability of elimination of L-dopa or its maximal reduction with the morbidity and mortality rate of the surgical team. Uncertainty, unpredictability and chance still play major roles in decision making for management of severe motor fluctuations in Parkinson’s. Whether

subthalamic DBS is better than best medical treatment is yet to be established.

References: 1. Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Stuer EN, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 2003; 24(2): 197-211. 2. Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K. Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 2004; 318(1): 121-134. 3. Langston JW. The Parkinson’s complex: Parkinsonism is just the tip of the iceberg. Ann Neurol 2006; 59(4): 591-96. 4. Iansek R, Rosenfeld JV, Huxham F. Deep brain stimulation of the subthalamic nucleus in Parkinson’s disease. Med J Aust 2002; 177(3): 142-46. 5. Deuschl G, Schade-Brittinger C, Krack P, Volkmann J, Schafer H, Botzel K et al. A randomized trial of deep brain stimulation for Parkinson’s disease. N Engl J Med 2006; 355: 896-908.

may – july 2007 | Consult Magazine