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e are very proud to announce our increased number to more than 1000 national specialists across 12 disease specialty areas that have joined our Editorial Advisory Board (EAB). Your expertise will be greatly appreciated and as an EAB member it is up to you what you contribute in terms of time and effort. This can take the form of an article in an area of personal interest, a comment on a new clinical study or issue arising in the media, providing feedback on a specific area of the website or could be more creative such as making a three-minute video on an area of interest to you. If you are a medical practitioner and would like to become a contributing member or receive a complimentary subscription to Consult Magazine, go to: to sign up or email: Dr Andrew Dean Medical Director Virtual Medical Centre

consult Magazine

Neuro 2

CGRP and Migraine Attacks

Professor Mervyn Eadie


Computer Aided Detection (CAD) in Radiology

Clinical Professor Lesley Cala

12 Sudden Unexpected Death in Epilepsy

Dr Glenys P Arthur

15 Huntington’s Disease and the Choreas

Dr Andrew Churchyard

18 Neurological Causes of Hip and Thigh Pain

Professor Gareth J Parry, Dr Lindsay F Haas

education 5

Your best online resource for healthcare information and education

Mr Barry Epstein


greetings from the


20 High Intensity Focused Ultrasound

Dr Alistair Cameron-Strange


23 Relaxin and Heart Disease

Dr Xiao-Jun Du

26 Advising Patients About Aerobic Exercise

Dr Stan P Woodhouse

29 Homocysteine, B-Vitamins and Cardiovascular Disease

Dr Kathleen Potter

weight loss

We acknowledge the important contribution of the Medical Directors: • Dr Peter Bremner • Dr Andrew Dean • Dr Nick de Felice • Dr Clay Golledge • Dr Roger Goucke • Professor Jeffrey Hamdorf • Professor Graeme Hankey • Dr Andrew McQuillan • Dr Brendan McQuillan • Dr Donald Ormonde • Dr Paul Snelling • A/Prof Rob Will • Dr Garry Wilson • Dr Steve Wilson • Dr Joe Kosterich (Medical Spokesperson)

31 Weight Loss: A Case Study

Dr Andrew Dean

The support of the following commercial entities are gratefully acknowledged:

Published by Virtual Medical PTY LTD (ABN: 120 975 935 87) MEDICAL DIRECTOR: Dr Andrew Dean MANAGING DIRECTOR: Wayne Hughes GENERAL MANAGER: Thomas Maher GENERAL MANAGER MARKETING: Barry Epstein PRODUCTION COORDINATOR: Katharina Kotte EDITOR: Jaci Moore(Aspermont Ltd), MEDICAL EDITOR: Elizabeth Tysoe, SUB EDITORS: Jen de Vos, Jennifer Hubble, Kathy Quinn ADVERTISING ENQUIRIES: 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: Website: 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 Medical 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.

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CGRP and Migraine Attacks Research is leading to a better understanding of the severe headaches which come with migraine, and the results could lead to an entirely new and very specific potential treatment for the attacks. Professor Mervyn Eadie, MD, PhD, FRCP Ed, FRACP; Editorial Advisory Board member: Virtual Neuro Centre


n recent years there has been interest in the part that the 37 amino acidcontaining peptide calcitonin generelated peptide (CGRP) plays in producing the manifestations of migraine, particularly the headache.1,2 CGRP is stored in, and released from, trigeminal neurones including those which terminate on the blood vessels of the scalp and meninges, and which have their cell bodies in the trigeminal ganglion itself.1 The peptide is a highly potent dilator of blood vessels, particularly cranial ones, and its release around cranial blood vessels during attacks of migraine could account for the dilatation of scalp and meningeal arteries that occurs at that time, whilst its effects on trigeminal afferent activity could produce or augment the experience of head pain in the attacks. Whilst CGRP occurs elsewhere in the body and in the brain, several lines of evidence point to trigeminal CGRP playing a significant part in the pathogenesis of migraine attacks. Measurements have shown increased CGRP concentrations in jugular venous blood draining from the side of the headache during unilateral migraine attacks.3 The venous CGRP concentration falls when migraine headaches subside spontaneously or are relieved by sumatriptan, and the degree of elevation of venous CGRP concentration appears related to headache severity.3 Furthermore, clinical trial evidence has recently become available showing that administration of a specific and potent antagonist at CGRP receptors will relieve migraine headache.4 Taken together, these observations encourage further exploration of the role of CGRP in migraine pathogenesis and in other head pain syndromes, and also raise the possibility that a new treatment approach has become available for a disorder whose current therapies are far from completely satisfactory. The study4 that showed the effectiveness

of the non-peptide CGRP antagonist usually designated BIBN 4096 BS, but recently named olcegepant, was a reasonably large multi-centre one involving patients who presented to participating institutions within the first six hours of the onset of migraine headache. The drug was given in a variety of doses between 0mg and 10mg over 10 minutes in a 5ml intravenous infusion. There was a 66% beneficial response in headache treated with the active substance as compared with a 22% placebo response rate. Adverse effects, mainly paraesthesiae, were comparatively mild. The experience of the study suggested that an intravenous dose of 2.5mg was likely to be optimal in practice. In the paper it was pointed out that the response rate was not as high as that obtained with parenteral sumatriptan but was comparable to the success rate from oral triptan therapy. However, without a proper head-to-head comparison with subcutaneous sumatriptan it may be premature to attach undue importance to the apparently lesser efficacy of the new agent. At the present time olcegepant seems a substance of great interest, both as a tool for elucidating the biochemical mechanisms underlying migraine and other forms of head pain, and as a promising therapeutic agent. The experience of the Olesen et al trial4 makes it likely that the drug could provide a suitable and perhaps preferable alternative to parenteral sumatriptan in patients who present to medical institutions during migraine attacks, so long as olcegepant also proves of comparable efficacy to the triptans and can be supplied at comparable cost, and no new problems appear as its use widens. The drug does have the advantage that it does not cause vasospasm or have adverse effects on the heart,5,6 unlike the triptans, and ergotamine and dihydroergotamine. However, if olcegepant is to achieve widespread use it will need to be available

in dosage forms suitable for patient selfadministration. On the basis of the data currently available, it seems likely that intramuscular or subcutaneous injection forms could be developed, and possibly preparations for intranasal or aerosol inhalation. At the present time it is unclear whether a preparation for oral administration will be practicable. If one is to be developed, it may be wise to keep in mind the lessons of the past. Parenteral ergotamine, when first employed in the 1920s, and parenteral sumatriptan, introduced some six decades later, both proved distinctly more effective than when the same substances were used orally. This was probably largely due to: the oral preparations being subject to the vagaries of altered alimentary tract motility during migraine attacks; the consequences of vomiting in the attacks; and, more in the case of the ergot derivatives than sumatriptan, to the consequences of high pre-systemic clearances resulting in low and probably variable oral bioavailabilities. Some pharmacokinetic data for olcegepant have been published.7,8 Unfortunately, no values for the oral bioavailability of the drug are available. The drug’s intravenous

August – October 2007 | Consult Magazine

at the present time. It is conceivable that receptor up-regulation might develop and thus defeat the purpose of prescribing the drug. Unless there are biologically active metabolites with longer durations of action than that of the parent substance, the drug’s relatively short half-life may also make it unattractive as a preventative because of the need for several doses to be taken each day. In the current state of publicly available knowledge, olcegepant seems to offer migraine sufferers the enticing prospect of a new therapeutic approach to their headache disorders, but much work will need to be done before the drug finds its definitive place in therapeutics.

References 1. Arulmani U, Ven Den Brink AM, Villalon CM, Saxena PR. Calcitonin gene related peptide and its role in migraine pathogenesis. European Journal of Pharmacology. 2004; 500: 315-30. 2. Goadsby PJ. Calcitonin gene-related peptide antagonists as treatments of migraine and other primary headaches. Drugs. 2005; 65: 2557-67. 3. Edvinsson L. Correlation between CGRP and migraine attacks. Cephalalgia. 2005; 25: 163-4.


4. Olesen J, Diener H-C, Husstedt IW, et al. Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. New England Journal of Medicine. 2004; 350: 1104-10. 5. Edvinsson L. Blockade of CGRP receptors in the intracranial vasculature: a new target in the treatment of headache. Cephalalgia. 2004; 24: 611-22. 6. Petersen KA, Birk S, Lassen LH, et al. The CGRP-antagonist, BIBN4096BS does not affect cerebral or systemic haemodynamics in healthy volunteers. Cephalalgia. 2005; 25: 139-47. 7. Iovino M, Feifel U, Yong C-I, Wolters J-M, Wallenstrin G. Safety, tolerability and pharmacokinetics of BIBN 4096 BS, the first selective small molecule calcitonin gene-related peptide receptor antagonist, following single intravenous administration in healthy volunteers. Cephalalgia. 2004; 24: 645-56. 8. Troconiz IF, Wolters J-M, Schaefer HG, Roth W. Population pharmacokinetic modelling of BIBN 4096 BS, the first compound of a new class of calcitonin gene-related peptide receptor antagonists. European Journal of Pharmaceutical CM Science. 2004; 22: 287-95.


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Consult Magazine | August – October 2007

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clearance is not particularly high (some 12 to 17 litres per hour). Only about 15% of the dose is excreted unmetabolised in urine, raising the possibility that biologically active metabolites may be formed, particularly after oral intake of the drug. The half-life of olcegepant is around 2.5 hours, but if there are slowly eliminated biologically active metabolites the pharmacological effect of the drug might persist for longer than its half-life would suggest. Development of various dosage forms of the drug will probably depend on first establishing its efficacy and safety relative to those of the triptans. If the new drug does not possess at least comparable efficacy and safety to the older agents, and is not advantageously priced, it may never achieve what currently appears to be its potential, unless it proves effective in patients in whom the triptans have failed, or when taken with a triptan enhances its effectiveness. This could happen since the mechanism of action of olcegepant (viz. CGRP receptor blockade) differs from that of the triptans (viz. agonism at 5-hydroxytryptamine type 1B, 1D, 1F receptors). There is also the possibility that olcegepant in continuous use might find a role as a migraine preventative, though the consequences of sustained blockade of CGRP receptors in humans are unknown

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Your best online resource for healthcare information and education

Mr Barry Epstein, BA (BioSci), Dip Diagnostic Ultrasonography, AIMM, is the General Manager Marketing for the Virtual Medical Centre that has prepared CONSULT magazine.


he Virtual Medical Centre provides reliable, trustworthy information for health professionals and consumers. Nearly 20,000 web pages have been written and are updated daily with input provided by more than 1,000 Australian medical specialists. The website also delivers 740 online healthcare education programs for doctors (CME) as well as online education for nurses.

A proven track record in supporting health professionals and consumers The Virtual Medical Centre (VMC) is an Australian owned company that has been in operation for more than six years. VMC provides accurate, timely, accredited, free and comprehensive medical information to a growing volume of health professionals and consumers. During this time, millions of Australian patients and their carers have visited the website to learn more about medical conditions that affect them or their loved ones. Many have gained valuable information that has provided real help in understanding their condition. is the preferred website for thousands of doctors, who actively refer patients with health questions to the site for reliable answers designed to complement the care being provided. These practitioners realise they may not always have enough time to provide patients with the level of detailed 200,000




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Historical monthly growth rate of unique visitors to the Virtual Medical Centre website.

information they require at the time of the consult. This is precisely why the website was initially established by leading oncologist Dr Andrew Dean. The original website was actually the, which is now just one of the 19 disease specialties that provide almost 20,000 pages of regularly updated information. Dr Dean discovered his patients had a real need for information on cancer. At times of great stress, when people have been devastated by a positive diagnosis of cancer or a life-threatening disease, information retention is at its poorest. Often, the patient will walk out of the doctor’s room feeling confused and uninformed. The Virtual Cancer Centre was set up as a resource for patients to understand more about their disease while they were being treated. From there, the site rapidly developed to include 18 other specialty centres. Clearly understanding a condition and its treatments encourages patients to comply with their treatments, and therefore enhances patient well-being. Patient information, feedback quizzes, educational videos and the provision of research and news articles can all assist the patient in coping with their condition or disease. A two-way communication with patients The website enables a two-way communication with patients, who can access the wide array of information on the website 24 hours per day, seven days per week. Thousands of patients regularly become members of the VMC website, receiving a free electronic newsletter (Health eNews) that delivers timely and topical healthcare information on a fortnightly basis. This newsletter presents complex information in a way that is relatively simple to understand.

Consult Magazine | August – October 2007

Benefits to health professionals Medical specialists, general practitioners and a range of other paramedical professionals may benefit from reduced consultation times as they provide patients with a way to access health education support information derived from 1,000 leading Australian specialists. Moreover, around 10,000 health professionals each month routinely access the articles and research reviews that are made available by their colleagues. Health professionals have a secure login to a separate area in the website that is dedicated to their needs, including access to a wide range of educational pre-recorded web seminars presented by specialists. Additionally, an electronic fortnightly newsletter is sent to those professionals who have registered (joined) with VMC. Doctors interested in joining can go to and click “Sign Up”. Continuing medical education program General practitioners can access a range of multi-media based online CME programs. They can select any of 740 different topics according to their personal or professional area of interest. GPs are able to participate in self-directed learning from the convenience of their surgery and-or home. All CME activities are accredited by: • The RACGP as a QA&CPD Category 1 Learning Activity (30 points); and • ACRRM as a PDP activity (12.75 points). The comprehensive CME program is administered by a dedicated and full-time professional, Professor Roderic Underwood, the Director of Education and Research at the Virtual Medical Centre. GPs wishing to access these programs simply need to visit and click “Sign Up”. Once membership is confirmed, they are free to start their chosen CME activity. For more information, they can

e d u c at i o n

Some of the topics covered include, but are not limited to: 3 3 3 3 3

Current disease information Medications Explanations of how treatments work Symptom management Latest news

email Prof Underwood at Online nursing education programs Another relevant educational initiative provided at the Virtual Medical Centre is a continuing professional educational resource for nurses that can be accessed at There is a wide range of online interactive and audio-visually based learning modules to choose from. These modules deliver current evidence-based information to allow nurses to continue their professional development. They are written by nurses who are experts in their fields, and are peer-reviewed before being released. Upon completion of a unit a certificate is awarded.

3 3 3 3 3

Explanation of investigations Anatomy and physiology Clinical research and trials Patient support Lifestyle information

The patient level is detailed, yet clear and easy to understand. The physician level is comprehensive, fully referenced and updated by our editorial advisory board members regularly.

Physician endorsed – over 1,000 medical specialist editors Dr Andrew Dean (oncologist) founded VMC and established a team of 13 other medical directors. Each medical director has recruited an Editorial Advisory Board (EAB) of medical professionals whose specialties relate to a particular Centre disease area. The medical director and the EAB work together to ensure the information on the sites are medically correct, accurate and credible.

An array of healthcare information across many disciplines

Editorial advisory board recruitment program

There are 19 disease specialty centres: allergy, blood, bone, cancer, cardiac, child’s health, endocrine, gastro, infection, men’s health, neurology, pain, psychiatry, renal, respiratory, rheumatology, skin, women’s health and weight loss. There are almost 20,000 pages of content on VMC, written on two levels.

The Virtual Medical Centre has an active recruitment initiative and requires more board members who are willing to contribute or review articles. Both medical specialists and GPs are sought, so please contact us at info@virtualmedicalcentre. com if you are interested in joining the editorial advisory board.

Growing support from major organisations VMC has garnered strong and growing support from some of the largest multinational pharmaceutical companies and other national organisations. Income to VMC, which is necessary to allow the comprehensive range of free, readily available healthcare information and educational programs, is derived from advertising (online, in the newsletters and in press such as this magazine) and online surveys. Educationally based promotional opportunities for companies The growing volume of medical practitioner readers of CONSULT and visitors to the website can strongly support marketing initiatives for nationally based organisations with products (pharmaceutical, medical devices, etc.) or services (diagnostics, procedures, facilities, etc) that desire to reach medical professionals. The highly graphic and audio-visual web seminar capabilities for the website and electronic newsletters represent an opportunity for these organisations to deliver educationallybased promotions showcasing their products or services. These promotions are evidence-based and fully accountable. The number of professionals that access this educational material, as well as the length of time they were online, can be clearly identified. If you are interested in discussing how educationally-based promotions could benefit your company, please contact us at CM

Medical Directors of Virtual Medical Centre

Dr Peter Bremner – Respiratory Physician FRACP MD MBChB FACCP Virtual Respiratory Centre

Dr Andrew Dean – Oncologist MBChB MRCP(UK) FRACP Virtual Cancer Centre

Dr Nick Felice – Psychiatrist MBBS FRANZCP Virtual Psych Centres

Dr Clay Golledge – Microbiologist BSc(Med) MBBS(Hons), MRCP(UK) FRCPA FACTM DTM&H Virtual Infection Centre

Dr Roger Goucke – Pain Physician MBChB DTM&GH MRCGP FANZCA FFPMANZCA FAChPM Virtual Pain Centre

Prof Jeffrey Hamdorf – General Surgeon MBBS PhD FRACS Virtual Weightloss Centre

Prof Graeme Hankey – Neurologist MBBS MD FRCP(Edin) FRCP(Lond) FRACP Virtual Neuro Centre

Dr Andrew McQuillan – Haematologist MBBS FRACP FRCPA Virtual Blood Centre

Dr Brendan McQuillan – Cardiologist MBBS PhD FRACP Virtual Cardiac Centre

Dr Donald Ormonde – Gastroenterologist MBBS PhD FRACP Virtual Gastro Centre

Dr Paul Snelling – Nephrologist FRACP MBBS Virtual Renal Centre

A/Prof Rob Will – Rheumatologist BSc(Hons) MBBS FRACP Virtual Rheumatology & Bone Centres

Dr Garry Wilson – General Practitioner MBBS General Practioners Board

Dr Steve Wilson – General Practitioner MBBS General Practioners Board

Dr Joe Kosterich – General Practitioner MBBS Medical Spokesperson Virtual Medical Centre

August – October 2007 | Consult Magazine

NEURO neuro

Computer Aided Detection (CAD) in Radiology Clinical Professor Lesley Cala.

Radiological examinations are complex now and consist of hundreds of images per study. The likelihood of perceptual error is high, even when an expert works under ideal conditions. A computer can continue indefinitely as the machine suffers no visual fatigue. Clinical Professor Lesley Cala, MD DMRD FRANZCR FRCR; Editorial Advisory Board member: Virtual Neuro Centre

Mammography In 1998 the FDA (USA) approved an automated software program which could act as a second reader to assist the radiologist. Computer aided detection (CAD), which sells at US$200,000 per unit, has since proved useful as a screening modality in communities. The software is not 100% sensitive though. It sometimes fails to mark an area the radiologist thinks may be a cancer and Ulissey1 urges that recall of the patient should not be cancelled because CAD did not locate the lesion. Conversely, experienced radiologists were shown to miss cancers. A study was undertaken of 1,000 follow-up mammograms that led to a diagnosis of breast cancer in women where an earlier mammogram had been considered normal.2 Some 67% of those cancers were visible on the earlier mammogram. Some were subtle findings, but 27% were visible and required action instead of being called normal. CAD found 77% of the cancers in that 27% sample. In another study 10,267 mammograms for women aged 50 years or older showed that a single reading with CAD led to 6.5% more cancers being detected than with a double reading by radiologists.3 However, the recall rate was also 32% higher for single readings with CAD. The development of CAD has introduced an interval change analysis of preselected regions of interest to improve radiologists’ accuracy in classifying masses as malignant or benign on digitised screenfilm mammograms. Interval change information extracted from previous and

current mammograms was used to estimate a malignancy rating. Ninety temporal pairs of 2-view serial mammograms, consisting of 47 malignant and 43 benign biopsy-proved masses where examined retrospectively.4 Using CAD, six radiologists correctly recommended additional biopsies for malignant masses and five fewer biopsies for benign masses. However, five radiologists incorrectly recommended additional biopsies for benign masses and one recommended fewer biopsies for malignant masses.

Chest CT-Detection of Lung Nodules and Cancer The first CAD system for CT images of the lung was approved in 2004, and another in 2006, by the FDA as a second reader of chest multi-detector CT scans (MDCT) to alert the radiologist to lesions that may have been missed in the first reading. Images from a MDCT scanner are received, the CAD unit then processes the data and marks regions of interest, and the radiologist can perform a second review of the scan. An analysis was done of 150 low-dose screening CT studies of lungs.5 Nodules were classified by size, density and location. CAD detected 72.6% of true nodules and nodules in six (4%) patients not identified by radiologists. This resulted in a change in the follow-up protocol. The combined review of low-dose CT scans by the radiologist and by CAD was necessary to identify a total of 1,106 nodules in the 150 subjects. An overall nodule detection sensitivity of

Consult Magazine | August – October 2007

70% was found in 393 thick section (10mm) low dose CT scans.6 When the method was trained specifically for malignant nodules, sensitivity of 80% was attained. This automated method needs to be compared with the findings on CT as determined by a radiologist, and software programs need to be written to incorporate criteria for classification of a nodule as benign or malignant. Thin-section CT (1mm thick slices) characteristics of malignant nodules where evaluated on the basis of appearance (pure ground glass opacity [GGO], mixed GGO or solid opacity) in comparison with the appearance of benign lesions. Some 222 cases were used which comprised of 59 cancers and 163 benign nodules. The study showed that among nodules with pure GGO, a round shape was found more frequently in malignant lesions than in those that were benign; mixed GGO (a subtype with GGO in the periphery and a high-attenuation zone in the centre) was seen much more often in malignant lesions. Amongst the solid nodules, a polygonal shape or a smooth margin was present less frequently in malignant than in benign lesions.7 Nevertheless, the gold standard for a final diagnosis of a nodule is biopsy. High-resolution CT (HRCT) findings of resected small pulmonary nodules 2cm or less in diameter were evaluated in 223 mass lesions. 90.7% of lesions with mixed solid and GGO components were adenocarcinoma. Pure GGO lesions without scale-down between several months were all adenocarcinomas or

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Figure 1. A slice from the brain of a new patient (right half of picture) shows an enlargement in the right frontal area, when compared with a slice at the same level in the brain of a patient from the database considered to be normal. The patient is then given an intravenous injection of contrast material (Figure 2).

atypical adenomatous hyperplasia. This group of patients holds good candidates for surgical resection. Spicular or pleural indentation was found in 75.2% of adenocarcinomas and all squamous cell carcinoma, but this finding was also found in benign conditions such as non-specific inflammation (for example, tuberculosis) so this feature is not peculiar to malignancy.8 The criteria established 7,8 needs to be incorporated into the software programs for automated detection and diagnosis. Mayo Clinic reported a five-year prospective study using CT scan to screen for lung cancer. Their preliminary results did not support the possibility of reducing mortality from lung cancer. In fact, concern was raised about the false-positive results and overdiagnosis actually resulting in more harm than good.9 CT screening permits detection of a large number of benign uncalcified lung nodules that will be expensive to diagnose and may impact on general wellbeing and mortality from intervention. With computer assisted detection able to identify even more nodules, one must examine this difficult question on a cost-benefit and ethical basis.

Prediction of Postoperative Lung Function A software tool that uses a preoperative chest multi-slice CT (MSCT) and pulmonary function test for the automated prediction of the postoperative forced expiratory volume in one second (FEV (1)) may be used to help predict the operability of patients with bronchial carcinoma. 10

Digital Chest Radiography The usefulness of a commercially available CAD system on 50 operable T1 cases of lung cancer and 50 normal controls using digital chest radiography equipment was

Figure 2. The enlarged area in the new case, shown by the arrow in Figure 1, is now clearly visible in the right half of the screen, after the injection of contrast. A brain tumour was confirmed by surgery.

evaluated.11 The overall detectability of lung cancer cases with the CAD system was 74%.

Coronary Artery Disease CT can score the calcium content of coronary arteries and this should be followed with CT coronary angiography.12 Predictors of diagnostic failure are: massive calcification, long-standing known coronary atherosclerosis or previous CABG-stent implantation, old age and diabetes mellitus.13

Liver 3D shape-based analysis of CT scans detected local recurrence of the tumour after radiofrequency ablation, even in the absence of abnormal contrast enhancement.14

Colon CT colonography can identify polyps with CAD and be further enhanced with 3D viewing to improve radiologists’ accuracy in classifying true-positive and falsepositive polyps.15

Brain Automated methods of analysis of CT scans are possible because of the quantitative nature of CT. An automated method was developed to identify hypodensity within the lentiform nucleus and insula in patients with acute middle cerebral artery stroke, and make comparisons with the contralateral side. The software correctly diagnosed 10 of 15 patients, showing two false-negative results in each of the lentiform nucleus and insular cortex, and one false-positive finding for the insular cortex. The original reading by human

Consult Magazine | August – October 2007

observers produced five false-negative interpretations, all of which were correctly identified by the automated algorithm.16 A fuller automation could be achieved by comparing in a database the new abnormal case with a normal standard. A system has been set up linking craniofacial landmark localisation and anatomical structure tracing on skull radiographs.17 This can be used for the process of ‘warping’, whereby the two skulls are made the same shape. The next step is to have all internal structures visible on a CT study exposed to pattern matching techniques, not just the skull shape. A prototype of a semi-automated system18 allows the cranial CT of a new patient to be compared, slice by slice, with another case from a database which has been considered by human observers to have no focal abnormality. If a localised abnormality is found in the new case, the radiologist then consults a library of examples from different disease categories with a few clicks of the mouse. The system adjusts for the fact that the two patients will invariably have heads of different sizes. Ongoing work will automate comparison. Software is available19 to detect intracranial aneurysms at the skull base by automated bone subtraction from CT angiograms (CTA). Four intracavernous and three paraclinoid aneurysms of the internal carotid artery were not visible or only partially visible on conventional 3D CTA, whereas these could all be seen well on bone-subtraction CTA.

Magnetic Resonance Imaging of Brain Diffusion Tensor Imaging (DTI) uses the phenomenon of diffusion-driven displacement of molecules to probe tissue structure at a microscopic scale


well beyond the usual image resolution. Anisotropic means having different values of a property (as refractive index, tensile strength, elasticity, electrical or heat conductivity, or rate of movement of a substance) in different directions, especially in a crystal or tissue. As diffusion of water in tissue is a threedimensional process, molecular mobility of water may not be the same in all directions. In other words, it can be anisotropic due either to a particular physical arrangement of the medium or the presence of obstacles that limit molecular movement in some directions. As diffusion is encoded in the MRI signal by using magnetic field gradient pulses, only molecular displacements along the direction of the gradient are visible. So the effect of diffusion anisotropy can be detected by observing variations in the diffusion measurements when the direction of the gradient pulses is changed. Diffusion anisotropy in white matter originates from its specific organisation in bundles of more or less myelinated axonal fibres running in parallel: diffusion of water in the direction of the fibres is faster than in the perpendicular direction. This feature is exploited to map out the orientation of the white matter tracts in the brain using a colour scale, on the assumption that the direction of the fastest diffusion indicates the overall orientation of the fibres. The technique has been shown useful in the diagnosis of multiple sclerosis, Alzheimer’s disease, leukoencephalopathy, Wallerian degeneration, and CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy).20 The degree of diffusion anisotropy in white matter increases during the myelination process, so diffusion MRI can assess brain maturation in children, newborns or premature babies. Abnormal connectivity in white matter based on DTI MRI data has been reported in the frontal regions in schizophrenia and in the left temporo-parietal regions in dyslexic adults.

Summary and Conclusions Developments in software can assist the radiologist to reveal abnormalities that are present, for example aneurysms close to bone on CT or individual white matter tracts on MRI, which would otherwise remain invisible. The computer can also be trained to locate abnormalities that are visible but might be overlooked by the radiologist working in a busy environment. Further refinements exist, such as suggesting whether an abnormality is ischaemic or whether a mass is benign or malignant. Nevertheless,


the final evaluation of an abnormality rests with the reporting radiologist, who has to weigh up all of the findings within the clinical context of the individual patient and based on his-her experience.

References 1. Ulissey MJ, Roehrig J. Mammography – computer-aided detection. emedicine 2005. radio/topic879.htm. 2. Warren-Burhenne LJ, Wood SA, D’Orsi CJ, Feig SA, Kopans DB, O’Shaughnessy KF, et al. Potential contribution of computer-aided detection to the sensitivity of screening mammography. Radiol 2000; 215(2): 554-62. 3. Gilbert FJ, Astley SM, McGee MA, Gillan MG, Boggis CR, Griffiths PM, et al. Single reading with computeraided detection and double reading of screening mammograms in the United Kingdom National Breast Screening Program. Radiol. 2006; 241(1): 47-53. 4. Hadjiiski L, Sahiner B, Helvie MA, Chan HP, Roubidoux MA, Paramagul C, et al. Breast masses: computer-aided diagnosis with serial mammograms. Radiol. 2006; 240(2): 343-56. 5. Yuan R, Vos PM, Cooperberg PL. Computer-aided detection in screening CT for pulmonary nodules. AJR. 2006; 186(5): 1280-7. 6. Armato SG 3rd, Roy AS, Macmahon H, Li F, Doi K, Sone S, et al. Evaluation of automated lung nodule detection on low-dose computed tomography scans from a lung cancer screening program (1). Acad Radiol. 2005; 12(3): 337-46. 7. Li F, Sone S, Abe H, MacMahon H, Doi K. Malignant versus benign nodules at CT scanning for lung cancer: comparison of thin-section CT findings. Radiol. 2004; 233(3): 793-8. 8. Nakashima Y, Yamada T, Tanahashi M, Hikosaka Y, Yoshitomi H, Niwa H. A study of high-resolution computed tomography (HRCT) findings of resected small pulmonary nodules 2 cm or less in diameter with reference to the malignant nature. Kyobu Geka. 2006; 59(10): 917-22. 9. Swensen SJ, Jett JR, Hartman TE, Midthun DE, Mandrekar SJ, Hillman SL, et al. CT screening for lung cancer: five-year prospective experience. Radiol. 2005; 235: 259-65. 10. Beyer F, Heindel W, Hoffknecht P, Kuhnigk J, Dicken V, Lange T, et al. CTbased software-supported prediction of the postoperative lung function after partial resection of the lung. Rofo. 2006; 178(9): 872-9. Abstract only in English. 11. Sakai S, Soeda H, Takahashi N, Okafuji

T, Yoshitake T, Yabuuchi H, et al. Computer-aided nodule detection on digital chest radiography: validation test on consecutive T1 cases of resectable lung cancer. J Digit Imaging. 2006 Jun 14; [Epub ahead of print]. 12. Dewey M, Hamm B. Cost effectiveness of coronary angiography and calcium scoring using CT and stress MRI for diagnosis of coronary artery disease. Eur Radiol. 2006 Oct 10; [Epub ahead of print]. 13. Musto C, Simon P, Nicol E, Tanigawa J, Davies SW, Oldershaw PJ, et al. 64multislice computed tomography in consecutive patients with suspected or proven coronary artery disease: initial single center experience. Int J Cardiol. 2006 Aug 10; [Epub ahead of print]. 14. Bricault I, Kikinis R, Morrison PR, Vansonnenberg E, Tuncali K, Silverman SG. Liver metastases: 3D shape-based analysis of CT scans for detection of local recurrence after radiofrequency ablation. Radiol. 2006; 241(1): 243-50. 15. Shi R, Schraedley-Desmond P, Napel S, Olcott EW, Jeffrey RB Jr, Yee J, et al. CT colonography: influence of 3D viewing and polyp candidate features on interpretation with computer-aided detection. Radiol. 2006; 239(3): 76876. 16. Maidjian JA, Chalela J, Kasner SE, Liebeskind D, Detre JA. Automated CT segmentation and analysis for acute middle cerebral stroke. AJNR. 2001; 22(6): 1050-5. 17. Yue W, Yin D, Li C, Wang G, Xu T. Automated 2-D cephalometric analysis on x-ray images by a model-based approach. IEEE Trans Biomed Eng. 2006; 53(8): 1615-23. 18. Cala LA, Parker K, Emelyanova I, Hicks N, Linggard R, Robbins P, et al. Computer-aided diagnosis (CAD) of cranial CT scans. Rivista de Neuroradiologica. 2003; 16: 947-52. 19. Tomandi BF, Hammen T, Klotz E, Ditt H, Stemper B, Lell M. Bone-subtraction CT angiography for the evaluation of intracranial aneurysms. AJNR. 2006; 27(1): 55-9. 20. Le Bihan D, Mangin J-F, Poupon C, Clark CA, Pappeta S, Molko N, et al. Diffusion tensor imaging: concepts and applications. J Magn Reson Imaging. 2001; 13: 534-46. 21. Pitman AG. Perceptual error and the culture of open disclosure in Australian radiology. Australas Radiol. 2006; 50: CM 206-21.

August – October 2007 | Consult Magazine


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Sudden Unexpected Death in Epilepsy Dr Glenys Arthur.

Sudden unexpected death [SUDEP] is the single most important category of death in persons with epilepsy. Medical practitioners should be acquainted with the condition and be aware that our knowledge of SUDEP has changed over the past 20 years. Dr Glenys P. Arthur, CNZM, MB, ChB, FRACP, FACRM, FAFRM; Neurologist Southern Cross Hospital, Southern Cross Health Care, 90 Hansen Street, Wellington, New Zealand;; Editorial Advisory Board member: Virtual Neuro Centre


pilepsy affects one in 200 persons in the general population and is well known to most medical practitioners because it is so common. Although the mortality of epilepsy from any cause is two to three times that of the general population1 it is much higher within a population of patients with epilepsy.2 This is due to a variety of causes3 but the single most important category of death in persons with epilepsy is sudden unexpected death [SUDEP] with no cause found at post mortem.4 Although an uncommon cause of death within the general population, medical practitioners may suddenly find themselves having to explain to those close to the victim what they know about the condition and why death could not have been prevented, as well as helping with shock and grief. Authorities may require assistance with determining cause of death. This may be difficult if circumstances suggest other possibilities for death including foul play. It is therefore useful to be acquainted with the condition and to be aware that our knowledge of SUDEP has changed over the past 20 years and is still changing, hence a brief outline of the subject is presented here. SUDEP has been described since the latter part of the nineteenth century and was attributed to asphyxiation from smothering as a result of seizure for years – probably because most victims are found lying prone and some had died in bed. More recent research has shown that this cause of


SUDEP is in fact so rare that smothering is no longer believed to be the usual cause of death from SUDEP. Sudden death is now defined as death occurring within an hour of a terminal process starting and should not be confused with instantaneous death. Anecdotal accounts of cases and reviews of SUDEP abound in the literature but difficulties in doing research into SUDEP have been encountered because of the rarity of the condition within the general population, the ethical need to treat patients with epilepsy soon after diagnosis, and difficulties with assembling a group of patients with epilepsy that is large enough and suitable for a study of this nature. Numbers studied have been small. It is therefore not surprising that of the trials done there has been enough variation in results to advise some caution in their interpretation but, nevertheless, information gained has still been very useful as have the results of animal studies. For the purposes of clinical drug trials the United States Food and Drug Administration [FDA] along with drug company Burroughs Welcome developed a definition of SUDEP in 1993. A definition from the United Kingdom called the International Agreed Definition soon superseded the FDA definition and is used when SUDEP is studied. It is as follows: “SUDEP is unexpected witnessed or un-witnessed, non traumatic and non drowning death in patients with epilepsy

with or without evidence of seizure and excluding documented status epilepticus in which post mortem examination does not reveal a toxicological or anatomic cause of death.”1,4 Although the incidence of sudden death in epilepsy varies between studies, most authors have found a higher incidence of the condition within the population of patients with epilepsy who attend epilepsy clinics for treatment than in the general population. Walzek4 wrote in 2003 that SUDEP occurs in approximately 2% of general population based cohorts to up to 25% of deaths; whereas in 2005 Black5 cited figures of 7.5% to 17% of all deaths in patients with epilepsy. Frequency of SUDEP has been found to be independent of type and severity of convulsions.6 Seizures that have led to SUDEP may be major or minor. Severity of seizure does not necessarily reflect the degree of neurological disturbance in the brain because the body can only respond to seizure in a limited and relatively stereotyped way. Nevertheless, most cases of SUDEP are said to be associated with frequent seizures of grand mal type. Most studies find age of death to be between 25 and 40 years. Uncontrolled studies have cited many risk factors for SUDEP that have not been reproduced in controlled studies.7 A case controlled study from Stockholm of 57 cases found more frequent seizures, poly therapy with antiepileptic drugs and

August – October 2007 | Consult Magazine

process is a response to severe post-seizure cerebral suppression. The bradyarrhythmia that follows the tachycardia is thought to be reflex in origin and is considered to lead to pulmonary oedema and cardiac arrhythmia from which death occurs. An obstructive component may exacerbate the apnoea. This explanation may not, however, be the mechanism of death in all cases of SUDEP and there is a suggestion that intrinsic cardiac abnormalities may also be relevant in some cases.4,9-17 More recent long-term electrocardiogram monitoring of patients over several months has revealed the occurrence of high-risk ictal arrhythmias in a greater portion of patients than previously thought.18 Casecontrolled studies have shown sudden, unexpected death in epilepsy to be associated with frequent generalised tonicclonic seizures and greater ictal maximal heart rate, especially during nocturnal attacks. Furthermore, supervision at night was associated with a lower risk of recurrence. More studies are required. Whatever the mechanism, the cause of death in SUDEP is cardio-respiratory failure that is triggered by a seizure.7 Unresolved is the ethical condition as to whether we should warn all patients with epilepsy of the risk of SUDEP at the time of the diagnosis of epilepsy.19


So far SUDEP may not be preventable, but until more information about its prevention becomes available we as medical practitioners can at least try to minimise its occurrence by optimising management of all patients with epilepsy in our care until means of preventing SUDEP are available.

References 1. Annegers JF, Pasternak C. SUDEP: Overview of definitions and review of incidence data. Seizure. 1999; 8: 34752. 2. Ficker DM. Sudden unexplained death and injury in epilepsy. Epilepsia. 2000; 41 (Suppl. 2) S7-S12. 3. Lhatoo SD, Sander JWAS. Sudden unexpected death in epilepsy. Hong Kong Med J. 2002; 8(5). 4. Walczak T. Do antiepileptic drugs play a role in sudden death in epilepsy? Drug Safety. 2003; 26(10): 673-83. 5. Black M, Graham DI. Sudden death in epilepsy. Current Diagnostic Pathology. 2002; 8: 365-72. 6. Opennheimer S. Forebrain lateralization and the cardiovascular correlates of epilepsy. Editorial Brain. Oxford University Press 2001. 7. Tomson T, Beghiettore, Sundqvist A, et al. Medical risks in epilepsy: a Continued on page 16.


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Consult Magazine | August – October 2007

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frequent changes in medication, a longer duration of epilepsy and idiopathic epilepsy. A United Kingdom study of 154 cases found generalised chronic tonic seizures, the greatest number of antiepileptic drugs ever taken by the patient, drug withdrawal during the three months prior to death, less supervision during turns and un-witnessed turns when victims cannot be helped.8 Annegers et al1 thought that seizure severity was the strongest risk factor. This was higher for acquired epilepsy primarily from traumatic brain injury than for idiopathic epilepsy. A prospective controlled study of 4,578 patients found SUDEP accounted for 18% of all deaths in patients with epilepsy, and in addition to tonic-clonic seizures and treatment with two or more anticonvulsant drugs identified a full-scale IQ of less than 70 as an independent risk factor for SUDEP.9 The cause of SUDEP is unknown. Studies suggest that in major or minor seizures hypoventilation of the lungs occurs, which is associated with instability of the autonomic nervous system. Tachycardia occurs, followed by transient bradycardia, and this has led to cardiac arrest (sinus arrest). This is now the favoured theory of cause of death in SUDEP. It is thought that the profound central apnoea in the respiratory centre of the brain at the beginning of the


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neuro NEU R O

Huntington’s Disease and the Choreas This review attempts to provide both an overview of a difficult area and an update of contemporary understanding of Huntington’s disease. Dr Andrew Churchyard, Director Huntington’s Disease Service, Calvary Healthcare Bethlehem, Kooyong Rd, Caulfield, VIC 3162. Editorial Advisory Board member: Virtual Neuro Centre

Introduction The choreas form a large group of disparate sporadic and inherited diseases in which the common feature is the clinical sign of chorea. Chorea may be defined as a twitching, non-stereotyped involuntary movement without compulsion to move. Phenomenologically there is overlap between chorea and other involuntary movements such as tics, mannerisms and motor stereotypy. The lack of compulsion generally allows diagnostic discrimination between chorea and tics. Occasionally, defining the movement disorder in an individual can be difficult, but the major diagnostic issue is generally between the different causes of chorea, of which Huntington’s disease (HD) is only one of many possibilities. For example, in the last three years the author has seen two cases of “phenotypic HD” in individuals at 50% risk of the condition who were gene negative but thyrotoxic. This brief review attempts to provide both an overview of a difficult area and an update of contemporary understanding of HD. Apart from HD, genetic cerebral degenerative causes of chorea include Wilson’s disease (autosomal recessive disorder of copper excretion with basal ganglia degeneration), spinocerebellar atrophy type 3 and the non-degenerative autosomal dominant benign familial chorea. Sporadic causes of chorea include thyrotoxicosis, anticardiolipin antibody syndrome, pregnancy/other high oestrogen states and Sydenham’s chorea. Idiopathic chorea remains an entity. A systematic approach to diagnosis and treatment of sporadic chorea is necessary. The remainder of the article will focus on HD (see ref. 1 for an overview of HD).

Genetics HD is an autosomal dominant condition in

which the gene is located at chromosome 4p16.3.2 As with many autosomal dominant neurodegenerative conditions HD is a triplet repeat disease. That is, the wildtype gene contains a sequence of 35 or fewer trinucleotide CAG triplet repeats whereas the mutant pathogenic gene includes an expanded CAG repeat sequence of 40 or more CAG repeats.2 Individuals with 40 or more repeats will inevitably develop HD. Those with a sequence of 36–39 CAG repeats are at intermediate (<100%) risk.2 The age of onset of HD is less as the size of the CAG repeat sequence increases. That is, an individual with 41 repeats will normally become symptomatic at a later age than another with 45. However, because of marked variability around the mean, the CAG repeat number does not allow prediction of age of onset in individuals. Nonetheless, those with intermediate repeats often become symptomatic in old age and 60 or more repeats ensure childhood or adolescent onset.2 Paternal transmission of the HD gene to children of either gender may be associated with the phenomenon of anticipation in which an increased CAG repeat number, and hence an earlier mean age of onset, occurs in the child. Childhood and adolescent onset HD is almost invariably associated with paternal transmission and a large CAG expansion.3 Anticipation accounts for most “new” families in which a male with 36–39 CAG repeats has a child with 40 or more repeats.2 Direct gene testing allows confident diagnosis of HD.

Natural History The typical age of onset of HD is at 35–45 years, after most people have had a family. Disease progression is inexorable and most people with the condition are severely disabled after 17 years of symptomatic disease. Typically, presentation is with a combination of chorea, executive dementia

Consult Magazine | August – October 2007

with relative sparing of short-term memory and psychiatric disease (depression, anxiety, obsessive compulsive disease and rarely, psychosis).3 However, an individual may not develop all the cardinal manifestations initially and atypical presentations including cerebellar ataxia, epilepsy and Parkinsonism are common in children and adolescents.

Rx There is no cure for HD at present. Treatment is therefore symptomatic. Chorea responds to disruption of dopaminergic transmission with either tetrabenazine (dopamine depletion) or antipsychotics such as haloperidol (dopamine receptor blockade). Mood disorders often respond to SSRIs and antipsychotics. Severe bulbar dysfunction is common in advanced HD. Hence speech therapy input to maintain nutrition and prevent aspiration pneumonia is invaluable. Occupational therapy and physiotherapy to facilitate mobility and transfers, providing equipment and assist carers is also invaluable.

Predictive Counselling The direct gene test allows those at risk of HD to be gene tested prior to the onset of symptoms. Learning one’s gene status may assist an individual to better make major life decisions such as whether or not to have a family, but might also have momentous and potentially adverse unforeseen consequences. As a consequence, guidelines outlining the counselling which those at risk should receive prior to gene testing have been developed in a remarkable collaboration between patient organisations (International Huntington’s Association) and the World Federation of Neurology. These guidelines are followed throughout Australia and ensure that all adults receive counselling from specialist counsellors prior to gene testing. Predictive



counselling and gene testing are not available to asymptomatic legal minors. Historically uptake rates have been approximately 20%.4 Predictive counselling is not required for adults or minors who are symptomatic.

Hot Topics and Future Directions in Research The characterisation of the specific mutation causing HD has unleashed a revolution in understanding of the mechanisms leading from mutation to cell death. Two particularly exciting developments in understanding have opened up with the development of transgenic mouse models where mutant transgenic mice carry the human HD gene and in which mutant animals eventually develop symptomatic neurodegeneration. It is now realised that mutant mice which are physically and intellectually stimulated develop symptomatic disease later than those kept in cages without activity.5 The mechanism(s) underlying this observation remain unclear and whether or not a similar effect occurs in humans is unknown, but is being studied in Australia. Transgenic mice carrying the human HD gene which has been further modified by introduction of yeast exons do not

develop symptomatic motor disease, striatal neuronal loss or striatal atrophy at 12 months if cleavage of mutant protein by caspase 6 is blocked, whereas prevention of cleavage by caspase 3 is without effect.6 These two developments raise the possibility of delaying or even preventing the onset of disease or modifying disease progression in those who are symptomatic. However, now that there is a real prospect of effective disease modifying treatments becoming available in the foreseeable future two key clinical tasks must be undertaken. Firstly, the natural history of very early symptomatic HD must be better defined. It is now apparent that chorea is not necessarily the first manifestation of HD and that cognitive and neuropsychiatric dysfunction are often the initial symptoms. Secondly, there are currently no validated biomarkers that predict the imminent onset of symptomatic disease. Currently there are several ongoing multicentre prospective observational trials (Predict HD, Cohort and Pharos) which seek to answer these urgent issues. Various Australian centres are participating in these studies.

no access to psychiatric services which are in general unwilling to provide useful help in any case; 3) long delays in gaining access to community support services; and 4) little counselling to children at risk of HD who must also cope with the parental HD. Getting meaningful help for dying patients and grieving families is subject to the never-ending merry-go-round of cost shifting and buck passing between state and federal government agencies so depressingly familiar to all. The result of such governmental moral and administrative failure is to compound the misery of those who have to live with this terrible disease. Will we provide better care in the future?


By virtue of its extreme severity, global (physical, cognitive and psychiatric) dysfunction and young age of onset, HD represents a severe challenge to our welfare and healthcare systems. Arthur Preston Residential Services in Melbourne was the first HD-specific residential facility in the world and still provides care for a small number of residents. Similar facilities exist in several other states, but most with HD use generic services which are designed for the aged and infirm. Major gaps in service delivery include: 1) accommodation of young adults in geriatric facilities; 2) poor or

1. Huntington’s disease, third edition, Bates G, Harper P and Jones L, eds. OUP 2002. 2. Gusella JF, MacDonald ME, Ambrose CM, Duayo MP. Molecular genetics of Huntington’s disease. Arch Neurol. 1993; 50: 1157-63. 3. Di Maio L, Squiteri F, Napolitano G, et al. Onset symptoms in 501 patients with Huntington’s disease. J Med Genet. 1993; 30: 289-92. 4. Meiser B, Dunn S. Psychological impact of genetic testing for Huntington’s disease: an update of the literature. J Neurol Neurosurg Psych. 2000; 69: 574-8. 5. Van Dellen A, Grote H, Hannan A. Geneenvironment interactions, neuronal dysfunction and pathological plasticity in Huntington’s disease. Clin Exp Pharmacol Physiol. 2005; 32: 1007-19. 6. Graham RK, Deng Y, Slow EJ, et al. Cleavage at the caspase -6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin. CM Cell. 2006; 125: 1179-91.

unexpected death in epilepsy (SUDEP). Am. J. END Technol. 2003; 43:1-12. 12. Ryvlin P, Montavont A, Kahane P. Sudden unexpected death in epilepsy: From mechanism to prevention. [Review] Current Opinion in Neurology. 2006; 19(2): 194-9. 13. Racoosin JA. Mortality in epilepsy. Searching for clues in populations and patients. Neurology. 2003; 60:363-4. 14. Stollberger C, Finsterer J. Cardiorespiratory findings in sudden unexplained/unexpected death in epilepsy (SUDEP). Epilepsy Research. 2004; 59: 51-60. 15. Tigaran S. Cardiac abnormalities in patients. Acta Neurol Scand. 2002; 105 (Suppl. 177): 9-32. 16. Tigaran S, Molgaard H, McClelland

R, et al. Evidence of cardiac ischemia during seizures in drug refractory epilepsy patients. Neurology. 2003; 60: 492-5. 17. Tigaran S, Codrea P, Dalager-Pederson S, et al. Sudden unexpected death in epilepsy: Is death by seizures a cardiac disease? The American Journal of Forensic Medicine and Pathology. 2005; 26(2). 18. Leung HK, Elger P. Finding the missing link between ictal bradyarrhythmia, ictal systole, and sudden unexpected death in epilepsy [Review] Epilepsy and Behaviour. 2006; 9(1): 19-30. 19. Black A. SUDEP - whether to tell and CM when? Med Law. 2005; 24: 41-9.

Failure of Service Delivery

Sudden Unexpected Death in Epilepsy from page 13

review with focus on physical injuries, mortality, traffic accidents and their prevention. Epilepsy Research. 2004; 60: 1-16. 8. Nashef L. Sudden unexpected death in epilepsy: Clinical studies. Cardiac Electrophysiology Review. Dec 2001; Health & Medical Complete. 9. Walczak T S, Lippik IE, D’Amelio M, et al. Incidence and risk factors in sudden unexpected death in epilepsy: A prospective cohort study. Epilepsia. 1997; 519-25. 10. Langan Y, Sander JWAS. Sudden unexpected death in patients with epilepsy. Definition, epidemiology and therapeutic implications. CNS Drugs. 2000; 13(5): 337-49. 11. Izac SM. The phenomena of sudden


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Neurological Causes of Hip and Thigh Pain It is relatively common for neurological referrals to relate to leg pain. This review will focus on non-compressive radiculopathies, lumbosacral plexus disorders and some less common neuromuscular disorders as causes of hip and thigh pain. Professor Gareth J Parry, MB, ChB, FRACP. Professor of Neurology, University of Minnesota; Editorial Advisory Board member: Virtual Neuro Centre Dr Lindsay F Haas, MB, ChB, BMedSc, FRACP. Neurologist and Clinical Leader, Department of Neurology, Wellington Hospital, New Zealand; Editorial Advisory Board member: Virtual Neuro Centre

Introduction It is relatively common for neurological referrals to relate to leg pain. Included in this group are patients who have already had a non-contributory cauda equina or lumbar spine MRI. Joint disease involving the lumbosacral facet, sacroiliac and hip joints are important causes of pain in this region but are beyond the scope of this review which will focus on noncompressive radiculopathies, lumbosacral plexus disorders and some less common neuromuscular disorders.

Neuromuscular Causes of Hip and Thigh Pain 1. Lumbosacral radiculopathy: a. Compressive b. Inflammatory c. Infiltrative d. Ischaemic 2. Lumbosacral plexopathy: a. Inflammatory: i. Diabetic vasculitis ii. Idiopathic lumbosacral plexitis iii. Systemic necrotizing vasculitis iv. Hereditary neuralgic amyotrophy b. Compressive/infiltrative: i. Retroperitoneal haematoma ii. Malignant infiltration c. Radiation plexopathy 3. Meralgia paraesthetica 4. Polymyalgia rheumatica 1. Lumbosacral radiculopathy most often results from compression by disc


protrusion or osteophyte encroachment on the neural foramina and the more caudal roots are usually affected. When upper lumbar roots are affected the pain occurs in the hip and thigh and is less likely to be compressive. Malignant leptomeningeal infiltration or epidural metastatic lesions may present with insidious onset of proximal pain (see below). Ischaemic radicular injury from diabetic vasculitis, akin to diabetic lumbosacral plexitis, may cause acute pain with normal imaging studies. Claudication of the cauda equina may present with proximal pain during exercise. 2. Lumbosacral plexopathy due to ischaemic nerve injury, presenting with unilateral or asymmetric thigh pain, weakness and paraesthesia, usually occurs in diabetics or even with impaired glucose tolerance alone. Non-diabetic patients occasionally develop an identical syndrome, rarely associated with systemic vasculitis. The illness has great morbidity. It is a subacute painful disorder which begins in the hip or thigh and may become bilateral. Pain is the predominant symptom early on, and generally doesnâ&#x20AC;&#x2122;t have the well-defined localisation of lumbar or S1 root pain such as seen with a lumbar disc or other focal cauda equina abnormalities. Late in the course weakness predominates. The syndrome evolves over about six months, stabilises and then slowly improves over one to two years. Residual weakness is common and disabling pain may persist

for years. In both the diabetic and non-diabetic illnesses increased concentration of csf protein, substantial weight loss and electomyographic abnormalities indicating patchy but widespread involvement of lumbosacral roots, plexus or peripheral nerves may occur. The main pathological process is a microvasculitis leading to ischaemic axonal degeneration. Weekly doses of high dose methylprednisolone (500mg) may result in marked and rapid improvement. Idiopathic lumbosacral plexitis, akin to brachial neuritis (ParsonageTurner syndrome), also occurs with a very similar presentation but a shorter course and better prognosis. Hereditary neuralgic amyotrophy is an identical condition that is inherited in an autosomal dominant pattern and may also affect the lumbosacral plexus. Tumours that frequently affect the lumbosacral plexus include colorectal, cervical, prostatic and bladder carcinomas, retroperitoneal sarcomas, lymphomas or metastatic tumours. Sacral components of the plexus are more commonly involved than lumbar. The distribution of back and leg pain depends whether the upper or lower plexus or both are involved. The aching leg pain of tumours involving the lumbar plexus is usually exacerbated by sudden movement or, at times, by lying supine. The pain is sometimes relieved by standing or walking. This may help distinguish tumours involving the plexus from disease of the pelvis or hip. (Patients with inflammatory

August â&#x20AC;&#x201C; October 2007 | Consult Magazine

3. Meralgia paraesthetica. This condition is due to a mononeuropathy of the lateral cutaneous nerve of the thigh. There is a long list of possible aetiologies. In most there is no identifiable cause and the condition probably relates to the nerve being kinked or compressed as it goes through, over or under the lateral inguinal ligament. The symptoms include paraesthesias and allodynia in an oval area of the anterolateral thigh. There may be varying degrees of pain, usually felt as an ache in the thigh, often aggravated by standing and walking and relieved by sitting down. A few have severe pain, making walking difficult or impossible. L2 radiculopathy, a lumbar plexus lesion and a femoral neuropathy are usually easily distinguished. The natural history is for resolution of symptoms. Tight abdominal belts or binders should be avoided. Analgesics may help. Repeated injections of local anaesthetic agents is an option. Very occasionally surgery is recommended. 4. Polymyalgia rheumatica (PMR). Less well recognised than the stiffness pains and aching of the shoulder girdle is the involvement of the lumbar spine and hip


lumbar sacral plexopathy do not experience relief of pain with weight-bearing walking. In fact, activity tends to make the pain worse.) With tumours of the lumbar plexus, when neurological symptoms other than pain appear there is usually first weakness with mild sensory symptoms. Though there may be focal findings they may be minimal. With cauda equina compression or leptomeningeal infiltration direct invasion of nerve roots frequently causes radicular pain, and sometimes mimics the pain from a herniated lumbar disc. In addition to pain, patients may have weakness, paraesthesia and bladder and bowel dysfunction. False-negative MR scanning in cytologically proven leptomeningeal disease may be decreased by using higher doses of gadolinium. CSF can also be non-contributory. If malignant cells are not found in the CSF, the lumbar puncture should be repeated up to three times over the next few days to few weeks. Retroperitoneal haematomas, usually seen in patients on chronic anticoagulation, can also cause unilateral hip and anterior thigh pain, usually associated with weakness of the quadriceps and loss of the knee jerk. Sensory loss is inconsistent. Computed tomography is usually sufficient to demonstrate the haematoma. Radiation injury to the lumbosacral plexus usually causes progressive and painless thigh weakness but can occasionally be painful. The symptoms typically appear six months to two years after the radiation.

girdle with this condition. The hip girdle may be involved without the shoulder girdle. The symptom of stiffness often predominates and is quite severe on waking in the morning. The disorder usually occurs after age 50. Most but not all patients have elevation of inflammatory parameters such as ESR, CRP and ferritin. We have seen one patient referred to a haematologist with a raised ferritin, and normal iron stores and ESR. The patient had symptoms of pelvic girdle PMR and the ESR subsequently became dramatically elevated. The stiffness can be incredibly incapacitating and can create the impression of leg weakness. We have seen a patient referred following a normal lumbar sacral spine MRI who was unable to sit in or drive his farm truck for eight months because of pelvic girdle and leg pain until the correct diagnosis was made and low dose prednisone treatment initiated. Another farmer was unable to kick-start his farm motorbike because of pelvic girdle discomfort. A brisk response to low dose corticosteroid along with the elevated inflammatory parameters confirms the diagnoses. Prednisone is often given in a dose of 15–20mg/day, given as a single morning dose. Sometimes the condition is associated with giant cell arteritis. In

Consult Magazine | August – October 2007

this situation a higher initiating dose of corticosteroid medication is required. Unfortunately many patients with this condition don’t have an early check on the ESR so the clinician is not alerted to the diagnoses.

References 1. Dyck PJB, Norell JE, Dyck PJ. Nondiabetic lumbosacral radiculoplexus neuropathy: natural history, outcome and comparison with the diabetic variety. Brain. 2001; 124:1197-207. 2. Dyck PJB, Norell JE, Dyck PJ. Methylprednisolone may improve lumbar sacral radiculoplexus neuropathy. Can J Neurol Sci. 2001; 28: 224-7. 3. Kilfoyle D, Kelkar P, Parr GJ. Pulsed methylprednisolone for diabetic amyotrophy. J Clin Neuromusc Dis. 2004; 4:168-70. 4. Posner JB. Neurological Complications of Cancer. FA Davies Company. Contemporary Neurology Series. 1995. Chapter 6 Spinal Metastases. p. 111-42. Chapter 7 Leptomeningeal Metastases. Chapter 8 Cancer Involving Cranial and Peripheral nerves. p. 172-95. 5. Stewart JD. Focal peripheral neuropathies. Raven Press. Second Edition 1993. Chapter 19. p. 401-6. CM




High Intensity Focused Ultrasound High Intensity Focused Ultrasound (HIFU) represents the next generation of minimally invasive treatments for early localised prostate cancer. HIFU offers a non-invasive, no incision, pain-free day-only or overnight treatment. Dr Alistair Cameron-Strange FRACS (Urology) FRCSEd, MBCHB, Senior Consultant Urologist at The Prince of Wales Hospital, Randwick, Sydney; Editorial Advisory Board member: Virtual Cancer Centre

Introduction Prostate cancer is responsible for more than 2,500 deaths in Australian men each year and is becoming of increasing significance as the population ages. There are multiple treatment strategies available to treat prostate cancer and these include surgical removal, definitive radiation therapy, hormone therapy or watchful waiting. The side-effect profile of surgery is unacceptable to many patients due to the associated morbidities of impotence and incontinence – no matter how skilled the surgeon professes to be and no matter which technique is used – robotic, laparoscopic or open. And prior to surgery there is no guarantee that the cancer is contained within the prostate. It is this ‘risk-versus-reward’ balance which is of great concern to patients and which has prompted the development of newer, less invasive treatments. High Intensity Focused Ultrasound (HIFU) represents the next generation of minimally invasive treatments for early localised prostate cancer. HIFU is currently in use in Europe, Canada, Japan, China, South America and more recently in Australia and South Africa. When patients are carefully selected to undergo this treatment, long-term results that compare favourably with alternative treatment methods are being recorded.

How it works Sunlight, when focused onto a leaf, can burn a hole in that leaf. By using an ultrasonic transducer transrectally, an ultrasound beam can be brought into a narrow focus in the prostate and by heating the prostatic tissue to 85-100°C, cause coagulative necrosis. Studies in both animals and humans have confirmed this ability of HIFU to cause tissue necrosis.1,2 The focal point in which this occurs is the size of a


rice grain. With the aid of a sophisticated computer and ultrasonic guidance, these HIFU lesions are created back to back until the prostate is destroyed from end to end and from side to side in a procedure which takes from two to three hours. The presence of the rectal wall between the prostate and the transducer dictates the need for a cooling device to prevent the rectal wall from being damaged by heat during the procedure. The Sonochill device circulates degassed ice-cold water around the ultrasound transducer within a balloon during treatment to prevent an increase in rectal wall temperature. Because of the proximity of the prostate to the transducer, it is possible to use ultrasound frequencies in the 3-4mHz range which results in small, very sharply defined lesions. This accuracy results in a very precise border between treated and untreated tissues. The great advantages of HIFU are that it is a non-invasive, no incision, pain free, day only or overnight treatment with outcomes similar to other treatment modalities in carefully selected patients. Furthermore there is better preservation of erectile function and urinary continence after HIFU than after either surgery or radiotherapy.

Patients suitable for HIFU At the present time HIFU is regarded as suitable for patients with: • prostate cancer localised to the prostate; • in patients unfit or unwilling to undergo major surgery; • in those over 70 years; • a PSA < 20; • a Gleason score of 7 or less; • a prostate gland < 40cc; • as an alternative to radiotherapy; and • where radiotherapy has failed. It is important that the prostate volume should be less than 40cc. If the prostate is

larger than 40cc, the patient will need to be treated with androgen deprivation therapy to debulk the gland.

Contraindications An absolute contraindication to this treatment is if a bowel resection has been performed and the anastamosis is adjacent to the prostate. Dense intraprostatic calcification interferes with the ultrasound beam and renders treatment inadequate. Rectal stenosis may prevent the probe from being placed. Those with a large middle lobe of prostate will need this to be resected prior to treatment.

The Procedure The patient will begin a bowel preparation 24 hours before HIFU as the presence of faeces and gas in the rectum prevents accurate imaging of the prostate and can be hazardous. A full general anaesthetic procedure is administered and the patient positioned supine on the operating table. A balloon is placed over the ultrasound transducer which is then positioned in the patient’s rectum and the prostate imaged in both the transverse and longitudinal planes. After careful planning, treatment is begun in the first of three zones, which will eventually overlap. The prostate is slowly and accurately destroyed, the tissue being closely monitored during this time with real-time ultrasound. Treatment time varies from between two to three hours depending on the size of the gland. At the end of the treatment a catheter is placed suprapubically which will need to remain in situ for 10-14 days. Alternately, one can do a limited TURP immediately before HIFU to reduce the duration of the post operative catheterisation time. The Continued on page 24.

August – October 2007 | Consult Magazine

PHARMACY ALLIANCE Freedom to choose

cardiac CA R DIAC

Relaxin and Heart Disease Dr Xiao-Jun Du.

Over the past 10 years there has been rapid growth in our understanding of relaxin peptide, its receptor and its bioactivity. Its actions on nonreproductive organs, in particular the cardiovascular system, have attracted great attention. Dr Xiao-Jun Du, MBBS, MMed, PhD, NHMRC Senior Research Fellow; Head Experimental Cardiology; Head Mouse Cardiology Core Facility; Experimental Cardiology Laboratory, Baker Heart Research Institute, Melbourne, Australia; Editorial Advisory Board member: Virtual Cardiac Centre

What is Relaxin? Relaxin is a peptide hormone that belongs to the insulin growth factor family. Relaxin is known to have a variety of biological actions on reproductive and non-reproductive organs.1,2 Its major biological activity is to remodel and soften the reproductive organs and nipples of pregnant females for smooth delivery of offspring and lactation.1 This is achieved by reducing the intracellular collagen content in these organs. Relaxin also plays a key role in pregnancy-related haemodynamic adjustment by regulating blood volume, renal function and vascular resistance.1 The major source of relaxin is the ovary but other tissues, including the prostate and heart, are able to produce relaxin and also respond to exogenous relaxin. Recent research has identified the relaxin receptor as a subgroup of the family of leucine-rich repeat containing guanine nucleotide-binding protein (G protein)coupled receptors (LGR7). Activation of LGR7 increases intracellular cyclic AMP and protein kinase-A (PKA) activity in some cell types. However, multiple alternative signal pathways that mediate bioactivities of relaxin have also been documented.

A New Biomarker of Heart Disease Dschietzig et al3 assayed relaxin levels in patients with congestive heart failure due to dilated or ischaemic cardiomyopathy, and found up to an eightfold increase in plasma relaxin concentration. Interestingly,

relaxin levels were found to correlate with the severity of heart failure and there was also an inverse correlation between relaxin and endothelin.1,3 Analysis of relaxin gene transcripts in the failing myocardium also revealed dramatic upregulation of this gene, suggesting a cardiac source of the elevated circulating relaxin.3 This finding fits well with experimental data on diseased animal models, such as pressure-overload cardiac hypertrophy or drug-induced toxic cardiomyopathy, showing a fourfold to fivefold upregulation of relaxin gene transcripts in the heart. Dschietzig et al3 proposed that relaxin is a biomarker of heart failure and likely to play a compensatory role in the setting of heart failure.3 Following this initial report, some, but not all, subsequent clinical reports confirmed the elevated circulating level of relaxin in patients with heart failure, but questioned relaxin as a new biomarker for heart failure.

Physiological Role Although at pharmacological doses relaxin has chronotropic and inotropic actions,1,2 at physiological range (up to 100ng/ml) such an action is not evident. Vasodilatation of renal arteries has been well documented both in human and laboratory animals,1,2 which is mediated by relaxinâ&#x20AC;&#x2122;s activation of nitric oxide synthases. Another welldocumented action of relaxin is its antifibrotic property. We observed that male but not female mice with relaxin gene deletion develop, with ageing, cardiac fibrotic

Consult Magazine | August â&#x20AC;&#x201C; October 2007

phenotype and diastolic dysfunction of the left ventricle (LV).4 This phenotype can be reversed by treating the relaxin knockout mice with relaxin peptide.5

Therapeutic Potential Several recent studies have provided strong evidence for the therapeutic potential of relaxin. Of these the anti-fibrotic action of relaxin has been documented by in vivo and in vitro studies. When tested in cultured fibroblasts from rat hearts, treatment with relaxin inhibited fibroblast activation, proliferation and collagen synthesis.5 Meanwhile, activation of collagen degrading enzymes MMPs is also promoted.5 Thus, relaxin is able to alter the balance of matrix collagen synthesis and degradation. We have shown in vivo and in vitro that relaxin only shows such action when collagen content is abnormally higher.5 In vivo studies using two disease models of cardiac fibrosis have shown that treatment with relaxin for a period of two weeks significantly reversed interstitial fibrosis.5,6 Interestingly, in the spontaneously hypertensive rat (SHR), renal fibrosis was also reversed by such treatment.6 We recently showed that systemic relaxin gene-delivery via adenovirus also achieved a similar efficacy in the reversal of cardiac fibrosis (manuscript submitted). There is also evidence that relaxin mediates cardiac protection against ischaemia/reperfusion injury or drug-induced cardiac toxicity.7



Using rodent and pig models of cardiac ischaemia and reperfusion, myocardial protection by relaxin has been shown with melioration of cardiomyocyte death, inflammatory response, calcium overload and accumulation oxidative products.7 Infarct size was found to be reduced by relaxin treatment.7 Relaxin regulates circulatory homeostasis by reducing vascular tone by enhancing nitric oxidedependent relaxation as well as antagonising the effect of several vasoconstrictors, and by regulating the balance of blood volume through its central actions on water intake and actions on the kidney.

Future Research Directions Currently research needs to peruse the pathophysiological role of relaxin and its therapeutic potential in heart disease. There has been limited knowledge on signalling mechanisms used by relaxin in the cardiovascular tissues. The implication of an elevated relaxin level in subjects with heart disease needs to be addressed. Further, other actions by relaxin need to be addressed, such as on vasculature under conditions of hypertension or atherosclerosis. In addition,

scar formation is closely associated with healing in the mammalian heart following myocardial infarction. There has been speculation that the fibrotic environment prevents the myocardial regeneration. It would be interesting to study whether the use of relaxin in this setting might act in favour of myocardial regeneration rather than scar formation. The use of genetically modified mouse models with relaxin or LGR7 gene deletion or over-expression would be of great help in addressing these key questions. Nevertheless, the current experimental findings have clearly justified the design of small-scale clinical trials testing the efficacy of relaxin in patients with cardiovascular disease, such as ischaemic heart attack or fibrosis.

References 1. Sherwood OD. Relaxin’s physiological roles and other diverse actions. Endocr Rev. 2004; 25: 205-34. 2. Conrad KO, Novak J. Emerging role of relaxin in renal and cardiovascular function. Am J Physiol Regul Integ comp Physiol. 2004; 287: R256-R261. 3. Dschietzig T, Richter C, Bartsch C, Laule

M, Ambruster FP, Baumann G, et al. The pregnancy hormone relaxin is a player in human heart failure. FASEB J. 2001; 15: 2187-95. 4. Du XJ, Samuel CS, Gao XM, Zhao L, Parry LJ, Tregear GW. Increased myocardial collagen and ventricular diastolic dysfunction in relaxin deficient mice: a gender-specific phenotype. Cardiovasc Res. 2003; 57: 395-404. 5. Samuel CS, Unemori EN, Mookerjee I, Bathgate RAD, Layfield SL, Mak J, et al. Relaxin modulates cardiac fibroblast proliferation, differentiation and collagen production and reverses cardiac fibrosis in vivo. Endocrinology. 2004; 145(9): 4125-33. 6. Lekgabe ED, Kiriazis H, Zhao C, Xu Q, Moore XL, Su Y, et al. Relaxin reverses cardiac and renal fibrosis in spontaneously hypertensive rats. Hypertension. 2005; 46: 412-8. 7. Perna AM, Masini E, Nistri S, Briganti V, Bigazzi M, Bani Sacchi T, et al Novel drug development opportunity for relaxin in acute myocardial infarction: evidences from a swine model. FASEB J. 2005; 19: CM 1525-7.

High Intensity Focused Ultrasound from page 20

patient is discharged the same day, and may return to work within 24 hours.

Complications Minor complications such as urinary infection, perineal irritation, epididymitis, urethral discomfort and bladder irritation may occur. Voiding is initially not possible due to the swelling of the gland as a result of the thermal effects. A catheter will therefore need to remain in situ for 10-14 days. Urethral stricture may also occur as well as a rectourethral fistula. Both of these complications are more likely to occur in post radiotherapy patients. With improved ultrasound imaging the development of a rectourethral fistula is now rare. Stress incontinence is secondary to treatment of apical prostatic tissue and is usually transient. Erectile dysfunction occurred in 24% of patients7 in a review of 462 patients.

Results The most important predictor of long-term outcome after treatment is the PSA nadir which takes three months to occur. Another way of assessing the result of treatment is to re-biopsy the prostate to determine the presence of residual cancer cells. Uchida et al in Japan3,4 in a study of 72 patients with previously untreated T1c – T2N0M0 disease and PSA levels < 20 ng/ml, using the Sonablate 500 achieved


negative post treatment biopsies in 68% of patients at 14 months. In a further study Gelet et al 5 report a five-year 78% disease free rate with negative post treatment biopsy and stable PSA in low risk patients – those with pretreatment PSA < 10ng/ml and Gleason Score six or less. Of 146 patients treated by Blana et al 6 with a pretreatment PSA of < 15 and a Gleason score of seven or less, a mean PSA nadir of 0.07ng/ml was reported at three months, but 43% of these patients had neoadjuvant hormonal treatment.

Conclusion HIFU is a relatively new treatment modality for prostate cancer and 10-year outcomes are not yet available. As further developments in both the software and hardware of the HIFU devices emerge, it is likely that the cancer cure rates will improve and side effects will decrease. It is however of increasing interest and currently under ongoing investigation in several centres overseas. Future studies will determine its eventual role in the treatment of prostate cancer. In carefully selected patients it offers the potential to eradicate the disease with a minimal side-effect profile, short hospital stay and an early return to daily activities. For further information please visit

References 1. Chapelon JY, Margonari J, Vernier F,

Gorry F, Ecochard R, Gelet A. In Vivo effects of high-intensity ultrasound on prostatic adenocarcinoma Dunning R3327. Cancer Res. 1992; 5 : 6353-7. 2. Beerlage HP,van Leenders GJ, Oosterhof GO et al. High-intensity focused ultrasound ( HIFU) followed after one to two weeks by radical retropubic prostatectomy: results of a prospective study. Prostate. 1999; 39: 41-6. 3. Uchida T, Ohkusa H, Nagata Y, Hyodo T, Satoh T, Irie A. Treatment of localised prostate cancer using high-intensity focused ultrasound. BJU Int. 2006; 97: 56-61. 4. Uchida T, Baba S, Irie et al. Transrectal high-intensity focused ultrasound in the treatment of localised prostate cancer: a multicenter study. Hinyokika Kiyo. 2005; 51: 651-8. 5. Gelet A, Chapelon JY, Bouvier R, Rouviere O et al. Prostate cancer control with transrectal HIFU in 242 consecutive patients. 5 year results. Eur. Urol. 2004; Suppl. 3: 214. 6. Blana A, Walter B, Rogenhofer S, et al. High-intensity focused ultrasound for the treatment of localised prostate cancer: 5-year experience. Urology. 2004; 63: 297-300. 7. Uchida T, Shoji S. HIFU for Localised prostate cancer: 6 year experience. Presented at the International Society for Therapeutic Ultrasound (ISTUS) in Boston, USA on October 28, 2005. CM

August – October 2007 | Consult Magazine

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Advising Patients About Aerobic Exercise Dr Stan P Woodhouse.

Using the Cooper Circuit as a guide, an aerobic exercise program for cardiac patients has been devised, along with a brochure for patientsâ&#x20AC;&#x2122; information. Dr Stan P Woodhouse MbChB FRACP, FCSANZ, Clinical Associate Professor, University of Queensland; Editorial Advisory Board member: Virtual Cardiac Centre.


ody fitness is a combination of cardiorespiratory reserve, muscle strength and flexibility. Limitation of any of these will result in changes to effort tolerance and/ or ability to perform usual physical tasks. In new thinking, derangements of skeletal muscle oxidative mechanisms and cell wall transport have been emphasised as a cause of insulin resistance, and therefore the development of metabolic syndrome and diabetes.4 This same mechanism results in loss of muscle function as we age6,7 and is also seen in patients with heart failure.2,5,8 Aerobic plus resistive exercise will benefit all these situations. Although regular exercise, with its caloric effects, will not significantly contribute to weight loss in the short term, it will help reduce appetite and control weight gain over a long period. In heart failure patients, exercise programs have been shown to improve life expectancy and reduce heart failure hospital admissions.9 Much of the limitation of exercise in heart failure patients is caused by peripheral muscle effects and ventilation inefficiency, rather than the reduction in ejection fraction which is the generally considered cause.5,7,8,11 Regular exercise also induces considerable psychological benefit together with an improved sense of wellbeing. Large numbers of people choose a lifestyle that includes regular, healthy exercise and healthy food choices, either to maintain their general health or as a part of their medical managements. Many age-related changes can be delayed or managed with a regular exercise program.3,6,7,10 The existing community resources based on hospital rehabilitation programs and gymnasium


membership are inadequate, and do not provide for a subsequent ongoing selfmanaged program. Indeed, the cost of the initial program is often beyond most individuals. As a consequence, many people wanting to improve their lifestyle resort to popular written material for information, or approach their family doctor for advice. This paper is an attempt to help individuals achieve and enjoy a fit, healthy life into old age by providing some useful techniques which I have used over many years. I have employed similar programs for cardiac patients with ischaemia and heart failure and they have proven to be both safe and effective.

In any successful exercise program, it is important for the individual to measure improvement. This helps them to maintain the program. Therefore, I will discuss a community resource, which can be easily developed in park areas by local councils, to measure improvement in these fitness modalities. Many years ago, Cooper described a circular running circuit with one metre markers, which allowed measurement of the distance run in 12 minutes. He then provided distances achieved by men and women, indicating the level of fitness (Fig 1). I have applied this principle to cardiac patients, both in post myocardial infarct and chronic heart


UNDER 30 YRS 0 - 1.6 1.62 - 1.98 1.99 - 2.38 2.39 - 2.78 2.80 +

30-39 YRS 0 - 1.52 1.53 - 1.82 1.83 - 2.22 2.23 - 2.62 2.63 +

40-49 YRS 0 - 1.36 1.37 - 1.66 1.67 - 2.06 2.07 - 2.46 2.47 +

50+ YRS 0 - 1.28 1.29 - 1.58 1.59 - 1.98 1.99 - 2.38 2.39 +

40-49 YRS 0 - 1.20 1.21 - 1.52 1.53 - 1.82 1.83 - 2.30 2.31 +

50+ YRS 0 - 1.04 1.05 - 1.34 1.35 - 1.66 1.67 - 2.14 2.15 +


UNDER 30 YRS 0 - 1.52 1.53 - 1.82 1.83 - 2.14 2.15 - 2.62 2.63 +

30-39 YRS 0 - 1.36 1.37 - 1.66 1.67 - 1.98 1.99 - 2.46 2.47 +

Figure 1. Cooper Circuit. Distance (km) run in 12 minutes and level of fitness for men and women.

August â&#x20AC;&#x201C; October 2007 | Consult Magazine

Figure 3. Distance run in 12 minutes and marathon time in non-athletes.

Figure 4. Distance run in 12 minutes and marathon time in athletes.

failure rehabilitation programs; however, rather than the initial running stage, I have used walking. I have found they are safe, effective and popular, as individuals can undertake the circuit at their own convenience, use it to independently assess how effective their program is, and continue to use it to maintain fitness after the formal program has been completed. Similar systems have been employed to determine exercise performance in heart failure patients using only a six-minute walking time.1 I have employed this circuit by using the distance run in 12 minutes to predict performance times in athletes and nonathletes. Fig 2 shows the results of bicycle exercise testing in an exercise laboratory, compared with the time to complete a marathon race. It is quite obvious that the results of bicycle testing in a laboratory do not predict marathon times. I placed some of these individuals on the Cooper

circuit, with continuous pulse monitoring, and found that good performers were those able to gauge a running speed that was maintainable for the time allotted. Bad performers could not do this as well, and their pulse rate varied widely during the 12-minute period. I asked individuals about to run a marathon to do a 12-minute run a few days beforehand. I compared the distance they achieved in their 12-minute run with their marathon completion time. There was a surprisingly excellent correlation in both committed athletes (Fig 4) and non-athletes (Fig 3), although the correlation was more significant in athletes. It would seem that in physically fit individuals used to running distances in training, servo feedback plays a part in the distance covered during the 12-minute run. This is reflected in the time taken for runs over a longer distance, suggesting that the Cooper circuit is an effective method to assess fitness and performance in both

Consult Magazine | August – October 2007



Figure 2. Laboratory bicycle ergometer compared with marathon time.

athletes and non-athletic populations. Debility and pain induces less exercise and results in a further reduction in exercise performance. Prolonged sitting results in musculo-tendinous shortening. This leads to a further decrease in muscle strength, and eventually to mobility problems beyond the basic physical or organ disability. I see many people with musculoskeletal chest pain, resembling angina, due in many cases to lack of exercise and loss of mobility about the shoulder girdle. Resolution of the chest pain occurs rapidly with exercises for the shoulder and back. Everyone can exercise, no matter the age or level of disability – it is only a matter of modality and extent. In the same way, everyone can stretch and do some sort of muscle strengthening. Some patients will resist a training program, saying they get enough exercise at work or in the home. Emphasise to them the additional benefits of a good outdoor-based program to muscles, joints and mental health. If they resist, ask them to wear a pedometer and show that they are achieving 10,000–15,000 steps a day. The key to cardio-respiratory fitness is aerobic exercise. Almost everyone can undertake this, provided some safety rules are followed. We say exercise is aerobic when it uses the large muscles of the body, lasts for 30–40 minutes and causes the heart rate to increase without a large increase in blood pressure. If there is a background of ischaemic heart disease, hypertension or symptoms suggestive of angina, I will usually conduct a treadmill ECG stress test, both for diagnosis and to assess a safe pulse rate if angina or ST depression occurs. For individuals with no symptomatology or ischaemia background, and who are not on digitalis or beta-blockers, use the pulse rate to determine exercise levels. Show patients where to find the carotid artery and count the pulse for 15 seconds. Multiply this by four to give the rate per minute. Alternatively, for patients in sinus rhythm, chest belts with a readout on a wrist watch will give the pulse rate, and will allow the maximum and minimum pulse rates to be locked in. This will help improve training, and also provide extra safety by ensuring that maximum pulse rates are not exceeded. Calculate the predicted maximum pulse rate as 220 minus their age in years. For younger people, advise training at 80% of this value. For older or sick patients, advise 70% of the predicted maximum pulse rate. Other safety advice that patients should be told is to not go above the 80% level or the rate determined from the stress test; to exercise in the cool of the day; and to not exercise after food or alcohol. It is good to exercise with others; if talking during exertion is easy, then the exercise is not excessive. Advise against


A SIX WEEK STARTING PROGRAM (after two weeks of limbering and stretching)

• Five minutes stretching & limbering up before & after exercise (see patient pamphlet). • Exercise at least three times a week. • Exercise heart rate 60% maximum with bursts of 30 seconds of 70% maximum every five minutes. • Slow down if you become short of breath, get chest pain, chest discomfort, palpitations or become excessively tired. • If there is excessive tiredness after exercise, slow down on the subsequent program. SWIMMING WEEK 1 WEEK 2 WEEK 3 WEEK 4 WEEK 5 WEEK 6


10 mins 15 - 20 mins 15 mins 20 - 30 mins 20 mins 30 - 40 mins 25 mins 40 - 50 mins 30 mins 50 - 60 mins From now on increase the distance covered in the same time period.

Figure 5. A six-week starting exercise program for cardiac patients.

exercise if the patient is feeling unwell or there are influenza-like symptoms. Patients on GTN should carry the spray with them. People should employ a circular course, if on foot or bicycle, to ensure that they do not overdo the distance by going too far in one direction, and to ensure that they do not get caught in a headwind on the way back. Encourage them to set up their exercise area with an eye to the road rules, use verges, footpaths or formed tracks, and to wear reflectors on clothing and shoes. They should carry on them identification, medical and drug information, small change for cab or bus fare in case of necessity, toilet paper and a mobile phone if possible. The key advice to maintain life-long exercise programs is based on identifying each individual’s preferences for exercise, with an eye on realistic forms based on age and underlying systemic, joint or muscle abnormality. A successful program for life should be based on what an individual likes to do, eg swimming, cycling, walking or jogging, tennis, dancing or, preferably, a mixture of these. If the pulse rate is used as an index of how much exercise an individual can do, then the risks are very small. Advise the use of proper quality footwear with insoles and air soles to reduce impact injury. Rome was not built in a day. Start on a low-level program and build up slowly over 4–6 weeks (Fig 5). Advise on proper stretching before and after exercise (see patient pamphlet). To maintain interest in the program, advise a variety of exercise,


take the dog or a friend, change routes and possibly join a walking or jogging group. You will already have addressed issues such as blood pressure, diabetes, lipid levels and cigarette use. People will ask about diet, and that will be discussed in a later paper. Starting the program is always worrying for the individual. The key is to care for joints, muscles and tendons which have probably shortened, weakened or deteriorated with inactivity. I begin a program with light exercise only for 2-3 weeks, initially emphasising stretching, strengthening and limbering up (see patient pamphlet). The process is to assess firstly cardiovascular, respiratory and muscle and joint status, followed by attention to risk factors of smoking, diabetes, hypertension and lipoproteins. Decide with individuals the exercise modalities most suited to their temperaments, and the realities of their bodies’ underlying limitations and habitus. Begin with at least two weeks of limbering up and stretching (see patient pamphlet) to reduce the risk of injury. After this, begin the aerobic program outlined above. Any musculo-tendinous injury occurring should be treated early, before the person gives in to pain. Once the aerobic program has been achieved for at least four weeks, I begin introducing some resistive muscle training, the methodology of which will be the subject of a follow-up paper. Regular follow-up is important to ensure the success of the program. Record pulse rates and regular distances on the Cooper circuit. These act as powerful

feedback for the individual, indicating the level of improvement. Weight and waist measurements will also improve, but will take a longer time to show. This is all simple but workable, and seeing a remarkable turnaround in wellbeing through purely physical means will provide a great sense of achievement for patient and practitioner alike. A pamphlet is available on the following website and may be printed out for patient use: Treatment.asp?sid=97

References 1. Abraham W T et al. Cardiac resynchronization in chronic heart failure. NEJM. 2002; 346:1845-53. 2. Belardinelli R et al. Low dose dobutamine echocardiography predicts improvement in functional capacity after exercise training in patients with ischaemic cardiomyopathy: prognostic implication. Am Coll Cardiol. 1998; 31:1027-34. 3. Briffa TG et al. Physical activity for people with cardiovascular disease: recommendations of the National Heart Foundation of Australia. Med J Aust. 2006; 184:71-5. 4. Carrel AL et al. Improvement of fitness, body composition, and insulin sensitivity in overweight children in a schoolbased exercise program: a randomised controlled study. Arch. Pediatr. Adolesc. Med. 2005; 159:963-8. 5. Davey P et al. Ventilation in chronic heart failure: effects of physical training. Br. Heart J. 1992; 68:473-7. 6. Fiatarone MA et al. The etiology and reversibility of muscle dysfunction in the aged. Gerontal. 1993; 48:77-83. 7. Kirkendall DT et al. The effects of ageing and training on skeletal muscle. Am. J Sports Med. 1998; 26:598-602. 8. Lipkin et al. Abnormalities of skeletal muscle in patients with chronic heart failure. Int J Cardiol. 1988; 18:187-95. 9. Piepoli M F et al. ExTraMATCH Collaborative Exercise Training MetaAnalysis of Trials in Chronic Heart Failure (ExTraMATCH). BMJ. 2004; 328:189. 10. Thompson PD et al. Exercise and physical activity in the prevention and treatment of atherosclerotic cardiovascular disease: a statement from the Council on Clinical Cardiology Circulation. 2003; 107:3109-16. 11. Tumminello G et al. Exercise ventilation inefficiency in heart failure: pathophysiological and clinical significance. Europ Heart J. 2007; CM 28:673-8.

August – October 2007 | Consult Magazine

cardiac CA R DIAC

Homocysteine, B-Vitamins and Cardiovascular Disease

Dr Kathleen Potter.

Extensive research has been conducted into the underlying causes and risk factors for cardiovascular disease. Of particular interest is the role of homocysteine in the development of cardiovascular disease. Dr Kathleen Potter, BMedSc, MBChB, School of Medicine and Pharmacology University of Western Australia; Editorial Advisory Board member: Virtual Cardiac Centre

The Role of Homocysteine Strong evidence supports an association between cardiovascular disease and homocysteine, a sulfur-containing, nonprotein forming amino acid that circulates in the plasma. Experimental evidence in humans and animals suggests that homocysteine causes changes in vascular structure and function typical of early atherosclerotic disease.1,2 Epidemiological data shows that increased plasma homocysteine concentrations are strongly associated with an increased risk of myocardial infarction and ischaemic stroke.3-7 Many plausible mechanisms by which homocysteine might damage the arterial wall or increase the risk of thrombosis have been proposed.8 However, it remains unclear whether homocysteine actually causes atherosclerosis or whether it is simply a marker for other cardiovascular risk factors or for the presence of existing disease.

Do B-vitamins Reduce Cardiovascular Disease? Folic acid and vitamin B12 reduce homocysteine levels by around 25%, even in people who are not obviously vitamindeficient.9 Over the last decade several large randomised placebo-controlled trials have investigated whether using Bgroup vitamins to lower homocysteine concentrations reduces cardiovascular events.10-12 These trials have tested various

combinations of B-vitamins in subjects at risk of vascular events or with proven atherosclerotic disease. All trials reported significant reductions in homocysteine levels in the vitamin-treated subjects compared with placebo.10-12 However, a meta-analysis of the data, published at the end of last year, found no significant reduction in the risk of cardiovascular disease, coronary heart disease, stroke or allcause mortality in almost 17,000 subjects.13 This result suggests that homocysteine is more likely to be a risk marker for atherosclerosis than a risk factor. However, the homocysteine question is not completely settled. All the trials to date have been conducted in subjects with proven vascular disease or with end-stage renal failure. It is possible that B-vitamins may be more effective if used in healthy subjects prior to the development of clinically evident disease, although this has yet to be demonstrated. There is also some evidence that reducing homocysteine may have more effect on stroke incidence than on myocardial infarction. The HOPE-2 study showed a modest reduction in the number of ischaemic strokes in vitamin-treated subjects.13 However, the same investigators reported that the vitamin-treated subjects were more likely to be hospitalised with unstable angina than those on placebo. Similarly, the NORVIT investigators reported a trend towards an increased risk of myocardial infarction, stroke or sudden death in subjects treated with B-

Consult Magazine | August â&#x20AC;&#x201C; October 2007

vitamins.11 While these results may be due to chance, they also raise the possibility that unanticipated adverse consequences of B-vitamin supplementation outweigh any benefit from reducing homocysteine.

Future Research Several large homocysteine trials are still ongoing.14,15 A meta-analysis of all trial results will include more than 50,000 participants and will have sufficient power to clearly determine whether lowering homocysteine reduces vascular event rates. Currently, however, there is no evidence to support the use of B-vitamin supplements in patients at risk of cardiovascular disease.

References 1. Chambers JC, Obeid OA, Kooner JS. Physiological increments in plasma homocysteine induce vascular endothelial dysfunction in normal human subjects. Arterioscler Thromb Vasc Biol. 1999; 19: 2922-7. 2. Lentz SR, Sobey CG, Piegors DJ, et al. Vascular dysfunction in monkeys with diet-induced hyperhomocyst(e)inemia. J Clin Invest. 1996; 98: 24-9. 3. Hankey GJ, Eikelboom JW. Homocysteine and vascular disease. Lancet. 1999; 354: 407-13. 4. Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: Probable benefits Continued on page 32.


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weight loss W EI G H T L O S S

Weight Loss: A Case Study Dr Andrew Dean presents a case study of a morbidly obese, diabetic patient, and discusses the efficacy of the Tony Ferguson weight loss program, patient compliance and outcomes. Dr Andrew Dean, MB ChB MRCP(UK) FRACP; Medical Director: Virtual Cancer Centre


eter presents as a 54-yearold public servant who was diagnosed with Type 2 (Maturity Onset) Diabetes six years ago. His control has steadily worsened over the past two years, and his medication has escalated accordingly. Peter also has hypertension. After problems with snoring and daytime somnolence, he underwent a sleep study and was diagnosed with Obstructive Sleep Apnoea. He has been using a home CPAP machine with variable effect on his symptoms. His weight has increased from 135kg to 150kg over the past three years. His height is 180cm. His current medication is: • Gliclazide MR 120mg daily • Metformin 1000mg bd • Diltiazem CR 240mg daily • Aspirin 150mg daily • Captopril 50mg bd His diabetic physician had started him on insulin in an attempt to improve his steadily rising HbA1c, which was 16% on last measurement. His insulin dose had increased to Lantus Glargine 60 units daily. He presents in crisis because his insulin dose has doubled in the past three months and his blood sugar control has steadily worsened, with frequent daytime readings being in the 20s. He says, “The more I increase my insulin, the higher my sugar gets.” Exercise: 1. What are the current management challenges facing you, his physician? 2. What physiological processes are occurring? 3. What investigations will be helpful? 4. What is your management plan? Peter is literally eating himself to death. His Body Mass Index is 45.28.

A complication of his morbid obesity is the ‘metabolic syndrome’, with development of insulin resistance leading to Type 2 Diabetes associated with hypertension. He also has Obstructive Sleep Apnoea, and the increased adrenergic drive will worsen both his glucose control and his hypertension. Effectively, the pharmacological management is palliative. The underlying problem is not being dealt with. It is vital to work out how to approach Peter’s overall health in an effective multidisciplinary way. We need to know more about Peter himself, his lifestyle and coping skills. Peter is a third generation Australian of Italian extraction. He enjoys pasta, a few beers with the boys, and is a keen fisherman. His wife also has a raised body mass index and suffers osteoarthritis of both hips and knees. Peter finds his job in the taxation office stressful and tends to comfort eat. In order to cure Peter it is necessary to institute a number of interventions. He needs a comprehensive care plan that views his weight as the target of therapy, not his diabetes or hypertension. The ideal care plan will include dietary assessment, psychological care and exercise, as well as adjustment of his medication to promote weight loss. Bariatric surgery is also an option, but this is most successful as an adjunct to dietary weight loss - it works best when significant weight loss is already in progress. Too many people expect it to be a one-hit wonder. Physiologically, his carbohydrate intake is way too high, which drives further insulin production (in an individual who is already insulin resistant). Increasing his exogenous insulin has unwittingly contributed to the problem by further driving weight gain. In this particular case, I believe that the gravity of the situation needs to be driven home to Peter. Some shock tactics

Consult Magazine | August – October 2007

might inspire him to make the life changes he needs if he is going to survive for any significant period. The easy approach of just further upping his insulin will not work. I would admit Peter to hospital, explain the gravity of his position and institute some emergency measures. Peter has Type 2 Diabetes, not Insulin Dependent Diabetes, and review of his tests show that he was negative for Anti GAD antibodies and his C-peptide levels were not reduced. Thus he should not become ketoacidotic. If his diet can be radically modified in a controlled manner, his insulin can be stopped and his sugars monitored in an inpatient environment. It is difficult to see how he is benefiting at all from his insulin. His sugar control is atrocious. Telling him to eat less is likely to be a non-starter, as it has never worked in the past. A behaviour modification process needs to be implemented to force him to change his ways. In fact, Peter was told to enrol in the Tony Ferguson meal replacement program. This was done for several reasons. It was new. Peter hadn’t heard of it and was willing to give it a try. He had been on ‘Modifast’ before, but had failed to persist for longer than two weeks due to the monotony of the taste. The fact that Tony Ferguson comes in a large variety of flavours makes it a great option for patients. As well as the cold ‘shakes’, it comes in a variety of soup flavours, so hot meals can be taken in this form, further adding to the variety. The low carbohydrate content will help his sugar control and hopefully reduce his insulin levels, which are driving his obesity. His insulin medication was stopped on admission and he was commenced on the Tony Ferguson program. Although the program recommends only two meal replacements per day, in view of the severity of Peter’s weight problem



and diabetes, he was placed on three meal replacements per day in a supervised environment. Given that his mean 60-days glucose was in the mid 20s, it was anticipated that Peter would have raised blood sugars. This required considerable patience and explanations to the nursing staff on the ward, who were rightly concerned about the sugar level being much higher than they would normally find acceptable. In fact, within the first two days, Peter’s sugars were below 20. Peter was weighed on a daily basis and was vigorously introduced to the diabetic education program. By the end of the first week, Peter had lost 9kg and his average blood sugar level was 13. Buoyed by this success, Peter was keen to proceed with the second week and so no changes were made. In an effort to further reduce his insulin resistance and aid weight loss, Pioglitazone (Actos) was introduced at a dose of 30mg daily. By the end of the second week, Peter’s blood sugars normalised and his Gliclazide MR dose had to be reduced to 60mg daily. As his hypertension control was also suboptimal, the Diltiazem was changed to Amlodipine 10mg daily and the Captopril was changed to a more modern ace inhibitor, in this case Perindopril 10mg daily. His hypertension control was then extremely satisfactory. This is an excellent example of what can be done to help people. Some might criticise the fact that Peter was admitted to hospital on a semi-elective basis when, in general, hospital beds throughout the nation are short. However, there is no doubt in my mind that in this particular case, admitting Peter to hospital has almost certainly prevented an acute admission with a significant problem such as myocardial infarction, stroke or other acute vascular

FOOD PYRAMID AS A GUIDE FOR WEIGHT MAINTENANCE New Food Pyramid. Courtesy of Scientific American Medicine 2004. Starting at the base of the pyramid and moving up:

eat less


eat moderately



eat more


event. If this weight loss can be maintained, Peter’s life expectancy will improve greatly and his likelihood of requiring in-hospital stays will be decreased. It would also be a good idea to measure Peter’s fasting insulin and glucose on the day of admission, to demonstrate to him that he does indeed have the ‘metabolic syndrome’. This also gives Peter another visual marker by which he can measure his success. At time of discharge, Peter was normotensive and normoglycaemic. His discharge medications were Gliclazide MR 60mg daily, Metformin 1000mg bd, Amlodipine 10mg daily, Aspirin

150mg daily, Perindopril 10mg daily, and Pioglitazone. Peter was advised to use the Tony Ferguson meal replacement for two meals per day and comply with the program as administered by the pharmacists at Terry White Chemists. Four months later, Peter has lost 35kg in weight and is now off all his antidiabetic medication. Technically, he is no longer diabetic with an HbA1c of 5.4%. The reduction in weight has allowed him to exercise more, which has improved his cardiovascular fitness. Peter plans to continue on the program to get down to his CM target weight of 95kg.

Homocysteine B-Vitamins and Cardiovascular Disease from page 29







of increasing folic acid intakes. JAMA. 1995; 274: 1049-57. Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ. 2002; 325: 1202. Casas JP, Bautista LE, Smeeth L, Sharma P, Hingorani AD. Homocysteine and stroke: evidence on a causal link from Mendelian randomisation. Lancet. 2005; 365: 224-32. Homocysteine Studies Collaboration. Homocysteine and risk of ischaemic heart disease and stroke: a metaanalysis. JAMA. 2002; 288: 2015-22. Weiss N. Mechanisms of increased vascular oxidant stress in hyperhomocysteinemia and its impact on endothelial function. Curr Drug Metab. 2005; 6: 27-36. Collaboration HLT. Lowering blood

homocysteine with folic acid based supplements: meta-analysis of randomised trials. Homocysteine Lowering Trialists’ Collaboration. BMJ. 1998; 316: 894-8. 10. Lonn E, Yusuf S, Arnold MJ, et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med. 2006; 354: 1567-77. 11. Bonaa KH, Njolstad I, Ueland PM, et al. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med. 2006; 354: 1578-88. 12. Toole JF, Malinow MR, Chambless LE, et al. Lowering homocysteine in patients with ischaemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA. 2004; 291: 565-75.

13. Bazzano LA, Reynolds K, Holder KN, He J. Effect of folic acid supplementation on risk of cardiovascular diseases: a meta-analysis of randomized controlled trials. JAMA. 2006; 296: 2720-6. 14. The VITATOPS Trial Study Group. The VITATOPS (Vitamins to Prevent Stroke) Trial: rationale and design of an international, large, simple, randomised trial of homocysteine-lowering multivitamin therapy in patients with recent transient ischaemic attack or stroke. Cerebrovasc Dis. 2002; 13: 120-6. 15. B-Vitamin Treatment Trialists’ Collaboration. Homocysteine-lowering trials for prevention of cardiovascular events: A review of the design and power of the large randomized trials. CM Am Heart J. 2006; 151: 282-7.

August – October 2007 | Consult Magazine

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