Consult 006 2011 by Virtual Medical Centre

consult The Australian Medical Magazine for Specialists and GPs Autumn 2011

Thrombosis

Why you donâ&#x20AC;&#x2122;t clot, and why you do

Radical Perineal Prostatectomy Robot-free Minimally Invasive Surgery

Pain

Pain Management in Older Persons

Neurotoxin

Botulinum Toxin Use in Medical Disorders

Scleroderma

The Changing Face of Scleroderma

Treating Parkinsonâ&#x20AC;&#x2122;s Disease Update on Pharmacotherapy

Superannuation

Cutting Superannuation Administration in Practices

Your Photography photography

Visum Best Holiday Photograph Competition

Magazine

New #

Now available for patients who have difficulty swallowing tablets1

Convenient and easy to administer options

Oral administration in water

Oral administration in apple or orange juice

Oral administration in apple sauce

Administration via nasogastric (NG) tube

Administration via percutaneous endoscopic gastrostomy (PEG)

For 24-hour symptom control you can trust PBS Information: Restricted Benefit. Gastro-oesophageal reflux disease; initial treatment of peptic ulcer; Zollinger-Ellison syndrome; scleroderma oesophagus. #Available as Somac 40mg granules. §During 12 months, percentages of heartburn free days/nights were significantly higher with Somac 40mg/day than with

ranitidine 150mg bd (p<0.05).3 Before prescribing, please review Approved Product Information. Full PI available from Nycomed Pty Ltd, ABN 71 095 610 870, 2-4 Lyonpark Road, North Ryde NSW 2113. Phone 1800 675 957. Date Prepared: March 2009 MINIMUM PRODUCT INFORMATION SOMAC® (pantoprazole) TABLETS and GRANULES. INDICATIONS: Adults: Symptomatic improvement and healing of duodenal and gastric ulcers; gastro-oesophageal reflux disease (symptomatic GORD and reflux oesophagitis); gastrointestinal lesions refractory to H2 blockers; Zollinger-Ellison Syndrome; maintenance of healed reflux oesophagitis in moderate-severe reflux oesophagitis; eradication of H. pylori; prevention of gastroduodenal lesions and dyspeptic symptoms associated with NSAIDs in increased risk patients on continuous non-selective NSAID treatment. Children (5 to 17 years): gastro-oesophageal reflux disease (symptomatic GORD and reflux oesophagitis). Treatment duration should not exceed eight weeks. CONTRAINDICATIONS: Hypersensitivity to ingredients; Combination therapy: hypersensitivity to any antibiotics used for H. pylori eradication or in patients with moderate to severe hepatic or renal dysfunction; cirrhosis; severe liver disease; concomitant atazanavir. PRECAUTIONS: If gastric ulcer suspected or present, exclude malignancy; patients at risk of vitamin B12 deficiency; monitoring for long-term use; investigation if non-responsive symptomatic GORD; pregnancy; lactation; children less than 5 years; coumarin anticoagulants; i.v. famotidine; drugs with pH dependent bioavailability e.g. ketoconazole; atazanavir. SIDE EFFECTS: Common side effects: fatigue; asthenia; increased sweating; headache; diarrhoea; severe eructation; constipation or flatulence; upper abdominal pain; metallic taste; others, see full PI. DOSAGE & ADMINISTRATION: Adults: Monotherapy: 20-40mg once daily depending on indication (dosage may be increased for Zollinger-Ellison Syndrome or reflux oseophagitis) see full PI. Combination therapy: 40mg twice daily (initial dosage should be reduced in patients with milder forms of liver disease), see full PI. Children (5 to 17 years): Symptomatic reflux: 20mg per day for children over 5 years; Reflux oesophagitis: 20mg daily for children 19-35kg or 40mg daily for children over 35kg. Tablets and Granules should not be chewed or crushed. Swallow tablets whole with water. Granules should be taken with applesauce, apple juice, orange juice or water; or are for administration via nasogastric or gastric tube (see full PI for instructions). Price: 20mg (30): Restricted Benefit - PBS: dispensed price $22.37; 40mg (30): Restricted Benefit - PBS: dispensed price $39.14. References: 1. Somac Product Information, February 2009. 2. Richter JE et al. Am J Gastroenterol 2000; 95: 3071-3080. 3. Richter JE et al. Aliment Pharmacol Ther 2004; 20: 567-575. 4. Scholten T et al. Aliment Pharmacol Ther 2003; 18: 587-594. 5. Grass U et al. 10th United European Gastroenterology Week Congress, UEGW 2002, Geneva, 19-24 October. ®Registered Trademark 09/09 NYCSO0165

2-5§

medical director

elcome to the autumn edition of CONSULT Magazine! We have gone green with CONSULT this issue, becoming an online publication and improving convenience as so many of you prefer to access your magazines via mobile devices. The website, www.virtualmedicalcentre.com has a new easy to navigate design so it is easier to find specific medical information, videos and animations and also to view all the past editions of CONSULT Magazine online. Visum, the largest doctors-only passwordprotected social networking website in Australia, has gained a lot of momentum over the last few months. There are over 700 doctors as regular users – some of whom are quite accomplished photographers! See some of their works on pp. 28-29. In other news, we are currently seeking re-accreditation of our Continuing Medical Education program from the RACGP for the 2011-2013 triennium. The Category A Learning Activities (QI&CPD – 40 points) have been considerably enriched as a result of feedback from the more than 500 GPs who participated in the 2008-2010 program. We are also actively engaged in developing a continuing education program to meet the needs of all Australian health professionals now required to undertake a formal professional development program. Please email me (adean@ virtualmedicalcentre.com) if you would like to join our EAB, or offer feedback on Virtual Medical Centre and CONSULT Magazine.

Thank you for your support, both for our magazine and the www.virtualmedicalcentre. com website. Andrew Dean MBChB MRCP(UK) FRACP Medical Director Virtual Medical Centre

consult Magazine

RAdical Perineal PRostatectomy 4

Nerve Sparing RPP - Robot-free Minimally Invasive Surgery

Dr Alistair Cameron-Strange

Pain in the Elderly 8

Pain Management in Older Persons

Guy Bashford and Françoise Joseph

Neurotoxin

10 Botulinum Toxin Use in Medical Disorders Dr Karl Ng

Scleroderma

13 The Changing Face of Scleroderma

contents

greetings from the

Professor Leslie Schrieber and Dr Bethan Richards

Treating Parkinson’s disease 17 Update on the Pharmacotherapy of PD

Professor James A Temlett

Why you don’t clot, and Why you Do 21 The Vessel Wall in Thrombosis

Associate Professor Nick Wickham

SUPERANNUATION

25 Cutting Superannuation Administration in Practices

Hank Jongen

YOUR PHOTOGRAPHY

28 Visum Best Holiday Photograph Competition 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 • Associate Professor Rob Will • Dr Garry Wilson • Dr Steve Wilson • Dr Joe Kosterich (Medical Spokesperson)

Published by Virtual Medical Centre.com Pty Ltd MANAGING EDITOR: Elizabeth Tysoe (elizabeth@virtualmedicalcentre.com) SUB EDITOR: Jennifer Browne, Dr Michael Banazis CONTRIBUTION COORDINATOR: Sylvia Möllenbeck (sylvia@virtualmedicalcentre.com), Jen de Vos (jen@virtualmedicalcentre.com) ADVERTISING SALES: Aman Madan (aman@virtualmedicalcentre.com) LAYOUT DESIGNER: Sylvia Möllenbeck SUBSCRIPTIONS: www.virtualmedicalcentre.com/consultsubscribe.asp CIRCULATION: 10,000 copies Virtual Medical Centre PO Box 1173, Osborne Park, Western Australia, 6017 Ph: Perth (08) 9388 0344 Fax: (08) 9388 0611 Email: consult@virtualmedicalcentre.com Website: www.virtualmedicalcentre.com MEDICAL DIRECTOR: Dr Andrew Dean MANAGING DIRECTOR: Wayne Hughes GENERAL MANAGER: Thomas Maher 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 permisson of the editor. Offenders will be prosecuted. DISCLAIMER: Virtual Medical Centre.com Pty Ltd (‘the publishers’), and 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.

R a d i c a l P e r i n e a l P r o s tat e c to m y

RPP

Nerve Sparing Radical Perineal Prostatectomy â&#x20AC;&#x201C; robot-free minimally invasive surgery Dr Alistair Cameron-Strange

The RPP remains unsurpassed for cancer control, continence and erectile outcomes when compared to newer surgical techniques. In terms of postoperative pain and early discharge it is without equal. Dr Alistair Cameron-Strange MbChb, FRCSEd, FRACS (Urol); Consultant Urologist, The Prince of Wales and The Prince of Wales Private Hospitals, NSW; Editorial Advisory Board Member: Virtual Cancer Centre; acams@bigpond.com

irst described by Hugh Hampton Young in 1905, the radical perineal prostatectomy (RPP) is a timehonoured surgical procedure for treatment of carcinoma of the prostate.1 In response to patient demands for minimally invasive surgery with decreased pain, shorter hospitalisation, and earlier return to normal activities, there has been an increasing interest in this procedure. The proximity of the prostate to the perineum is the major advantage of the perineal approach, which provides optimal exposure for accurate removal of the prostate. Excellent nerve sparing2 can be performed through the perineal approach with similar oncologic outcomes. Continence results are comparable to those obtained through traditional transabdominal retropubic prostatectomy.3 In addition, RPP offers many benefits including minimal blood loss, a 1â&#x20AC;&#x201C;2 day hospitalisation, little postoperative pain and excellent surgical outcomes.

Figure 1: Position of the patient on the operating table using Yellowfin stirrups.

Figure 3: The neurovascular bundles are demonstrated running vertically left and right. The prostate is in situ deep in the wound with a green catheter within.

Figure 2: The perineal incision.

Figure 4: Completed anastamosis and bilateral nerve sparing (Image courtesy of Mike Harris in Michigan).

The neurovascular bundles are clearly seen and dissected off the surface of the prostate and swept laterally, after which the urethra, bladder neck, vasa, seminal vesicles and prostatic pedicles are divided to remove the gland. It should be noted that in all of the other radical prostatectomy techniques the dorsal venous complex must be divided, which can lead to serious bleeding. In the perineal

approach the dorsal venous complex is left undisturbed. As the urethra is superficial in this surgical approach, the anastomosis between the urethra and bladder neck can be performed both easily and accurately. Exposure for this step is unsurpassed when compared to open or laparoscopic prostatectomy. A urethral catheter is then placed at the end of the procedure, the

The procedure RPP is performed through an inverted U skin incision in the perineum between the scrotum and the anus, medial to the ischial tuberosities. After division of the conjoint tendon, the rectourethralis muscle, which attaches the rectum to the urethra, is carefully divided and the rectum reflected posterior to the prostate. This allows an extrasphincteric approach to the prostate so as not to disturb the external anal sphincter.

Autumn 2011 | Consult Magazine

Figure 5: The perineal wound has been closed with the drain in situ.

The operation can be performed in less than 2 hours. Postoperatively, patients require minimal analgesia. The patient may commence free fluids and a light diet the evening of the procedure.

Results The three most important outcomes that the urologist is aiming for in prostate cancer surgery are:

1. 2. 3.

Removal of the prostate with clear surgical margins; Preservation of continence; and Preservation of erectile function.

RPP is able to achieve similar outcomes to those of the retropubic approach. In one study 173 patients with clinically organconfined disease were treated with either radical perineal prostatectomy or radical retropubic prostatectomy. The authors found no difference in the incidence of invasion of cancer into the bladder, urethra or seminal vesicles, or penetration through the capsule of the prostate. The incidence of positive surgical margins was nearly identical in both patient populations, with 29% in the perineal group and 31% in the radical retropubic prostatectomy group. There was no difference in histopathological cancer control, progression or probability of survival. The authors concluded that radical perineal prostatectomy offers an excellent opportunity for cancer control.3 In a prospective study of 508 patients undergoing RPP by a single surgeon, there was an overall positive margin rate of 18%.4 The continence outcomes from this procedure are excellent. In a study involving 752 patients undergoing RPP, 95% of patients had pad-free continence at 12 months.5 Another study reported that 66â&#x20AC;&#x201C;84% of patients at 12 months had returned to baseline urinary function and bother scores.6 Postoperative pad-free rates with RPP have been shown to be 38% at 1 month, 53% at 2 months, 74% at 4 months,

Consult Magazine | Autumn 2011

85% at 6 months and 96% at one year.4 A validated patient self-assessment tool demonstrated that contemporary nervesparing RPP is efficacious in promoting the recovery of erectile function in appropriately selected patients, as well as possibly offering advantages with reduced recovery time to urinary continence.7 With regards to outcomes for potency, the nerve-sparing radical prostatectomy group had a 77% potency rate after more than one year post-operatively.3 This is similar to the outcomes in another study which reported erections sufficient for intercourse in 76% of preoperatively potent men treated with open radical prostatectomy with bilateral nerve-sparing surgery.8 In a study on quality of life outcomes between radical perineal and radical retropubic prostatectomy, the perineal approach showed better longitudinal profiles in the general and disease-specific quality of life outcomes during the first year after surgery.9 In men with an existing renal transplant, radical prostatectomy for localised prostate cancer is the best curative option. The perineal approach is optimal because it avoids the retropubic space, where surgery could potentially cause graft damage, or damage an area that might be needed in the future should a second transplant be required. RPP can also be used in morbidly obese patients with localised prostate cancer. The authors of one study found

that a radical perineal prostatectomy was feasible in 18 consecutive morbidly obese patients without intra-operative surgical or anaesthesia-related complications, or transfusion requirement. Favourable outcomes were obtained in all of these patients.10

Complications Bleeding Bleeding requiring transfusion is unusual in RPP as the dorsal vein complex is left undisturbed. For example, one study transfused 1% of 508 patients.4 Rectal injury It is most important that the patient has a thorough preoperative bowel preparation prior to this procedure, and indeed to all radical prostatectomy operations. Due to the proximity of the prostate to the rectum it is possible to inadvertently enter the rectum and, provided this is recognised, the perforation can easily be closed at the time of surgery. Closure of a rectal perforation should be performed in two layers and return to a full diet delayed for a further 24 hours. In a series of 752 patients undergoing RPP, the rectal injury rate was 0.006%.5 Neuropraxia With the patient in extreme lithotomy there is the possibility that lower extremity neuropraxia can occur, but with the use

Advantages of radical perineal prostatectomy 1. A small hidden incision which is relatively pain-free. 2. Minimal bleeding. 3. Early discharge from hospital at 12â&#x20AC;&#x201C;36 hours. 4. A very low transfusion rate. 5. A shorter operation therefore requiring a shorter anaesthetic. 6. Suitable for patients who have had a renal transplant or hernia repair using mesh. 7. Excellent visualisation of the prostatic apex. 8. Excellent visualisation of the neurovascular bundles facilitating a nervesparing procedure.

Disadvantages of radical perineal prostatectomy The only disadvantage to RPP is that if a pelvic lymphadenectomy is indicated, it will need to be performed through a small separate abdominal incision or laparoscopically.

R a d i c a l P e r i n e a l P r o s tat e c to m y

perineum closed with a soft rubber drain, and a nerve block performed.

R a d i c a l P e r i n e a l P r o s tat e c to m y

of the Yellowfin stirrups this now seldom occurs. Postoperative pain A nerve block is performed at the end of the operation and patients seldom need any analgesia stronger than paracetamol. Narcotic analgesia is sometimes required. Bladder spasm With the urethral catheter indwelling, bladder spasms can occur, and these are best treated with anticholinergics. Anal sphincter incontinence This is rare with Young’s approach to this procedure. One study did not demonstrate any difference in faecal incontinence rates

References 1. Young HH. The early diagnosis and radical cure of carcinoma of the prostate. Bull Johns Hopkins Hosp 1905;16:315-21. 2. Weiss JP, Schlecker BA, Wein AJ, Hanno PM. Preservation of periprostatic autonomic nerves during total perineal prostatectomy by intrafascial dissection. Urology. 1985; 26(2): 160-3. 3. Frazier HA, Robertson JE, Paulson DF. Radical prostatectomy: The pros and cons of the perineal versus retropubic approach. J Urol. 1992; 147(3 Pt 2): 888-90. 4. Harris MJ. Radical perineal prostatectomy: Cost efficient, outcome effective, minimally invasive prostate cancer management. Eur Urol. 2003; 44(3): 303-8. 5. Boustead G, Coetzee L. Radical perineal prostatectomy: A combined UK and South African series of 752 patients. Urology. 2006;

between the two groups of patients who had either a radical perineal prostatectomy or a radical retropubic prostatectomy.11 Urinary continence Continence outcomes are similar to those of open or laparoscopic prostatectomy. Urinary incontinence does improve after time, but 2–3% of patients will require additional surgery to cure incontinence. More recently, worse incontinence outcomes have been reported in men undergoing laparoscopic or robotic assisted laparoscopic radical prostatectomy.12 Who is suitable? Patients with a PSA of ≤ 10 and a Gleason score ≤ 7 are suitable for RPP. If the PSA is

68 Suppl 1: 143-4. 6. Young MD, Weizer AZ, Silverstein AD, Crisci A, Albala DM, Vieweg J, et al. Urinary continence and quality of life in the first year after radical perineal prostatectomy. J Urol. 2003; 170(6 Pt 1): 2374-8. 7. Wiygul JB, Harris MJ, Dahm P. Early patient self-assessed outcomes of nerve-sparing radical perineal prostatectomy. Urology. 2005; 66(3): 582-6. 8. Kundu SD, Roehl KA, Eggener SE, Antenor JA, Han M, Catalona WJ. Potency, continence and complications in 3,477 consecutive radical retropubic prostatectomies. J Urol. 2004; 172(6 Pt 1): 2227-31. 9. Shiroki R, Mori S, Miyakawa S, Kusak M, Hayakawa K, Ishikawa K, et al. SIU 2007 MP (18.20): Comparison of prospective and longitudinal assessment of health and disease related QOL between radical perineal and

> 10 and the Gleason score > 7, then an initial pelvic lymphadenectomy should be performed using a laparoscopic approach, or an approach through a small surgical incision. For patients with more aggressive disease, a retropubic prostatectomy with extended pelvic lymph node dissection should be considered.

Contraindications 1. Men with prostates > 100 cc may provide a technical challenge. These can best be treated with initial neoadjuvant hormone therapy to shrink the prostate prior to surgical removal by the transperineal route. 2. Patients with a history of colitis. CM

retropubic prostatectomy in men with localised prostate cancer. Presented at the 29th Congress of the Société Internationale d’Urologie (SIU). Paris, France: 5 September 2007. 10. Dahm P, Yang BK, Salmen CR, Moul JW, Gan TJ. Radical perineal prostatectomy for the treatment of localized prostate cancer in morbidly obese patients. J Urol. 2005; 174(1): 131-4.7. 11. Korman HJ, Mulholland TL, Huang R. Preservation of fecal continence and bowel function after radical perineal and retropubic prostatectomy: A questionnaire-based outcomes study. Prostate Cancer Prostatic Dis. 2004; 7(3): 249-52. 12. Hu JC, Gu X, Lipsitz SR, Barry MJ, D’Amico AV, Weinberg AC, et al. Comparative effectiveness of minimally invasive vs open radical prostatectomy. JAMA. 2009; 302(14): 1557-64.

Autumn 2011 | Consult Magazine

THREE LINES OF VISION GAINED

3-5

TO HIM, IT’S THE WORLD

*Based on ANCHOR and MARINA trials, at least one third of patients treated with Lucentis gained 3 lines of vision

The vision loss caused by neovascular AMD is devastating and extremely distressing to patients.1,2 Lucentis is proven to help patients gain and sustain vision.3-5 In fact, over 30% of Lucentis treated patients gained vision at two years.3,5 For many patients looking at going blind, Lucentis does more than restore their vision. By allowing them to maintain independence,6 it restores their hope.

Please refer to the Product Information before prescribing. Product Information is available from Novartis Pharmaceuticals Australia Pty Limited or visit www.novartis.com.au. For further information please contact Medical Information & Communication on 1800 671 203. Indication: Treatment of neovascular (wet) age-related macular degeneration (AMD). 0.5 mg or 0.3 mg is recommended to be administered by intravitreal injection once a month. Dosage and administration: Recommended dose is 0.5 mg (0.05 mL) or 0.3 mg (0.03 mL) given monthly. Interval between doses should not be shorter than 1 month. Treatment might be reduced to one injection every 3 months after the first three injections but, compared to continued monthly doses, dosing every 3 months may lead to an approximate 5-letter (1-line) loss of visual acuity benefit, on average, over the following 9 months. Patients should be evaluated regularly. Must be administered by a qualified ophthalmologist using aseptic techniques. Broad-spectrum topical microbicide and anaesthetic should be administered prior to injection. Patient should self-administer antimicrobial drops four times daily for 3 days before and after each injection. Not recommended in children and adolescents. Contraindications: Hypersensitivity to product components, active or suspected ocular or periocular infections, active intraocular inflammation. Precautions: Intravitreal injections have been associated with endophthalmitis, intraocular inflammation, rhegmatogenous retinal detachment, retinal tear and iatrogenic traumatic cataract. Proper aseptic injection techniques must be used. Monitor patients during the week following injection to permit early treatment if an infection occurs. Intraocular pressure and perfusion of the optic nerve head must be monitored and managed appropriately. Safety and efficacy of administration to both eyes concurrently have not been studied. There is a potential risk of arterial thromboembolic events following intravitreal use of VEGF inhibitors. A numerically higher stroke rate was observed in patients treated with ranibizumab 0.5mg compared to ranibizumab 0.3mg or control, however, the differences were not statistically significant. Patients with known risk factors for stroke, including history of prior stroke or transient ischaemic attack, should be carefully evaluated by their physicians as to whether Lucentis treatment is appropriate and the benefit outweighs the potential risk. As with all therapeutic proteins, there is a potential for immunogenicity with Lucentis. Lucentis has not been studied in patients with concurrent eye conditions such as retinal detachment or macular hole. No formal interaction studies have been performed. Should not be used during pregnancy unless clearly needed; use of effective contraception recommended for women of childbearing potential; breastfeeding not recommended. Patients who experience temporary visual disturbances following treatment must not drive or use machines until these subside. Side effects: Very common: Intraocular inflammation, vitritis, vitreous detachment, retinal haemorrhage, visual disturbance, eye pain, vitreous floaters, conjunctival haemorrhage, eye irritation, foreign body sensation in eyes, lacrimation increased, blepharitis, dry eye, ocular hyperaemia, eye pruritus, intraocular pressure increased, nasopharyngitis, headache, arthralgia. Common: Retinal degeneration, retinal disorder, retinal detachment, retinal tear, detachment of the retinal pigment epithelium, retinal pigment epithelium tear, visual acuity reduced, vitreous haemorrhage, vitreous disorder, uveitis, iritis, iridocyclitis, cataract, cataract subcapsular, posterior capsule opacification, punctuate keratitis, corneal abrasion, anterior chamber flare, vision blurred, injection site haemorrhage, eye haemorrhage, conjunctivitis, conjunctivitis allergic, eye discharge, photopsia, photophobia, ocular discomfort, eyelid edema, eyelid pain, conjunctival hyperaemia, stroke, influenza, urinary tract infection*, anaemia, anxiety, cough, nausea, allergic reactions (rash, pruritus, urticaria, erythema). Uncommon: Blindness, endophthalmitis, hypopyon, hyphaema, keratopathy, iris adhesions, corneal deposits, corneal oedema, corneal striae, injection site pain, injection site irritation, abnormal sensation in eye, eyelid irritation. Rare but serious adverse reactions related to intravitreal injections include endophthalmitis, rhegmatogenous retinal detachment, retinal tear and iatrogenic traumatic cataract. Lucentis® solution for intravitreal injection 2.3 mg, PBS dispensed price $1976.36. (luc020610m.doc)

*Please note changes to Product Information in italics.

1. Brown MM, et al. Can J Ophthalmol. 2005;40:277-287. 2. Williams RA, et al. Arch Ophthalmol. 1998;116:514-520. 3. Rosenfeld PJ, et al. N Engl J Med. 2006;355:1419-1431. 4. LUCENTIS Approved Product Information. 5. Brown DM, et al. Ophthalmol. 2009;116:57-65. 6. Chang TS, et al. Arch Ophthalmol. 2007;125:1460-469. Novartis Pharmaceuticals Australia Pty Limited, ABN 18 004 244 160. 54 Waterloo Road, North Ryde NSW 2113. ® Novartis Pharmaceuticals Australia Pty Limited. LUC0251.

PBS Information: Authority Required. Refer to PBS Schedule for full Authority Required Information.

3-6

Pa i n i n t h e E l d e r ly

PAIN

Pain Management in Older Persons Guy Bashford

Pain in the elderly is frequently underdiagnosed and undertreated. A sensible approach to pain recognition and treatment in the frail elderly can have a large impact on quality of life. Françoise Joseph; MBBS BSc Senior Registrar in Rehabilitation Medicine, Port Kembla and Bulli Hospitals; Francoise.Joseph@sesiahs.health.nsw.gov.au Guy Bashford; MB BS Dip MSM FFPMANZCA FAFRM Director of the Illawarra Pain Management Service, Port Kembla Hospital; Clinical Associate Professor at the Graduate School of Medicine, University of Wollongong; Editorial Advisory Board Member: Virtual Pain Centre; Guy.Bashford@sesiahs.health.nsw.gov.au

hilst both acute and persistent pain are somewhat more common in the elderly compared to the young and middle aged, it is by no means an inevitable aspect of ageing. The prevalence of persistent pain has even been shown to decline in the old compared with the young.1 Nevertheless, the elderly tend to be underdiagnosed and undertreated for pain symptoms in our society. The elderly tend to be reluctant to report unrelieved pain. They may deny pain or use different terms such as ‘ache’ or ‘soreness’.2 Identification of pain tends to be associated with multiple barriers such as cognitive or communication impairments (dementia, dysphasia, dysarthria, hearing/vision loss) and social diversity (educational, cultural, language differences).3 Many elderly patients don’t actively seek pain relief,4 believing that there is little that can be done. Compared to younger patients, they may hold greater concerns regarding opioid use for analgesia.5 Carers may also share the elder’s nihilistic attitudes to pain relief. A proactive approach towards identification and treatment of pain as the ‘fifth vital sign’ is required in the elderly. In those whose cognition or communication is impaired, a collateral history from the patient’s general practitioner, carers and

relatives may also provide an insight into possible causes of pain which are not always obvious to the patient. In those with very poor communication skills, the possibility of undertreated pain may be inferred through facial expression (frown, grimacing, distorted expression), verbalisation (moaning, groaning, grunting, verbal abuse), body movements (tense, fidgeting, gait/mobility changes, restricted

Françoise Joseph

movements), changes in interpersonal interactions or routines as well as mental state changes (crying, confusion, distress).3 Pain assessment should be flexible with the clinician being able to ‘think outside the box’. A thorough pain and general medical history as well as physical examination are the keys to identifying the type and cause of pain. A thorough psychosocial functional drug and alcohol history as

Key management tips •

Chronic pain is not universal in older populations.

•

Pain in the elderly is treatable.

•

Identification of pain in the cognitively impaired elderly requires recognition of the broad range of pain behaviours.

•

Non-pharmacological interventions may hold safety advantages over pharmacological approaches.

•

Beware of polypharmacy and the possibility of creating new problems for the patient.

•

Always ensure that the patient is reviewed in a timely fashion after management has started.

Autumn 2011 | Consult Magazine

Side effects

Nonsteroidal anti-inflammatory agents (NSAIDs)

• • •

GI bleeding, ulceration or perforation Oedema, hypertension and cardiac failure Decreased urea excretion

Opioids

• • • •

Constipation, nausea Bronchospasm, respiratory depression Sedation, confusion Tolerance, abstinence symptoms

Tricyclic antidepressants

• • • •

Anticholinergic effects (dry mouth, constipation, urinary retention) Arrhythmias Sedation, confusion Serotonin syndrome

Antiepileptics (pregabalin, gabapentin)

• •

Sedation, dizziness Oedema, weight gain

Pa i n i n t h e E l d e r ly

Medication

Table 1: Common analgesics and adverse effects

well as medication review will also aid in assessment.2 Assessment of pain should include an evaluation of psychiatric comorbidity, as both depression and anxiety are commonly associated with chronic pain.6 The use of assessment tools such as the Resident’s Verbal Brief Pain Inventory (RVBPI) and Numeric Rating Scale (NRS) can be used in communicative patients. These tests have been shown to be reliable in older populations.7 In non-communicative patients, one should consider the Abbey Pain Scale, which was developed to measure pain in demented patients who cannot verbalise.3 Because of the increased incidence of pharmacological adverse events in the elderly, non-pharmacological management approaches are important. These approaches include exercise (deconditioning is particularly hazardous

References 1. Blyth FM, March LM, Brnabic AJ, et al. Chronic pain in Australia: A prevalence study. Pain. 2001; 89(2-3): 127-34. 2. Therapeutic Guidelines: Analgesic. Version 5. Melbourne: Therapeutic Guidelines Limited; 2007. 3. Goucke R, Scherer S, Katz B, et al. Australian Pain Society. Pain in Residential Aged Care Facilities: Management Strategies. North Sydney, NSW: Australian Pain Society;

Consult Magazine | Autumn 2011

in the aged), heat, cold, massage, transcutaneous electric nerve stimulation (TENS), relaxation techniques and use of modified equipment to reduce strain and disability.6 Psychological approaches to pain management are more usually applied to younger patients with persistent pain, but there is evidence that older patients can benefit as well.8 Identification and treatment of psychological co-morbidities, including sleep disturbance, depression and anxiety, may help as much as treating the pain itself. In alert elderly persons, simple cognitive behavioural approaches can be very helpful.3,8 The pharmacological management of pain in the elderly is complex, rarely following a simple algorithm due to co-morbidities, variability in response, compliance, side effects and medication interactions. ‘Starting low and going slow’ applies to the drug treatment of older

2005. 4. Sengstaken EA, King SA. The problem of pain and its detection among geriatric nursing home residents. J Am Geriatr Soc. 1993; 41(5): 541-4. 5. Weiner DK, Herr K. Comprehensive interdisciplinary assessment and treatment planning: An integrated overview. In: Weiner DK, Herr K, Rudy TE (eds). Persistent Pain in Older Adults: An Interdisciplinary Guide for Treatment. New York: Springer; 2002:

people with pain.2 The clinician should try to differentiate between nociceptive and neuropathic pain in a patient. The use of paracetamol and topical treatments may be first line choices for mild nociceptive pain in the elderly, although NSAIDs are associated with greater risk. In more severe forms of nociceptive pain, opioids may be used carefully. Where renal impairment is or may become an issue, the transdermal patch opioid preparations (buprenorphine and fentanyl) may be preferable to the oral controlled release opioids, which are renally excreted. Care should always be taken when introducing opioids to a naïve older patient or when swapping from one opioid to another. Even physicians experienced in managing older patients’ pain routinely refer to dose equivalence CM tables and monitor frequently.

18-57. 6. Monti DA, Kunkel EJS. Practical geriatrics: Management of chronic pain among elderly patients. Psychiatr Serv. 1998; 49(12): 1537-9. 7. Herr KA, Garand L. Assessment and measurement of pain in older adults. Clin Geriatr Med. 2001; 17(3): 457-78. 8. Kerns RD, Marcus KS, Otis J. Cognitivebehavioral approaches to pain management for older adults. Top Geriatr Rehabil. 2001; 16(3): 24-33.

N e u r otox i n

Neurotoxin

Botulinum toxin use in medical disorders Dr Karl Ng

It has been over 30 years since botulinum toxin was first used for the treatment of strabismus. This article highlights the increasing medical indications for this versatile neurotoxin, and its role in various neurological conditions. Dr Karl Ng, MBBS (Hons1) MRCP FRACP CCT Clinical Neurophysiology (UK); Senior Lecturer, Sydney Medical School, University of Sydney; Consultant Neurologist, Royal North Shore Hospital, St Leonards, Sydney; Sydney North Neurology and Neurophysiology; Editorial Advisory Board Member: Virtual Neuro Centre; kng@med.usyd.edu.au

n recent years, the use of botulinum toxin for medical (as well as cosmetic) purposes has grown immensely. It is a potent neurotoxin derived from the bacterium Clostridium botulinum. Botulism comes from the Latin word for sausage (‘botulus’), which was first used to describe ingestion poisoning. This purified neurotoxin, in minute amounts, can be very useful in a variety of disorders where there is muscle overactivity, hypersecretory states and certain pain disorders.1 The therapeutic use of this drug has been known for some time since its initial use in strabismus in the 1970s. The toxin exerts its effect via the inhibition of acetylcholine release at the presynaptic nerve terminal of the neuromuscular junction. This is achieved by first being internalised in the nerve terminal, and then catalysing proteolysis of SNAP-25, one of the SNARE proteins responsible for facilitating acetylcholine exocytosis. Muscular contraction is inhibited, and at other sites such as the salivary glands and skin, it stops parasympathetic and sympathetic cholinergic function.2,3 The toxin paralyses muscle in a dose dependent and reversible manner. The mechanism of action in states of muscle overcontraction appears self-explanatory, but it is becoming evident that in some disorders, there is a blockage of afferent signals from muscle because of chemodenervation, resulting in central neuromodulation.4 This adds to the body of evidence on the pathophysiology of certain dystonic conditions, where the beneficial effects of toxin are disproportionate to those expected from pure paralysis.5

Medical Indications • • • • • • • • • • •

Hemifacial spasm* Blepharospasm* Cervical dystonia/ Torticollis* Spasticity: Cerebral palsy and stroke-upper* and lower limb, other cerebral and spinal disorders (e.g. MS) Other focal dystonia (e.g. writer’s cramp, oromandibular dystonia) Tremor Strabismus Spasmodic dysphonia Hypersecretory disorders: Primary hyperhidrosis, hypersalivation (e.g. in Parkinson’s disease) Bladder: Detrusor-sphincter dyssynergy and detrusor instability Headache: Tension and migraine * PBS-subsidised indications

Hemifacial spasm and blepharospasm Hemifacial spasm is a unilateral involuntary spasm involving the muscles of the face. It is often caused by a loop of vessel near the brainstem, such as the anterior inferior cerebellar artery, contacting the facial nerve close to its exit. It begins in the upper face around the eye, occasionally narrowing the palpebral fissure, and can progress to involve the corner of the mouth with elevation or lateral pulling. The differential diagnosis includes facial tics and post-Bell’s palsy synkinesis. Initial injection is via several sites in the orbicularis oculi.6 Side effects include bruising, ptosis, diplopia, and epiphora.7,8 Blepharospasm is an inappropriate forced eye closure, often bilateral, and can be associated with extrapyramidal disorders.

Frequently beginning in the fifth to seventh decades of life, patients may complain of local eye discomfort and photophobia. Without therapy, some cases can become protracted and progressive. Rare cases are certified blind. Similar patterns of injections are used as for hemifacial spasm around the eye.

Cervical dystonia (spasmodic torticollis) In this condition, there is involuntary posturing of the head away from its normal central position. There may be a sustained posture, spasms, jerks, tremor, or a combination. Sufferers may seek help because of disability, social embarrassment or pain. It was not uncommon in the past for this condition to be regarded as a psychiatric disorder. There may be subtle sensory tricks (‘geste antagonistique’) such as placing a finger or a hand on the chin, which may

Autumn 2011 | Consult Magazine

Spasticity Spasticity is a velocity-dependent hyperreflexia caused by disease of the brain and spinal cord. There is hypertonia, and an increased resistance to passive muscle stretch and limb movement. The primary aim of botulinum toxin use in this setting is to maintain muscle length and allow the normal positioning of limbs to prevent secondary soft tissue changes.10 A multidisciplinary rehabilitation service is desirable, with access to physiotherapy and casting as necessary. It is important to define the treatment aims before commencing therapy. This may be as simple as facilitating adequate hygiene in certain parts of the limb and torso.

Other dystonias and tremor A range of other dystonias can be treated, including writer’s cramp, limb and truncal dystonia. An intimate knowledge of anatomy and the use of EMG guidance for injections are essential, especially in spasmodic dysphonia.11 Also known as laryngeal dystonia, spasmodic dysphonia is a condition in which there are involuntary spasms of laryngeal muscles,

References 1. Jankovic J. Botulinum toxin in movement disorders. Curr Opin Neurol 1994;7:358-66. 2. Bushara KO, Park DM, Jones JC, Schutta HS.Botulinum toxin--a possible new treatment for axillary hyperhidrosis. Clin Exp Dermatol. 1996 Jul;21(4):276-8. 3. Ellies M, Laskawi R, Götz W, Arglebe C, Tormählen G. Immunohistochemical and morphometric investigations of the influence of botulinum toxin on the submandibular gland of the rat. Eur Arch Otorhinolaryngol. 1999;256(3):148-52. 4. Priori A, Berardelli A, Mercuri B, Manfredi M. Physiological effects produced by botulinum toxin treatment of upper limb dystonia: Changes in reciprocal inhibition between forearm muscles. Brain 1995;118:801-7. 5. Ng K, Jones SJ. The “enhanced N35” somatosensory evoked potential: Its associations and potential utility in the clinical evaluation of

Consult Magazine | Autumn 2011

causing strangled or breathy breaks in connected speech. The average age of onset is 39 years12 and women typically make up 60-80% of the patient population.13 Clinical assessment is aided by flexible nasopharyngoscopy of the vocal folds. The differential diagnosis includes essential tremor and muscle tension dysphonia. Some tremors can be successfully treated with botulinum toxin, especially if there is a dystonic component.

Hypersecretory disorders Primary hyperhidrosis, especially of the axillary area, can be very troublesome for patients, affecting their quality of life. Multiple minute intradermal injections are placed for this condition.14 Drooling is common in adults with Parkinson’s disease and other extrapyramidal disorders, as well as in children with cerebral palsy. Injection of the glands with or without ultrasound guidance can be effective.

Bladder Toxin injection via cystoscopy can be used in difficult cases of detrusor-sphincter dyssynergy and detrusor instability.15

Headache: Tension and migraine There is an increasing practice of injecting botulinum toxin into muscles of the head and neck for these conditions. Although not in routine use, treatment success is certainly noted in select cases.16

dystonia and myoclonus. J Neurol 2007;254:4652. 6. Yoshimura DM, Aminoff MJ, Tami TA, Scott AB. Treatment of hemifacial spasm with botulinum toxin. Muscle Nerve 1992;15:1045-9. 7. Allergen Australia Pty Ltd. Product Information: Botox. 6 August 2009. 8. Ipsen Pty Ltd. Product Information: Dysport. 9 November 2005. 9. Comella CL, Buchman AS, Tanner CM, BrownToms NC, Goetz CG. Botulinum toxin injection for spasmodic torticollis: Increased magnitude of benefit with electromyographic assistance. Neurology 1992;42:878-82. 10. Snow BJ, Tsui JK, Bhatt MH, Varelas M, Hashimoto SA, Calne DB. Treatment of spasticity with botulinum toxin: A double-blind study. Ann Neurol 1990;28(4):512-5. 11. Whurr R, Lorch M, Fontana H, Brookes G, Lees A, Marsden CD. The use of botulinum toxin in the treatment of adductor spasmodic dysphonia.

Limitations and side effects

Botulinum toxin A is available in Australia in two forms: BotoxTM (Allergan) and DysportTM (Ipsen). Because of the unequal dose equivalence, interchangeably using the name ‘Botox’ with generic references should be discouraged. The main limitation of injection is the difficult nature of the procedure; accurate placement of the injections often requires specialised equipment and highly-skilled medical personnel. Re-injection is usually required at 3-4 monthly intervals. Aside from the local effects of excessive paralysis or diffusion to muscles not intended, minor local site reactions and flu-like symptoms may be experienced initially. Anaphylaxis is rare. The toxin can be immunogenic, especially with booster doses and young patients, resulting in reduced efficacy.17 As a Category B3 medication, its use is not recommended in pregnancy and lactation, as safety has not been established.

Declaration of interests Dr Ng has received educational grants and support for his supervised fellows from both Allergan and Ipsen pharmaceuticals. More information See www.virtualmedicalcentre.com/ Treatments.asp?sid=61 for referral form - Sydney North Neurology and CM Neurophysiology.

J Neurol Neurosurg Psychiatry 1993;56:526-30. 12. Blitzer A, Brin MF, Stewart CF. Botulinum toxin management of spasmodic dysphonia (laryngeal dystonia): a 12-year experience in more than 900 patients. Laryngoscope. 1998; 108: 1435–41. 13. National Spasmodic Dysphonia Association: Research Priorities in spasmodic dysphonia [online]. [cited Feb 2010]. Available from: URL: http://www.dysphonia.org/news.asp?id=222 14. Grunfeld A, Murray CA, Solish N. Botulinum toxin for hyperhidrosis: A review. Am J Clin Dermatol 2009;10(2):87-102. 15. Morrisroe SN, Chancellor MB. Botulinum toxin use in the lower urinary tract. ScientificWorldJournal 2007;7:808-17. 16. Silberstein SD, Mathew N, Saper J, Jenkins S. Botulinum toxin type A as a migraine preventive treatment. Headache 2000;40:445-50. 17. Jankovic J, Schwartz K. Response and immunoresistance to botulinum toxin injections. Neurology 1995;45:1743-6.

N e u r otox i n

temporarily alleviate symptoms. Commonly injected muscles are the splenius capitis and sternocleidomastoid muscles. Needle EMG guidance is sometimes recommended to assess activity and facilitate accurate placement.9 The most common adverse effects are dysphagia, neck weakness and local pain.7,8

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Scleroderma

(Systemic Sclerosis)

Professor Leslie Schrieber

Scleroderma has long been a neglected disorder. However, the development of new treatments has led to a major upsurge of interest in this condition. Professor Leslie Schrieber MBBS (Hons) MD FRACP; Associate Professor of Medicine, University of Sydney; Department of Rheumatology, Royal North Shore Hospital, NSW; Editorial Advisory Board Member: Virtual Rheumatology Centre; lschrieb@med.usyd.edu.au Dr Bethan Richards MBBS (Hons) MMed; Senior Rheumatology Registrar, Department of Rheumatology, Royal North Shore Hospital, NSW; brichard@med.usyd.edu.au

diagnosis of scleroderma (systemic sclerosis) traditionally conjures up an image of a patient with a rapidly progressive, frequently fatal disease for which no treatments are effective. However, with earlier diagnosis, recognition of the wide spectrum of this illness, the emergence of specialty clinics and more effective treatments, this view is now unduly pessimistic. The last two decades have witnessed significant breakthroughs in understanding the pathogenesis of this disease, leading to more targeted therapies. Although a more optimistic prognosis is warranted, challenges naturally remain. However, with the upsurge of interest in this condition by medical researchers and the pharmaceutical industry, the future looks brighter. This article addresses some new developments in the treatment of scleroderma and the changing prognosis of this condition.

Epidemiology The annual incidence of scleroderma is estimated to be 10â&#x20AC;&#x201C;20 cases per one million persons.1 This figure is probably an underestimation as scleroderma encompasses a wide spectrum of problems, ranging from limited cutaneous and oesophageal involvement, to widespread

Consult Magazine | Autumn 2011

Dr Bethan Richards

systemic disease resulting in diffuse fibrosis and major internal organ failure.

Clinical features The most common subsets of scleroderma are limited cutaneous (60%), where skin thickening is restricted to areas distal to the elbows and knees; and diffuse cutaneous (40%), which affects the proximal limbs and/or trunk. The term CREST (Calcinosis, Raynaudâ&#x20AC;&#x2122;s, Esophagus, Sclerodactyly and Telangiectasia) associated with limited scleroderma is now outdated. This is because many patients do not fulfil all the criteria for this syndrome, and furthermore it is not discriminating as all these features also occur in diffuse disease.

Treatment Systemic treatment Multiple immunomodulatory and antifibrotic therapies have been trialled in scleroderma. Antifibrotic therapies such as low dose D-penicillamine2 showed promise in early trials. However a subsequent large randomised study comparing high with low dose D-penicillamine failed to demonstrate improvement in survival. This treatment has largely gone out of vogue. Combination cyclophosphamide and glucocorticoid therapy modestly improved pulmonary outcomes.3 Cyclosporine,4 methotrexate5 and mycophenolate mofetil6 have all

shown benefit in open studies. However, the significant side effects of these agents must be weighed against their potential therapeutic benefit. Better understanding of the pathogenesis of scleroderma has now also raised the possibility of targeted therapy. For example, a recent case study has shown promise with imatinib mesylate7 (a tyrosine kinase inhibitor usually used in the treatment of chronic myeloid leukaemia). The selective inhibition of tyrosine kinase interferes with the signalling of both platelet-derived growth factor (PDGF) and transforming growth factor (TGF)-beta, two mediators pivotal in the development of fibrosis. The use of combinations of anticytokine therapies, for example using agents directed against both TGF-beta and connective tissue growth factor (CTGF), are also being explored. Immunoablative therapy followed by autologous haematopoietic stem cell infusion remains experimental but has been used with some success in patients with severe scleroderma. However, mortality rates are significant, with a progression free five-year survival mortality of 64%.8 Several randomised trials of autologous stem cell transplantation are underway. Vascular Disease Raynaudâ&#x20AC;&#x2122;s phenomenon is the most common manifestation in scleroderma,

C h a n g i n g Fac e o f S c l e r o d e r m a

The Changing Face of Scleroderma

C h a n g i n g Fac e o f S c l e r o d e r m a

Mechanism of action

New developments

B cell depletion

•

Rituximab

Antifibrotic agents

• • • • •

Imatinib, dasatinib, nilotinib IVIg Antitransforming growth factor-b1 antibody (TGF β1) CTGF inhibitor Histone deacetylase inhibitors (Trichostatin A)

Immune system “reset”

•

Autologous stem cell transplantation

Raynaud’s phenomenon, digital ischaemia and ulcers

Non-selective endothelin receptor antagonist

•

Bosentan

Scleroderma renal crisis

Angiotensin II inhibition

•

Angiotensin II inhibitors

Pulmonary hypertension

Non-selective endothelin receptor antagonist

•

Bosentan

Selective type A endothelin-1 receptor antagonists

• •

Ambrisentan (US) Sitaxentan (Australia/Europe)

Immunosuppression

•

Mycophenolate mofetil

Immune system “reset”

•

Autologous stem cell transplantation

Systemic therapy

Interstitial lung disease

Table 1: New developments in scleroderma

and when associated with scleroderma, can lead to digital ischaemia, ulceration and gangrene. Raynaud’s can effectively be managed by avoiding triggers, keeping the whole body warm, using warm gloves and the cessation of smoking. For more refractory cases, calcium channel blockers9 (e.g. nifedipine), topical nitrates, angiotensin receptor blockers (losartan) and antiplatelet therapy may be useful.10 Raynaud’s complicated by digital ischaemia can be managed by the “off-label” intravenous use of the prostacyclin analogue iloprost.11 This treatment is expensive and requires special access scheme approval, and an admission to hospital for several days. Sympathectomy (cervical or localised digital), may be considered in severe cases but its role is not well established. Scleroderma renal crisis (SRC) Scleroderma renal crisis (SRC) occurs in 10% of patients with diffuse cutaneous disease. Prior to the introduction of angiotensin converting enzyme inhibitors (ACEIs), this was the most common fatal complication of scleroderma. Patients usually develop SRC within the first three years of their disease. Risk factors include rapidly progressive disease, corticosteroid dose > 15 mg/day, and the antiRNA-polymerase antibody. Patients develop sudden onset of hypertension, often followed

by oliguric renal failure, proteinuria, microangiopathic anaemia and microscopic haematuria. Early recognition and aggressive introduction of ACEIs to reverse the hypertension are critical to preserving renal function. Since their introduction, mortality has fallen appreciably (from 85% at 1 year, to 24% at 1 year in a single centre).12 Home monitoring of blood pressure and early review of elevated pressures facilitate early detection and improve management. A persistent increase of 20 mmHg systolic blood pressure or a 10 mmHg rise in diastolic blood pressure should trigger further evaluation. Pulmonary manifestations Scleroderma lung complications include interstitial lung disease (ILD) and

Figure 1: Chest X-ray showing changes of interstitial lung disease

pulmonary hypertension (PHT). ILD occurs in approximately 40–50% of patients with diffuse scleroderma and 30% of patients with limited scleroderma. The clinical course varies from mild and asymptomatic to severely debilitating. High resolution CT scans and pulmonary function tests (including diffusing capacity) are the investigations of choice. With the recent development of effective treatment for fibrosing alveolitis, modest preservation of lung function (FVC) and improved health-related outcomes (skin thickening, quality of life, dyspnoea and function) may be achieved if instigated early.13,14 Significant B cell infiltration has been demonstrated within pulmonary lesions and suggests that B cell depletion therapies (rituximab) are an appealing avenue of

Figure 2: High resolution CT scan image showing interstital lung disease in a patient with scleroderma.

Autumn 2011 | Consult Magazine

References

1. Silman AJ, Hochberg MC, Cooper C, Croft P, Raspe H, Rigby A. Epidemiology of the Rheumatic Diseases. Oxford, UK: Oxford University Press; 1993: 192. 2. Clements PJ, Furst DE, Wong WK, Mayes M, White B, Wigley F, et al. High-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis: Analysis of a two-year, double-blind, randomized, controlled clinical trial. Arthritis Rheum. 1999; 42(6): 1194-203. 3. Valentini G, Paone C, La Montagna G, Chiarolanza I, Menegozzo M, Colutta E, et al. Low-dose intravenous cyclophosphamide in systemic sclerosis: An open prospective efficacy study in patients with early diffuse disease. Scand J Rheumatol. 2006; 35(1): 35-8. 4. Clements PJ, Lachenbruch PA, Sterz M, Danovitch G, Hawkins R, Ippoliti A, et al. Cyclosporine in systemic sclerosis. Results of a forty-eight-week open safety study in ten patients. Arthritis Rheum. 1993; 36(1): 75-83. 5. van den Hoogen FH, Boerbooms AM, Swaak AJ, Rasker JJ, van Lier HJ, van de Putte LB. Comparison of methotrexate with placebo in the treatment of systemic sclerosis: A 24 week randomized doubleblind trial, followed by a 24 week observational trial. Br J Rheumatol. 1996; 35(4): 364-72.

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6. Stratton RJ, Wilson H, Black CM. Pilot study of anti-thymocyte globulin plus mycophenolate mofetil in recent-onset diffuse scleroderma. Rheumatology (Oxford). 2001; 40(1): 84-8. 7. van Daele PL, Dik WA, Thio HB, van Hal PT, van Laar JA, Hooijkaas H, et al. Is imatinib mesylate a promising drug in systemic sclerosis? Arthritis Rheum. 2008; 58(8): 2549-52. 8. Nash RA, McSweeney PA, Crofford LJ, Abidi M, Chen CS, Godwin JD, et al. High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for severe systemic sclerosis: Long-term follow-up of the US multicenter pilot study. Blood. 2007; 110(4): 1388-96. 9. Thompson SE, Shea B, Welch V, Fenlon D, Pope JE. Calcium-channel blockers for Raynaudâ&#x20AC;&#x2122;s phenomenon in systemic sclerosis. Arthritis Rheum. 2001; 44(8): 1841-7. 10. Dziadzio M, Denton CP, Smith R, Howell K, Blann A, Bowers E, et al. Losartan therapy for Raynaud phenomenon and scleroderma: Clinical and biochemical findings in a fifteen-week, randomized, parallel-group, controlled trial. Arthritis Rheum. 1999; 42(12): 2646-55. 11. Pope J, Fenlon D, Thompson A, Shea B, Furst D, Wells G, et al. Iloprost and cisaprost for Raynaudâ&#x20AC;&#x2122;s phenomenon in

in short term studies. Trials adding this to endothelin receptor antagonist treatment are currently underway. Gastrointestinal manifestations Gastro-oesophageal reflux disease (GORD) and dysphagia are almost universal in patients with scleroderma, although the majority of patients are asymptomatic. Proton pump inhibitors are the mainstay of treatment. Promotility agents (metoclopramide, domperidone) may be useful in patients with intestinal dysmotility, and antibiotics/probiotics may be used to treat malabsorption secondary to bacterial overgrowth.

Changing prognosis The future is looking brighter for patients with scleroderma. New developments have significantly improved the morbidity and mortality associated with complications such as renal crisis, interstitial lung disease and pulmonary hypertension. Multidisciplinary clinics specialising in the treatment of this multisystem disease are leading to earlier detection of complications and therefore prompt instigation of treatment. Intense research and the development of drugs targeted at specific pathways are already underway and we eagerly await the results CM of these new, promising agents.

progressive systemic sclerosis. Cochrane Database Syst Rev. 2000; (2): CD000953. 12. Steen VD, Costantino JP, Shapiro AP, Medsger TA Jr. Outcome of renal crisis in systemic sclerosis: Relation to availability of angiotensin converting enzyme (ACE) inhibitors. Ann Intern Med. 1990; 113(5): 352-7. 13. Tashkin DP, Elashoff R, Clements PJ, Goldin J, Roth MD, Furst DE, et al. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med. 2006; 354(25): 2655-66. 14. Khanna D, Yan X, Tashkin DP, Furst DE, Elashoff R, Roth MD, et al. Impact of oral cyclophosphamide on health-related quality of life in patients with active scleroderma lung disease: Results from the scleroderma lung study. Arthritis Rheum. 2007; 56(5): 1676-84. 15. Rosas V, Conte JV, Yang SC, Gaine SP, Borja M, Wigley FM, et al. Lung transplantation and systemic sclerosis. Ann Transplant. 2000; 5(3): 38-43. 16. Denton CP, Humbert M, Rubin L, Black CM. Bosentan treatment for pulmonary arterial hypertension related to connective tissue disease: A subgroup analysis of the pivotal clinical trials and their open-label extensions. Ann Rheum Dis. 2006; 65(10): 1336-40.

C h a n g i n g Fac e o f S c l e r o d e r m a

investigation for scleroderma lung disease. These are now being investigated. Lung transplantation is an option for patients with severe ILD that is not responsive to pharmacologic interventions and when carefully selected (no cutaneous ulcers, recurrent episodes of aspiration,

renal failure, or left ventricular dysfunction) have a four year survival of approximately 70%.15 Autologous haematopoietic stem cell transplantation, as discussed below, is another alternative treatment option in rapidly progressive lung disease. PHT (mean pulmonary artery pressure > 25 mmHg on right heart catheterisation) is more common in patients with limited scleroderma. This may be either due to a primary obliterative pulmonary arteriopathy or secondary to ILD. Dyspnoea on exertion is the earliest symptom, but occurs relatively late when the disorder is moderately advanced. Routine screening with lung function tests (particularly diffusing capacity) and echocardiography enable earlier detection, and now new treatments have significantly improved morbidity and mortality. Bosentan and, more recently, the selective type A endothelin-1 receptor antagonists ambrisentan (US) and sitaxsentan (Europe) have dramatically improved patient survival (1 year 68% to 86% and 2 year 47% to 73%).16 Sildenafil (Viagra, Revatio), a phosphodiesterase type 5 inhibitor, has also shown promise

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Pfizer Australia Pty Limited 38–42 Wharf Road, West Ryde NSW 2114

Professor James A Temlett

Parkinson’s disease requires drug therapy to modify progressive motor symptoms. Levodopa, the mainstay of therapy, has problems of long term motor fluctuations, and thus demands consideration of adjuvant pharmacotherapy. Ergot dopamine agonists have emerging limitations. Professor James A Temlett PhD FRACP FRCP; Clinical Associate Professor, Department of Neurology & University Department of Medicine, Royal Adelaide Hospital and University of Adelaide SA; james.temlett@adelaide.edu.au

arkinson’s disease (PD) is a common progressive neurodegenerative illness affecting 0.3% of the population, or 40,000 Australians.

independence over the next decade. Early dementia, postural reflex abnormalities or pseudobulbar presentations present diagnostic and management challenges.1

Diagnosis of PD

There has been an increasing awareness of non-motor features of PD. These include neuropsychiatric symptoms of depression (60%), dementia (50%), anxiety (49%), apathy (54%), visual hallucinations (44%), delirium (15–40%) and paranoid ideations. Autonomic dysfunction causes sialorrhoea, sweating, nocturia, constipation, postural hypotension, impotence and fatigue. Pain, sleep deprivation, dysphagia, dysarthria and frontal dysexecutive syndromes induce apathy, lethargy, personality changes and emotional withdrawal (see Table 2). Falls (30%) may be due to impaired balance or freezing (28%). Gait limitation and ignition failure (akinesia) are more common in PD patients who have no resting tremor, and rather present with a “rigid akinetic syndrome”.

PD is characterised by bradykinesia, resting asymmetrical limb tremor, and diffuse muscular rigidity with progressive postural reflex abnormalities affecting gait and balance. What we label “idiopathic”, or α-synuclein positive Lewy body PD, turns out to be incorrect in more than 25% of patients, at post-mortem. These Parkinson’s mimics may be called patients with “parkinsonism”. Conditions may include multiple system atrophy (either nigrostriatal Parkinsonism or cerebellar degeneration); tauopathies (Steele-Richardson-Olszewski syndrome, sometimes called PSP, or corticobasal degeneration); or other dementias affecting the frontal or temporal lobes or hippocampus. PD presents sporadically (less than 10% of all PD patients are familial) with an asymmetric resting tremor of the upper limbs, and always develops progressive bradykinesia. It will invariably respond to a trial of oral levodopa (at least 250 mg), often dramatically so. The diagnosis of PD remains clinical, since no reliable biomarkers or genetic tests are currently available. MRI scans may be useful in parkinsonism but rarely so in PD, which relentlessly progresses, from mild to severe incapacity, over 20 or more years. Loss of work capacity may occur in a decade,

Consult Magazine | Autumn 2011

Non-motor features of PD

Pharmacotherapy Since 1969, levodopa replacement has been shown to reliably improve the motor syndrome, but not the “non-dopaminergic” features of PD. All PD patients develop end of dose “wearing off ”, while freezing and “on-off ” motor fluctuations are encountered. In young onset PD (< 50 years), patients commonly develop “peak dose” or “biphasic” dyskinesias, affecting

10% of Parkinsonian patients overall per year. Ergot dopamine agonists (DAgs) emerged in the eighties, followed by non-ergot DAgs since 2006.2 All were shown to be effective in combination with levodopa. Unfortunately de novo use in PD is insufficient for long term therapy. Furthermore, it is complicated by endocardial hypersensitivity or behavioural and impulse disorders. Surgical procedures have re-emerged offering thalamotomy for tremors; globus pallidus pallidotomy (improving rigidity, bradykinesia and severe dyskinesias); and deep brain stimulation (DBS) targeting the internal globus pallidus or bilateral subthalamic nuclei. Emerging targets include the parapontine reticular formation (PPRF) for refractory gait and balance problems (which do not improve on pharmacotherapy). New basal ganglia stereo tactic targets continue to evolve. PD patients may experience 20–30 years on pharmacotherapy, hence a long term therapeutic strategy should be developed early. Various treatment algorithms have emerged. Critical issues include: • When to initiate treatment? • What initial drug choice or combination? • When to introduce adjuvant therapy? • What combination avoids motor fluctuations? • The place of complimentary surgical approaches?

T R EATING P A R K INSON ’ S DISEASE

Update on the Pharmacotherapy of Parkinson’s Disease

T R EATING P A R K INSON ’ S DISEASE

Drug Name

D2-3 receptor selectivity

D1 affinity

NA receptor cross selectivity

5HT-1 affinity

Peak Effect

Half Life (hrs)

Average daily dosage mg po (Range)

ERGOT DERIVATIVES Bromocriptine

Partial D1 antagonism

+/-

1-1.5

6-8

2015- (10-30)

Cabergoline

2.5

3 (2-6)

Dihydroergocryptine (DHEC)

Partial D1 agonist

12-16

Lisuride

+/-

2 (1-5)

Pergolide

D2>D3

1-2

2 (1-4)

NON-ERGOT DERIVITIVE DRUGS Apomorphine

D2=D3

0.2

0.5

4 (0.5-12)

Piribedil

D3>D2

+/- a2 antagonist)

200 (200-400)

Ropinirole

D3>D2

1.4

16 (8-24)

Rotigotine

D3>D2

5-71

8 (4-16)

Pramipexole

D3>D2

+/- (a2)

3 (1.5-6)

1-3

Table 1: Dopamine agonists in the treatment of Parkinson’s disease2

Levodopa Levodopa remains the most effective individual drug in PD management, specifically correcting all cardinal motor symptoms and improving quality of life. Levodopa with the decarboxylase inhibitor (DCI) benserazide (Madopar) or carbidopa (Sinemet) will, at some point, produce motor fluctuations. Motor fluctuations may be limited by using small levodopa dosages (less than 600 mg daily), introduced as late as possible in the course of disease progression. Dose limiting side effects such as nausea, emesis, hypotension and cognitive impairment may demand dose reduction or concomitant domperidone (Motilium). The Earlier versus Later Levodopa Therapy in Parkinson Disease (ELLDOPA) study examined different doses of levodopa in a double blind, placebo controlled trial in early Parkinson’s disease. This study showed that higher doses better improved PD motor deficit, but resulted in more motor fluctuations and dyskinesias. Sustained release formulations (Sinemet CR, and Madopar HBS) have a longer duration of levodopa motor benefit, but at the cost of delayed latency to onset. Catechol-O-methyl transferase (COMT) inhibitors entacapone and tolcapone are employed either to modify emerging dyskinesias or motor fluctuations. Combinations of levodopa with a DAg,

COMT inhibitor or MAO (monoamine oxidase) inhibitor hence aim to increase delivery of brain dopamine. What evidence is published that de novo use of DAgs are better than initial levodopa alone?

Dopamine agonists (DAgs) Ergot DAgs were introduced with bromocriptine (1971), lisuride (1975), pergolide (1978) and cabergoline (1980) (see Table 1).2 Ergot DAgs, initially introduced as an adjunct to levodopa, were eventually employed as monotherapy, with a tendency to increasingly use de novo therapy. DAgs alone will not prove sufficiently powerful to ameliorate motor symptoms, inevitably requiring levodopa introduction within a few years. Most patients will then note a rapidly improved motor state. Increasing the daily dopamine agonist dose as an alternative, not only proved insufficient for improving motor response, but also had the possibility of creating disorders of impulse control or endocardial fibrosis, or damaging the endocardium and

heart valves. Some countries have therefore withdrawn pergolide and cabergoline, stimulating a switch to “non-ergot dopamine agonists” such as ropinirole and pramipexole or rotigotine. An advantage of this strategy is an overall levodopa reduction of 20–30%. Other

Figure 1: Pharmacotherapy Aims: • • • •

Prevent disease progression Symptomatic motor control Prevention of motor fluctuations Control of non-motor features

Intervention Choices: •

• •

Drugs • Amantadine • Anticholinergics • Levodopa • MAO inhibitors • COMT inhibitors • Dopamine agonists (Table 1, ergot versus non-ergot subtypes) • Control of nausea, psychiatric, hypotension or GIT features. Surgery Physical and home improvement measures

Autumn 2011 | Consult Magazine

In combination, with COMTI or Dopa agonists

Dyskinesias

++++

DAg reduce incidence of peak dose dyskinesia

Wearing Off

+++

DAg reduce incidence of peak dose dyskinesia

Motor fluctuations

+++

DAg reduce incidence of peak dose dyskinesia

Freezing

+++

Common in advanced disease

Postural imbalance and falls

Common in advanced disease

Dopamine agonists

De Novo DAgs

Functional implication

Dopamine dysregulation syndrome

++++

T R EATING P A R K INSON ’ S DISEASE

Ne Novo levodopa

Levodopa

Comment

Demand for more and more medication

All ergot DAgs

Limb oedema

Ankle swelling, or rashes

Ergot DAgs

Somnolence

Driving

Pramipexole > Other non-ergot DAgs

Impulse control disorders

+++

Punding, collecting, hypersexuality, shopping or gambling

All ergot DAgs

Nausea

Rx with meals, or Motilium

Early, all, use Motilium

Postural hypotension

Falls in BP, wait for cerebral autoregulation

All

Neuropsychiatric

+++

Hallucinations, anxiety, panic attacks, psychosis, delusions

All

Fibrosis

Mediastinal, peritoneal or endocardial valve thickening, 5-HT sensitivity

All ergot DAgs, pergolide and cabergoline withdrawn due to rare endocardial fibrosis

Table 2: Complications of therapy in PD

routes of administration, via intraduodenal infusions, subcutaneous apomorphine rescue injections or agonist skin patches, may also smooth out dyskinesias and assist motor function, creating some recent exciting advances in PD management options.

Limitations of DAgs Initially nausea, vomiting, and dizzyness commonly improve. Postural hypotension; neuropsychiatric side effects, including hallucinations or psychosis; and worsening of levodopa dyskinesias may limit their usage (see Table 2). Ergots can produce Raynaud’s phenomenon, skin rashes, retroperitoneal or mediastinal fibrosis, weight gain, endocrine abnormalities or pedal oedema. Impulse control disorders may include pathological References 1. Langston JW. The Parkinson’s complex: Parkinsonism is just the tip of the iceberg. Ann Neurol. 2006; 59(4): 591-6.

Consult Magazine | Autumn 2011

punding, gambling, hypersexuality, shopping or eating disorders.3 Dopamine antagonists (antiemetics or antipsychotic agents) should be avoided in Parkinson’s disease. Unpredictable hypersomnolence may also limit driving ability. In the final analysis levodopa remains the “gold standard”, both with efficacy and tolerability, against which all drugs, including DAgs, are measured. Initial choice of therapy is affected by motor disability, functional status, age, comorbidities and presence of dementia or falls (see Figure 1). Accepting the risk of dyskinesias, many of which do not trouble PD patients, conventional levodopa (Sinemet or Madopar) de novo is one choice, but we retain a threshold for low dose levodopa, perhaps deferring levodopa 2. Lang A et al. Overview of dopamine agonists: MDS Taskforce. Movement Disorders Supplement 2002, 17 Suppl4; S52-155.

initiation by using amantadine or MAO inhibitors such as selegiline or rasagiline (never anticholinergics today) and possibly introducing medication as late as motor deficit allows. I reserve the introduction of non-ergot DAgs for younger patients, or where rapid progression of PD symptoms demands potentiation of levodopa therapy. Once dyskinesias are present, modified adjuvant therapy with COMT inhibitors or DAgs are introduced. DAgs are avoided when postural drops in BP occur, in early dementia or with existing myocardial disease. It would appear that the treatment pendulum has swung firmly back toward levodopa usage, considering the current best management CM of PD. 3. Antonini A, Tolosa E, Mizuno Y, Yamamoto M, Poewe WH. Review: A reassessment of risks and benefits of dopamine agonists in Parkinson’s disease. Lancet Neurol. 2009; 8(10): 929-37.

17% of male patients with type 2 diabetes may have overt low testosterone.1 Testosterone replacement therapy may reduce HbA1c levels, waist circumference and improve insulin resistance – this may help reduce type 2 diabetes patients’ cardiovascular risk profile.2,3 Blood tests may identify patients with low testosterone. For more information log on to www.bayermenshealth.com.au

Please review Full Product Information before prescribing. Full Product Information is available from Bayer Australia Ltd.

Testogel® (Minimum Product Information) Testogel is 1% testosterone gel. Indications: testosterone replacement therapy for male hypogonadism when testosterone deficiency has been confirmed by clinical features and biochemical tests. Dosage: 5 g of gel applied once daily about the same time preferably in the morning. Depending on clinical/laboratory response, the daily dose can be adjusted by 2.5 g steps to a maximum of 10 g of gel per day. Contraindications: Known or suspected prostate/ breast carcinoma, use in women/children, hypersensitivity to testosterone or any ingredient. Precautions: Regular prostate monitoring. Patients with severe cardiac/hepatic/renal insufficiency, ischaemic heart disease, hypertension, epilepsy, migraine, hypercalcaemia. Risk of sleep apnoea. Testosterone transfer to others via skin contact, check periodically for polycythemia. Pregnancy Category D. Adverse Effects: reaction at the application site, erythema, acne, dry skin, changes in laboratory tests, headache, prostatic disorders, gynaecomastia, mastodynia, dizziness, paraesthesia, amnesia, hyperaesthesia, mood disorders, hypertension, diarrhoea, alopecia. For other events refer to full PI. PBS dispensed price: Testogel: 5mg (30 sachets) $95.12. Reandron® 1000 (Minimum Product Information) REANDRON 1000mg/4mL, solution for injection: Testosterone Undecanoate. Indication: testosterone replacement in primary and secondary male hypogonadism. Dosage: 1 ampoule injected i.m. every 10-14 weeks into gluteal muscle. The first injection inte rval may be reduced to a minimum of 6 weeks to achieve steady-state testosterone levels more rapidly. Contraindications: Prostate/breast carcinoma, hypercalcaemia accompanying malignant tumours, hypersensitivity to testosterone undecanoate or the excipients, past or present liver tumours, use in women. Precautions: Inject strictly i.m. and very slowly to avoid pulmonary microembolism. Regular prostate and haemoglobin/ haematocrit monitoring. Patients with severe cardiac/hepatic/renal insufficiency, hypertension, epilepsy or migraine, bleeding or coagulation disorder. Risk of sleep apnoea. Adverse Effects: polycythaemia, diarrhoea, weight increased, leg pain, arthralgia, dizziness, increased sweating, headache, respiratory disorder, acne, pruritus, skin disorder, testicular pain, prostate disorder, breast pain, gynaecomastia, hot flush, injection site reactions including subcutaneous haematoma at the injection site. For other events refer to full PI. PBS dispensed price: Reandron 1000: 1000mg (1 ampoule) $147.41. References: 1. Kapoor D et al. Diabetes Care 2007; 30(4): 911-7. 2. Grossmann M et al. J Clin Endrinol Metab 2008; 93(5): 1834-40. 3. Kapoor D et al. Eur J Endocrinol 2006; 154(6): 899-906. Bayer Australia Ltd. ABN 22 000 138 714, 875 Pacific Highway, Pymble NSW 2073. ® Registered Trademark of Bayer AG, Germany L.AU.GM.01.2011.0074. BAAN4176. 02/11.

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

Thrombosis

Associate Professor Nick Wickham

The ability of blood to clot is vital when one is injured, but can be lifethreatening if it occurs inappropriately. The vessel wall, and in particular the endothelium, plays a vital regulatory role in the clotting process. Associate Professor Nick Wickham MA MB BChir FRACP FRCPA; Consultant Haematologist, Adelaide Cancer Centre; Editorial Advisory Board Member, Virtual Blood Centre; endothelium@yahoo.com

here is a central paradox relating to blood, in that it is required to remain fluid to perform its function, but, equally importantly, it is required to become solid in the event of vessel wall injury to prevent life-threatening haemorrhage. The ‘natural experiment’ of haemophilia bears witness to the central importance of coagulation in maintaining vascular integrity. When removed from the body, even when placed in a theoretically ‘optimal container’, the natural tendency of blood is to coagulate. Inside the body, however, the endothelium plays a critical role in vascular homeostasis by maintaining an anticoagulant profile. 1 But, when activated, whether by trauma, inflammation, sepsis, drugs or changes to normal blood flow, this anticoagulant function may be lost. 2 Thus, the final

Consult Magazine | Autumn 2011

arbiter of whether coagulation occurs in the body is the blood vessel wall and, in particular, the endothelium.

Anticoagulant properties of the endothelium

The endothelium is an active metabolic tissue which provides an anticoagulant layer over highly thrombogenic connective tissue. Its anticoagulant properties depend on features relating to surface structural elements in its cell wall, the expression of a variety of molecules (both pro- and anti-coagulant) on its surface, and the local and systemic release of molecules both luminally into the circulation, and abluminally to the neighbouring intercellular space and, in particular, to smooth muscle cells that control vascular tone.3,4 The importance of the interaction between the vessel wall, the constituents of the blood, and the nature of blood

flow in predisposing to thrombosis was recognised by Virchow in his classic paper published over 150 years ago. Research has since revealed some of the details underlying his original and prescient insights.5

Vessel wall 1) Endothelial cell wall structure Heparan sulphated proteoglycan molecules, known as heparans, include the naturally-occurring anticoagulant heparin, and are found on most mammalian cells. Heparans are capable of interacting with and regulating the function of a variety of molecules, including growth factors, cytokines, lipoproteins, superoxide dismutase and antithrombin III (ATIII). The anticoagulant nature of heparans and heparin depends on this ATIII binding, which is mediated by a pentasaccharide sequence that not only binds to, but also activates, the ATIII. This ATIII/heparan binding and activation has several consequences. Firstly, it localises antithrombin activity to the vasculature, allowing coagulation to continue unhindered outside a blood vessel. Secondly, the conformational change increases the binding affinity for the coagulation proteases such as thrombin and, in particular, factor Xa. Thirdly, the binding of the ATIII/heparan complex with coagulation factor proteases reverses the ATIII binding to heparan molecules, resulting in the release of an ATIII/protease complex into the circulation (where it will be metabolised in the liver), thus freeing

W HY YOU DON ’ T CLOT, AND W HY YOU DO

The Vessel Wall in Thrombosis

W HY YOU DON ’ T CLOT, AND W HY YOU DO

Risk factor

Estimated relative risk

Stasis and venous valves

Acquired conditions Major surgery / trauma (risk varies with extent)

5–200

History of venous thromboembolism

Age > 50 years

Age > 60 years

Lupus anticoagulant

Pregnancy

Major illness with hospitalisation

Oestrogens - oral contraceptive pill

- hormone replacement therapy

Oestrogen receptor modulators -…Tamoxifen

-…Raloxifene

Elevated anticardiolipin antibodies

Obesity

1–3

Inherited conditions ATIII deficiency

Protein C deficiency

Protein S deficiency

Factor V Leiden mutation - heterozygous

Factor V Leiden mutation - homozygous

Prothrombin gene mutation - h … eterozygous

2.5

Dysfibrinogenaemia

Hereditary, environmental or idiopathic conditions Hyperhomocysteinaemia

Elevated levels of factor VIII

Elevated levels of factor IX

2.3

Elevated levels of factors XI

2.2

Table 1: Risk factors for venous thromboembolism13,14,15

up the vessel wall heparans to repeat the process by binding and activating further uncomplexed ATIII.6 2) Surface expression of specific molecules Thrombomodulin, endothelial protein C receptor, P-selectin. Thrombomodulin is a transmembrane protein which, together with protein S, acts as a co-factor for the thrombin-catalysed activation of protein C. Activated protein C acts as an anticoagulant by inhibiting the activated clotting factors Va and VIIIa; it can also bind to and interfere with thrombin activity. Thrombomodulin is widely distributed on most but not all endothelial surfaces, and also lines the maternal sinuses of the syncytiotrophoblast. Its expression can be down-regulated by a variety of factors such as the inflammatory cytokines, interleukin-1, tumour necrosis factor, and endotoxin.7 Endothelial protein C receptor further augments protein C activation by the thrombin-thrombomodulin complex, and is involved in the response

Blood flow

to inflammation including sepsis and thrombosis.8 P-selectin is expressed on endothelial cell surfaces in hypoxia and inflammation, and attracts leukocytes and leukocyte microparticles expressing tissue factor (factor III), which activates the extrinsic coagulation pathway. This may partly explain why thrombosis can occur in veins secondary to stasis without obvious signs of vascular damage in those cases examined at autopsy.9 3) Release of procoagulant and anticoagulant molecules Endothelial activation and/or damage can result in modulation of the release of a variety of molecules including prostacycline, nitric oxide, tissue plasminogen activator and its inhibitors, and von Willebrand factor.10 Abluminal release of nitric oxide contributes to the control of microvascular blood flow. Luminal release has potential anticoagulant effects by decreasing platelet aggregation and reducing plasminogen activator inhibitor-1 (PAI-1) activity.11

The circulation involves changes in blood flow and pressure, ranging from relatively high pressure and high flow in the major systemic arteries, to extremely low pressure and low flow in the capillaries and post-capillary venules, to the highly variable low and high pressure (due to muscle contractions) of the larger veins. The vascular system is closed, and therefore venous return is of necessity dependent on the systemic arterial blood pressure and flow to drive it, but optimal venous return depends on muscular contraction, particularly in the lower limbs, and its system of one-way valves to prevent blood pooling in the lower extremities. Valves produce local turbulent flow, resulting in vascular micro-climates in venous valvular sinuses, which are more predisposed to thrombosis, due to the local changes in vascular endothelial function and the increased haematocrit found in these regions. The relative stasis due to inactivity further tips the balance, and it is no surprise that non-surgical deep venous thrombosis is found to arise in association with venous valves.9 Blood flow and atrial fibrillation Atrial fibrillation (AF) also involves a combination of stasis and turbulence which causes changes to endothelial cell function with increased P-selectin expression, increased von Willebrand factor release, evidence of increased fibrin turnover with increased D-dimer levels, an increase in platelet microparticles, and decreased nitric oxide release. Furthermore, patients with AF have higher levels of C-reactive protein and increased production of vascular endothelial growth factor, both of which are capable of causing increased expression of tissue factor in monocytes, which make up part of the inflammatory cellular component of plaques. Aortic plaques are found in over 50% of patients with AF, and complex aortic plaques, which are thicker and more likely to be associated with thrombosis, occur in 25% of patients with AF. Finally, the severity of AF, as measured by atrial size adjusted for body weight, correlates with the risk of thromboembolism.12

Risk factors and the prevention of VTE Endothelial cell dysfunction acts as the final common pathway for the common clinically recognised risk factors for venous thromboembolism (VTE) detailed in table 1 on the left. The (mostly) rarer inherited or congenital conditions contribute a further risk.

Autumn 2011 | Consult Magazine

W HY YOU DON ’ T CLOT, AND W HY YOU DO

Ageing is a major risk factor, with the annual incidence of VTE rising from 1 in 10,000 in young adults to 1 in 100 for those aged 60 years, and any illness will further add to this risk.13 As the hospital population is composed of mostly older patients, VTE is of particular concern in this setting. The routine use of appropriate prophylaxis in hospitals remains disappointingly low, despite the fact that it can result in a reduction of VTE associated with hospital admissions by up to 60%.16 To address this failure, the National Health and Medical Research Council References

1. Gimbrone MA Jr. Vascular endothelium: Nature’s blood container. In: Gimbrone MA Jr (ed). Vascular Endothelium in Haemostasis and Thrombosis. New York: Churchill Livingstone; 1986. pp 1-13. 2. Hunt BJ, Jurd KM. Endothelial cell activation: A central pathophysiological process. BMJ. 1998;316:1328-9. 3. Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987;327:524-6. 4. Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobyashi M, Mitsui Y, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332:411-5. 5. Virchow R. Phlogose ung Thrombose in Gefessystem. Gesammelte Abhandlungen zur Wissenschaftlichen Medicine. Frankfurt-am-Main: Meidinger Sohn and Company; 1856. 6. Jin L, Abrahams JP, Skinner R, Petitou M, Pike RN, Carrell RW. The anticoagulant

Consult Magazine | Autumn 2011

(NHMRC) undertook a systematic review of the literature and published an evidencebased guideline for VTE prophylaxis for patients in hospital. Since printing in December 2009, over 400 hard copies have been distributed and over 1,000 have been downloaded from the National Institute of Clinical Studies website.17 Since publication, new drugs such as the oral direct thrombin inhibitors (dabigatran) and factor Xa inhibitors, both direct (rivaroxaban) and indirect (fondaparinux), have become available (others are in development), and an updated guideline is activation of thrombin by heparin. Proc Natl Acad Sci USA. 1997;94:14683-8. 7. Maruyama I, Bell CE, Majerus PW. Thrombomodulin is found on endothelium of arteries, veins, capillaries, and lymphatics, and on syncytiotrophoblast of human placenta. J Cell Biol. 1985;101:36371. 8. Taylor FB Jr, Peer GT, Lockhart MS, Ferrell G, Esmon CT. Endothelial cell protein C receptor plays and important role in protein C activation in vivo. Blood. 2001;97:1685-8. 9. Esmon CT. Basic mechanisms and pathogenesis of venous thrombosis. Blood Rev. 2009;23:225-9. 10. Wu KK, Thiagarajan P. Role of endothelium in thrombosis and hemostasis. Annu Rev Med. 1996;47:315-31. 11. Freeman JE, Loscalzo J. Nitric oxide and its relationship to thrombotic disorders. J Thromb Haemost. 2003;1(6):1183-8. 12. Watson T, Shantsila E, Lip GY. Mechanisms of thrombogenesis in atrial fibrillation: Virchow’s triad revisited.

already being developed. In conclusion, when the endothelial anticoagulant function fails, replacement therapy with anticoagulant prophylaxis becomes essential. For up-to-date advice on how best to achieve this, the NHMRC clinical practice guideline can be highly recommended. It provides comprehensive but concise recommendations for most clinical situations, with references to the best available evidence, and as such, has brought clarity where before there was CM considerable confusion.

Lancet. 2009;373:155-66. 13. Bates SM, Ginsberg JS. Clinical practice: Treatment of deep-vein thrombosis. N Engl J Med. 2004;351(3):268-77. 14. Rosendaal FR. Venous thrombosis: A multicausal disease. Lancet. 1999;353:1167-73. 15. Kearon C. Epidemiology of venous thromboembolism. Semin Vasc Med. 2001;1:7-26. 16. Selby R, Geerts W. Prevention of venous thromboembolism: Consensus, controversies, and challenges. Hematology Am Soc Hematol Educ Program. 2009:28692. 17. National Health and Medical Research Council. Clinical practice guideline for the prevention of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in patients admitted to Australian hospitals. Melbourne: National Health and Medical Research Council; 2009. Cited Mar 26 2010. Available from URL: http://www.nhmrc.gov.au/nics/ programs/vtp/prevention.htm

“I got my life back.” Neurostimulation for the Management of Chronic Pain A cost-effective therapy helping many patients reduce their pain, increase their activity levels and improve their overall quality of life. sjmneuro.com

Indications for Use: Chronic, intractable pain of the trunk and limbs. Contraindications: Demand-type cardiac pacemakers, patients who are unable to operate the system or who fail to receive effective pain relief during trial stimulation. Warnings/Precautions: Diathermy therapy, cardioverter defibrillators, magnetic resonance imaging (MRI), explosive or flammable gases, theft detectors and metal screening devices, lead movement, operation of machinery and equipment, postural changes, pediatric use, pregnancy, and case damage. Patients who are poor surgical risks, with multiple illnesses, or with active general infections should not be implanted. Adverse Events: Painful stimulation, loss of pain relief, surgical risks (e.g., paralysis). Clinician’s manual must be reviewed prior to use for detailed disclosure. For more information please call St Jude Medical Neuromodulation Division, Australia Pty Ltd 61 2 9936 1200. ST. JUDE MEDICAL, the nine-squares symbol and MORE CONTROL. LESS RISK. are trademarks and service marks of St. Jude Medical, Inc. and its related companies. ©2011 St. Jude Medical, Inc. All rights reserved.

administration in practices Hank Jongen,

Human Services Portfolio General Manager (Human Services is the overarching department of Medicare, Centrelink and Child Support).

free government service is now available to help medical practices with fewer than 20 employees to meet their superannuation guarantee obligations and cut red tape. The Small Business Superannuation Clearing House is an optional service that reduces the time and paperwork involved in paying employee contributions to numerous funds. It simplifies the process to a single electronic payment and allows medical practices to discharge their superannuation guarantee obligations as soon as the payment is accepted by the clearing house. Practice managers using the clearing house report it saves up to half a day of paperwork a month, providing more time to support medical practitioners and patients. The introduction of Choice of Fund rules in 2005 means practices can be faced with having to make payments to multiple superannuation funds, each with their own set of rules for accepting contributions and accompanying information. The processes can be complicated for practices that pay contributions by a variety of methods, including cheque. For example, before signing up to the clearing house the Perth-based Woodlands Family General Practice made monthly contributions to 12 different funds. Practice Manager Laura Swithenbank said she used to have to dedicate an afternoon to mostly writing cheques. “It was very tedious and I didn’t look forward to it at all,” Ms Swithenbank said. “Now I just put the contribution amounts into the clearing house and it’s done.

Consult Magazine | Autumn 2011

SU P E R ANNUATION

Cutting superannuation

SU P E R ANNUATION

“In a busy practice it means I have extra time for more important jobs to support medical staff and patients.” About 38% of businesses use only cheques to meet superannuation commitments and 22% use a combination of cheques and electronic payments, according to a Colmar Brunton Social Research survey provided to the Australian Government’s Super System Review. Another consequence of dealing with many superannuation funds can be complicated rules and authorities required for making payments. Before registering for the clearing house, the NSW Central Coast-based Bay Village Medical Centre Practice used to seek authority for each separate payment through business management software. “It was very time consuming,” Practice Manager Debbie Smith said. “With the clearing house, it is much easier and more streamlined. You do it with one payment at no cost to us.” Like all small businesses, medical practices are obliged by law to make super payments at least four times a year, by the quarterly payment cut-off dates, including notifying a fund if an employee didn’t earn money. A Western Australian therapy provider, Sensory Connections, uses the clearing house to meet its legal obligations. “Once I have made the payment, the clearing house takes the legal responsibility of the employer to make it … that way I can always be sure I have met the legal requirements,” Director Michael Eyre said. Once a payment has been accepted by the clearing house, the medical practice has met their superannuation guarantee obligations. The medical practice makes one payment for all employees and the clearing house sends the nominated contributions to the correct superannuation funds – avoiding the need for the practice to deal with multiple funds. Eligible practices only need to register, receive a password and enter their employees’ details once to begin making payments. Once registered and set up, it takes a few minutes to make payments. Each time the service is used, only the contribution amount for each registered employee needs to be entered and an option is available to nominate a regular contribution amount. The clearing house stores employees’ details and keeps a record of their contributions to make it easy for practices to know how much has been paid. Previous employees’ details also continue to remain visible in the clearing house through a separate listing, providing

medical practices with the flexibility to reactivate employees if required. More than 99% of payments to the clearing house are processed within two business days. It has already been used to make over 26,000 employee payments with a value of over $13.5 million. The clearing house operates from a secure website administered by Medicare Australia. The Australian Government selected Medicare Australia to deliver the service because of its capacity in payment processing and ability to leverage its existing infrastructure and capabilities, whilst ensuring the privacy of information and the security of funds. Any information related to the clearing house is stored separately to health- and benefit-related data. Medicare Australia has a strong electronic payment processing system and currently processes more than 500 million services annually, with a total value of over $30 billion, through sophisticated systems which run 24 hours a day, seven days a week. Medicare Australia consulted extensively with the small business community and the

superannuation industry in the design of its clearing house system to ensure it reflects industry needs, as well as being userfriendly and intuitive for small businesses to use. Registering for the clearing house service is easy. Medical practices simply need to go to Medicare Australia’s website at www. medicareaustralia.gov.au/super and register their business details. A user ID and password will be sent to the address registered. Once the employer receives their user ID and password, they can logon to the clearing house to finalise their registration. Medicare Australia provides a range of quick reference guides and support to answer questions about using the clearing house. For more information, visit www. medicareaustralia.gov.au/super, call 1300 660 048 or email SBSCHenquiries@ medicareaustralia.gov.au For more information about superannuation guarantee obligations, see the “employers’ superannuation essentials” information on the Australian Taxation CM Office website at www.ato.gov.au

Autumn 2011 | Consult Magazine

Now approved for up to 13 weeks treatment2 When a hypnotic is indicated in patients over 55 with primary insomnia, prolonged-release melatonin should be tried ďŹ rst.3 Circadin delivers quality restorative sleep4,5,6 with no evidence of rebound insomnia, tolerance, dependence or withdrawal even after 6 months of treatment.2,4,5,6,7,8 Patients awake refreshed and ready to face the day.

PBS Information: This product is not listed on the PBS. Please review Product Information (PI) before prescribing. *Please note changes in the Product Information.

Full PI is available on request from Aspen Pharma Pty Ltd: 1300 656 755. Minimum Product Information for CircadinÂŽ (melatonin) Prolonged Release Tablets 2mg Indications: Monotherapy for the short term treatment* of primary insomnia characterized by poor quality of sleep in patients who are aged 55 or over. Contraindications: Hypersensitivity to any ingredient of Circadin. Precautions: May cause drowsiness. Should avoid engaging in hazardous activities such as driving or operating machinery although Circadin has negligible influence on these. Not recommended in patients <18 years old; with autoimmune diseases, hepatic impairment, or rare hereditary problems of galactose intolerance (Circadin contains lactose); breastfeeding and pregnancy (Category B3). Caution in the elderly (due to decreased metabolism) and patients with renal insufficiency. Interactions: Melatonin levels may be increased by: quinolones, fluvoxamine, 5- or 8- methoxypsoralen, cimetidine, oestrogens. Melatonin levels may be decreased by: carbamazepine, rifampicin, cigarette smoking. Circadin may cause increased effects of: hypnotics, thioridazine, imipramine. Circadin effects are reduced by alcohol. Melatonin may also interact with the following: adrenergic agonists/antagonists, opiate agonists/antagonists, antidepressants, prostaglandin inhibitors, benzodiazepines and tryptophan. Adverse Effects: Most common: Headache, *nasopharyngitis, back pain, and *arthralgia. For more information, please refer to full disclosure PI document. Dosage and Administration: The recommended dose is 2mg swallowed whole once daily, 1-2 hours before bedtime and after food. *This dosage may be continued for up to thirteen weeks. Based on Full PI dated 4 January 2011. References: 1. Zisapel N. Sleep and sleep disturbances: biological basis and clinical implications. Cell. Mol. Life Sci. 2007;64:1174-1186. 2. Circadin Australian Approved Product Information 4th January 2011. 3. Wilson SJ et al. British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders. Journal of Psychopharmacology 2010:24(11):1577-1600. 4. EPAR, Assessment report for Circadin. Procedure No.EMEA/H/C/695. 5. Wade A et al. Nightly treatment of primary insomnia with prolonged release melatonin for 6 months: a randomized placebo controlled trial on age and endogenous melatonin as predictors of efficacy and safety. BMC Medicine 2010;8:51. 6. Lemoine P et al. Prolonged-release melatonin improves sleep quality and morning alertness in insomnia patients aged 55 years and older and has no withdrawal effects. J Sleep Res. 2007;16:372-380. 7. Luthringer R et al. The effect of prolonged-release melatonin on sleep measures and psychomotor performance in elderly patients with insomnia. Int Clin Psychopharmacol 2009;24(5):239-249. 8. Wade AG et al. Prolonged release melatonin in the treatment of primary insomnia: evaluation of the age cut-off for short- and long-term response. Currrent Medical Research & Opinion 2011;27(1):87-98. Circadin is a registered trademark of Neurim Pharmaceuticals Limited used under licence by Aspen Pharma Pty Ltd. Aspen Pharma Pty Ltd 34-36 Chandos Street St Leonards NSW 2065. Email info@aspenspecialty.com.au Infoline 1300 656 755. www.aspenpharma.com.au AS/Circadin/Ad/2011 ETAL3554ORP

YOU R P HOTOG R A P HY

Visum Best Holiday Photograph Competition

isum is the largest passwordprotected social networking website in Australia for medical professionals only. You can discuss anything with your colleagues in a fast, dynamic and safe environment where only Australian GPs and specialists are welcome. Topics include medicine, practice management, clinical issues, leisure, finance, politics, education, news and media, and anything else that interests you. Visum was launched in November 2009 and currently has over 700 doctors using the website. The competition was run to find the best holiday photo taken by an Australian doctor. It was a fun and interactive way for Visum members to share their holiday and travel experiences with one another. Dr Richard Wardlaw, the winner of the Best Holiday Photograph competition,

won a Canon Powershot D10 underwater camera valued at over $599. The quality of all photographs submitted during the competition were of a very high standard. It was a very hard choice, but in the end the judges chose a stunning underwater photograph of two divers in the Coral Sea. The judges chose the winning image because they agreed “the photo captures the moment well, with its strong use of colour, line, shape and texture, and the use of complementary blue and orange colours.” They admired

Dr Wardlaw’s inclusion of nature, landscape and people in the one image whilst maintaining a simple, balanced composition. The low camera angle offers a unique perspective, and the coral leads the eye to the two silhouetted figures. Overall, it is a high impact image. The following images were awarded Highly Commended by the judges.

Diving the Coral Sea by Richard Wardlaw “This image was taken on Flinders Reef in the Coral Sea. I was on holiday on a live aboard dive boat out of Townsville. The diving there is absolutely spectacular.” “I took this picture using a Nikonas V camera with 20mm lens shooting 100ASA Ektachrome slide film at f22. I shot upwards towards the sun with a fill flash for the foreground coral. This allows a greater depth of field. This technique can produce very satisfying images with vivid foreground colours and sharp background silhouettes. It is very hard to do with digital, as shooting directly into the sun seems to play havoc with a digital camera sensors.”

Autumn 2011 | Consult Magazine

YOU R P HOTOG R A P HY

Polarbird by Dr Alex Burk “The image was taken on my trip to the Antarctic as ship’s doctor. My ship, the ‘MV Polarbird’ was an older style, but a very competent ice-strengthened cargo ship. The photo was taken beyond ‘60 South’, when we became stuck in ice for more than a month. Unlike older wooden ships, we were in no danger of being crushed, and hot meals were available regardless. We sat down on the ice drinking mulled wine watching these emperor penguins slowly come from nowhere (we were still hundreds of kilometres from land). The ice was thick enough to allow the scientists to do their ice coring, and I saw real krill come up with their ice samples. We also played a game of soccer on ice.”

Surya Temple (Sun Temple) by Dr Kamlesh Bhatt “This is a photo of Surya Temple (Sun Temple) in Gujrat state, on the western side of India. Here the temple is built in such a way that the first ray of the sun in the morning falls directly on the head of the deity of the temple where there used to be a diamond which would illuminate the whole room. I find this photo interesting as it captures the first flight of the pigeons in the morning, along with the fantastic art work on the temple.”

Traditional Theatre in China by Dr Judith Findlay “The photo was taken inside the theatre during the performance near ChengDu in SiChuan province in China. I was fortunate enough to position myself in the middle of the second row. I used my Nikon D40 with the 55-200mm lens attachment with flash. I used the ‘sport’ setting because the dancers were moving around quite a bit.”

Pondering by Dr Briana Van Beekhuizen “This photo was taken whilst I was visiting a Masai Village in Tanzania. Amidst the dancing and visiting Mzungu’s (Swahili meaning ‘white person’) this child captured my attention as she pondered life.”

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Consult Magazine | Autumn 2011

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