Michael Zandi – Advances and Challenges in Neuropsychiatric Systemic Lupus Erythematosus
Adam Cassidy – Pathophysiology of Idiopathic Focal Dystonia
Angharad V Walters – Developmental Delay - Causes and Investigations
INSIDE >
Prof Michael Bagshaw – Fitness to Fly
ACNRMJ10:Layout 1 23/4/10 05:24 Page 1
Azilect ® 1mg tabletsPrescribing information (Please refer to the Summary of Product Characteristics (SmPC) before prescribing) Presentation: Tablets containing 1mg rasagiline (as the mesilate). Indication: Treatment of idiopathic Parkinson’s disease as monotherapy or as adjunct to levodopa in patients with end of dose fluctuations. Dosage and administration: Oral, 1mg once daily taken with or without food and with or without levodopa. Elderly: No change in dosage required. Children and adolescents (<18 years): Not recommended. Patients with renal impairment: No change in dosage required. Patients with hepatic impairment: Predominant hepatic metabolism. Do not use in patients with severe impairment. Avoid use in patients with moderate impairment. Use with caution in patients with mild impairment and stop if progresses to moderate. Overdose: Symptoms reported following rasagiline overdose (3-100mg) included dysphoria, hypomania, hypertensive crisis and serotonin syndrome. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Do not use in patients with severe hepatic impairment. Co-administration of other monoamine oxidase (MAO) inhibitors is contraindicated due to risk of hypertensive crises. Concomitant pethidine treatment is contraindicated. Allow at least 14 days off rasagiline before using other MAO inhibitors or pethidine. Special warnings and precautions: Administer antidepressants with caution as serious adverse reactions have been reported with concomitant use of selective serotonin reuptake inhibitors (SSRIs), serotonin noradrenaline reuptake inhibitors (SNRIs), tricyclic and tetracyclic antidepressants, and MAO inhibitors. Cases of serotonin syndrome have been reported post-marketing
in patients treated concomitantly with antidepressants/SNRIs and rasagiline. Avoid concomitant use with fluoxetine or fluvoxamine. Leave at least five weeks between discontinuation of fluoxetine and initiation of treatment with rasagiline. Leave at least 14 days between discontinuation of rasagiline and initiation of treatment with fluoxetine or fluvoxamine. Administer potent CYP1A2 inhibitors with caution. Co-administration with dextromethorphan or sympathomimetics not recommended. Avoid use in patients with moderate hepatic impairment. Use caution in patients with mild hepatic impairment. Use with caution in pregnancy or lactation. There is an increased risk of skin cancer in Parkinson’s disease, not associated with any particular drug. Suspicious skin lesions require specialist evaluation. Cases of elevated blood pressure have been reported in the post-marketing period, including one report of hypertensive crisis associated with the ingestion of unknown amounts of tyramine. Undesirable effects in clinical trials: Monotherapy: >1%: headache, influenza, skin carcinoma, leucopenia, allergy, depression, hallucinations, conjunctivitis, vertigo, angina pectoris, rhinitis, flatulence, dermatitis, musculoskeletal pain, neck pain, arthritis, urinary urgency, fever, malaise. <1%: decreased appetite, cerebrovascular accident, myocardial infarction, vesiculobullous rash. Adjunct therapy: >1%: dyskinesia, decreased appetite, hallucinations, abnormal dreams, dystonia, carpal tunnel syndrome, balance disorder, orthostatic hypotension, abdominal pain, constipation, nausea and vomiting, dry mouth, rash, arthralgia, neck pain, decreased weight, fall. <1%: skin melanoma, confusion, cerebrovascular accident, angina pectoris. Please refer to the SmPC for the rates of adverse events. Basic NHS Price: Azilect® (tablets) 1mg x 28 £70.72 Legal category:
POM Marketing Authorisation Number: 1mg tablets (28 pack size) EU/1/04/304/003 Marketing Authorisation Holder: Teva Pharma GmbH, Kandelstr 10, D-79199 Kirchzarten Germany Date last revised: December 2009. Further information available from: Lundbeck Limited, Lundbeck House, Caldecotte Lake Business Park, Caldecotte, Milton Keynes, MK7 8LG
References:1. Olanow CW et al. N Engl J Med 2009;361:1268-78.2. Parkinson Study Group. Arch Neurol 2002;59:1937-1943.3. Horstink M et al. Eur J Neurol 2006;13:1170-1185.
Adverse events should be reported. Reporting forms and information can be found at
www.yellowcard.gov.uk. Adverse events should also be reported to Teva Pharmaceuticals Ltd on
telephone number: 01296 719768.
Make a lasting impression
Simple and effectivewhen it matters
By initiating early Azilect monotherapy, you can maintain your patients’ overall motor performance.1,2
So make a lasting impression – initiate Azilect monotherapy early in the course of Parkinson’s disease.3
Job No. 0210/AZL/501/053 Date of preparation: April 2010
ACNRMJ10:Layout 1 23/4/10 18:42 Page 2
ACNR > VOLUME 10 NUMBER 2 > MAY/JUNE 2010 > 3
AWA R D S A N D A P P O I N T M E N T S
Otto Bock Healthcare has received an award for‘Prosthetic or Orthotic Product Innovation’ from TheLimbless Association for E-MAG Active, a newlylaunched electronically controlled knee-joint system.
E-MAG Active enables patients with partial orcomplete paralysis as a result of stroke to achieve anatural, smoother gait pattern when walking. Users aretherefore able to maximise mobility and benefit fromimproved quality of life. For further information [email protected] or call 0845 430 1231. www.ottobock.co.uk
E-MAG Active – LimblessAssociation award Roger Barker is co-editor of ACNR, and is Honorary Consultant in
Neurology at The Cambridge Centre for Brain Repair. His main area ofresearch is into neurodegenerative and movement disorders, in particularparkinson's and Huntington's disease. He is also the university lecturer inNeurology at Cambridge where he continues to develop his clinical researchinto these diseases along with his basic research into brain repair using neu-ral transplants.
Editorial board and contributors
Professor Riccardo Soffietti, Italy: Chairman of the Neuro-Oncology Service, Dept ofNeuroscience and Oncology, University and S. Giovanni Battista Hospital.
Professor Klaus Berek, Austria: Head of the Neurological Department of the KH Kufstein.
Professor Hermann Stefan, Germany: Professor of Neurology /Epileptology in theDepartment of Neurology, University Erlangen-Nürnberg.
Professor Nils Erik Gilhus, Norway: Professor of Neurology at the University of Bergen andHaukeland University Hospital.
International editorial liaison committee
Peter Whitfield is ACNR’s Neurosurgery Editor. He is a ConsultantNeurosurgeon at the South West Neurosurgery Centre, Plymouth. His clini-cal interests are wide including neurovascular conditions, head injury,stereotactic radiosurgery, image guided tumour surgery and lumbarmicrodiscectomy. He is an examiner for the MRCS and is a member of theSAC in neurosurgery.
Alastair Wilkins is our Case Report Co-ordinator. He is Senior Lecturer inNeurology and Consultant Neurologist, University of Bristol. He trained inNeurology in Cambridge, Norwich and London. His research interests arethe basic science of axon degeneration and developing treatments for pro-gressive multiple sclerosis.
Andrew Larner is the editor of our Book Review Section. He is aConsultant Neurologist at the Walton Centre for Neurology andNeurosurgery in Liverpool, with a particular interest in dementia and cogni-tive disorders. He is also an Honorary Apothecaries' Lecturer in the Historyof Medicine at the University of Liverpool.
David J Burn is the editor of our Conference News Section and isProfessor in Movement Disorder Neurology & Honorary Consultant,Newcastle General Hospital. He runs Movement Disorders clinics inNewcastle-upon-Tyne. Research interests include progressive supranuclearpalsy and dementia with Lewy bodies. He is also involved in several drugsstudies for Parkinson's Disease.
Stephen Kirker is the editor of the Rehabilitation Section of ACNR andConsultant in Rehabilitation Medicine in Addenbrooke's NHS Trust,Cambridge. He trained in neurology in Dublin, London and Edinburghbefore moving to rehabilitation in Cambridge and Norwich. His mainresearch has been into postural responses after stroke. His particular inter-ests are in prosthetics, orthotics, gait training and neurorehabilitation.
Alasdair Coles is co-editor of ACNR. He is a University Lecturer inNeuroimmuniology at Cambridge University. He works on experimentalimmunological therapies in multiple sclerosis.
Heather Angus-Leppan is ACNR's ABN representative on the EditorialBoard. She is Head of the Neurology Department at Barnet Hospital andConsultant Neurologist, Honorary Senior Lecturer and Epilepsy Lead at theRoyal Free Hospital, London, UK. She is the Honorary Assistant Secretary ofthe Association of British Neurologists, Honorary Secretary of theNeurosciences Section of the Royal Society of Medicine and current Chairof the Map of Medicine Epilepsy Group, UK.
Mike Zandi is co-editor of ACNR. He is an Honorary Specialist Registrar inNeurology at Addenbrooke's Hospital, Cambridge and a Research Fellow atCambridge University. His research interest is in the immunological aspectsof neurological and psychiatric disease.
Professor John Duncan (Institute of Neurology, London) hasbeen appointed as a National Institute for Health Research(NIHR) Senior Investigator. Senior Investigators are NIHR’smost pre-eminent researchers and include some of thenation’s most outstanding leaders of patient and peoplebased health and social care research.
Prof John Duncan appointed as NIHRSenior Investigator
Professor Malcolm Grant, President and Provost of UCL said, “ This is a trulyexceptional achievement. Fyssen is a French Foundation that promotes scientificinquiry into the cognitive mechanisms, including thought and reasoning, whichunderlie animal and human behaviour; their biological and cultural bases, andphylogenetic and ontogenetic development. Its prize is awarded annually to ascientist who has conducted distinguished research in the areas supported by theFoundation such as ethology, paleontology, archaeology, anthropology, psychology,epistemology, logic and the neurosciences. The Foundation offers a range ofresearch grants and post-doc study grants, but only one prize."
'Brainwashed by the Black Stuff" will be delivered at the RoyalLondon Hospital on June 24th at 5pm. Professor Lees is analumnus of the Royal London and the lecture will beintroduced by Professor John Hardy.
Prof Chris Frith awarded 2009 FyssenInternational Prize
Prof Andrew Lees awarded the First LordBrain Memorial Lecture
Professor Gérard Said of Paris, France, President-elect of theENS, will assume office in a ceremony on Monday, 21 June2010, during the 20th Meeting of the ENS. The inaugurationas President will take place at the International Congress Center of Berlin prior tothe start of the Presidential Symposium of this Meeting. Professor Said succeedsProfessor José Ferro of Lisbon, Portugal, as President of the Society, and will occupythe office of President until the next Meeting of the European NeurologicalSociety convenes in Lisbon, Portugal, on 28-31 May 2011.
Inauguration of Prof GérardSaid as President of the ENS
Prof Matthew Wood at the University of Oxford has beenawarded a 12 month innovation grant of £35,000 fromParkinson’s UK, to develop a ready supply of the dopaminenerve cells needed for research into a cure. Producing nervecells from stem cells is complex and the current success rate islow. However, molecules called microRNAs can direct the waycells develop and one known as miR-124a specifically helpsdopamine cells. People with Parkinson’s typically have less miR-124a than others do. The team will investigate whether miR-124a will improve results. They’ll also search for othermicroRNAs that might push stem cells in the right direction.For more information see www.parkinsons.org.uk
Gaynor Norris, MarketingManager at Otto BockHealthcare, receiving the2009 Limbless Associationaward for ‘Prosthetic orOrthotic Product Innovation’for E-MAG Active.
New ways to produce dopamine cells forstudying Parkinson’s
ACNRMJ10:Layout 1 23/4/10 05:24 Page 3
ACNRPublished by Whitehouse Publishing, 1 The Lynch, Mere, Wiltshire, BA12 6DQ.Publisher. Rachael HansfordE. [email protected]
ADVERTISING Rachael HansfordT. 01747 860168 M. 07989 470278E. [email protected]
DESIGN & PRODUCTION DEPARTMENTE. [email protected] BYManson Group Ltd. Tel. 01727 848 440
Copyright: All rights reserved; no part of this publication maybe reproduced, stored in a retrieval system or transmitted inany form or by any means, electronic, mechanical, photo-copying, recording or otherwise without either the prior written permission of the publisher or a license permittingrestricted photocopying issued in the UK by the CopyrightLicensing Authority. Disclaimer: The publisher, the authors and editors accept noresponsibility for loss incurred by any person acting or refrain-ing from action as a result of material in or omitted from thismagazine. Any new methods and techniques describedinvolving drug usage should be followed only in conjunctionwith drug manufacturers' own published literature. This is anindependent publication - none of those contributing are inany way supported or remunerated by any of the companiesadvertising in it, unless otherwise clearly stated. Commentsexpressed in editorial are those of the author(s) and are notnecessarily endorsed by the editor, editorial board or publish-er. The editor's decision is final and no correspondence willbe entered into.
CONTENTSC O N T E N T S
03 Awards & Appointments
04 From the Editor...
Review Article08 Advances and Challenges in Neuropsychiatric Systemic Lupus
Erythematosus – Michael Zandi
Review Article14 Pathophysiology of Idiopathic Focal Dystonia – Adam Cassidy
Famous Neurologists20 David Marsden, 1938-1998 – Niall Quinn
Rehabilitation Article23 Fitness to Fly – Michael Bagshaw
Neurological Signs28 Critchley Revisited: Personification of a Neurologically Dysfunctional
Limb – Andrew Larner
Personal Perspectives29 Dancing Eye Syndrome – Mandy Caunter
Book Reviews30 Oxford Handbook of Clinical Rehabilitation31 The Confabulating Mind: How the brain creates reality
Confabulation: Views from neuroscience, psychiatry, psychology, and philosophy
Paediatric Neurology32 Developmental Delay – Causes and Investigation
– Angharad V Walters
ABNT35 Touting for Trade;Attracting Future Neurologists
– Rose Bosnell, Boyd Ghosh, Biba Stanton
Neurology Research Series36 Seeing the Wonder in Research – Dan Blackburn
37 The ABN Research Network and the Second Annual ABN Research Forum – Patrick Chinnery, Beth Mallam
37 New Opportunities for Clinical Research Training in Neurology – Patrick Chinnery
38 Route Finding for Tomorrow’s Neurologist – Alastair Compston
Cover Photograph: Francis Lees, and Nathan Doidge (seated) –student pilots. The British Disabled Flying Association are aregistered charity offering flight experiences and full flyingtraining to PPL/NPPL, for disabled people, together withaircraft hire for disabled BDFA members. www.aerobility.net
– Turn to page 23.
ACNRSSN 14 3-9 48 VOLUME 10 SSUE 2 MAY/ UNE 010
www acnr co uk
ADVANCES IN CLINICAL NEUROSCIENCE & REHABILITATION
NEWS REV EW > CON ERENCE R PORTS > BOOK REV EWS > JOURNAL REVI WS > EV NTS D ARY
In this issue
M chael Zandi Advances and Challenges in Neuropsychiatric Sys emic Lupus Erythematosus
Adam Cass dy Pathophysiology of Idiopa hic Focal Dys onia
Angharad V Walters Developmental Delay Causes and Investigations
INS DE >
Prof M chael Bagshaw Fitness o Fly
4 > ACNR > VOLUME 10 NUMBER 2 > MAY/JUNE 2010
ACNRMJ10:Layout 1 23/4/10 18:35 Page 4
You can’t put a price on the value of an efficient home delivery service. So we don’t.
For your patients with advanced Parkinson’s Disease
With the Momentum Service, apomorphine comes with Free expert backup,Free phone support, Free home delivery, Free state of the art pump and Freedom to do more for your Parkinson’s patients.
Ample reason for you to call Archimedeson 0118 931 5060 and add momentum to your therapy.
Information about adverse event reporting can be found at www.yellowcard.gov.uk Adverse events should also be reported to Archimedes Pharma UK Limited by e-mail to [email protected] or by telephone on 0118 931 5084.
ABBREVIATED PRESCRIBING INFORMATION.
Please refer to the full Summary of Product Characteristics before prescribing. Apomorphine 10mg/ml solution for injection: Each ml contains 10mg of apomorphine hydrochloride. Indication: The treatment of disabling motor fIuctuations (“on-off” phenomena) in patients with Parkinson’s disease which persist despite individually titrated treatment with levodopa (with a peripheral decarboxylase inhibitor) and/or other dopamine agonists. Dosage and Administration: Apomorphine 10mg/ml solution for injection is for subcutaneous use by either intermittent bolus injection or by continuous subcutaneous infusion. Initiation of therapy should be in a specialist clinic. The patient must be established on domperidone, usually 20mg three times daily for at least two days prior to initiation of therapy. Levodopa therapy, with or without dopamine agonists, should be optimised before starting apomorphine therapy. The optimal dosage of apomorphine varies between individuals but, once established, remains relatively constant. It is recommended that the total
daily dose of apomorphine should not exceed 100mg and individual bolus injections should not exceed 10mg. Continuous Infusion: Continuous infusions should start at a rate of 1mg of apomorphine (0.1ml) per hour. Rate increases should not exceed 0.5mg per hour per 4 hour period. Hourly infusion rates may range between 1mg and 4mg (0.1ml and 0.4ml), equivalent to 0.015 – 0.06mg/kg/hour. Infusions should run for waking hours only. Unless the patient is experiencing severe night-time problems, 24 hour infusions are not advised. Contraindications: Apomorphine 10mg/ml solution for injection is contraindicated for children and adolescents up to 18 years of age, in patients with respiratory depression, dementia, psychotic diseases or hepatic insufficiency. Intermittent apomorphine treatment is not suitable for patients who have an ‘on’ response to levodopa that is marred by severe dyskinesia or dystonia. Subcutaneous apomorphine should not be given to patients who are hypersensitive to apomorphine or other product constituents. Pregnancy and lactation: Caution should be exercised if prescribing apomorphine to pregnant women and women of childbearing age. Interactions: Neuroleptic medicinal products may have an antagonistic effect if used with apomorphine. There is a potential interaction between clozapine and apomorphine. Precautions: Apomorphine may produce hypotension, even under anti-emetic cover, so care should be exercised in patients with pre-existing cardiac disease, those taking vasoactive medications and those with pre-existing postural hypotension. Apomorphine 10mg/ml solution for injection contains sodium metabisulphite which may rarely cause severe allergic reactions
and bronchospasm. Haemolytic anaemia has been reported in patients treated with levodopa and apomorphine. Haematology tests should be undertaken at regular intervals as with levodopa, when given concomitantly with apomorphine. Neuropsychiatric disturbances may be exacerbated by apomorphine. Pathological gambling, increased libido and hypersexuality have been reported in patients treated with dopamine agonists for Parkinson’s disease, including apomorphine. Side Effects: Very common: Local induration, nodules and pruritis at subcutaneous injection/infusion sites. At high doses of apomorphine these may persist and produce areas of erythema, tenderness and induration. Panniculitis has been reported where a skin biopsy has been undertaken. Common: Nausea and vomiting, transient sedation at initiation of therapy and somnolence. Uncommon: Postural hypotension, dyskinesias during ‘on’ periods. Local and generalised rashes. Haemolytic anaemia and positive Coombs’ test. Breathing difficulties. Rare: Eosinophilia. Presentation and Basic NHS Cost: Apomorphine ampoules contain apomorphine hydrochloride 10mg/ml, as follows: 20mg in 2ml – basic NHS cost £34.16 per carton of 5 ampoules. 50mg in 5ml – basic NHS cost £59.95 per carton of 5 ampoules. Marketing Authorisation Number: Apomorphine 10mg/ml solution for injection: PL12406/0024. Legal Category: POM. Date of last revision: April 2009. For further information please contact: Archimedes Pharma UK Ltd, 250 South Oak Way, Green Park, Reading, Berkshire, RG2 6UG, UK. AP0054. Date of Preparation: January 2010.
0514 ACNR 210x297_v1 indd 1 01/02/2010 17 25
6 > ACNR > VOLUME 10 NUMBER 2 > MAY/JUNE 2010
The younger generation have provided the review articles for this issue of ACNR– Adam Cassidy from Newcastle writes about focal dystonia and Mike Zandi onthe neuropsychiatry of SLE.
In the first of the review articles, Mike Zandi explores the neuropsychiatric fea-tures of lupus and highlights the difficulty in knowing what this means in terms ofclinical features and the problems this creates for diagnosis and treatment. For any-one who has seen such patients this dilemma is a real one, and Mike offers helpfuladvice on how to approach this issue.
Adam Cassidy discusses the pathophysiology of idiopathic focal dystonia andexplores the basis of the sensorimotor cortical reorganisation of body parts thatseems to lie at the heart of this condition. This discussion also draws in the basalganglia which feed out into these cortical regions, and by so doing contribute to thedevelopment of this movement disorder. This article is a very interesting and stimu-lating account of idiopathic focal dystonia, as it attempts to knit the different strandsof evidence into a unifying pathophysiological model for this condition.
In the Rehabilitation article, Fitness to Fly by Michael Bagshaw takes us throughthe physics of flight in terms of partial pressures of oxygen, before going on to dis-cuss relevant issues relating to pilots, cabin crew and passengers. This clearly writ-ten account is very helpful, not just in better understanding what happens when oneflies oneself, but also helps in advising others, including patients with neurologicalproblems.
Andrew Larner introduces us to Trevor, a right hand with a functional movementdisorder. In this short article, Andrew describes the personification of neurologicallyaffected limbs which has its origins in the writings of Macdonald Critchley.
How do you investigate a child with developmental delay or an adult with a neu-rological problem in which this was a feature of their history? Angharad V Walterstells us how to approach this problem and the likely causes in the next article in theseries on Paediatric Neurology edited by Anna Maw.
One of the most successful recent series in ACNR has been the one edited byBoyd Ghosh on academic neurology and how one can engage with it at all levels ofmedical training. This series sadly comes to a conclusion in this issue, but ends instyle with a feast of very helpful articles by a range of authors including an overviewof academic neurology past, present and future by the current ABN President,Alastair Compston.
Continuing in this theme, one of the most outstanding clinical scientists inNeurology of the late 20th century was the late David Marsden – a man who pub-lished a paper on average every 12 days of his professional life! For those of us whowere fortunate enough to know him and be taught by him, he was inspirational andencyclopaedic in his knowledge, but to me his greatest attribute was his ability to lis-ten and learn from others regardless of “rank”, always striving to know and under-stand more about how the brain works in health and disease. We are therefore veryfortunate to have a personal account on David Marsden written by someone whospent many years working (and drinking) with him – Niall Quinn – and which is areal testament to an extraordinary man.
Not that many may know of the Dancing eyes syndrome, but this rare conditioncan strike early in life sometimes in the context of neuroblastomas. This devastatingcondition causes opsoclonus and myoclonus and results in significant disabilityincluding ataxia, behavioural and cognitive deficits. Mandy Caunter, in our PersonalPerspectives section, describes the journey she has made with her daughter EllieMarie who was to develop this condition in 2000 just after she was one-year-old. Thisis a moving account of the struggles of diagnosis and the long term consequencesthat such disorders cause within the developing CNS.
Finally, as the general election comes closer, Heather Angus-Leppan calls us to bemore active and get involved with the ABN so that we can all play our part and influ-ence what No10 does about neurology and our health service post May 6th.
Finally, we have our usual reviews, as well as a Supplement for the forthcoming
ENS meeting in Berlin in June. We hope you enjoy this new issue of the journal. l
PRESCRIBING INFORMATION (Please consult the Summary of Product Characteristics (SPC) before prescribing.) Vimpat® Lacosamide Active Ingredient: Tablets: lacosamide 50 mg, 100 mg, 150 mg and 200 mg. Syrup: lacosamide 15 mg/ml. Solution for infusion: lacosamide 10 mg/ml. Indication: Vimpat is indicated as adjunctive therapy in the treatment of partial-onset seizures with or without secondary generalisation in patients with epilepsy aged 16 years and older. Dosage and Administration: Adults and adolescents from 16 years: Recommended starting dose is 50 mg twice a day which should be increased to an initial therapeutic dose of 100 mg twice a day after 1 week. Maximum daily dose of 400 mg (in two 200 mg doses). For solution for infusion: Infused over a period of 15 to 60 minutes twice daily. Can be administered i.v. without further dilution. Elderly: No dose reduction necessary. Age associated decreased renal clearance with an increase in AUC levels should be considered. Paediatric patients: Not recommended. Patients with renal impairment: No dose adjustment necessary in mild and moderate renal impairment. Dose adjustment is recommended for patients with severe renal impairment and patients with end-stage renal disease (see SPC). Dose titration should be performed with caution. Patients with hepatic impairment: No dose adjustment needed in mild to moderate impairment. In accordance with current clinical practice, if Vimpat has to be discontinued, it is recommended this be done gradually (e.g. taper the daily dose by 200 mg/week). Contraindications, Warnings, etc: Contraindications: Hypersensitivity to lacosamide or to any of the excipients. Known second- or third-degree atrioventricular block.
In addition for tablets, hypersensitivity to peanuts or soya. Precautions: Lacosamide has been associated with dizziness. Use with caution in patients with known conduction problems, severe cardiac disease or in elderly. Excipients in the syrup may cause allergic reactions (possibly delayed), should not be taken by those with fructose intolerance and may be harmful to patients with phenylketonuria. Monitor patients for signs of suicidal ideation and behaviours. Advise patients and carers to seek medical advice should such signs emerge. Interactions: Prolongations in PR interval with lacosamide have been observed in clinical studies. Use with caution in patients treated with products associated with PR prolongation and those treated with class I antiarrhythmic drugs. Strong enzyme inducers such as rifampicin or St John’s Wort may moderately reduce the systemic exposure of lacosamide. No significant effect on plasma concentrations of carbamazepine and valproic acid. Lacosamide plasma concentrations were not affected by carbamazepine and valproic acid. No clinically relevant interaction with ethinylestradiol and levonorgestrel. No effect on pharmacokinetics of digoxin. Pregnancy and Lactation: Should not be used during pregnancy. For precautionary measures, breast feeding should be discontinued during treatment with lacosamide. Driving etc.: Patients are advised not to drive a car or operate other potentially hazardous machinery until they are familiar with the effects of Vimpat on their ability to perform such activities. Adverse Effects: Very common (≥10%): Dizziness, headache, diplopia, nausea. Common (between 1%-10%): Depression, balance disorder, abnormal coordination, memory impairment, cognitive disorder,
somnolence, tremor, nystagmus, blurred vision, vertigo, vomiting, constipation, flatulence, pruritus, gait disturbance, asthenia, fatigue, fall, skin laceration. Adverse reactions associated with PR prolongation may occur. Consult SPC in relation to other side effects. Pharmaceutical Precautions: Tablets: None. Syrup: Do not store above 30°C. Use within 4 weeks of first opening. Solution for infusion: Do not store above 25°C. Use immediately. Legal Category: POM Marketing Authorisation Number(s): 50 mg x 14 t ab s : EU/1/08/470/001 ; 100 mg x 14 t ab s : EU/1/08/470/004; 100 mg x 56 tabs: EU/1/08/470/005; 150 mg x 14 tabs: EU/1/08/470/007; 150 mg x 56 tabs: EU/1/08/470/008; 200 mg x 56 tabs: EU/1/08/470/011; Syrup (15 mg/ml) x 200 ml: EU/1/08/470/014; Solution for Infusion (10 mg/ml) x 20 ml: EU/1/08/470/016. NHS Cost: 50 mg x 14 tabs: £10.81; 100 mg x 14 tabs: £21.62; 100 mg x 56 tabs: £86.50; 150 mg x 14 tabs: £32.44; 150 mg x 56 tabs: £129.74; 200 mg x 56 tabs: £144.16; Syrup (15 mg/ml) x 200 ml: £38.61; Solution for Infusion (10 mg/ml) x 20 ml: £29.70. Marketing Authorisation Holder: UCB Pharma SA, Allée de la Recherche 60, B-1070 Bruxelles, Belgium. Further information is available from: UCB Pharma Ltd, 208 Bath Road, Slough, Berkshire, SL1 3WE. Tel: 01753 534655. Fax: 01753 536632. Email: [email protected] Date of Revision: 01/2010 (10VPE0010). Vimpat is a registered trademark References: 1. VIMPAT® Summary of Product Characteristics. 2. Beyreuther BK et al. CNS Drug Rev 2007; 13(1): 21–42. 3. UCB Data on fi le. Date of preparation: February 2010. 10VPE0024
It’s hard to live life to the full if part of you is alwaysexpecting the next seizure. VIMPAT® is an anti-epileptic drug with an innovative mode of action.1,2 In clinical trials, VIMPAT® has shown improved seizure controlwhen added to fi rst and second generation AEDs.3
Prescribe VIMPAT® when you want your patients to lookforward with the confi dence of additional seizure control.1,3
Life w
ith epilepsy can be much mor
e
than just a gap bet ween se
izure
s
Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk. Adverse events should also be reported to UCB Pharma Ltd.
For further information please visit www.vimpat.co.uk
P17128_A4_ACNR_C0_A1_AW indd 1 17/02/2010 16 54
8 > ACNR > VOLUME 10 NUMBER 2 > MAY/JUNE 2010
Systemic lupus erythematosus is a commonautoimmune disease (4.71 per 100,000 age-standardised incidence in the UK in the
1990s),1, 2 and many lupus patients have heteroge-neous neurological and psychiatric symptoms(collectively termed neuropsychiatric or NP‘events’; see table) at some point in their lives. Butis this neuropsychiatric lupus (NPSLE), and isNPSLE one, two or many diseases? Research crite-ria and attempts at classification of NPSLE havebeen overly inclusive, which has set back thefield.3 For example, in these criteria, headache isgenerally attributed to lupus and is the most com-mon manifestation, but careful analysis of pub-lished data shows no association betweenheadache and lupus.4 Underpinning the clinicalhetereogeneity is pathological heterogeneity. Ishall argue that it is useful to split the pathologyinto two groups. First, symptoms and signs due toantibody-mediated and inflammatory pathology,and second, collectively, the rest: cerebrovasculardisease, low mood, anxiety, migraine, or function-al symptoms (of course, this second group has anatural divide between vascular disease and theothers). The latter collective group is far moreprevalent, and the distinction between groupsimportant because of treatment implications.Cerebrovascular disease is arguably the mostimportant manifestation of NPSLE, but requiresconventional preventative therapy, and is not like-ly to respond to immunotherapy. In contrast, anti-bodies or inflammation may cause some forms ofmyelopathy, psychosis, seizures and epilepsy, andthus immunosuppression may work (althoughwith which drug is as yet unclear). Thus, we needmarkers to distinguish between these two groups,as such an aetiological classification is likely toprove more useful in diagnosis and therapy thana neuroanatomical one.
Recent modifications to the 1999 AmericanCollege of Rheumatology criteria for NPSLE havemoved the criteria forward in this regard (sum-marised in the table). In these modifications, laidout by the Systemic Lupus InternationalCollaborating Clinics (SLICC) group, neurologicalsymptoms and signs are attributed to or not tolupus on the basis of severity, exclusion of mimicsand temporal relation to lupus diagnosis (with-out acknowledgment of aetiology).5 8 This alreadycuts a 40% prevalence of NPSLE to 13% using themost stringent criteria in the largest prospectivestudy, but more needs to be done.8 In this brief
review I shall summarise the current understand-ing of the pathogenesis of NPSLE, progress in thesearch for markers of immunotherapy-responsiveforms, and the evidence base for therapy. The fig-ure below gives a timeline of selected clinicaland immunological advances.
PathogenesisLet us consider lupus generally and then NPSLE.Lupus, like multiple sclerosis, is a complex genet-ic trait. Genome wide association studies havestarted to add risk loci to multiple regions withinHLA, complement components and other genesalready known to confer risk.9 A current model isof multiple paths to lupus, with a general ‘compro-mise’ of innate and adaptive immunity.10 A criticalnumber of ‘hits’ may be required before diseasedevelops. There are defects in clearance of apop-totic cellular debris; activation of innate mecha-nisms which sense DNA and other nuclear mate-rial; and B and T cell over-activity.10 For CNS dis-ease, rare monogenic forms of lupus with strikingCNS associations may provide clues. Inheritedcomplement component C1q deficiency is rarebut associated with a severe CNS vasculitis, themechanism of which is uncertain.11 There aremany reports of antibodies in lupus sera bindingto neurons in vitro.12 The rare childhoodencephalopathy Aicardi-Goutières Syndrome isdue to mutations in the gene for DNA three primerepair exonuclease 1, TREX1, and is associatedwith high CSF levels of interferon-alpha (IFNα)and serological markers typical of lupus.13 This,together with the type 1 IFN peripheral blood sig-nature seen in active lupus,14 and a lupus-like cog-nitive syndrome seen in patients with Hepatitis Cor melanoma treated with IFNα,15 provides suffi-cient support for a study of the role of IFNα inCNS lupus. Antibodies and cytokines may there-fore have a role in the pathogenesis of someforms of NPSLE. See the figure for a summary ofanimal models which support this.
Pathological and serological studies show thatischaemia is the main pathology, but less com-mon antibody mediated mutations also exist. Theneuropathological studies from the 1970s and1980s paint a picture of vasculopathy, infection,and infarction - with vasculitis a rarity.16 21 Otherstudies, limited generally by the choice of controlgroup, suggest that subcortical, white matterlesions (see later) are linked to the cognitivedeficits of lupus, and associated with sustained
Advances and Challengesin NeuropsychiatricSystemic LupusErythematosus
Michael Zandiis co-editor of ACNR and is anHonorary Specialist Registrar inNeurology at Addenbrooke'sHospital, Cambridge and aResearch Fellow at CambridgeUniversity. His research interest isin the immunological aspects ofneurological and psychiatric disease.
Designed for concordanceOnce-a-day doseSimple evening doseEasy to swallow minitabletsHigh patient acceptabilityConcordance reduces seizure frequency
Adverse events should be reported. Reporting forms andinformation can be found at www.yellowcard.gov.uk. Adverseevents should also be reported to Beacon Tel: 01892-506958
EPISENTA (Prolonged-Release Sodium Valproate)ABBREVIATED PRESCRIBING INFORMATIONSee Full SmPC for Details. Episenta 150mg & 300mg capsules and Episenta 500mg & 1000mg sachets contain prolonged release sodium valproate minitablets. Indication: The treatment of all forms of epilepsy. Dose: Give in 1 - 2 single doses. Monotherapy: Adults: Start at 600mg daily increasing by 150-300mg at three day intervals to a max of 2500mg/day until control is achieved. Children over 20kg: Initial dosage - 300mg/day increasing to max. of 35 mg/kg bw/day until control is achieved. Children under 20kg: 20mg/kg bw/day; max 40mg/kg/day. Patients with renal insufficiency: May require decreased dose. Combined Therapy: Dosage adjustments may be required. Administration: Swallow without chewing the prolonged-release minitablets. Contraindications: Liver disease. Personal or family history of hepatic problems. Porphyria. Hypersensitivity to valproate. Precautions: Suicidal ideation reported. The onset of an acute illness is an indication of the early stages of hepatic failure and requires immediate withdrawal of the drug. Routinely measure liver function in those at risk. Discontinue if signs of liver damage occur or if serum amylase levels are elevated or if spontaneous bruising or bleeding occurs. Review patients who have issues with pancreatitis, renal insufficiency, SLE, hyperammonaemia, weight gain, diabetes or blood tests. Withdrawal of sodium valproate should be gradual. The indigestible cellulose shell of the prolonged-release granules, seen as white residue in the stools of the patient, is of no concern. Interactions, Pregnancy and Lactation: See full SPC. Undesirable Effects: See full SPC. Further information & MA Holder: Beacon Pharmaceuticals Ltd. 85 High St., TN1 1YG UK. Presentations & Prices: POM. Episenta 150mg capsule x 100 PL 18157/0021, Episenta 300mg capsule x 100 PL 18157/0022, Episenta 500mg sachet x 100 PL 18157/0023, Episenta 1000mg sachet x 100 PL 18157/0024 have the following NHS prices: £5.70, £10.90, £18.00 & £35.00 respectively. Date of text: July 2009. Advert prepared December 2009 Ref: ACNR091218
10 > ACNR > VOLUME 10 NUMBER 2 > MAY/JUNE 2010
and high titre cardiolipin antibodies (whichare not specific to CNS disease).22,23
Atherosclerosis is accelerated in lupus.24
Vascular damage may well account for manyneurological symptoms, especially in long-standing disease. But this is not the wholestory. It is now well-accepted that myastheniagravis,25 and some forms of longitudinallyextensive transverse myelitis (LETM) andrecurrent optic neuropathy (aquaporin-4 anti-body associated)26 are associated with lupus.For the latter, aquaporin-4 immunity mayexplain some cases of myelopathy in lupusand Sjögren’s. In a recent series, all six lupuspatients with LETM and both of the two withrecurrent optic neuritis possessed aquaporin-4antibodies.26 For common manifestations suchas seizures (42% of 41 patients in a recent ret-rospective series from southwestern Englandand south Wales, in which visual failure andmovement disorders were also prominent27),the pathology therefore may be ischaemicdamage in the majority, but in some the samephenotype may be due to pathogenic anti-body (see below).
Finding a marker of immunotherapy-responsive NPSLEAntibodies hold the most promise as markersof forms of NPSLE, as SLE is characterised bytheir abundance. The discovery of aquaporin-4immunity in lupus and Sjögren’s disease hasshed light on the nature of myelopathy inthese conditions, which has yet to happen forother forms of NPSLE because no antibodyhas been found. Meanwhile, the evidence thatantibodies to native forms of neuronal chan-nels can cause various forms of encephalitishas been reproduced by several groups (SeeVincent update, ACNR 10.1).28 Studies of neu-
ropil encephalitis and variants have shownthat cell surface antigens are the only oneslikely to be clinically meaningful,28 but inlupus the literature is full of intracellular tar-gets with soft associations. A couple of candi-dates have come close. Antibodies to riboso-mal protein subunits have been variablyreported in lupus psychosis, and one group
has reported a novel neuronal surface antigento which some of these antibodies cross-react,though this study has not been replicated.29
Some lupus ds-DNA antibodies have beenreported to cross react with a short peptidesequence, DWEYS, on the NR2a and NR2b sub-units of the NMDA receptor (long beforerecognition of NMDAR encephalitis30), but rou-
R E V I E W A RT I C L E
Figure: Timeline of selected clinical (top) and immunological (bottom) developments. Abbreviations. ACR, American College of Rheumatology. BAFF, B cell activating factor. BLISS-52 and -76, A Study of Belimumab in Subjects With Systemic Lupus Erythematosus (52 and 76 weekstudies). BLK, B lymphoid tyrosine kinase gene. CNS, central nervous system. EXPLORER, A Study to Evaluate the Efficacy and Safety of Rituximab in Patients With Severe Systemic LupusErythematosus. ITGAM, integrin alpha M. lpr, lymphoproliferation gene. LUNAR, A Study to Evaluate the Efficacy and Safety of Rituximab in Subjects With ISN/RPS Class III or IV LupusNephritis. MRL, murine lupus. NPSLE, neuropsychiatric lupus. NZB/NZW, New Zealand Black/New Zealand White. NZM88, New Zealand mixed strain 88. RCT, randomised controlled trial.STAT4, signal transducer and activator of transcription 4 gene. TNFAIP3, tumor necrosis factor alpha-induced protein 3 gene. TREX1, three prime repair exonuclease 1 gene. References are not given due to space limitiations.
Table. Evolving research classifications of neuropsychiatric lupus (NPSLE)
1. American College of Rheumatology (ACR) 1999case definitions of neuropsychiatric lupus: the ‘NPevents’.3
Central nervous systemAseptic meningitisCerebrovascular diseaseDemyelinating syndromeHeadache (including migraine and benign intracranial hypertension)Movement disorder (chorea)MyelopathySeizure disordersAcute confusional stateAnxiety disorderCognitive dysfunctionMood disorderPsychosis
‘exclusions’ and ‘associations’ for the above found here:http://www.rheumatology.org/publications/ar/1999/aprilappendix.asp (accessed 30 Mar 2010)
2. Systemic Lupus International Collaborating Clinics(SLICC) attribution models, 2007.6
strict model ‘A’1. use ACR ‘exclusions’ and ‘associations’2. exclude cases which fall out of an enrollment window up to six months prior to diagnosis of SLE andup to 15 months after diagnosis3. exclude “minor” neuropsychiatric events (Ainiala5):all headache, anxiety, ‘mild’ cognitive dysfunction (<3 domains), polyneuropathy unconfirmed by nerveconduction studies and electromyography.
modified model ‘B’As above, but a 10-year window prior to diagnosis ofSLE is allowed, and use of ACR ‘exclusions’ but not‘associations’.
3. Published SLICC results so far:
2008, antibody associations. For 214 events in 133 of412 patients (32.3%) (model A: 32/214, model B: 77/214),there was no strong association between NP events,however attributed, and anti-ribosomal P, DWEYS-NR2(see text), lupus anticoagulant(LAC), cardiolipin, and 2-glycoprotein I antibodies measuredat variable times after the NP event. However, a suggestive signal exists for ribosomal P and psychosis,and LAC and cerebrovascular disease.7
2010, outcome. For 843 events in 486 of 1206 (40%)patients (model A: 149/843, model B: 258/843), attributable events occur early and have a favourableoutcome compared to non-attributable events. A therapeutic window?8
ACNRMJ10:Layout 1 23/4/10 05:24 Page 10
Rebif® is available in multidose cartridges for use with the RebiSmart™ electronic autoinjector device
Up to 70% of RRMS patients treated with DMDs are non-adherent with therapy*3
RebiSmart™ is the only device in MS which allows adherence to be reviewed
Rebif®: established, effective treatment for people with relapsing–remitting multiple sclerosis (RRMS)1,2
Delivered through innovation to help address adherence
* Retrospective analysis of 1606 RRMS patients treated with interferon-ß-1a (44µg sc tiw or 30µg im qw) or interferon-ß-1b; adherence was de ned as a medication possession ratio of ≥85% over a period of 360 days.
DMD: disease-modifying drug. sc: subcutaneous. tiw: three times weekly. im: intramuscular. qw: once weekly.
REBIF® 8.8 MICROGRAMS AND 22 MICROGRAMS SOLUTION FOR INJECTION IN PRE-FILLED SYRINGEREBIF® 22 MICROGRAMS SOLUTION FOR INJECTION IN PRE-FILLED SYRINGEREBIF® 44 MICROGRAMS SOLUTION FOR INJECTION IN PRE-FILLED SYRINGEREBIF® 8.8 MICROGRAMS/0.1ML AND REBIF® 22 MICROGRAMS/0.25ML SOLUTION FOR INJECTION IN CARTRIDGEREBIF® 22 MICROGRAMS/0.5ML SOLUTION FOR INJECTION IN CARTRIDGEREBIF® 44 MICROGRAMS/0.5ML SOLUTION FOR INJECTION IN CARTRIDGE
Interferon beta-1a
Presentation Rebif 8.8μg and 22μg: Pre-filled glass syringe containing 8.8μg or 22μg of Interferon beta-1a in respectively 0.2 or 0.5ml. Rebif 22μg or 44μg: Pre-filled glass syringe containing 22μg or 44μg Interferon beta-1a in 0.5ml. Rebif 8.8μg/0.1ml and Rebif 22μg/0.25ml: Pre-filled glass cartridge containing 132μg of Interferon beta-1a in 1.5ml. Rebif 22μg/0.5ml or Rebif 44μg/0.5ml: Pre-filled glass cartridge containing 66μg or 132μg of Interferon beta-1a in 1.5ml. Indication Treatment of relapsing multiple sclerosis. Efficacy has not been demonstrated in patients with secondary progressive multiple sclerosis without ongoing relapse activity. Dosage and administration Initiate under supervision of a physician experienced in the treatment of multiple sclerosis. Administer by subcutaneous injection. Recommended dose: Weeks 1 and 2: 8.8μg three times per week (TIW); weeks 3 and 4: 22μg TIW; week 5 onwards: 44μg TIW (22μg TIW if patients cannot tolerate higher dose). Rebif solution for injection in cartridge is for multidose use and should only be used with the RebiSmart autoinjector device following adequate training of the patient and/or carer. Follow the instructions provided with the RebiSmart device. Limited published data suggest that the safety profile in adolescents aged 12–16 years receiving Rebif 22 TIW is similar to that in adults. Do not use in patients under 12 years of age. Prior to injection and for 24h afterwards, an antipyretic analgesic is advised to decrease flu-like symptoms. Evaluate patients at least every second year of the treatment period. Contraindications History of hypersensitivity to natural or recombinant interferon beta, or to any of the excipients; treatment initiation in pregnancy; current severe depression and/or suicidal ideation. Precautions Inform patients of most common adverse reactions. Use with caution in patients with previous or current depressive disorders and those with antecedents of suicidal ideation. Advise patients to report immediately any symptoms of depression and/or suicidal ideation. Closely monitor patients exhibiting depression and treat appropriately. Consider cessation of therapy. Administer with caution in patients with a history of seizures and those receiving anti-epileptics, particularly if epilepsy is not adequately controlled. Closely monitor patients with cardiac disease for worsening of their condition during initiation of therapy. Patients should use an aseptic injection technique and rotate injection sites to minimise risk of injection site necrosis. If breaks in skin occur, patients should consult their doctor before continuing injections. If multiple lesions occur, discontinue Rebif until healed. Use with caution in patients with history of significant liver disease, active liver disease, alcohol abuse or increased serum ALT. Monitor serum ALT prior to the start of therapy, at months 1, 3 and 6 and periodically thereafter. Stop treatment if icterus or symptoms of liver dysfunction appear. Treatment has potential to cause severe liver injury including acute hepatic failure. Full haematological monitoring is recommended at months 1, 3 and 6 and periodically thereafter. All monitoring should be more frequent when initiating Rebif 44μg. New or worsening thyroid abnormalities may occur. Thyroid function testing is recommended at baseline and if abnormal every 6–12 months. Use with caution in, and closely monitor patients with, severe renal and hepatic failure or severe myelosuppression. Serum neutralising antibodies may develop and are associated with reduced efficacy. If a patient responds poorly and has neutralising antibodies, reassess treatment. Use with caution in patients receiving medicines with a narrow therapeutic index cleared by cytochrome P450. Women of childbearing potential should use effective contraception. Limited data suggest a possible increased risk of spontaneous abortion. During lactation, either discontinue Rebif or nursing. If overdose occurs, hospitalise patient and give supportive treatment. Side effects In the case of severe or persistent undesirable effects, consider temporarily lowering or interrupting dose. Very common: flu-like symptoms, injection site inflammation/reaction, headache, asymptomatic transaminase increase, neutropenia, lymphopenia, leucopenia, thrombocytopenia, anaemia. Common: injection site pain, myalgia, arthralgia, fatigue, rigors, fever, pruritus, rash, erythematous/maculo-papular rash, diarrhoea, vomiting, nausea, depression, insomnia, severe elevations of transaminase. Serious side effects include: injection site necrosis, hepatitis with or without icterus, severe liver injury, anaphylactic reactions, angioedema, erythema multiforme, erythema multiforme-like skin reactions, seizures, thromboembolic events, thrombotic thrombocytopenic purpura/haemolytic uremic syndrome, suicide attempt, Stevens-Johnson syndrome, dyspnoea, retinal vascular disorders. Consult the Summary of Product Characteristics for more information relating to side effects. Legal category POM. Price Rebif 8.8μg and 22μg: 6 (0.2ml) + 6 (0.5ml) syringes – £552.19; Rebif 22μg: 12 syringes (0.5ml) – £624.77; Rebif 44μg: 12 syringes (0.5ml) – £813.21; Rebif 8.8μg/0.1ml and 22μg/0.25ml: 2 cartridges – £406.61; Rebif 22μg/0.5ml: 4 cartridges – £624.77; Rebif 44μg/0.5ml: 4 cartridges – £813.21; For prices in Ireland, consult distributors Allphar Services Ltd. Marketing Authorisation Holder and Numbers Merck Serono Europe Ltd, 56 Marsh Wall, London, E14 9TP; EU/1/98/063/007; 003; 006; 010; 008; 009. For further information contact: UK: Merck Serono Ltd, Bedfont Cross, Stanwell Road, Feltham, Middlesex, TW14 8NX. Tel: 020 8818 7373. Republic of Ireland: Merck Serono, 3013 Lake Drive, Citywest Business Campus, Dublin 24. Tel: 01 4661910. Date of Preparation January 2010.
Date of Preparation: March 2010 REB10–0057
References:1. PRISMS Study Group. Lancet 1998;352:1498–1504.2. Kappos L et al. Neurology 2006;67:944–953.3. Steinberg SC et al. Clin Drug Investig 2010;30(2):89–100.
Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk. In the Republic of Ireland information can be found at www.imb.ie. Adverse events should also be reported to Merck Serono Limited - Tel: +44(0)20 8818 7373 or email: [email protected].
tine serological testing has not proved to be useful, due to lack of speci-ficity.7,31 Conversely, only one patient in the published data so far frompatients with neuropil encephalitis, with AMPAR antibodies, has hadlupus serology, namely dsDNA antibodies. But, this patient was not givena diagnosis of lupus and also had a thymic carcinoma, which was theprobable driver of AMPAR antibody.32 It is probably the strategies used bygroups working on neuropil encephalitis, including proteomicapproaches, that will discover cell surface antigens in lupus.33
What is the role of brain imaging? In a diagnostic work-up, brain imag-ing (and CSF examination) is done first to exclude other pathology, prin-cipally vascular or infection, including progressive multifocal leucoen-cephalopathy (PML) which was on the scene long before the biologicaltherapeutics era.34,35 Small white matter lesions in lupus are common,non-specific and may reflect ischaemic damage. One small study byAppenzeller in a Brazilian population revealed some correlation of suchlesions (present in roughly half of the patients studied) in time withsteroid dosage, cardiolipin antibodies, or previous neurological symp-toms.23 A few studies have revealed white matter atrophy and alteredneurometabolic profiles on spectroscopy in patients with lupus, correlat-ing with cognitive dysfunction.36 So although imaging seems unlikely tooffer a diagnostic test for immunotherapy responsive NPSLE, it has use inlongitudinal follow up of vascular disease and in the detection of PML.
SLE as a differential diagnosis in neurologySLE features among many lists of differential diagnoses in neurology, andthe serological tests now available can be misleading. Antinuclear anti-body (ANA) and double stranded DNA (dsDNA) antibody tests are bothproblematic. ANA is over-sensitive and positivity is common in the gen-eral population, in particular with increasing age. dsDNA antibody ismuch more specific for lupus but less sensitive, and absolute levels arenot useful in monitoring response to therapy.37 A good rule of thumbwhen faced with a discordant ANA result in a neurology clinic, withoutclinical features of systemic lupus, is to ignore it at first. Antiphospholipidsyndrome (either primary or secondary to lupus) is an important diag-nosis that can mimic multiple sclerosis, and the presence of sustainedhigh titre phospholipid antibodies are useful in diagnosis.
TreatmentThere is no clear evidence base for the treatment of NPSLE. However,to put this in context, neither is there a standard of care in lupusnephritis, which is more common and better studied. Achieving sus-tained remission with minimal steroid usage is the ultimate goal.There remains just one published randomised controlled study inNPSLE – a small study in which 18 of 19 patients treated with intra-venous schedules of cyclophosphamide responded compared to 6 of13 in the methylprednisolone group.38 But, the case mix of NPSLEmanifestations (mainly seizures, transverse myelitis and peripheralneuropathy) and the differences between the groups make firm con-clusions from this study difficult to make. Well designed retrospectivestudies exist, and show that intensive immunotherapy is probably agood thing. The University College London group have reported 10 of11 cases of lupus psychosis from a 485 patient cohort, in whom a vari-ety of treatments including steroids, plasmapheresis, cyclophos-phamide and azathioprine were used. Most of the patients had a goodlong term outcome with no recurrence, particularly if treated aggres-sively.39 The best controlled studies of immunosuppression in lupushave been in nephritis, and support the use of low-dose-cyclophos-phamide, azathioprine, and mycophenolate mofetil (MMF). Ten-yearfollow up data from the Euro-lupus nephritis trial reveals that lowdose cyclophosphamide followed by azathioprine is effective atinducing and maintaining sustained remission.40 MMF is probably aseffective as cyclophosphamide in inducing remission in nephritis, butsafer.41
B cell depletion therapy, with the monoclonal chimeric anti-CD20antibody, rituximab, has had the most promising open label data in thelast few years, for refractory lupus in particular. The drug appears effec-tive in open studies of refractory severe NPSLE42,43, but there have beenno randomised controlled trials. Two phase III trials in which severeNPSLE was an exlusion criterion (EXPLORER,44 all lupus; and LUNAR,
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ACNR > VOLUME 10 NUMBER 2 > MAY/JUNE 2010 > 13
nephritis) have shown no increased efficacy of rituximab over conven-tional treatment. This could be due to inclusion of mild disease, fixed‘damage’, and concomitant immunosuppression usage.45 One should bealert to the risk of PML after rituximab, but this seems small.35 Another Bcell centred agent, belimumab, a monoclonal antibody which inhibits B-cell activating factor (BAFF), suffered similar negative results at phase II,but after rigorous trial re-design has recently had success (in all lupus,but again with CNS lupus excluded) in phase III studies, BLISS-52 andBLISS-76.46 The consensus among rheumatologists who have led thesestudies is that trial design may have let rituximab down. But even the verybasics of trial design in NPSLE have not yet been achieved.
So, having excluded infection and vascular pathologies, a pragmatictreatment approach is to use steroids, followed by plasmapheresis or intra-venous immunoglobulin if the disease manifestation seems antibody-mediated (e.g. LETM, and possibly psychosis), for induction of remission,
and then azathioprine or MMF for maintenance therapy.Cyclophosphamide or rituximab are reserved for severe refractory dis-ease. Warfarin is used for thrombotic events associated with the antiphos-pholipid syndrome, but the intensity and duration of therapy remainsunclear.47
ConclusionNPSLE is heterogeneous, and current classification criteria are mislead-ing. We need a marker that distinguishes immunotherapy-responsive dis-ease from ischaemic, infectious or other aetiologies. One marker exists forLETM and optic neuritis in lupus: aquaporin-4 antibodies. There is a smallevidence base for therapy of NPSLE, which suggest, for carefully selectedcases, initial treatment with steroids followed by MMF or azathioprine.Cyclophosphamide and rituximab are reserved therapies for severerefractory disease. l
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42. Tokunaga M et al. Efficacy of rituximab (anti-CD20) for refractory systemic lupus erythe-matosus involving the central nervous system. Ann Rheum Dis 2007;66:470-5.
43. Ramos-Casals M, Soto MJ, Cuadrado MJ & Khamashta MA. Rituximab in systemic lupuserythematosus: A systematic review of off-label use in 188 cases. Lupus 2009;18:767-76.
44. Merrill JT et al. Efficacy and safety of rituximab in moderately-to-severely active systemiclupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythemato-sus evaluation of rituximab trial. Arthritis Rheum 2010;62:222-33.
45. Favas C & Isenberg DA. B-cell-depletion therapy in SLE--what are the current prospects forits acceptance? Nat Rev Rheumatol 2009;5:711-16.
46. Dall'Era M & Wofsy D. Connective tissue diseases: Belimumab for systemic lupus erythe-matosus: breaking through? Nat Rev Rheumatol 2010;6:124-5.
47. Erkan D & Lockshin MD. New approaches for managing antiphospholipid syndrome. NatClin Pract Rheumatol 2009;5:160-70.
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The term dystonia refers to a group of condi-tions in which sustained muscular contrac-tions lead to abnormal posturing and repeti-
tive movements.1 The primary or idiopathic dys-tonias are non-degenerative conditions wheredystonia (with the possible exception of a co-existent tremor) is the only clinical abnormality.Within this group are the focal dystonias in whichdystonic movements of the eyelids (ble-pharospasm), neck (cervical dystonia), mouthand jaw (oro-mandibular dystonia), vocal cords(laryngeal dystonia) or hand (focal hand dysto-nia) develop in adulthood. Focal hand dystoniais often task specific, affecting fine, repetitivehand movements. The commonest forms arewriter’s cramp and musician’s dystonia. This arti-cle will give a brief overview of the aetiology ofidiopathic focal dystonia, concentrating oninsights gained from neurophysiological abnor-malities detected in patient studies.
GeneticsTo date, no causative genetic mutations havebeen identified in late onset idiopathic focal dys-tonia. In those patients with a positive family his-tory, inheritance is mostly complex and non-mendelian, although a small number of familieswith autosomal dominant inheritance have beenreported. DYT4 has been described in a singlefamily, with the majority of affected memberspresenting with laryngeal dystonia, which even-tually becomes generalised.2 No chromosomallocus has been identified. DYT7 was identified ina family with affected members displaying eithercervical or focal hand dystonia.3 Linkage analy-sis has mapped this condition to chromosome18. The same locus has been implicated in a sep-arate family with three brothers affected bywriter’s cramp.4 DYT13 has been reported in afamily with dystonia presenting in the head andneck or in the arms5 and has been mapped tochromosome 22.6
A mutation within the DYT1 gene (torsin A) isthe commonest identifiable cause of primarygeneralised dystonia. It most commonly pres-ents in childhood with focal lower limb dystoniafollowed by generalisation, with a tendency tospare the head and neck.7 However, there is adegree of phenotypic variability and mutationshave been identified in patients with multifocalor segmental dystonia presenting as writer’scramp in both childhood and adulthood.8 DYT6is a more recently recognised form of gener-alised dystonia caused by mutations in theTHAP1 gene on chromosome 8.9 It typically pres-ents in childhood or adolescence with focal
onset dystonia of the head, neck or limbs andthere is often generalisation. Frequent involve-ment of the cervical, laryngeal and cranial mus-cles differentiates this condition from DYT1.Again, there is wide phenotypic variability and itcan present with late onset focal or segmentaldystonia.10
The above points clearly demonstrate that aparticular gene can be associated with a varietyof forms of dystonia. This suggests that differentforms of late onset focal dystonia share a com-mon genetic background, and that the expres-sion of a particular dystonic phenotype rests onthe interplay between other genetic and environ-mental factors.11
Cortical reorganisation Monkeys trained to carry out repetitive handmovements over many months can developabnormal posturing reminiscent of focal handdystonia.12 Subsequent recordings from individ-ual neurones in sensory cortex of these monkeysrevealed enlarged receptive fields and overlap-ping representations of individual digits. Thischange in cortical representation is presumed tobe because the maintenance of precise somato-topy depends upon the temporal and spatial sep-aration of afferent inputs, which breaks downduring unnaturally repetitive fine motor tasks.13
Such movements are comparable with thoserequired for hand writing or playing a musicalinstrument and similar abnormalities of corticalreorganisation have been demonstrated inpatients with musician’s dystonia.14 It has beenhypothesised that these enlarged receptive fieldsmap inappropriately onto networks of neuronesin the motor system and in doing so producedystonic movements.13
Sensory overload from repetitive hand move-ments may well contribute to the developmentof focal hand dystonia. Given that painful stim-uli15 and peripheral nerve injury16 are also knownto produce abnormal cortical reorganisation,such forms of sensory overload could contributeto other types of focal dystonia. In keeping withthis idea, case control studies have revealed anassociation between blepharospasm and oculardisease,17 cervical dystonia and blunt neck trau-ma18 and laryngeal dystonia and sore throat.19
There are also a number of reported cases of oro-mandibular dystonia occurring shortly afterfacial injury or surgery.20
Similar abnormalities of cortical organisationhave been found in the motor system. A studyusing transcranial magnetic stimulation (TMS)has demonstrated displacement of upper limb
Pathophysiology ofIdiopathic FocalDystonia
Adam Cassidyis a Neurology Specialty Registrarand NIHR Academic ClinicalFellow at Newcastle University. Hisresearch focuses on motor learningand plasticity in dystonia.
Acknowledgements:I am very grateful to Dr Mark Bakerand Dr Anaïs Thouin for their helpful comments on the manuscript.
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Zonegran is indicated as adjunctive therapy in the treatment of adult patients with partial seizures, with or without secondary generalisation.
ABBREVIATED PRESCRIBING INFORMATIONZonegran®▼ (zonisamide)Please refer to the SmPC before prescribing.Presentation: Hard capsules containing 25 mg, 50 mg or 100 mg zonisamide. Indication: Adjunctive therapy in adult patients with partial seizures, with or without secondary generalisation. Dose and administration: Adult: Must be added to existing therapy. Initial daily dose is 50 mg in two divided doses. After one week, increase to 100 mg daily. Then increase at one weekly intervals in 100 mg increments. Can be taken once or twice daily after titration. In renal or hepatic impairment and patients not receiving CYP3A4-inducing agents consider two weekly intervals. Withdraw gradually. Elderly and patients with renal or hepatic impairment: Caution (see SmPC). Not recommended in severe hepatic impairment. Children and adolescents under 18 years: Not recommended. Contra-Indications: Hypersensitivity to zonisamide, sulphonamide or any excipient. Pregnancy: Zonegran must not be used during pregnancy unless clearly necessary in the opinion of the physician, and only if potential benefi ts justify the risks. Specialist advice should be given to women who are likely to become pregnant. Women of childbearing potential must use contraception during treatment and for one month after discontinuation. Lactation: Excreted into breast milk. A decision must be made to either discontinue Zonegran or stop breast-feeding. Warnings and Precautions: Serious rashes occur in association with Zonegran therapy, including cases of Stevens-Johnson syndrome. Zonegran contains a sulphonamide group which are associated with serious immune based adverse reactions. Closely supervise and consider discontinuation in patients with unexplained rash. Cases of agranulocytosis, thrombocytopenia, leukopenia, aplastic anaemia, pancytopenia and leucocytosis have been reported. Monitor for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Use with caution in patients with risk factors for nephrolithiasis, including
prior stone formation, a family history of nephrolithiasis and hypercalcuria. Evaluate and monitor serum bicarbonate levels in patients who have: underlying conditions which might increase the risk of metabolic acidosis; increased risk of adverse consequences of metabolic acidosis; symptoms suggestive of metabolic acidosis. If metabolic acidosis develops and persists, consider reducing the dose, discontinuing or alkali treatment. Use with caution in patients treated with carbonic anhydrase inhibitors, e.g. topiramate. Decreased sweating, elevated body temperature and heat stroke have been reported. Patients should maintain hydration and avoid excessive temperatures. Monitor pancreatic lipase and amylase levels in patients taking Zonegran who develop clinical signs and symptoms of pancreatitis, consider discontinuation. In cases of severe muscle pain/weakness with or without fever, assess markers of muscle damage and consider discontinuation. Zonegran 100 mg capsules contain E110. Caution in patients less than 40 kg. In patients with weight loss consider dietary supplement, increased food intake or discontinuation. Drug Interactions: No clinically relevant pharmacokinetic effects on carbamazepine, lamotrigine, phenytoin, sodium valproate, oral contraceptives (ethinylestradiol or norethisterone). Insuffi cient data with carbonic anhydrase inhibitors, e.g.topiramate. Zonegran was not affected by lamotrigine or CYP3A4 inhibitors. Caution with drugs which are P-gp substrates. Avoid concomitant administration with drugs causing urolithiasis. Zonisamide is metabolised partly by CYP3A4, N-acetyl-transferases and conjugation with glucuronic acid; therefore caution with substances that can induce or inhibit these enzymes. Side effects: The most common adverse reactions in controlled adjunctive-therapy studies were somnolence, dizziness and anorexia. Adverse reactions associated with Zonegran in clinical studies and post-marketing surveillance: Very common effects (≥1/10): anorexia, agitation, irritability, confusional state, depression, ataxia, dizziness, memory impairment, somnolence,
diplopia, decreased bicarbonate. Common effects (≥1/100, <1/10): ecchymosis, hypersensitivity, affect lability, anxiety, insomnia, psychotic disorder, bradyphrenia, disturbance in attention, nystagmus, paraesthesia, speech disorder, tremor, abdominal pain, constipation, diarrhoea, dyspepsia, nausea, rash, nephrolithiasis, fatigue, infl uenza-like illness, pyrexia, weight decreased. Uncommon (≥1/1000, <1/100): pneumonia, urinary tract infection, hypokalemia, anger, aggression, suicidal ideation, suicidal attempt, convulsion, vomiting, cholecystitis, cholelithiasis, calculus urinary. For very rare side effects see SmPC. Isolated cases of Sudden Unexplained Death in Epilepsy Patients (SUDEP). Post-marketing data suggests patients aged ≥65 years report a higher frequency of Stevens-Johnson syndrome and Drug Induced Hypersensitivity syndrome. Legal Category: POM. Basic UK NHS cost: Zonegran 25 mg: packs of 14 £8.82, Zonegran 50 mg: packs of 56 £47.04, Zonegran 100 mg: packs of 56 £62.72. Irish price to wholesaler: Zonegran 25 mg: packs of 14 €10.95, Zonegran 50 mg: packs of 56 €58.07, Zonegran 100 mg: packs of 56 €77.59. Marketing authorisation numbers: Zonegran 25 mg 14 capsules: EU/1/04/307/001, Zonegran 50 mg 56 capsules: EU/1/04/307/003, Zonegran 100 mg 56 capsules: EU/1/04/307/004. Marketing authorisation holder: Eisai Ltd. Further Information from/Marketed by: Eisai Ltd, European Knowledge Centre, Mosquito Way, Hatfi eld, Hertfordshire, AL10 9SN. Date of preparation: July 2009.
Date of Preparation: July 2009 ZON-UK2299a
Adverse events should be reported. Reporting forms and Information can be found at www.yellowcard.gov.uk. Adverse events should also be reported to Eisai Ltd on 020 8600 1400/0845 676 1400 or [email protected]
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corticomotor maps in patients with writer’scramp,21 a finding that was later extended topatients with cervical dystonia.22 These abnor-malities were temporarily reversed followingthe injection of botulinum toxin into theaffected muscles, leading the authors to spec-ulate that the observed change in corticaltopography was caused by altered afferentfeedback from the dystonic muscles. At thesame time, the presence of neurophysiologi-cal abnormalities in clinically unaffectedbody parts suggests that this may occuragainst a background of a more generaliseddisturbance of sensorimotor control.
Sensory abnormalitiesWhile dystonic patients do not have clinicallyapparent sensory loss they are impaired inmeasures of both temporal and spatial tactilediscrimination.23 These impairments are notjust limited to body parts affected by dystonia;they have been found bilaterally in the handsof patients with unilateral focal hand dysto-nia,24 cervical dystonia and blepharospasm.25
They have also been found in unaffected rela-tives of patients with dystonia, suggesting thatthey may be carrying a genetic risk factor forthe future development of the condition.26 Inaddition to these behavioural findings, a studyusing magnetoencephalography in patientswith unilateral focal hand dystonia showedabnormalities in the somatotopic organisa-tion of the sensory cortex.27 Similar to theresults detailed above, these abnormalitieswere bilateral in patients with unilateral symp-toms.
These findings may result from a failure toadequately focus sensory afferent inputs.When somatosensory evoked potentials(SEPs) are produced simultaneously fromboth the ulnar and median nerves, the com-bined SEP is smaller than the sum of the indi-vidual SEPs. Similarly, when two SEPs areevoked in quick succession from the samesite, the first SEP inhibits various componentsof the second. These inhibitory interactionsare either impaired or absent in patients withfocal hand dystonia and it has been suggestedthat this may be secondary to a generaliseddefect in lateral inhibition.28
Impaired motor inhibitionAbnormalities in motor inhibitory circuits areseen at all levels of the central nervous systemin patients with dystonia. For example,patients with writer’s cramp have reduced lev-
els of reciprocal inhibition in forearm mus-cles29 and TMS protocols have revealed under-activity of cortical inhibitory circuits.30 Thesechanges are not, however, sufficient to gener-ate dystonic movements as they can be seenbilaterally in patients with unilateral symp-toms.
There is evidence to suggest that the outputof the motor system is controlled by a processof surround inhibition.31 It has been shownthat at the onset of a voluntary contraction ofa hand muscle, both neighbouring and con-tralateral hand muscles are less readily stimu-lated with TMS. In this way the motor systemcan focus muscle activity and facilitate pre-cise, individuated movements. In patientswith focal hand dystonia this mechanism isimpaired32 and this could help to explain theco-contraction and overflow of muscle activi-ty that typifies this condition.
Excessive neuroplasticityNeuroplasticity refers to the ability of neu-ronal circuits to undergo structural and func-tional changes in connectivity and underliesthe process of learning and memory. Pairedassociative stimulation (PAS) is a paradigmused to measure plasticity in the humanbrain.33 Repeated afferent impulses generatedby electrical stimulation of the median nerveare timed to reach the cerebral cortex justbefore the delivery of a TMS pulse sufficient toactivate muscles of the thumb supplied by thesame nerve. Depending on the exact inter-stimulus interval used, subsequent TMS pulsescan lead to either enhanced or depressedmotor evoked potentials, and this change isrestricted to those muscles supplied by themedian nerve. These alterations outlast theconditioning protocol by around thirty min-utes and are thought to represent long-termpotentiation and long-term depression. Whenapplied to patients with writer’s cramp thisfacilitation is exaggerated and the spatialspecificity is lost.34 Such changes are unlikelyto be secondary to dystonic movements asthey are also present in the asymptomatichands of patients with blepharospasm andcervical dystonia.35 Excessive neuroplasticitycould drive the maladaptive reorganisation ofcortical sensorimotor maps thought to under-lie the generation of dystonic movements.
Basal ganglia involvementSecondary dystonia is the term used todescribe dystonia that is the result of an iden-
tifiable metabolic insult or structural lesion.The majority of such lesions are found toaffect the basal ganglia, thalamus or their con-nections36 and it is likely that abnormal activi-ty in basal ganglia–thalamo–cortical loopsplays a large part in the aetiology of all formsof dystonia. Indeed, neurophysiological stud-ies on patients undergoing deep brain stimu-lation (DBS) for generalised dystonia havefound patterns of neuronal activity in theglobus pallidus internus (GPi) and motor thal-amus that correlate with dystonic EMG activi-ty.37 Imaging studies in dystonia have yieldedmany conflicting results, likely due to varia-tion in methodology and patient selection,but a relatively consistent finding is the pres-ence of both increased functional activity andincreased grey matter volume in the basalganglia.38 Perhaps the strongest evidence forthe role of abnormal basal ganglia output inthe pathogenesis of dystonia is the simple factthat modulation of the GPi and motor thala-mus with DBS is an effective treatment forboth generalised39 and focal dystonias.40
Cerebellar involvementWhile the basal ganglia undoubtedly play akey role in the genesis of dystonic movementsthere is mounting evidence to suggest that thecerebellum may also be involved.41 Recentwork looking at eye blink classical condition-ing, a process that is dependent on cerebellarfunction,42 has been particularly informative.Within this experimental paradigm an audito-ry tone is played immediately prior to thedelivery of an electrical stimulus to the supra-orbital nerve. After repeated stimulus pairingsnormal subjects produce conditionedresponses consisting of eye blinks that beginafter the onset of the tone but prior to theonset of the electrical stimulus. Data fromstroke patients have localised this process tothe territory of the superior cerebellar artery.43
This area includes lobules V and VI of thecerebellar cortex, which have been shown tobe structurally abnormal in patients with focalhand44 and cervical dystonia.45 The findingthat patients with focal dystonia haveimpaired eye blink conditioning providesphysiological evidence for cerebellar dys-function in this group of conditions.46
Putting it all togetherResearch into focal dystonia has revealedabnormalities in basal ganglia function, cere-bellar function, sensory processing, motor
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...the emerging model is that genetically mediated abnormalities of basal gangliafunction, sensorimotor inhibition and neuroplasticity culminate in a brain statethat, when exposed to particular patterns of sensory stimulation, facilitates aprocess of maladaptive cortical reorganisation that ultimately leads to dystonicmovements.
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inhibition, neuroplasticity and somatotopiccortical organisation. How these separatestrands interact to explain the development ofdystonia is uncertain and a perennial difficul-ty is establishing which elements arecausative and which are simply epiphenome-na. Despite this, some necessarily speculativesuggestions can be made.
The diffuse abnormalities of sensory pro-cessing and motor inhibition may be second-ary to a fundamental problem with lateralinhibition, which could in turn reflect a gener-al functional disturbance of corticalGABAergic interneurones.28 Such a mecha-nism could account for reorganisation of thesensory and motor cortices, as pharmacologi-cal blockade of cortical inhibitory neuroneswith the GABA antagonist bicuculline hasbeen shown to expand cortical representa-tions in rat brain,47 presumably by unmaskingpreexisting lateral excitatory connections. Ageneralised reduction in inhibitory activitycould also fail to adequately gate synapticinputs and so lead to circuits that more readi-ly undergo long-term potentiation and depres-sion. In this way enhanced neuroplasticitycould be a direct consequence of impairedinhibition.28 However, in patients with psy-chogenic “fixed” dystonia, cortical inhibitionis reduced48 while measures of neuroplasticityremain normal.49 Similarly, measures of corti-cal inhibition have been found to be abnor-mal in both manifesting and non-manifestingcarriers of the DYT150 mutation while levels ofneuroplasticity were found to be enhancedonly in manifesting carriers.51 Furthermore,non-manifesting carriers were found to havereduced levels of plasticity when comparedto normal subjects, suggesting that underactiv-ity of this mechanism confers protection toindividuals who are otherwise at risk ofbecoming symptomatic. These findings wouldplace abnormalities in the control of neuro-plasticity as a primary force behind the devel-opment of dystonic symptoms, with impairedsurround inhibition resulting from anincreased tendency of the brain to form newexcitatory connections.
The basal ganglia are generally accepted tobe involved in both the activation of appropri-ate motor programmes and the concurrentinhibition of competing patterns of motoractivity52 and so are well placed to control sur-round inhibition in the sensory and motorcortices. On this basis it has been proposedthat abnormal basal ganglia activity coulddrive the aforementioned impairment ofinhibitory interneurone function.28 In dyston-ic patients the basal ganglia generate abnor-mal patterns of oscillatory activity and neu-ronal synchrony. Given that neuronal oscilla-tions have been shown to enhance corticalplasticity,53 it has also been suggested thatabnormal basal ganglia oscillations coulddirectly underlie the aberrant levels of plastic-ity seen in dystonia.54
The relevance of abnormal cerebellar func-tion in the aetiology of dystonia remains
unclear. One possibility is that the cerebellumrepresents simply one node within a complexmotor network that also includes thedopaminergic system, the basal ganglia andcerebral cortex.55 Dysfunctional activity at anyof these sites could disrupt the activity of thenetwork as a whole and contribute to the neu-rophysiological abnormalities detailed in thisreview.
Abnormalities of sensory processing, soma-totopic organisation, motor inhibition andneuroplasticity have been found repeatedly inareas not displaying dystonic movements.These changes may represent geneticallymediated risk factors for the future develop-ment of focal dystonias and are often referredto as endophenotypic traits.27 Against thisbackground of generalised disturbed sensori-motor function and enhanced neuroplasticity,an external drive to further plastic change(repetitive hand movements, excessive blink-ing, peripheral injury etc) could then lead tofurther, localised somatotopic reorganisation.Once this reaches a level where the sensori-motor feedback loop is sufficiently compro-mised, motor control is disturbed and dyston-ic movements ensue.56
Evidence to support this general schemacomes from studies that demonstrate a nor-malisation of various neurophysiologicalparameters in response to treatment.Sensorimotor retuning is one of a number ofrehabilitative strategies found to be partiallyeffective in the treatment of musician’s dysto-nia. This strategy involves splinting the unaf-fected digits and exposing individual affecteddigits to systematic training with the relevantmusical instrument. It has been shown thatclinical improvement is associated with a nor-malisation of somatotopic organisation asassessed by magnetoencephalography.57 In
general, such rehabilitative approaches pro-duce only temporary clinical improvements,58
a finding that is to be expected if there is anunderlying defect in sensorimotor processingand plasticity that is continually driving fur-ther aberrant cortical reorganisation.
DBS of the GPi is an effective treatment forgeneralised dystonia, although its precisemechanism of action is unknown. In contrastto the immediate response of parkinsoniansymptoms to DBS in patients with Parkinson’sdisease, the clinical response in patients withdystonia is progressive, taking place over a num-ber of months. Serial measures of brainstem59
and spinal cord60 inhibition taken pre-operative-ly and over a period of six months post-opera-tively have been shown to normalise in linewith this clinical improvement. Furthermore,measures of PAS in patients treated with DBSfor six months show levels of neuroplasticitycomparable to those seen in normal controls.61
These findings suggest that modulating theoscillatory output of the basal ganglia may nor-malise levels of inhibition and neuroplasticity,allowing for the gradual replacement of aber-rant sensorimotor networks with more physio-logical patterns of activity.54
ConclusionA number of consistent physiological abnor-malities have been identified in various formsof idiopathic dystonia. How these elementsinteract to produce dystonia remains uncer-tain but the emerging model is that genetical-ly mediated abnormalities of basal gangliafunction, sensorimotor inhibition and neuro-plasticity culminate in a brain state that, whenexposed to particular patterns of sensory stim-ulation, facilitates a process of maladaptivecortical reorganisation that ultimately leads todystonic movements (Figure 1). l
Figure 1: A possible model for the development of focal dystoniasAbnormalities of neuronal inhibition, neuroplasticity and basal ganglia function appear to promote a state of corticalreorganisation. The relative importance of each factor and the interactions between them remain unclear, but a number offindings point to enhanced neuroplasticity as having a central role (see main text). In combination with particular patterns ofsensory input, further focal cortical reorganisation presumably occurs, with dystonic movements appearing when this reaches athreshold.
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37. Zhuang P, Li Y, Hallett M. Neuronal activity in the basalganglia and thalamus in patients with dystonia. ClinicalNeurophysiology 2004:115;2542.
38. Breakefield XO, Blood AJ, Li Y, Hallett M, Hanson PI,Standaert DG. The pathophysiological basis of dystonias.Nature Reviews Neuroscience 2008:9;222.
39. Vidailhet M, Vercueil L, Houeto JL, Krystkowiak P,Benabid AL, Cornu P, et al. Bilateral deep-brain stimula-tion of the globus pallidus in primary generalized dysto-nia. New England Journal of Medicine 2005:352;459.
40. Hung SW, Hamani C, Lozano AM, Poon YY, PiboolnurakP, Miyasaki JM, et al. Long-term outcome of bilateral pall-idal deep brain stimulation for primary cervical dystonia.Neurology 2007:68;457.
41. Jinnah HA, Hess EJ. A new twist on the anatomy of dys-tonia: the basal ganglia and the cerebellum? Neurology2006:67;1740.
42. Gerwig M, Kolb FP, Timmann D. The involvement of thehuman cerebellum in eyeblink conditioning. Cerebellum2007:6;38.
43. Gerwig M, Dimitrova A, Kolb FP, Maschke M, Brol B,Kunnel A, et al. Comparison of eyeblink conditioning inpatients with superior and posterior inferior cerebellarlesions. Brain 2003:126;71.
44. Delmaire C, Vidailhet M, Elbaz A, Bourdain F, Bleton JP,Sangla S, et al. Structural abnormalities in the cerebellumand sensorimotor circuit in writer's cramp. Neurology2007:69;376.
45. Draganski B, Thun-Hohenstein C, Bogdahn U, WinklerJ, May A. "Motor circuit" gray matter changes in idiopath-ic cervical dystonia. Neurology 2003:61;1228.
46. Teo JTH, van de Warrenburg BPC, Schneider SA,Rothwell JC, Bhatia KP. Neurophysiological evidence forcerebellar dysfunction in primary focal dystonia. Journalof Neurology Neurosurgery and Psychiatry 2009:80;80.
47. Jacobs KM, Donoghue JP. Reshaping the cortical motormap by unmasking latent intracortical connections.Science 1991:251;944.
48. Avanzino L, Martino D, van de Warrenburg BP,Schneider SA, Abbruzzese G, Defazio G, et al. Corticalexcitability is abnormal in patients with the "fixed dysto-nia" syndrome. Movement Disords 2008:23;646.
49. Quartarone A, Rizzo V, Terranova C, Morgante F,Schneider S, Ibrahim N, et al. Abnormal sensorimotorplasticity in organic but not in psychogenic dystonia.Brain 2009:132;2871 .
50. Edwards MJ, Huang YZ, Wood NW, Rothwell JC, BhatiaKP. Different patterns of electrophysiological deficits inmanifesting and non-manifesting carriers of the DYT1gene mutation. Brain 2003:126;2074.
51. Edwards MJ, Huang YZ, Mir P, Rothwell JC, Bhatia KP.Abnormalities in motor cortical plasticity differentiatemanifesting and nonmanifesting DYT1 carriers.Movement Disorders 2006:21;2181.
52. Mink JW. The basal ganglia: Focused selection and inhibi-tion of competing motor programs. Progress inNeurobiology 1996:50;381.
53. Buzsaki G, Draguhn A. Neuronal oscillations in corticalnetworks. Science 2004:304;1926.
54. Tisch S, Rothwell JC, Limousin P, Hariz MI, Corcos DM.The physiological effects of pallidal deep brain stimula-tion in dystonia. IEEE Transactions on Neural Systemsand Rehabilitation Engineering 2007:15;166.
55. Vidailhet M, Grabli D, Roze E. Pathophysiology of dysto-nia. Current Opinion in Neurology 2009:22;406.
56. Sanger TD, Merzenich MM. Computational model of therole of sensory disorganization in focal task-specific dysto-nia. Journal of Neurophysiology 2000:84;2458.
57. Candia V, Wienbruch C, Elbert T, Rockstroh B, Ray W.Effective behavioral treatment of focal hand dystonia inmusicians alters somatosensory cortical organization.Proceedings of the National Academy of Sciences U S A2003:100;7942.
58. Cogiamanian F, Barbieri S, Priori A. Novel nonpharmaco-logic perspectives for the treatment of task-specific focalhand dystonia. Journal of Hand Therapy 2009:22;156.
59. Tisch S, Limousin P, Rothwell JC, Asselman P, Quinn N,Jahanshahi M, et al. Changes in blink reflex excitabilityafter globus pallidus internus stimulation for dystonia.Movement Disorders 2006:21;1650.
60. Tisch S, Limousin P, Rothwell JC, Asselman P, Zrinzo L,Jahanshahi M, et al. Changes in forearm reciprocal inhi-bition following pallidal stimulation for dystonia.Neurology 2006:66;1091.
61. Tisch S, Rothwell JC, Bhatia KP, Quinn N, Zrinzo L,Jahanshahi M, et al. Pallidal stimulation modifies after-effects of paired associative stimulation on motor cortexexcitability in primary generalised dystonia. ExperimentalNeurology 2007:206;80.
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XEOMIN® Abbreviated Prescribing Information.Please refer to Summary of Product Characteristics (SmPC) beforeprescribing. Presentation: 100 LD50 units of ClostridiumBotulinum neurotoxin type A (150 kD), free from complexingproteins, as a powder for solution for injection. Indications:Symptomatic management of blepharospasm and cervical dystoniaof a predominantly rotational form (spasmodic torticollis) and ofpost-stroke spasticity of the upper limb presenting with flexed wristand clenched fist in adults. Dosage and Administration: Pleaserefer to SmPC for full information. Reconstitute with sterileunpreserved normal saline (0.9% sodium chloride for injection).Blepharospasm: The initial recommended dose is 1.25-2.5 Uinjected into the medial and lateral orbicularis oculi of the upper lid and the lateral orbicularis oculi of the lower lid. The initial doseshould not exceed 25 U per eye but this can be subsequentlyincreased. The total dose should not exceed 100 U every 12 weeks.Spasmodic torticollis: Xeomin® is usually injected into thesternocleidomastoid, levator scapulae, scalenus, splenius capitis and/ or the trapezius muscle(s). However the dosing should be tailoredto the individual patient. The maximum total dose is usually notmore than 200 U but doses up to 300 U may be given. No morethan 50 U should be given at any one injection site. Post-strokespasticity of the upper limb: The exact dosage and number of injection sites should be tailored to the individual patient basedon the size, number and location of muscles involved, the severityof spasticity, and the presence of local muscle weakness. Themaximum total recommended dose is up to 400 units per treatmentsession. Contra-indications: Known hypersensitivity to Botulinum
neurotoxin type A or to any of the excipients, generalised disordersof muscle activity (e.g. myasthenia gravis, Lambert-Eaton syndrome)and presence of infection at the proposed injection site. Dysphagiahas also been reported following injection to sites other than thecervical musculature. Warnings and Precautions: Adrenaline andother medical aids for treating anaphylaxis should be available.Xeomin® contains albumin a derivative of human blood. Prior toadministration the physician must make himself familiar with thepatients anatomy and any changes due to surgical procedures. Sideeffects related to spread of botulinum toxin have resulted in deathwhich in some cases was associated with dysphagia, pneumoniaand /or significant debility. Patients with a history of dysphagia andaspiration should be treated with extreme caution. Patients orcaregivers should be advised to seek immediate medical care ifswallowing, speech or respiratory disorders arise. Xeomin® shouldbe used with caution if bleeding disorders occur, in patientsreceiving anticoagulant therapy, patients suffering from amyotropiclateral sclerosis or other diseases which result in peripheralneuromuscular dysfunction and in targeted muscles which displaypronounced weakness or atrophy. Reduced blinking followinginjection of the orbicularis muscle can lead to corneal exposure,persistent epithelial defects and corneal ulceration. Careful testingof corneal sensation should be performed in patients with previouseye operations. Xeomin® as a treatment for focal spasticity has beenstudied in association with usual standard care regimens, and is notintended as a replacement for these treatment modalities. Xeomin®
is not likely to be effective in improving range of motion at a joint
affected by a fixed contracture. Undesirable effects: The followingadverse reactions were reported with Xeomin®: Frequency byindication defined as: Common (≥1/100, <1/10), Uncommon(≥1/1,000, <1/100). Blepharospasm: Common: ptosis, dry eyes.Uncommon: paraesthesia, headache, conjunctivitis, dry mouth, skin rash, muscle weakness inflicted injury. Spasmodic torticollis:Common: dysphagia, muscle weakness, back pain. Uncommon:headache, tremor, eye pain, dysphonia, diarrhoea, dry mouth,vomiting, colitis, skin rash, erythema, pruritus, increased sweating,skeletal pain, myalgia, asthenia, injection site inflammation,injection site tenderness. Post-stroke spasticity: Common:injection site pain, injection site haematoma, muscular weakness.Uncommon: feeling hot, asthenia, oedema peripheral, pain inextremity, joint swelling, myalgia, dysphagia, nausea, dry mouth,dysaesthesia, headache, hypoaesthesia, haematoma, cough,erythema. Xeomin® may only be used by physicians withsuitable qualifications and proven experience in theapplication of Botulinum toxin. Prescriber should consult theSmPC for full information regarding side effects. LegalCategory: POM. Basic NHS Price: 100 U/vial £129.90. ProductLicence Number: PL29978/0001. Marketing AuthorisationHolder: Merz Pharmaceuticals GmbH, 60048 Frankfurt Main,Germany. Further information available from: Merz Pharma UKLtd., 260 Centennial Park, Elstree Hill South, Elstree, HertfordshireWD6 3SR. Date of revision of text: December 2009. Xeomin®
is a registered trademark of Merz GmbH. Botox® is a registeredtrademark of Allergan Inc.
Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk. Adverse events should also be reported to Merz Pharma UK Ltd at theabove address or by e-mail to [email protected] or by calling or on 0333 200 4143.
ACNRMJ10:Layout 1 23/4/10 05:24 Page 19
20 > ACNR > VOLUME 10 NUMBER 2 > MAY/JUNE 2010
Prof Niall Quinn is Emeritus Professor of Neurologyat the UCL Institute of Neurologyand Honorary ConsultantNeurologist at the NationalHospital for Neurology andNeurosurgery, Queen Square. Heworked with David Marsden firstas SHO in 1976, and later continu-ously for 18 years from 1980 to1998, and has been secretary ofMDS and Chair of MDS-ES.
The portrait of David Marsden isby David Graham and was commissioned by the MovementDisorder Society and hangs in theGilliatt Lecture theatre in theInstitute of Neurology, QueenSquare. It is reproduced with thepermission of the President of theMovement Disorder Society, Philip Thompson.
(Charles) David Marsden (“CDM”) died inBaltimore, USA, in September 1998 at the age of 60,just three weeks into his first ever sabbatical, at NIH.He was arguably the leading academic neurologistand neuroscientist of his generation in the UK andwas responsible, together with Stanley Fahn in NewYork, for putting movement disorders firmly on themap as a distinct and leading subspeciality.
Born in Croydon, he was educated atCheltenham College (from which he was suspend-ed for smoking, but allowed to sit his A levels). Hethen went to St Thomas’ Hospital in 1956 to readmedicine. There, in addition to winning three schol-arships, an exhibition, five prizes, and two medals,he also represented the hospital at cricket andrugby (he had earlier captained EnglandSchoolboys as scrum half), and was clearly goingplaces.
After preclinical training he got a first in his inter-calated BSc in 1959, and went on to obtain an MScin 1960 with a thesis on pigmentation in the sub-stantia nigra that established his abiding interest indiseases of the basal ganglia. He qualified in 1963.By 1965, when he became MRCP, he had sevenpapers to his name, including two in the Journal ofAnatomy, two in Nature, and two on parkinsoniantremor in the Lancet with Dr (now Lord) DavidOwen. He was then lecturer in medicine at StThomas' for two years, and following this spent twoyears as senior resident house physician at TheNational Hospital, Queen Square, where he co-authored papers on spinal muscular atrophy andpainful legs and moving toes, and continued todevelop his work on human neurophysiology, firstwith John Meadows, and later as part of the “3M’s”
(Marsden, Merton and Morton).In 1970, only seven years after qualifying, he was
appointed Senior Lecturer in Neurology at theInstitute of Psychiatry and Honorary ConsultantNeurologist to the Maudsley and Bethlem RoyalHospitals and to King's College Hospital. Two yearslater, aged thirty-four, he was the first appointee tothe newly established joint chair of neurology atthe Institute of Psychiatry and King's CollegeHospital Medical School. There he founded anddirected the Medical Research Council HumanMovement and Balance Unit (HMBU). This was thevehicle for several strands of research – first experi-mental neuropharmacology, together with PeterJenner, then human neurophysiology, with JohnRothwell and Brian Day, and then the neuropsy-chology of movement disorders with RichardBrown and later Marjan Jahanshahi. He also co-founded, with Andrew Lees, the UK’s first PD BrainBank.
Marsden’s time at Denmark Hill really constitut-ed his golden years of productivity and cama-raderie with a host of Fellows and visitingresearchers drawn by his growing reputation. Thefirst was Roger Duvoisin (USA), followed by manyothers including Paul Bedard (Canada), MarkHallett and Dan Tarsy (USA), Eldad Melamed(Israel), Wolfgang Oertel and Reiner Benecke(Germany), Alfredo Berardelli, Alberto Albanese,Giovanni Abbruzzese and Fabrizio Stocchi (Italy),Tony Lang (Canada), Jose Obeso (Spain) andPhilip Thompson (Australia), all since professorsand international leaders in the field of movementdisorders. He established the UK’s first specialist PDclinic with David Parkes, and with David Chadwick
David Marsden 1938-1998
FA M O U S N E U R O L O G I S T S
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Zebinix is indicated as adjunctive therapy in the treatment of adult patients with partial seizures, with or without secondary generalisation.
Small changeBig difference
PRESCRIBING INFORMATIONZebinix® ▼ (eslicarbazepine acetate)Please refer to the SmPC before prescribing. Presentation: Tablets containing 800 mg eslicarbazepine acetate. Indication: Adjunctive therapy in adults with partial-onset seizures with or without secondary generalisation. Dose and administration: May be taken with or without food. Starting dose is 400 mg once daily which should be increased to 800 mg once daily after one or two weeks. The dose may be increased to 1200 mg once daily. Withdraw gradually to minimise the potential of increased seizure frequency. Elderly patients: Caution (See SmPC). Children and adolescents <18 years of age: Not recommended. Patients with renal impairment: The dose should be adjusted according to creatinine clearance (CLCR) (see SmPC). Not recommended in severe impairment. Patients with hepatic impairment: No dose adjustment in mild to moderate impairment. Not recommended in severe impairment. Contra-Indications: Hypersensitivity to the active substance, other carboxamide derivatives (e.g. carbamazepine, oxcarbazepine) or any excipients. Known second or third degree AV block. Pregnancy: No data on the use of Zebinix in pregnant women. If women receiving Zebinix become pregnant or plan to become pregnant, the use of Zebinix should be carefully re-evaluated. Minimum effective doses should be given. Zebinix interacts with oral contraceptives. An alternative, effective and safe method of contraception should be used during treatment and up to the end of the current menstrual cycle after treatment has been stopped. Lactation: Excretion in human breast milk is unknown. Breastfeeding should be discontinued during treatment. Warnings and precautions: Zebinix has been associated with some CNS reactions such as dizziness and somnolence. Concomitant use with oxcarbazepine is not recommended. Rash has been reported. If signs or symptoms of hypersensitivity develop, Zebinix must be discontinued. Presence of HLA-B*1502 allele in individuals of Han Chinese and Thai origin has been shown to be strongly associated with the risk of developing Stevens-Johnson syndrome (SJS) when treated with carbamazepine. Screening for this allele should be undertaken in such individuals. Serum sodium levels should be examined before and during treatment in patients with pre-existing renal disease or in patients concomitantly treated with medicinal products which may lead to hyponatraemia. Serum sodium levels should be determined if clinical signs of hyponatraemia occur. If clinically relevant hyponatraemia develops, discontinue Zebinix. Use in primary generalised seizures is not recommended. Prolongations in PR interval have been observed. Caution in patients with medical
conditions or when taking concomitant medicinal products associated with PR prolongation. Monitor for signs of suicidal ideation and behaviours. Appropriate treatment should be considered. Drug interactions: In vitro eslicarbazepine is a weak inducer of CYP3A4 and UDP-glucuronyl transferases. In vivo eslicarbazepine may have an inducing effect on the metabolism of medicinal products which are mainly eliminated by metabolism through CYP3A4 or conjugation through the UDP-glucuronyl transferases. When initiating or discontinuing treatment with Zebinix or changing the dose, it may take 2 to 3 weeks to reach the new level of enzyme activity. Time delays must be taken into account when Zebinix is being used just prior to or in combination with other medicines that require dose adjustment when co-administered with Zebinix. Eslicarbazepine has inhibiting properties with respect to CYP2C19. Interactions can arise when co-administering high doses of eslicarbazepine acetate with medicinal products that are mainly metabolised by CYP2C19. Phenytoin: concomitant use may require an increase of Zebinix dose and a decrease of phenytoin dose. Lamotrigine and topiramate: no dose adjustments are required. However, clinical review should be considered. Valproate and levetiracetam: Concomitant administration with valproate or levetiracetam appeared not to affect the exposure to eslicarbazepine but has not been verified by conventional interaction studies. Carbamazepine: Concomitant treatment with carbamazepine increased the risk of the diplopia, abnormal coordination and dizziness. An increase in other adverse reactions caused by co-administration of carbamazepine and eslicarbazepine acetate cannot be excluded. Carbamazepine increases eslicarbazepine clearance. Zebinix slightly increases the clearance of carbamazepine. Oral contraceptives: Interacts with the oral contraceptive. Women of childbearing potential must use adequate contraception during treatment with Zebinix, and up to the end of the current menstruation cycle after the treatment has been discontinued. Warfarin: Zebinix has been shown to decrease exposure to S-warfarin. There are no effects on R-warfarin or coagulation. Monitoring of INR should be performed in the first weeks after initiation or ending concomitant treatment. Digoxin: no effect. MAOIs: an interaction between eslicarbazepine acetate and MAOIs is theoretically possible. Side effects: Adverse reactions were usually mild to moderate in intensity and occurred predominantly during the first weeks of treatment with Zebinix. Very common effects (≥1/10): dizziness, somnolence. Common effects (≥1/100, <1/10): Headache, abnormal coordination, disturbance in attention, tremor, diplopia, vision blurred, vertigo, nausea, vomiting, diarrhoea, rash, fatigue, gait disturbance. Uncommon (≥1/1,000 to <1/100): anaemia, hypersensitivity, hypothyroidism, increased appetite, decreased appetite, hyponatraemia, electrolyte imbalance, cachexia, dehydration, obesity, insomnia, apathy, depression, nervousness, agitation, attention deficit/hyperactivity disorder, confusional state, mood swings, crying, psychomotor retardation, stress, psychotic disorder, memory impairment, balance disorder, amnesia, hypersomnia, sedation,
aphasia, dysaesthesia, dystonia, lethargy, parosmia, autonomic nervous system imbalance, cerebellar ataxia, cerebellar syndrome, grand mal convulsion, neuropathy peripheral, sleep phase rhythm disturbance, nystagmus, speech disorder, dysarthria, hypoaesthesia, ageusia, burning sensation, vision disturbance, oscillopsia, binocular eye movement disorder, ocular hyperaemia, saccadic eye movement, eye pain, ear pain, hypoacusis, tinnitus, palpitations, bradycardia, sinus bradycardia, hypertension, hypotension, orthostatic hypotension, dysphonia, epistaxis, dyspepsia, gastritis, abdominal pain, dry mouth, abdominal discomfort, abdominal distension, duodenitis, epigastric discomfort, gingival hyperplasia, gingivitis, irritable bowel syndrome, melaena, odynophagia, stomach discomfort, stomatitis, toothache, liver disorder, alopecia, dry skin, hyperhidrosis, erythema, nail disorder, skin disorder, myalgia, back pain, neck pain, nocturia, menstruation irregular, asthenia, malaise, chills, oedema peripheral, adverse drug reaction, peripheral coldness, blood pressure decreased, weight decreased, blood pressure diastolic decreased, blood pressure increased, blood pressure systolic decreased, blood sodium decreased, haematocrit decreased, haemoglobin decreased, heart rate increased, transaminases increased, triglycerides increased, triiodothyronine (T3) free decreased, thyroxine (T4) free decreased, drug toxicity, fall, joint injury, poisoning, skin injury. For rare side effects see SmPC. When treated concomitantly with carbamazepine, diplopia, abnormal coordination and dizziness are reported more frequently. Use of Zebinix is associated with an increase in the PR interval. Adverse reactions associated with PR interval prolongation may occur. No second or higher degree AV block was seen in Zebinix treated patients. Rare adverse reactions such as bone marrow depression, anaphylactic reactions, severe cutaneous reactions (e.g. Stevens- Johnson Syndrome), systemic lupus erythematosus or serious cardiac arrhythmias did not occur during clinical studies. However, they have been reported with oxcarbazepine and their occurrence during treatment with Zebinix cannot be excluded. Legal Category: POM. Basic UK NHS cost: Zebinix 800 mg: pack of 30 £154.20. Marketing authorisation numbers: EU/1/09/514/012-020. Marketing authorisation holder: Bial-Portela & Cª., S.A. À Av. da Siderurgia Nacional 4745-457 S. Mamede do Coronado – Portugal. Further Information from: Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Herts, AL10 9SN, UK. Date of preparation: July 2009.
Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk Adverse events should also be reported to Eisai Ltd on 0208 600 1400/0845 676 1400 or [email protected]
Date of preparation: October 2009Zebinix-UK2019i
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22 > ACNR > VOLUME 10 NUMBER 2 > MAY/JUNE 2010
and others explored clinical, physiologicaland pharmacological aspects of myoclonus.He was one of the pioneers of the clinicalapplication of evoked potentials, and of elec-trical and magnetic stimulation of the brainand, with Peter Jenner, developed the MPTPmarmoset model of PD. Parkinsonian disor-ders were the main thrust of his work, but hemade his most important mark in the field ofdystonia, bringing it out of the dark ages whenso many cases were thought to be psychiatric,and placing it on a firm organic footing.
CDM’s most critical interaction and collabo-ration, however, was with Stanley Fahn,Houston Merritt Professor of Neurology at theNeurological Institute in ColumbiaPresbyterian Hospital in New York. Together, in1986, they founded the Movement DisordersJournal, of which they were both co-editors forits first ten years, and shortly later theMovement Disorder Society (MDS).
In 1987 Roger Gilliatt, the first Chair ofNeurology at the Institute of Neurology atQueen Square, was to retire, and David wasappointed to succeed him, so Peter Jennerand I organised a Festschrift* in recognition ofhis 17 years at Denmark Hill, little realising thatanother chance would not come.
At Queen Square in the late 1980’s specialistclinics still tended to be frowned upon, butthey began to thrive under David, and fellowscontinued to arrive from all corners of theworld. The clinical and scientific field of neu-rogenetics was burgeoning, and we had theenormous good fortune to have AnitaHarding, married to PK Thomas, to lead in thisarea. After eight years holding the QueenSquare Chair of Clinical Neurology, Daviddecided to step down and become Dean, andAnita was appointed, but tragically died ofbowel cancer aged 42, just weeks before shewas due to take up the Chair, which was thenoccupied by Ian MacDonald.
Anita’s death was a terrible blow, particular-ly to David. He did not really enjoy beingDean, and when his term ended three yearslater he was looking forward to getting back toresearch – one of his plans at the time was tofurther unravel the mysteries of apraxia and toexplain it to the world, but he never lived tocomplete this.
David was exceptional. He was highly intel-ligent and clearly ‘driven’ to be extraordinarilyproductive. One secret of his success was hisattention to detail whilst at the same timeclearly seeing the bigger picture. He had a rareability to make complicated matters seem sim-ple, and to share his thought processes with
others. His teaching method was by example.He never acted as if his students should reallyalready know through some osmotic processwhat he was deigning to teach them. Insteadhe revelled in taking them on a voyage of dis-covery. He did this best not in his lectures,which were of course outstanding models ofclarity, but particularly in his clinics and wardrounds, and especially in his “book rounds”.These weekly gatherings would bring togetherthe junior staff on the firm, the clinical fellows,and the notes of the current inpatients. TheSHO or registrar would begin the history andafter several sentences David would say “Stop!”and ask one of the fellows what he or shethought of the story so far, and by iterating thisprocess gave insight into the way he wouldapproach the question of differential diagno-sis, and imprinted the same analytical andteaching technique on his successors.
David was a complex personality, quite shyand private in some ways, so that few really feltthey knew him really well personally. Yet hehad an extraordinary ability to motivate peo-ple through charm, charisma, cajoling, andexample. He could also be forceful in gettingwhat he thought was important, althoughalways relying first on the diplomatic route, butwas always scrupulously fair. His long-termlieutenants were mainly from the UK, butalmost all of his fellows were from abroad,which made for a cosmopolitan flavour, andhas spread his influence around the globe.
David worked hard but also played hard,and had a legendary capacity to party late intothe night when away at meetings, only to deliv-er a brilliant lecture the following morning.Although he gave up smoking for a few yearsin the 1980’s, for most of his life he chain-smoked Malboro cigarettes, and was often tobe found enveloped in a cloud of smoketogether with Anita and Philip Thompson. Hisrecreation listed in Who’s Who was “the humanbrain”, but he also enjoyed sailing, bird-watch-ing and gardening.
In listing his professional achievements it isdifficult to know where to start or to finish. Hispublished work is extensive – 740 originalpapers, plus over 208 chapters, 76 reviews and100 letters and notes – one publication everytwelve days for over 30 years, covering clinicalneurology, neuropsychology, neurochemistry,neuropathology, neuropharmacology and neu-rophysiology. He was Editor of JNNP for adecade, on the editorial boards of another 20journals, member of 12 foreign societies, andheld 36 visiting professorships, received 10major awards, and gave numerous major invit-
ed lectures. He was awarded the MRCPsych in1978, was elected FRS in 1983 and awarded aDSc from London University in 1984, and wason numerous advisory boards including thecouncils of the Royal Society, the MRC and theRoyal College of Physicians. However, hisbiggest legacies to world Neurology have beenhis fellows, his Journal and his Society. l
FA M O U S N E U R O L O G I S T S
Selected further reading
Meadows JC, Marsden CD, Harriman DG. Chronic spinalmuscular atrophy in adults. Parts 1 & 2. J Neurol Sci1969;9:527-50 & 551-6.Spillane JD, Nathan PW, Kelly RE, Marsden CD. Painful legsand moving toes. Brain 1971;94:541-56.Marsden CD, Merton PA, Morton HB. Servo action in humanvoluntary movement. Nature 1972;238:140-3.Marsden CD, Harrison MJ. Idiopathic torsion dystonia (dysto-nia musculorum deformans). A review of forty-two patients.Brain 1974;97:793-810.Asselman P, Chadwick DW, Marsden CD. Visual evokedresponses in the diagnosis and management of patients sus-pected of multiple sclerosis. Brain 1975;98:261-82.Hallett M, Chadwick D, Marsden CD. Cortical reflexmyoclonus. Neurology 1979;29:1107-25.Marsden CD. The mysterious motor function of the basal gan-glia: the Robert Wartenberg Lecture. Neurology 1982;32:514-39.Merton PA, Hill DK, Morton HB, Marsden CD. Scope of atechnique for electrical stimulation of human brain, spinalcord, and muscle. Lancet 1982;2:597-600.Jenner P, Rupniak NM, Rose S, Kelly E, Kilpatrick G, Lees A,Marsden CD. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in the common marmoset. NeurosciLett 1984;50:85-90.Marsden CD. Hysteria--a neurologist's view. Psychol Med1986;16:277-88.Quinn NP, Koller WC, Lang AE, Marsden CD. PainfulParkinson's disease. Lancet. 1986;1:1366-9.Benecke R, Rothwell JC, Dick JP, Day BL, Marsden CD.Disturbance of sequential movements in patients withParkinson's disease. Brain 1987;110:361-79.Day BL, Dressler D, Maertens de Noordhout A, MarsdenCD, Nakashima K, Rothwell JC, Thompson PD. Electric andmagnetic stimulation of human motor cortex: surface EMGand single motor unit responses. J Physiol 1989;412:449-73.Erratum in: J Physiol 1990;430:617.Quinn NP & Jenner PJ. Disorders of Movement. Clinical,pharmacological and physiological aspects. 1989 London:Academic Press (Marsden Festschrift book, informallyknown as the Butterfly book because of the CamberwellBeauty chosen to grace the cover).Marsden CD, Harding AE, Obeso JA, Lu CS. Progressivemyoclonic ataxia (the Ramsay Hunt syndrome). Arch Neurol1990;47:1121-5.Lindvall O, Brundin P, Widner H, Rehncrona S, Gustavii B,Frackowiak R, Leenders KL, Sawle G, Rothwell JC, MarsdenCD, et al. Grafts of fetal dopamine neurons survive andimprove motor function in Parkinson's disease. Science1990;247:574-7.Brown P, Thompson PD, Rothwell JC, Day BL, Marsden CD.Axial myoclonus of propriospinal origin. Brain1991;114:197-214.Jahanshahi M, Brown RG, Marsden CD. Simple and choicereaction time and the use of advance information for motorpreparation in Parkinson's disease. Brain 1992;115:539-64.Nutt JG, Marsden CD, Thompson PD. Human walking andhigher-level gait disorders, particularly in the elderly.Neurology1993;43:268-79.Bhatia KP, Marsden CD. The behavioural and motor conse-quences of focal lesions of the basal ganglia in man. Brain1994;117:859-76.Marsden CD, Obeso JA. The functions of the basal gangliaand the paradox of stereotaxic surgery in Parkinson's disease.Brain 1994;117:877-97.
I seem to be the only person here who hasnever written a paper with David Marsden!(Gerald Stern at CDM’s Denmark Hill Festschrift, June 1987)
*
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ACNR > VOLUME 10 NUMBER 2 > MAY/JUNE 2010 > 23
The consideration of fitness to fly after neurolog-ical injury or disease is a wide ranging subjectmeriting a substantial chapter in the appropri-
ate textbook (see Further Reading). As with allaspects of aviation medicine, an understanding ofthe physics of the flight environment coupled with athorough knowledge of the pathological processwill assist in assessing fitness to fly. The aeromedicaldisposition is concerned with the likelihood of sud-den or gradual incapacitation during flight as wellas the effect of the injury or disease on physical andcognitive function; this is obviously of importancefor a pilot being able to perform the flying task, butit is also so for the well-being of the patient flying aspassenger and the effect on the safe and expedi-tious conduct of the flight. The prediction of futureevents in a disease requires knowledge of the natu-ral history and epidemiology, which is essential forassessing the flight safety risk in the hypobaric envi-ronment and the confines of an aircraft.
The hypobaric environmentThe atmosphere is compressible and has mass. Theair at the surface of the earth is supporting the massof air above it and its molecules will therefore bepressed close together, causing the density of the airto be greatest at the surface. With increasing alti-tude, there is a fall in atmospheric pressure togetherwith a decrease in density and temperature.Fortunately, the relationship between the oxygensaturation of haemoglobin and oxygen tension min-imises the effect of the reduction in partial pressureof oxygen. Ascent to an altitude of 10,000ft producesa fall in the partial pressure of oxygen in the alveolibut only a slight fall in the percentage saturation ofhaemoglobin with oxygen. However, once altituderises above 10,000ft the percentage saturation ofhaemoglobin falls quickly, resulting in the conditionof hypoxia. The cabin of a commercial airliner ispressurised to maintain an equivalent altitudebelow 8,000ft irrespective of the aircraft’s operatingaltitude. Occupants of light aircraft and gliders usepersonal oxygen equipment if flying at altitudes inexcess of 10,000ft.
Mechanical effects of pressure changeIn civilian passenger and transport aircraft, theclimb to cruise altitude takes about 30 minutes andinvolves a maximum fall of about 200mmHg(26.6kPA) in cabin pressure (to the equivalent of8000ft (2440m)). Descent to land takes much thesame time. Body fluids and tissues generally are vir-tually incompressible and do not alter shape to any
important extent when such pressures changes areapplied. The same is true of cavities such as thelungs, gut, middle ear, and facial sinuses that containair, provided that they can vent easily. Gas-containingspaces that cannot vent easily behave differently.
The thoraco-abdominal wall can develop trans-mural pressures of +100mmHg or so briefly, but isnormally flaccid and has a transmural pressure of afew millimetres of mercury. Gas within will usuallybe at a pressure very close to that outside, and mustfollow Boyle’s law. Ascent from ground level(760mmHg) to 8000ft (2440m) (565mmHg) willexpand a given volume of trapped gas in a com-pletely pliable container by about 35%. This maycause slightly uncomfortable gut distension inhealthy people but it is not an important problem.
Even very diseased lungs can vent themselvesover a minute or so. In consequence, the risk of lungrupture in normal flight is extremely rare.
The cavity of the middle ear vents easily, butsometimes fails to fill because the lower part of theEustachian tube behaves as a non-return valve, espe-cially when it is inflamed. As a result, the cavity equi-librates quite easily on ascent but does not refill ondescent, and the ear-drum bows inwards, causingpain that can be severe (otic barotrauma).
Fitness to flyDifferent medical requirements apply to the variousclasses of flying licence defined by the InternationalCivil Aviation Organisation. Class 1 medical certifica-tion is required by airline transport and commercialpilots and Class 2 by private pilots. Standards areapplied in the UK by the Aeromedical Section(AMS) of the Civil Aviation Authority on behalf ofthe European Aviation Safety Agency, using require-ments originally formulated by the European JointAviation Authorities. In the UK there is another classof licence, the National Private Pilot Licence, forwhich the driving medical standards laid down bythe Driver Vehicle and Licensing Authority areapplied. This licence may be held by pilots of sim-ple light aircraft, micro-lights and gliders, gyro-planes, balloons and airships. There are no statutorylicence requirements for hang-glider or paragliderpilots or for parachutists, although supervision iscarried out by their sport associations.
For passengers, the individual airline has a legalright to refuse carriage, with the ultimate authorityresting with the aircraft captain. Many airlinesemploy a medical adviser, and the major companiesprovide website information on flying with, or after,medical conditions. The Aerospace Medical
Prof Michael Bagshaw is Visiting Professor of AviationMedicine at King’s CollegeLondon and at CranfieldUniversity. Previously Head ofMedical Services at BritishAirways, prior to which he wasConsultant in neuro-otology at St George’s Hospital, London, anda GP in Berkshire. This followed a16-year career in the Royal AirForce as a medical officer, pilot,flying instructor and test pilot.He is Honorary CivilianConsultant Adviser in AviationMedicine to the British Army,Aeromedical Adviser to Airbus,and Medical Adviser to NetjetsEurope.
Further readingHastings JD. Aerospace Neurology.In: Davis JR et al (eds). Fundamentalsof Aerospace Medicine 4th ed.Lippincott; 2008:392-405.Merry TG. Neurological Disease. In:Rainford DJ, Gradwell DP (eds).Ernsting’s Aviation Medicine 4th ed.Hodder Arnold; 2006:683-93.
Fitness to Fly
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Association and the International Air TransportAssociation provide similar web-based infor-mation, as does the UK Civil Aviation Authority.
For pilots, aeromedical disposition followingany injury or disease is predicated on the so-called 1% rule, which is an attempt to quantifyrisk assessment. By seeking to ensure that noindividual with an incapacitation risk of overone per cent per annum operates as a pilot, itaims to achieve a target fatal accident rate of0.1 fatal accidents per one million flying hoursfor commercial aviation. For non-commercial
private aviation, the acceptable risk is greaterand an arbitrary 2% risk of incapacitation maybe acceptable. This rule is not used in assessingfitness for the UK National PPL.
Neurological ConditionsIt is impossible in a short paper to provide acomprehensive guide to fitness to fly as affect-ed by all neurological conditions. As in anyclinical situation, the following questionsshould be considered:1. Is the condition affected by reduction in
ambient pressure or hypoxia?2. Is the condition static? If so, what is the
degree of functional incapacitation?3. Is the condition progressive? If so, is the
course predictable or unpredictable?4. Can the condition be monitored
successfully?5. Can the condition result in sudden
incapacitation?6. Can the condition result in subtle
incapacitation?7. In the case of assessing fitness to fly as a
passenger, does the condition impedemobility?
PilotsThe regulatory authority approves a networkof aeromedical examiners (AMEs) who haveundergone specialist training in aviation med-icine, and are often pilots themselves. TheseAMEs perform the regular recurrent medicalassessments required for maintenance ofClass 1 and 2 licences, as well as the initialmedical examination for Class 2 private pilots,and a bond of understanding and trust devel-ops between the pilot and AME. Statutorylicence holders have a legal duty to inform theAeromedical Section (AMS) if they becomeunfit to exercise the privilege of their licencethrough injury or illness, and they frequentlydo this via the AME.
There is a partnership between the pilot, theAME and the AMS and in the event of illness orinjury, the partnership extends to include theGP and/or the specialist. The AMS requires spe-cialist reports from the treating clinician whichassist in the assessment of fitness to return toflying. This decision is taken by the AMS afterconsidering the clinical and operational fac-tors affecting flight safety. It is the pilot’sresponsibility to ensure that the appropriatereports are sent to the AMS. An excerpt fromthe relevant medical requirements for neuro-logical conditions is given in Table 1.
For recreational pilots holding a UKNational PPL, the procedure is different.Medical assessment does not use the networkof AMEs, but relies on a declaration of medicalfitness by the pilot. To validate this declaration,and to prevent concealment of disease, it hasto be endorsed by a doctor with access to thepilot’s medical records, usually the GP. Thepaperwork is reviewed by the National PPLMedical Advisor at the CAA MedicalDepartment.
Following neurological disease, the pilot’sstate of health is compared with the DVLAmedical standards of fitness to drive. If thepilot wishes to carry passengers (maximum ofthree) then the standards for DVLA Group 2professional drivers must be met. For soloflight, DVLA Group 1 standards will suffice.DVLA standards are available on-line viawww.dvla.gov.uk/at_a_glance/content.htm
Pilots with disabilitiesPeople with a wide range of disabilities maylearn to fly. The British Disabled FlyingAssociation aims “to get people with crutches
R E H A B I L I TAT I O N A RT I C L E
Table 1. Excerpt from JAR FCL-MED for Pilot Medical Requirements
FCL 3.210 Neurological requirements
(a) An applicant for or holder of a Class 1/2 medical certificate shall have no establishedmedical history or clinical diagnosis of any neurological condition which is likely tointerfere with the safe exercise of the privileges of the applicable licence(s).
(b) Particular attention shall be paid to the following (see Appendix 11 to Subpart B):
(1) Progressive disease of the nervous system,
(2) Epilepsy and other causes of disturbance of consciousness,
(3) Conditions with a high propensity for cerebral dysfunction,
(4) Head injury,
(5) Spinal or peripheral nerve injury.
(c) Electroencephalography is required when indicated by the applicant's history or on clinicalgrounds [(see Appendix 11 to Subpart B)] .
Appendix 11 to Subparts B and C - Neurological requirements
1 Any stationary or progressive disease of the nervous system which has caused or is likelyto cause a significant disability is disqualifying. However' in case of minor functionallosses' associated with stationary disease the Aeromedical Section (AMS) may consider afit assessment after full evaluation.
2 A history of one or more episodes of disturbance of consciousness of uncertain cause isdisqualifying. In case of a single episode of such disturbance of consciousness' which canbe satisfactorily explained' a fit assessment may be considered by the AMS' but arecurrence is normally disqualifying.
3 Epileptiform paroxysmal EEG abnormalities and focal slow waves normally aredisqualifying. Further evaluation shall be carried out by the AMS.
4 A diagnosis of epilepsy is disqualifying' unless there is unequivocal evidence of asyndrome of benign childhood epilepsy associated with a very low risk of recurrence' andunless the applicant has been free of recurrence and off treatment for more than 10 years.One or more convulsive episodes after the age of five are disqualifying. However' in caseof an acute symptomatic seizure' which is considered to have a very low risk ofrecurrence by a consultant neurologist acceptable to the AMS' a fit assessment may beconsidered by the AMS.
5 An applicant having had a single afebrile epileptiform seizure which has not recurred afterat least 10 years while off treatment' and where there is no evidence of continuingpredisposition to epilepsy' may be assessed as fit if the risk of a further seizure isconsidered to be within the limits acceptable to the AMS. For a Class 1 fit assessment amulti-pilot (Class 1 `OML') limitation shall be applied.
6 Any head injury which has been severe enough to cause loss of consciousness or isassociated with penetrating brain injury must be assessed by the AMS and be seen by aconsultant neurologist acceptable to the AMS. There must be a full recovery and a lowrisk (within the limits acceptable to the AMS) of epilepsy before a fit assessment ispossible.
7 Assessment of applicants with a history of spinal or peripheral nerve injury shall beundertaken in conjunction with the musculo-skeletal requirements' Appendices andManual Chapter.
8 The assessment of malignant conditions in this system is also explained in the OncologyChapter of the Manual which provides information regarding assessment and should beconsulted together with the Chapter specific to this system. All intracerebral malignanttumours are disqualifying.
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and wheelchairs into the air”, for which theyhave some modified training aircraft and qual-ified instructors. A number of scholarships areoffered annually, and individuals with severedisabilities have gone on to gain their privatepilot’s licence. Each case is assessed individu-ally by an AME representing the CAA. The website is http://www.bdfa.net/index.html
Cabin CrewCabin crew in the UK do not hold a statutorylicence with an associated medical certificate.However they are required to be fit to carryout their safety function which includes theability to open doors, operate fire fightingequipment, deploy escape slides, and controland evacuate passengers. They work in a dryhypobaric environment and experience sleepdisruption and circadian dysrhythmia. Theemployer has a duty of care to ensure fitnessfor employment in the particular environ-ment, and this function is normally dischargedby the occupational health adviser in consul-tation with the employee’s GP and/or medicalspecialist.
PassengersMedical clearance is required when:• fitness to travel is in doubt as a result of
recent illness, hospitalisation, injury, surgeryor instability of an acute or chronic med-ical condition;
• special services are required (e.g. oxygen,stretcher or authority to carry or useaccompanying medical equipment suchas a ventilator or a nebuliser).
Medical clearance is not required for carriageof an invalid passenger outside these cate-gories, although special needs (such as awheelchair) must be reported to the airline atthe time of booking.
It is vital that passengers remember to carrywith them any essential medication, and notpack it in their checked baggage.
Deterioration on holiday or on a businesstrip of a previously stable condition, or an acci-dent, can often give rise to the need for med-ical clearance for the return journey. A stretch-er may be required, together with medical sup-port, and this can incur considerable cost. It isimportant for all travellers to have adequatetravel insurance.
Assessment criteriaThe passenger’s exercise tolerance can pro-vide a useful guide on fitness to fly; if unable towalk a distance greater than about 50m with-out developing dyspnoea, there is a risk thatthe passenger will be unable to tolerate the rel-ative hypoxia of the pressurised cabin.
As well as the reduction in ambient pres-sure and the relative hypoxia, it is important toconsider the physical constraints of the pas-senger cabin. A passenger with a disabilitymust not impede the free egress of the cabinoccupants in case of emergency evacuation.There is limited leg space in an economy classseat and a passenger with an above-knee legplaster or an ankylosed knee or hip may sim-
ply not fit in the available space. The long peri-od of immobility in an uncomfortable positionmust be taken into account, and it is impera-tive to ensure adequate pain control for theduration of the journey, particularly followingsurgery or trauma. Even in the premium classcabins with more available leg room, there arelimits on space. To avoid impeding emergencyegress, immobilised or disabled passengerscannot be seated adjacent to emergency exits,despite the availability of increased leg roomat many of these positions. Similarly, a plas-tered leg cannot be stretched into the aislebecause of the conflict with safety regulations.There is limited space in aircraft toilet com-partments and, if assistance is necessary, a trav-elling companion is required. Cabin crew can-not provide individual personal assistance.
The complexities of the airport environ-ment should not be underestimated, and mustbe considered during the assessment of fitnessto fly. The formalities of check-in and departureprocedures are demanding and can be stress-ful, and this can be compounded by illnessand disability as well as by language difficul-ties or jet lag. The operational effect of the useof equipment such as wheelchairs, ambu-lances and stretchers must be taken intoaccount, and the possibility of aircraft delaysor diversion to another airport must be consid-ered. It may be necessary to change aircraftand transit between terminals during thecourse of a long journey, and landside medicalfacilities will not be available to a transitingpassenger. At London’s Heathrow Airport, forexample, transfer traffic accounts for morethan 40% of all passengers.
There is often a long distance between thecheck-in desk and the boarding gate. Not allflights depart from or arrive to jetties, and itmay be necessary to climb up or down stairsand board transfer coaches. It is thus impor-tant for the passenger to specify the level of
assistance required when booking facilitiessuch as wheelchairs.
Guidance can be found on the websites of the Aerospace Medical Association
(www.asma.org), the International Air TransportAssociation (http://www.iata.org/ps/
publications/medical-manual.htm) and the British Thoracic Society
(www.brit-thoracic.org.uk/docs/flyingguidelines.pdf), as well as individual airlines.
Training in aviation medicineIn the UK, aviation medicine is considered asub-specialty of occupational medicine. Theprime post-graduate qualification is theDiploma in Aviation Medicine awarded by theFaculty of Occupational Medicine of the RoyalCollege of Physicians. Diploma is a misnomerfor what is a high level qualification requiringsix months full time study at King’s CollegeLondon (KCL) and the Royal Air Force Centreof Aviation Medicine (RAFCAM), prior to theacademic examination. This is recognised byKCL with the award of an MSc in AerospacePhysiology & Health following satisfactorycompletion of a further six months researchproject.
KCL also offers a Basic and an AdvancedAviation Medicine course, each of two weeksduration, intended for medical practitionerswishing to be appointed as AMEs. These cours-es are ideal for those wishing to gain an under-standing of the practical principles of aviationmedicine. The website is www.kcl.ac.uk
Cranfield University offers a taught modulein aviation medicine as part of the MSc inHuman Factors & Safety Assessment inAeronautics. The module is a two week taughtcourse followed by a written examination inthe Department of Systems Engineering andHuman Factors. l
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The British Disabled Flying Association are a registered charity offering flight experiences and full flying training to PPL/NPPL,for disabled people, together with aircraft hire for disabled BDFA members. The aircraft fleet includes Piper PA28s adaptedwith hand rudder controls to allow pilots with spinal injury, lower limb weakness, amputation or spasticity to fly in safety.Pilots and student pilots with widely varying disabilities are catered for, enabling them to share the uniquely stimulating chal-lenges provided by flying light aircraft. www.aerobility.net
Photograph: Francis Lees, and Nathan Doidge (seated) – student pilots.
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ABBREVIATED PRESCRIBING INFORMATIONARICEPT® (donepezil hydrochloride fi lm-coated tablet) ARICEPT EVESS® (donepezil hydrochloride orodispersible tablet)Please refer to the SmPC before prescribing ARICEPT 5 mg, ARICEPT 10 mg, ARICEPT EVESS 5 mg or ARICEPT EVESS 10 mg. Indication: Symptomatic treatment of mild to moderately severe Alzheimer’s dementia. Dose and administration: Adults/elderly; 5 mg daily which may be increased to 10 mg once daily after at least one month. Aricept Evess orodispersible tablets should be placed on the tongue and allowed to disintegrate before swallowing with or without water. Aricept fi lm-coated tablets are taken orally. Treatment with Aricept or Aricept Evess should be initiated and supervised by a physician with experience of Alzheimer’s dementia. A caregiver should be available to monitor compliance. Monitor regularly to ensure continued therapeutic benefi t, consider discontinuation when evidence of a therapeutic effect ceases. No dose adjustment necessary for patients with renal impairment. Dose escalation, according to tolerability, should be performed in patients with mild to moderate hepatic impairment. Children; Not recommended. Contra-Indications: Hypersensitivity to donepezil, piperidine derivatives or any excipients used in Aricept or Aricept Evess. Pregnancy: Donepezil should not be used unless clearly necessary. Lactation: Excretion into human breast milk unknown. Women on donepezil should not breast feed. Warnings and Precautions: Exaggeration of succinylcholine-type muscle relaxation. Avoid concurrent use of anticholinesterases, cholinergic agonists, cholinergic antagonists. Possibility of vagotonic effect on the heart which may be particularly important with “sick sinus syndrome”, and supraventricular conduction conditions. There have been reports of syncope and seizures - in such patients the possibility of heart block or long sinusal pauses should be considered. Careful monitoring of patients at risk of ulcer disease including those receiving NSAIDs. Cholinomimetics may cause bladder outfl ow obstruction. Seizures occur in Alzheimer’s disease and cholinomimetics have the potential to cause seizures and they may also have the potential to exacerbate or induce extrapyramidal symptoms. Care in patients suffering from asthma and obstructive pulmonary disease. No data available for patients with severe hepatic impairment. In three 6-month clinical trials in individuals with vascular dementia (VaD), the combined mortality rate was numerically higher, in the donepezil group (1.7%) than in the placebo group (1.1%), but this difference was not statistically signifi cant. In pooled Alzheimer’s disease studies (n=4146), and in Alzheimer’s disease studies pooled with other dementia studies including vascular dementia studies (total n=6888), the mortality rate was numerically higher in the placebo group than in the donepezil group. Aricept fi lm-coated tablets contain lactose and should not be used in patients with rare hereditary problems of galactose intolerance, the Lapp lactase defi ciency or glucose-galactose malabsorption. Donepezil has minor or moderate infl uence on ability to drive/use machines so this should be routinely evaluated. Drug Interactions: Interaction possible with inhibitors or inducers of cytochrome P450; use such combinations with care. May interfere with anticholinergic agents. Possible synergistic activity with succinylcholine-typemuscle relaxants, beta-blockers, cholinergic agents. Side effects: Most commonly diarrhoea, muscle cramps, fatigue, nausea, vomiting, and insomnia. Very common effects ( 1/10): diarrhoea, nausea, headache. Common effects ( 1/100, <1/10): common cold, anorexia, hallucinations, agitation, aggressive behaviour, syncope, dizziness, insomnia, vomiting, abdominal disturbance, rash, pruritis, muscle cramps, urinary incontinence, fatigue, pain, accident. Uncommon effects ( 1/1,000, <1/100): seizure, bradycardia, gastrointestinal haemorrhage, gastric &duodenal ulcers, minor increases in serum creatine kinase Rare( 1/10,000, <1/1,000): extrapyramidal symptoms, sino-atrial block, atrioventricular block, liver dysfunction including hepatitis. Presentation and basic NHS cost: Blister packed in strips of 14. ARICEPT 5 mg; white, fi lm coated tablets marked 5 and Aricept, packs of 28 £59.85 ARICEPT 10 mg; yellow, fi lm coated tablets marked 10 and Aricept, packs of 28 £83.89 ARICEPT EVESS 5 mg; white, embossed, orodispersible tablets marked 5 and Aricept, packs of 28 £59.85. ARICEPT EVESS 10 mg; yellow, embossed, orodispersible tablets marked 10 and Aricept, packs of 28 £83.89. Marketing authorisation numbers: ARICEPT 5 mg; PL 10555/0006. ARICEPT 10 mg; PL 10555/0007. ARICEPT EVESS 5 mg; PL 10555/0019 ARICEPT EVESS 10 mg; PL 10555/0020. Marketing authorisation holder: Eisai Ltd. Further Information from: Eisai Ltd, EKC, Mosquito Way, Hatfi eld, Hertfordshire, AL10 9SN and Pfi zer Limited, Walton Oaks, Dorking Road, Tadworth, Surrey KT20 7NS. Legal category: POM. Date of preparation: December 2009.
Date of preparation: January 2010.
Adverse events should be reported.Reporting forms and information can be
found at www.yellowcard.gov.uk. Adverse events should also be reported to
Macdonald Critchley described personificationof paralysed limbs in hemiplegics followingan initial anosognosia over 50 years ago. He
reported personal knowledge of patients who calledtheir hemiplegic limbs “George”, “Toby”, “silly billy”,“floppy Joe”, “baby”, “gammy”, “the immovable one”,“the curse”, “lazy bones”, and “the nuisance”. He foundit strange that this phenomenon had not been previ-ously described in the literature.1 A case of personifica-tion of a presumed functional neurological disabilityis presented.
A 30-year-old right-handed man was referred tothe neurology clinic following attendance at A&Ewith an abrupt onset movement disorder affectingthe right arm and leg. Asked what the problem was,he held up his shaking right hand and laughed, say-ing “This is Trevor”. Present for about a month, theshaking had become less noticeable in the leg, var-ied from time to time, and was worse with reachingfor, rather than holding on to, objects. It had occa-sioned the loss of his job as a graphic designer.There was no prior or family history of movementdisorder, but the patient was treated for depressionwith paroxetine and had been investigated for jointpains with no explanation found. His examinationshowed no abnormalities, specifically no neglect,aside from a tremor of the right hand and arm whichwas reduced with distraction and could beentrained with contralateral fast finger movements.The patient’s affect was ostensibly cheerful, jokey,and lacking in concern. A provisional diagnosis of
psychogenic tremor was made based on the historyof abrupt onset, positive entrainment, absence of fin-ger tremor, and the history of depression and proba-ble somatoform disorder.2 Standard brain magneticresonance imaging was normal and EEG showed nocorrelate with the shaking movement which waspresent throughout the recording.
Although most of the cases reported by Critchleyoccurred in the context of left hemiplegia, he noted atleast one such case in a right-handed man with a right-sided paralysis. A number of other common featureswere also noted, particularly a detached attitudetowards the deficit which was treated with insou-ciance and cheerful acceptance, reminiscent of theanosodiaphoria characterised by Babinski.3 These fea-tures were shared by this patient, although since therewas no history of prior anosognosia it may be a falsegeneralisation to compare this case with personifica-tion of hemiplegia.
Critchley mentioned that personification might alsooccur in amputees with phantom limbs, as well as inhemiplegics,1 but no previous accounts of personifica-tion of neurological deficits of presumed functionalorigin have been identified. Apparent anosognosia fora movement disorder (hemiballismus) was mentionedby Weinstein & Kahn.4
The neurobiological mechanisms in the currentcase are unknown, but presumably involve some formof dissociation or alteration of body image or schema.It might also fall under the rubric of motor conversiondisorder. l
Critchley Revisited:Personification of a NeurologicallyDysfunctional Limb
AJ LarnerCognitive Function Clinic, Walton Centre for Neurology and Neurosurgery,
1. Critchley M. Personification of paralysed limbs in hemiplegics. BMJ 1955;ii:284-6.2. Bhatia KP, Schneider SA. Psychogenic tremor and related disorders. J Neurol 2007;254:569-74.3. Babinski JM. Contribution à l’étude des troubles mentaux dans l hémiplégie organique cérébrale (anosognosie). Revue Neurologique 1914;27:845-8.4. Weinstein EA, Kahn RL. The syndrome of anosognosia. Arch Neurol Psychiatry 1950;64:772-91.
REFERENCES
Clinical Research Training FellowshipsThe Association of British Neurologists is co-ordinating a new funding opportunity for clinically qualified trainees in neurologyand related clinical disciplines. The scheme is supported by: Ataxia UK • The Guarantors of Brain • The Multiple Sclerosis Society • The Parkinson's Disease Society • The Patrick Berthoud Charitable Trust managed by the Charities Aid Foundation
Applications are invited to fund 3 year clinical research training fellowships in any neurological discipline, with additional opportunities for projects in ataxia, multiple sclerosis, and Parkinson’s disease. Salary, university fees, reasonable travel costs, and laboratory consumables will be funded.
Closing date: 31th May 2010Interviews for shortlisted candidates: 29th July 2010. Funding decision: early September 2010
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On Tuesday 10th July 2000, I gave birth to ahealthy girl, Ellie Marie Caunter. Shortlyafter taking her home she never seemed to
settle down. I took Ellie to see the GP, who diag-nosed it as colic. This went on continuously forthree months with constant crying throughout.After that period Ellie started to settle down, grow-ing into a beautiful little girl. We celebrated Ellie’s1st birthday watching her take her first steps; it was-n’t until shortly after this that her health started todeteriorate.
Our first concerns were at dinnertimes whenEllie would purge on her food, the second concernwas that Ellie constantly wanted me holding herand would scream for hours on end, the only timeEllie seemed settled was when she was in my arms.Thirdly, when feeding Ellie her bottle, I noticed hereyes would roll to the back of her head showingthe whites of her eyes. This caused me great con-cern as I thought she was having a fit. The finalthing was when all Ellie’s motor skills had gone, herspeech had stopped, her ability to walk, sit and bal-ance herself were lost.
I was so alarmed that I took her straight to thedoctors. How could my daughter just wake up onemorning and lose all her abilities? The GPinformed me it was just a common cold; theybooked an appointment to see a paediatricianwho I was to see in a fortnight at Torbay hospital.Whilst waiting for my appointment date Ellie dete-riorated so much so that we noticed her head wastilted to her left hand side. It was a mother’s instinctthis was no cold, so I took matters into my ownhands and took Ellie to A and E. I explained allEllie’s symptoms to the junior doctor includingEllie’s head constantly sitting to the left hand side,he suggested it was teething and was sending mehome with paracetemol. I was adamant this wasnot a teething problem, after bringing up my othertwo sons I knew this was not normal behaviour forany child.
Therefore, I asked to see a paediatrician; theytook one look at Ellie and admitted her. During thedays ahead Ellie went through every test imagina-ble, this was very distressing for me and my hus-band to watch our little girl go through. After aweek of tests ranging from blood test to brain scansetc, all results came back clear, no one could pinpoint what was wrong with her.
We met with Dr A, a paediatric consultant. Shetold me of one other case that she had seen beforeshe was quite confident taking into account allEllie’s symptoms that it was the same diagnosis, avery rare condition, opsoclonus-myoclonus, alsoknown as dancing eye syndrome. It took her onlyone week to diagnose Ellie.
Dr A told us that we would have to travel toFrenchay Hospital in Bristol for Ellie’s medication.On arrival straight from Torbay hospital we weremet by Dr B who had waited behind to see us as itwas a late Saturday afternoon. We weren’t to beseen till the Monday therefore Dr B felt it necessaryto see Ellie on her first arrival. He tested Elliestraight away, noticing on first glance Ellie’s eyes.
After taking a closer look he saw Ellie’s abnormaleye movements and confirmed the erratic eyemovement as dancing eye syndrome. He put Ellieon 10mg of steroid. We were left in the dark allweekend, devastated not knowing anything aboutthe condition and what our poor daughter wasgoing through. We were living a nightmare, my twosons were back in Torbay with family, too young toknow what was going on and missing us, whilst ouryoungest child and only daughter was deterioratingright in front of our eyes. Her ability to sit and sup-port her own bodyweight had just gone. She wasconstantly in our arms as she was screaming, herhands were shaking and she couldn’t settle to go tosleep. We were so distressed just wanting to help her.
Monday arrived and we saw Dr B first thing at9am. Once he started telling us about the dancingeye syndrome, we had the most devastating newsany parent could hear, there was a possibility our13-month-old daughter could have a tumour. Wejust couldn’t believe what we were hearing. Ellieunderwent a brain scan for the second time; thiswas a mistake on the hospital’s behalf they weremeant to be carrying out a scan on her abdomento see if they could find a tumour. Our daughterhad been put out unnecessarily and had toundergo the same procedure again this time tolook for a tumour on her abdomen. After the sur-gery they confirmed they had found a tumour onEllie’s adrenal gland. We had the option for it to beremoved and me and my husband thought it bestto remove it.
During this time I also went to see an oncologist.They told me that Ellie was stable at the time but ifpurple spots were to appear anywhere on her bodythen this could be fatal. At that last word we wentinto shock, all the family rushed up the motorwayto comfort us, we didn’t know how much time Elliehad left. It was such an emotional time for the fam-ily. For three weeks we had to stay at Frenchay, mon-itoring her medication which was oral: steroids of10mg daily and medication to help her sleep.
After Frenchay, we were allowed to take Elliehome with us until we were moved onto Bristolchildren’s hospital. It was such a relief to be takingmy daughter home to be back with the family andmy two boys. Although this was only a short visit asin seven days time we had to be at Bristol chil-dren’s hospital, this is where Ellie underwent sur-gery to have the tumour removed.
Whilst at Bristol hospital they took videofootage to record Ellie’s abnormal eye movement.The surgery went ahead and the outcome was aneuroblastoma capsulated so Ellie didn’t have tohave any follow-up treatment. We left the hospitala week later; at this stage Ellie’s eyes were goingabsolutely ballistic. Ellie was very distressed atthis time.
I would now like to talk about Ellie’s behaviourwhen she was first diagnosed to the present day.
Behaviour was a huge issue; the constantscreaming fits, the head banging, the aggressive-ness in her and just her general frustration and dis-tress. To calm Ellie’s screaming I would constantly
Dancing Eye Syndrome
Mandy Caunter mother to Ellie Marie Caunter,who was diagnosed with a veryrare condition, OpsoclonusMyoclonus, in 2001. Ellie was just13 months old when medics diagnosed her with the conditionalso known as Dancing EyeSyndrome. Ellie is now 9 yearsold.
have to have Ellie sat on my hip and keepingher moving. My husband would have to takeher out in her pram, at all hours of the nightjust to calm her down. The head banging hap-pened when I physically couldn’t carry herany longer. I would place her on the floor andimmediately she would start banging her headon the floor until she was back in my arms. Heraggressiveness was a problem to her olderbrothers, in her frustration she would pinchthem and be very nasty towards them. Forcomfort she would play with her dad’s ears,making them bleed. This was all due to frustra-tion again. Ellie would be very distressed whenaround loud noises and sudden movements.Moving traffic and car journeys made her evenworse. When in her car seat she would find thestrength to release herself so that she could beon my lap. Her strength was abnormal. Asevery year went by slowly being weaned offher medication, her behaviour steadilyimproved. Ellie is now nine years old, she does-n’t really have any major behaviour problemsbut when becoming ill we notice she can stillbe slightly aggressive. Also Ellie is very protec-tive over her possessions and doesn’t likechange. She will notice the smallest of differ-ences whether it is a new piece of furniture orsomething not being in its usual place.
The emotional side of things have been veryhard for all the family. When Ellie was in theprime of her illness, the emotional strain wasunbearable. The constant attention Ellie bothwanted and needed was a massive strain for theimmediate family. Ellie was very sensitive toeverything. My husband had to give up work asit became impossible for me to care for Ellie24hours a day as well as keeping a normal fam-ily environment. Our much loved family dogthat had been with us for five years had to go as
we just couldn’t look after him any longer. Thestrain got so bad on my two sons who were only11 and 13 that they stayed with their grandpar-ents. This was just for them to get peace andquiet as they were both at school. Myself andmy husband’s marriage was at breaking pointdue to the stress and strains of looking after achild with dancing eye syndrome. Sleep was ahuge factor, as we were lucky to get 2-3 hours anight. Ellie would sleep in bed with us as this isthe only place she would settle. This went onuntil the age of seven.
There were times when we couldn’t see anylight at the end of the tunnel. Ellie had been offsteroids for six months where she was makingreally good progress. Then she had a virus andshe lost all of her abilities again. At this stage Ijust couldn’t take anymore, I became so lowthat I didn’t really want to carry on. The doctorprescribed me anti-depressants which helped.As each year has gone by Ellie has improvedslightly with her emotions. She is still very sen-sitive and shy. She finds it hard to play in agroup and prefers to have one to one compa-ny. She has a very caring and gentle nature, tothe extent that I have concerns especially withher school life which I will go into further now.
Ellie found starting school hard as she wasso used to being with me 24hours a day. Shewent to playschool, where she had one to onesupport. The hardest part was separating herfrom me; I had to stay with her as it was impos-sible to leave her. After a year of being at playschool she accepted me leaving her, althoughat times it was hard. She started mainstreamschool still with the problem of being awayfrom me. They suggested that a statementwouldn’t be needed as they didn’t detect anylearning difficulties at this stage. They wantedto concentrate more on settling Ellie into the
schooling environment as this was the mainconcern of the time. As Ellie progressedthrough the years it was evident Ellie hadquite severe learning difficulties. It was quiteevident that Ellie needed to be statemented inyear three. I felt they had left it too late as Elliewas so far behind. I strongly believe that achild with dancing eye syndrome should bestatemented as soon as they start schooling.She struggles with the academic pace as testshave proven that she is about two and halfyears behind her peers. She gets a lot of pres-sure from her peers as they notice she can’tkeep up as well as they do. She accepts nowthat she has to go to school but doesn’t enjoyit. She has one to one help every morning atschool with her maths and literacy and in theafternoons she is left to her own devices. Ellieis very behind with her reading and writingskills, hopefully she will be able to pick it upone day. Ellie is in year five now so in a year’stime she will be moving onto secondaryschool. We have been advised by the senco ather school that Ellie would benefit more aca-demically if she went to a special needsschool. My husband and I are at the stage nowwhere we are going to have to make the bestdecision for Ellie’s future.
On a positive note, Ellie is a happy go luckylittle girl. We never thought she would be ableto ride a bike without stabilisers but she can.She is a very good swimmer and belongs to aswimming club which she enjoys very much.We feel very lucky as the dancing eye syn-drome seems to have disappeared from herbut unfortunately it has left her with severelearning difficulties. Life now is so much easi-er for the whole family unit, it’s been a toughride but things have definitely improved overtime. l
P E R S O N A L P E R S P E C T I V E S
B O O K R E V I E W S
Oxford Handbook of ClinicalRehabilitation Second Edition
It is daunting to review an Oxford handbook, especial-ly when written by colleagues whom I admire and whoare experts in the field of rehabilitation. The handbookhas the reputation for being an essential part of everyrehabilitation clinician’s bookshelf. It is primarilyaimed at a wider multidisciplinary audience and notjust at doctors in the field of clinical rehabilitation. Iwould like to emphasise that this review of the book ismore from the perspective of a medic within the multi-disciplinary team and specifically a trainee’s view-point.
The book easily fits in the coat pocket with less than500 pages of standard Oxford handbook size. The initialfive chapters deal with the general concepts of rehabil-itation like the ICF and multidisciplinary team. Theseare followed by chapters on management of somecommon clinical themes encountered in rehabilitationlike spasticity, continence, sexuality, eating and swallow-
ing disorders, communication, technical aids, cognitiveand behavioural problems. And then there are chaptersdedicated to specific neurological conditions like mul-tiple sclerosis, stroke, etc.
The ICF model and general concepts in epidemiolo-gy are brilliantly summarised. The chapters on the reha-bilitation team and services are relevant and to thepoint. The chapter on assessment and outcome meas-ures describes the types of scales and some scales rele-vant to common clinical problems. This is an areawhich is emphasised more in rehabilitation practicethan in other clinical specialties, and which every reha-bilitation MDT member (medic, physio, occupationaltherapist, speech and language therapist, etc.) shouldbe well informed about. I think a brief description ofthe different psychometric properties like validity, relia-bility, and floor and ceiling effect could be included inthis chapter for the benefit of junior clinicians. One
Edited by: M Barnes, A Ward, S Ryan, S Stark Published by: Oxford UniversityPress (2009) Price: £27.95 ISBN: 9780199550524
topic missing in the initial chapters is ‘assess-ment of capacity’ with reference to the MentalCapacity Act (MCA) and the recent Deprivationof Liberty Safeguards (DOLS).
Among the clinical theme chapters, the sys-tematic approach to treating spasticity and uri-nary continence is very useful. The book right-ly has a separate chapter dealing with sexualproblems in complex neurological conditions.The chapters on behavioural disorders, psychi-atric problems and cognitive dysfunction care-fully define the role of psychological strate-gies/medication and the fine balance betweenthe two needed in a rehabilitation setting. Theflow chart on vocational rehabilitation and sec-tion on challenges during transition to adultlife are impressive. It is a surprise not to findmanagement of sialorrhoea in the chapter onswallowing disorders.
The chapters on specific neurological con-ditions deal excellently with the epidemiology,management and most importantly prognosiswhich are core essential facts needed whendealing with family and carers. The conditions
covered are multiple sclerosis, stroke, traumaticbrain injury, spinal cord injury, Parkinson’s dis-ease, MND, peripheral nerve disorders, epilepsyand dementia. There are two chapters dealingwith common (non-inflammatory) muscu-loskeletal conditions and inflammatoryrheumatologic conditions.
The practice of neurorehabilitation andmusculoskeletal rehabilitation is very closelylinked in countries outside UK because reha-bilitation physicians are trained in both beforethey sub-specialise in their areas of interest.Oxford handbooks usually have substantialinternational readership and to maximise this,I feel the handbook should provide more roomfor musculoskeletal rehabilitation. For exam-ple, the latest evidence on different rehabilita-tion approaches for chronic back pain likefunctional restoration programmes could beadded in the section on chronic back pain. Theevidence for specific exercise regimens, steroidinjections, autologous blood injections(approved by NICE) in the rehabilitation oftendinopathy could be included in the rele-
vant chapters. Rehabilitation of concussion insport could also be considered for inclusion.
The chapter on amputation is brief and coulddo with more facts on prostheses, it omits man-agement of phantom pain altogether (in fact itdoes not feature anywhere in the book). Normalgait cycle (and abnormal gait patterns) is anoth-er important topic missing from the book. Thereis a section on ‘chronic pain’ in one of the earlierchapters but it lacks sufficient detail. A dedicatedchapter on pain management among the initialchapters would have been ideal.
Overall, this is an excellent pocket guide ona par with other Oxford handbooks. A littlemore expansion in a few chapters and someadditional topics would make the handbookmore appealing to doctors in the field and giveit a better international readership. There isalready sufficient blank space in the book andsuch expansion can easily be made withoutincreasing the volume of the book. I am awarethe blank space is meant for reader’s notes andobservations, but frankly speaking how oftendoes this happen? l
Two books on confabulation published within a yearby OUP: one thinks, perhaps, of London buses, but, bycontrast, these books are an experience well worthwaiting for. For example, did you know that inGerman, WIGAN is a non-word (Schnider, p 149)?
Schnider’s monograph is suffused with his clinicalexperience of trying to rehabilitate confabulatingpatients: even in the midst of the science he acknowl-edges that this is a “gruelling experience” (p243). Areview of the history of confabulation, includingtranslations from the early works of Korsakoff,Kraepelin, Pick and others, is followed by the thornyissue of classification, with Schnider developing a 4-fold schema of intrusions, momentary confabula-tions, fantastic confabulations, and behaviourallyspontaneous confabulations (p63-4), of which the lat-ter form his main area of study. The aetiology is exam-ined, with anterior limbic structures thought culpa-ble, and the pathogenesis, including a wide variety ofdiseases, along with associated disorders (amnesia,disorientation, false recognition syndromes includingthe Capgras delusion, and anosognosia).Mechanisms are elucidated by means of psychophys-ical and neuroimaging studies, leading to the propo-sition that confabulators have reality confusion and afailure to integrate contradictory information due tothe failure of a filtering process, 200-300 ms after stim-ulus presentation and before recognition and re-encoding, which normally permits suppression ofcurrently irrelevant memories. This is a fascinating
book, systematic in its approach. For those disin-clined to battle through the detail, the conclusions toeach chapter are excellent.
Hirstein’s multi-author volume is, as expected,more diffuse than Schnider’s but none the less stimu-lating. False memories, only briefly touched on bySchnider, are described at greater length here, in twochapters (from Loftus and Zaragoza) the import ofwhich I found rather chilling: our brains have a sur-prising cognitive vulnerability to forced fabrication (Iwould be interested to know if this also applies toeidetics). Coltheart & Turner present evidence thatthe normal response to questions we don’t know theanswer to is not, as might be imagined, to admit igno-rance with an “I don’t know” response, but to indulgein confabulation, a tendency exacerbated in certainbrain disease states (and by some clinicians?).Wheatley, in what is the best chapter (or worst,depending on your degree of concreteness) I haveread in many moons, demolishes the notion of thebrain as veridical. The book is more philosophicallyoriented than Schnider’s, and perhaps more peripher-al to clinical interests, though still grounded in clini-cal neuroscience.
In summary: in the human brain, memory is a con-struction, confabulation is normative, perception isillusion, and “meaning” is privileged over accuracy. Anihilist might conclude that life mediated throughsuch a prism is an essay in futility, and aporia the onlytenable neurophilosophy. l
The Confabulating Mind. How the brain creates reality
Confabulation. Views from neuroscience, psychiatry, psychology, and philosophy
Reviewed by:AJ Larner, Cognitive Function Clinic,
WCNN, Liverpool, UK.
Editor: W Hirstein Published by: Oxford UniversityPress 2009 Price: £29.95 ISBN: 978-019920891-3
Introduction and definitionsThis article provides a systematic approach to thecauses of developmental delay and the impor-tance of its rigorous investigation. It particularlyhighlights practical aspects relevant to adult neu-rological practice.
Delayed development most commonly followsthe usual pattern of development where skills areacquired more slowly (e.g. Down’s syndrome).Less commonly, skill acquisition can be disor-dered (e.g. autism). ‘Delay’ is a misnomer – chil-dren with developmental problems rarely ‘catchup’, and will usually have continuing difficultieswith learning later in life.
Developmental delay is common, affecting 1-3% of the population.1 Developmental delay isdefined as significant delay (more than two stan-dard deviations below the mean) in one or moreof the following developmental domains:2
m Gross motorm Vision & Fine motorm Hearing, Speech & Languagem Social, Emotional & BehaviouralDevelopmental delay is a descriptive term used forchildren whose difficulties are apparent earlier inchildhood where a cause is not yet established. Itdoes not imply a particular organic or syndromiccause, and the term does not appear in ICD-10.3
The focus of this article is Global Developmental Delay.
Causes of Global Developmental DelayGlobal developmental delay can be the present-ing feature of a huge number of neurodevelop-mental disorders (from learning disability to neu-romuscular disorders). It is not possible to pro-vide an exhaustive list; Table 1 gives an approachto aetiology.
Careful evaluation and investigation can reveala cause in 50-70% of cases.4,1 This leaves a largeminority where the cause is not determined. It isstill useful to investigate globally delayed devel-opment whatever the age of the child (occasion-ally older children with significant disability maynot have been investigated adequately).
Developmental Delay –Causes and Investigation
Angharad V Walters is a Specialist Registrar in Paediatric Neurology atAddenbrooke’s Hospital,Cambridge. She studiedPhysiology and Medicine atBristol University. She is trainingin paediatric Neurodisability andhas a particular interest in learning disability and behaviour.
TABLE 1: Causes of global developmental delay (adapted from Forsyth and Newton 20075).
Category Comments
Genetic or Syndromic • Easily identified syndromes e.g. Down’s syndromeIdentified in ~ 20% of those without • Genetic causes that are less obvious in early childhood e.g. Fragile X, Velo-cardio-facial syndromeneurological signs, dysmorphic features (22q11 deletion), Angelman’s, Soto’s, Rett's, maternal Phenylketonuria, Mucopolysaccharidoses,or a family history Duchenne Muscular Dystrophy, Tuberous Sclerosis, Neurofibromatosis Type 1, and subtelomeric
deletions
Metabolic • Nationwide universal neonatal screening for Phenylketonuria (PKU) and Medium-chain acyl-Co A Identified in ~1% of those without Dehydrogenase deficiency (MCAD).neurological signs, dysmorphic features • e.g. Urea Cycle disorders.or a family history
Endocrine • There is universal neonatal screening for congenital hypothyroidism
Traumatic • Acquired brain injury
Environmental Causes • Children require their basic needs for food, clothes, warmth, love and stimulation to be met to develop normally.
• Children in neglectful, abusive, fearful, under stimulated environments may not show normal development.• This can be a contributory factor co-existing with other pathology and where the child’s needs are
outside the parents’ capacity to provide for them.
Cerebral Malformations • e.g. Neuronal Migration Disorders
Cerebral Palsy and Developmental • Motor difficulties can prejudice development in generalCoordination Disorder (Dyspraxia)
Infections • Perinatal e.g. Rubella, CMV, HIV• Neonatal meningitis
Toxins • Fetal: Maternal alcohol or drugs in pregnancy• Childhood: Lead toxicity
Developmental Delay can be dividedinto:
Global developmental delay – delay in two or more domains (often delayed in all domains)
Specific developmental delay (e.g. Motor or Speech & Language) – delay in a single domain
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Why is finding a cause important?Establishing a cause has many benefits for thechild and family and improves overall qualityof life:4
m The family gains understanding of the condition, including prognostic information
m Lessens parental blamem Ameliorates or prevents co-morbidity by
identifying factors likely to cause secondary disability that are potentially preventable e.g. surveillance of other systems such asvision and hearing
m Appropriate genetic counselling aboutrecurrence risk for future children and thewider family
m Accessing more support (e.g. within education services and specific syndrome support groups)
m To address concerns about possible causese.g. events during pregnancy or delivery1
m Potential treatment for a few conditions
Investigation of Global DevelopmentalDelayThorough history and examination are vital toproduce a formulation of the child’s problemand target investigations appropriately.4,6 Thediagnosis may occasionally be immediatelyobvious from history and examination. Moreoften time is needed to review clinical fea-tures, case notes, prior investigations and toconsult the literature, dysmorphology and neu-rogenetic databases.4
Transfer of a patient into your clinic frompaediatric services is a good opportunity toreview the diagnostic process. Most investiga-tions are likely to have been performed earlyin the child’s life; medical advances especiallyin genetic investigations and neuroimagingtechniques may allow further diagnostic possi-bilities now. Clinical geneticists are an invalu-able source of diagnostic acumen and sugges-tions for further suitable investigations.
The evidence base for investigation of devel-opmental delay is poor and published work ismainly consensus opinion.2 There is no one
agreed recipe for the investigation of globaldevelopmental delay and there is much varia-tion in practice. Historically, there has beenpatchy introduction of tests as they becameavailable. This means it is well worth reviewingwhat investigations have actually been done.
A scheme illustrating the investigations con-sidered for global developmental delay isshown in Figure 1. You should expect the firstline investigations to have been done, and rel-evant second line investigations depending onclinical circumstances.
Practicalities: The approach to performing investigations isinfluenced by:m identifying treatable conditionsm identifying prevalent serious conditions
(e.g. Creatinine Kinase for DuchenneMuscular Dystrophy)
m economic considerations (inexpensive,easy to perform tests for less common disorders, e.g. Fragile X)
m the practicalities of performing the investigations on young children
PA E D I AT R I C N E U R O L O GY
First LineChromosomesFragile XU & ECreatinine KinaseThyroid FunctionFBCFerritin Vision and Hearing assessments
MetabolicFamily HistoryConsanguinityRegressionOrganomegalyCoarse FeaturesSeizuresAbnormal Head SizeEpisodic decompensationCongenital AtaxiaSensory impairment Including Glue Ear
GeneticsDysmorphismAbnormal GrowthSensory ImpairmentUnusual BehavioursFamily History
Second Line
Figure 1: A scheme illustrating the investigationsconsidered for global developmental delay (adapted fromMcDonald et al 20062 and ‘A guide to investigation ofchildren with developmental delay in East Anglia 2005’)1.
Figure 1 Notes:
• MECP2 = gene for Rett’s• VLCFA = Very Long Chain Fatty Acids are for
Peroxisomal disorders (e.g. Adrenoleukodystrophy)• GAGs = Glycosaminoglycans are for
Mucopolysaccharidoses (e.g. MPS type III Sanfilippo)• WC enzymes = White cell enzymes. These and
oligosaccharides are tests for lysosomal storagedisorders (e.g. GM1 Gangliosidosis).
• Transferrins are for congenital disorders ofglycosylation (CDG) e.g. type 1a
• 7-dehydrocholesterol is for Smith-Lemli-Opitz• Paired CSF and plasma lactate are to investigate
mitochondrial disorders where there are concernsabout growth, multisystem involvement, visual andhearing impairments, and abnormal MRI brain.1
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PA E D I AT R I C N E U R O L O GY
Simple blood tests can be achievedwithout too much difficulty.MRI brain may require a general anaes-thetic. This may have been delayed if thechild was approaching an age (~ 5yrs ordevelopmental equivalent) where theycould manage an MRI without an anaes-thetic. If an anaesthetic is planned, considera-tion should be given to whether otherinvasive investigations can be doneunder the same anaesthetic e.g. bloodtests, lumbar puncture, and skin or mus-cle biopsy.
GeneticsChromosome analysis yields the highest num-ber of abnormalities when investigating globaldevelopmental delay, even where there are noclinical features of a genetic problem.2
Chromosomes and Fragile X testing are firstline investigations if history and examinationdo not reveal an obvious aetiology. Fragile X isthe commonest cause of inherited learningdisability, but remains a rare disorder. Its dys-morphisms are difficult to recognise clinicallyin younger children and girls.
Subtelomeric rearrangements are karyotyp-ically invisible and are traditionally looked forwhere the karyotype is normal but a geneticabnormality is still suspected. Specific tests forsub-microscopic microdeletions (e.g. forWilliam’s or Velo-cardio-facial syndrome) canbe requested when clinical index of suspicionis high.1
The new advances in Microarray technolo-gy offer up to 15% more diagnoses than con-ventional karyotyping for global developmen-tal delay. They are cost-effective and, althoughnot yet used routinely, are likely to be adoptedwidely in the future.7
NeuroimagingCranial MRI in young children (≤5-6yrs)requires day case admission to hospital forsedation or general anaesthesia. It is a secondline investigation performed in the circum-stances outlined in Figure 1, in addition toglobal developmental delay. Neuroimagingperformed in the first two years of life beforecerebral myelination has been completedshould be repeated after an interval of about ayear.
The proportion of neuroimaging abnormal-ities found in children with delayed develop-ment varies widely between studies (9-80%).8
Where high proportions are reported, some ofthe reported abnormalities are in childrenwhere the diagnosis would have been obviousclinically, not contributory to the diagnosis, orof uncertain significance. The yield of useful,diagnostic abnormalities is higher (60%+)using newer imaging techniques and in a pop-ulation selected for global developmentaldelay with the clinical features outlined inFigure 1.1,2
CT scanning is only used where cerebralcalcification is suspected (e.g. perinatal infec-tion) or to look for an abnormality of skullbones.
MetabolicIndividual Inborn Errors of Metabolism (IEM)are a rare cause of global developmentaldelay (~1%). However, they can present withnon-specific developmental delay and someare amenable to treatment. Metabolic investi-gations are targeted and selective (there is nosuch thing as a ‘metabolic screen’). Usefulmetabolic investigations and the clinical cir-cumstances in which they are considered areoutlined in Figure 1.1,2
Biotinidase deficiency uncommonly pres-ents with global developmental delay withoutother features, but early diagnosis and treat-ment improves outcome. This is not a universalfirst line investigation in many parts of the UK,but some authors argue that it should be.2 Manycountries screen for this disorder as part of uni-versal neonatal screening; the UK does not.
BiochemistryCKBoys with Duchenne Muscular Dystrophy canpresent with delay in more than one domainof their development (e.g. language and motordelay); therefore Creatinine Kinase (CK) ismeasured as a first line investigation in boyswith global developmental delay. CK measure-ment is considered in girls with severe global(and especially motor) developmental delay.
Renal, BoneElectrolytes and Urea are first line investiga-tions, and Calcium measurement can assist inthe diagnosis of Velo-cardio-facial and Williamssyndromes, and pseudohypoparathyroidism.
TFTThyroid Function tests are easy to perform andhave historically been part of investigations fordevelopmental delay. TSH is measured as partof universal neonatal screening. In addition,many chromosomal abnormalities are associat-ed with an increased and ongoing risk ofhypothyroidism (e.g. Turner’s, Velo-cardio-facialsyndromes). Thyroid function tests are worthrepeating periodically in those at risk as theclinical diagnosis of hypothyroidism is more dif-ficult in those with developmental difficulties.
LeadChronic lead toxicity has long-lasting develop-mental effects (developmental delay, behav-ioural change and poor coordination) and ispotentially treatable by chelation. Despite evi-dence that children with developmental prob-lems have higher blood levels of lead than thegeneral child population;9 interpretation ofblood lead levels remains controversial.10
FBCA Full Blood Count (FBC) and Ferritin identi-fies Iron deficiency which can cause globaldevelopmental delay and is easily treated.2
NeurophysiologyEEG should not be performed routinely, butreserved for those with seizures, or speechregression (looking for Landau-Kleffner) asso-ciated with global developmental delay.
Other InvestigationsAll children with global developmental delayshould have Visual and Audiology assessmentsearly on. An Ophthalmology opinion shouldbe sought if there are concerns about visualfunction, abnormal appearance of the eyes orwhen looking for clues to the underlying diag-nosis.
A TORCH screen for congenital infection isperformed in children with IntrauterineGrowth Retardation (IUGR), microcephaly, orsensory impairments. PCR for infective organ-isms can be performed retrospectively on theblood spots taken for the neonatal screeningprogramme, even many years later.
Radiographs are performed primarily forsuspected skeletal dysplasia, or lead toxicity.Subtle skeletal dysplasia can be difficult todiagnose on radiographs performed whenmost of the skeleton is not yet ossified andmay need to be repeated at a later date.
Conclusionsm Global developmental delay is a common
problem in paediatric practice and has awide aetiology.
m Selective investigations are useful in deter-mining the cause, but the cornerstone of thediagnostic process is careful clinical exami-nation.
m Finding a cause confers many medical andsocial benefits for the child and family.
m Recent technological advances, especiallyin Genetics and Neuroimaging, make itimportant to review the need for repeat orupdated investigations.
m The transfer of a patient to your practicefrom paediatrics is an opportunity to reviewthe diagnosis (or lack of one), and to evalu-ate the need for further investigation. l
1. A guide to investigation of children with developmentaldelay in East Anglia 2005. Accessed atwww.phgfoundation.org/file/2366 on1/03/10
2. McDonald L, Rennie A, Tolmie J, Galloway P, McWilliamR. Investigation of global developmental delay. Arch DisChild 2006;91:701–5.
3. Williams J. Global developmental delay – globally help-ful? Dev Med Child Neurol 2010;52(3):227.
4. Whiting K. Investigating the child with learning difficul-ty. Current Paediatrics 2001;11:240-7.
5. Forsyth R and Newton R. Paediatric Neurology, OxfordUniversity Press, 2007.
6. Maw, A. Paediatric Neurology – History andExamination. Advances in Clinical Neuroscience andRehabilitation 2009;9(5):34-6.
7. Wordsworth S, Buchanan J, Regan R, Davison V, SmithK, Dyer S, Campbell C, Blair E, Maher E, Taylor J, andKnight S. Diagnosing idiopathic learning disability: acost-effectiveness analysis of microarray technology in theNational Health Service of the United Kingdom. GenomicMed 2007 September;1(1-2):35–45.
8. Schaefer GB and Bodensteiner. JB. Radiological findingsin developmental delay. Seminars in Pediatric Neurology1998;5(1):33-8.
9. Lewendon G, Kinra S, Nelder R, Cronin T. Should chil-dren with developmental and behavioural problems beroutinely screened for lead? Arch Dis Child2001;85:286-8.
10. Aicardi J. Diseases of the Nervous system in childhood.3rd Edition, MacKeith Press, 2009.
REFERENCES
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Neurology in the UK has traditionally beena popular and competitive specialty, withno difficulty in attracting applicants from
amongst the best medical graduates. Dramaticchanges in neurology training have occurred inrecent years.1,2 Alongside this, it seems that neu-rology may be beginning to have difficultyrecruiting trainees. Although neurologyremained the second most competitive medicalspecialty nationally in 2007, there are nowunfilled training posts in parts of the country. Inone region, not a single ST2 trainee listed neurol-ogy as their first choice of specialty in 2009. Thisarticle will discuss possible reasons behinddecreasing interest in neurology as a careerchoice and consider ways to combat this.
Future career choices are still strongly influ-enced by both experience of a subject as a med-ical student and a particular teacher and depart-ment.3 Neurology has suffered from being per-ceived as a difficult specialty intellectually, caus-ing many students and junior doctors to develop‘neurophobia’ .4 In a UK based survey of medicalstudents, senior house officers and GPs, neurolo-gy was ranked as the most difficult of seven med-ical specialities and was the speciality in whichthey had the least knowledge and clinical confi-dence.5 Knowledge of basic neuroscience wasranked as the most important factor for perceiveddifficulty in neurology, with poor teaching, reputa-tion of neurology and complexity of examinationalso highlighted. It is perhaps not surprising thatneurophobia develops when medical studentteaching in neurology is only two weeks in thetotal medical course in some centres.
Exposure to medical specialties prior to enter-ing specialty training also influences futurecareer choices. In more than 55% of junior doc-tors surveyed one and three years after graduat-ing, experience and enthusiasm for the job wasshown to have influenced future career choicein medical hospital specialties ‘a great deal’.6
The recent change in training for foundationdoctors and core medical trainees may beimpacting on entry to neurology training.Foundation posts in neurology are rare com-pared to other medical specialities and are oftenreported as being linked to less attractive posts.In the past, stand-alone neurology SHO postsattracted post-membership trainees with a clearinterest in the specialty, but today’s core medicaltrainees have less control over the specialtiesthey are exposed to. Changes in working pat-terns may also have reduced the opportunitiesfor neurology SHOs to take part in clinics andother useful training opportunities.
Are the revolutions in neurological trainingdiscussed by Fuller 20071 now having down-stream impact on applications to the speciality?In the annual report from the JRCPTB to the
PMETB ‘acting down’ of specialist trainees tocover gaps in rotas from reduction in core med-ical trainee numbers was identified as a key con-cern.7 The ABN trainees’ committee is aware thisis still a major issue, exacerbated by rotademands from the European Time WorkingDirective. This could easily result in trainee dissat-isfaction resulting in negative publicity of thespecialty to future trainees. However, despitethese difficulties, overall satisfaction among neu-rology trainees still remains at over 70%.8
We are now entering a stage where neurologistsneed to compete with their fellow specialties toattract applications to specialist training. As a spe-cialty we are in a good position to do this. Britishneurology has retained its strong academicrecord whilst now giving greater opportunity tothose wanting to be involved in front line acuteneurology.9,10 It seems vital to encourage potentialneurologists from the very earliest stages of theircareers. Changes in teaching style at medicalschools can alter the perception and knowledgebase of neurology in medical students. This hasbeen shown by the teaching program at Guy’s,King’s and St Thomas’ Medical school11 which con-centrates on teaching core neurology skills andcommon neurological conditions as stipulated inthe ABN curriculum. The use of multimedia hasbeen expounded by Singapore neurologists, usingvideo clips as well as a neurolocalisation comput-er game to try to demystify neurology.12
The initiative of the ABN to host a roadshowfor medical students and foundation year doc-tors at the 2010 ABN Meeting is a positive step inraising the profile of neurology (see box below).As trainees we are working on compiling anational CD of interesting neurological videoclips to try to provoke interest at local careerfairs. Updating the ABN website, with more openaccess areas may also encourage interest in ourspeciality. We need to nurture and encourageour SHOs, making sure that their training needsare not lost amid the pressures of service deliv-ery. Finally, the power of the individual teacher intrainees’ career choices should not be forgotten:inspiring individuals have influenced the careersof many current neurologists, who we hope cannow go on to inspire the next generation. l
Touting for Trade;Attracting Future Neurologists
Rose Bosnell Treasurer, ABN Trainees committee-ABNT
A S S O C I AT I O N O F B R I T I S H N E U R O L O G I S T T R A I N E E S
1. Fuller G. Revolutions in neurological train-ing. Pract Neurol. 2007 Nov;7(6):356-9.
2. Aminoff MJ. Training in neurology.Neurology. 2008 May 13;70(20):1912-5.
3. Goldacre MJ, Turner G, Lambert TW.Variation by medical school in career choic-es of UK graduates of 1999 and 2000. MedEduc. 2004 Mar;38(3):249-58.
4. Jozefowicz RF. Neurophobia: the fear of neu-rology among medical students. ArchNeurol. 1994 Apr;51(4):328-9.
5. Schon F, Hart P, Fernandez C. Is clinicalneurology really so difficult? J NeurolNeurosurg Psychiatry. 2002May;72(5):557-9.
6. Goldacre MJ, Lambert TW, Laxton L. Careerchoices made for the hospital medical spe-cialties by graduates from UK medicalschools, 1974-2005. Clin Med. 2009Feb;9(1):42-8.
7. Joint Royal Colleges of Physicians TrainingBoard. Annual Specialty Report forNeurology. JRCPTB, 2009.
8. Post-graduate Medical Education andTraining Board. National Training Survey2008-9: Key findings. PMETB, 2009.
9. Carroll C, Zajicek J. Provision of 24 houracute neurology care by neurologists: man-power requirements in the UK. J NeurolNeurosurg Psychiatry. 2004Mar;75(3):406-9.
10. Werring DJ, Brown MM. New NICE guide-line on acute stroke and TIA: need for majorchanges in delivery of stroke treatment.Heart. 2009 May;95(10):841-3.
11. Ridsdale L, Massey R, Clark L. Preventingneurophobia in medical students, and sofuture doctors. Pract Neurol. 2007Apr;7(2):116-23.
12 Lim EC, Seet RC. Demystifying neurology:preventing 'neurophobia' among medical stu-dents. Nat Clin Pract Neurol. 2008Aug;4(8):462-3.
REFERENCES
For more information and support to participate in a local careers fair contactChristine Burness (librarian of the [email protected]).
The medical student and foundation yearroadshow, will be held before the main ABNconference in Bournemouth, on the morningof the 11th May. Contact Josie Shew([email protected]) for more details.
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The Research Series
Boyd Ghoshis currently carrying out researchfor a PhD in Cambridge,investigating biomarkers andsocial cognition in progressivesupranuclear palsy. He is the current secretary for the ABNT.
Correspondence to:Clinical Research Associate andHonorary Clinical Fellow,Department of Neurology,Addenbrooke's Hospital,Herchel Smith BuildingRobinson Way,Cambridge, CB2 0SZ.Tel: +44 (0)1223 768006,Email: [email protected]
N E U R O L O GY R E S E A R C H S E R I E S
In this, the last issue of the research series, wehave come full circle. A year ago we started theseries with a review of the first annual research
forum which took place at the Association ofBritish Neurologists (ABN) conference inLiverpool. Set up with the aim of inspiring andfacilitating young neurologists to pursue researchin their career, the review started the researchseries well. The inspiration behind the researchforum, Dan Blackburn, talked about his vision forthe research forum in the future, a vision whichhas now been taken up by the Clinical Researchand Academic Committee (CRAC) chaired byPatrick Chinnery, with Beth Mallam as the traineesrepresentative.
Since then, in the intervening issues, we havetravelled along the academic pathway, frommedical student to principal investigator, withguides along the way to point out the path. Inthis final issue, we consolidate this route finding.Dan Blackburn, the inspiration behind the
research forum, talks of his sense of wonder atthe start of the path and provides us with thefuel to start our journey. Beth and Patrick showhow CRAC have provided us with a team ofguides, in the form of the research forum inBournemouth and the ABN research network,who are available to show us how to pass treach-erous parts of our journey ahead, if we only ask.Finally, we are lucky to have one of the mostinfluential neurologists of our time, AlastairCompston, to show us what lies ahead from hishigh vantage point above.
The research forum inspired the trainees com-mittee of the ABN (ABNT) to help those traineesinterested in research to get involved. We hopethat we have gone some way to doing this. Wehope that for anyone stuck at the fork, uncertainof the way, that this series will help you to choosethe route that is right for you. l
Boyd Ghosh, Series Editor.
Seeing the Wonder in Research
The quotes above are the reasons why I chose todo research. As I prepare to submit, these are thesame reasons why I would like to carry out moreresearch and ponder over my results from the lastfive years. The horizon of ignorance is slighterwider and there is more mystery than ever aboutwhat astrocytes and microglia do in motor neu-ron disease. What is more, there are scientificexperiments, such as real-time imaging of glialfunction in animals running around in a cage,which seem to me, like magic.
I started my research as ignorant as any. I haddone a BSc in psychology, so had no experiencein basic science research. I had no idea what Iwas letting myself in for.
There are many reasons why we choose to doresearch, from thinking it will make us a better cli-nician, to wanting to become a professor. How dowe start a research project? What should we do?Who should we choose to be our supervisor? Istruggled with these questions. The strategies weusually use to answer these questions are usuallystraightforward, if slightly limited in scope. We canfind a supervisor and ask them what project theyhave, or we can ask the deanery to see if they canadvise what is available.
During my research, I travelled to America topresent a poster at the American academy ofNeurology. At this conference, there was aresearch forum where scientists at different stages
of their careers gave brief talks and took ques-tions. Most importantly, scientists were identifiedfrom different groups with different research top-ics. Anyone interested in those research topics orwilling to live in that geographical location wereencouraged to approach these scientists, not justto ask about potential research posts, but also toask for general advice, support and mentorship.Having struggled with these issues myself, I recog-nised that a research forum would be invaluablein the UK. After some planning we had a researchforum in Liverpool. There were researchers fromdifferent levels giving talks and taking questions.However this first forum was in a lecture theatreand there was no opportunity to ask informalquestions.
What next?Reading this is a good start. As Patrick Chinneryand Beth Mallam have highlighted, there is a web-site with information on who is doing what andwhere. There is also a second research forum atBournemouth, with ample opportunity to haveinformal discussions with researchers.
Please look at the website when it goes liveand please come to the second research forum inBournemouth. Try to find a mentor, ask questionsthat may seem silly, but come and join the questto expand the field of ignorance and performmagic. l
“Any sufficiently advanced technology is indistinguishable from magic” Arthur C Clarke
“In the expanding field of knowledge we but increase the horizon of ignorance”Henry MillerDan Blackburn
My neurology training includes anSHO post in King's college and registrar posts in Wolverhampton,Singapore, Nottingham and nowSheffield. I am preparing for my Phdviva on the glial cell involvement inMotor neuron disease. It has takenme an extra two years after leavingthe lab to write up and submit.
The restructuring of clinical academic training fol-lowing the “Walport Report” has opened up newopportunities for trainees to begin a clinical aca-demic career at different levels. In addition to thetraditional route, typically involving nationallyfunded pre- and post-doctoral fellowships, thereare now NHS-funded academic foundation pro-grammes, clinical fellowships, and clinical lecture-ships throughout the UK. The expectation is thattrainees will use these NHS-funded posts as aspring-board towards nationally competitive fel-lowships. This is intended to restore and evenenhance the number of trainee neurologists seek-ing nationally funded fellowships, and as a result,both the Medical Research Council and WellcomeTrust have dramatically increased the number of
fellowships on offer to aspiring clinical academics.In recent years, neurology and neuroscience
have done extremely well in the national competi-tion, managing to secure a greater proportion ofclinical research training fellowships (CRTFs)than would be expected given the size of the clin-ical specialities – but resources will undoubtedlybecome stretched given the current economic cri-sis, placing greater emphasis on alternativesources of funding.
In neurology we are fortunate to have a healthynumber of disease-specific charities, each contribut-ing to the massive research effort. However, charityhas tended to operate its own selection process. Thissituation is not ideal. For trainees, there are manyorganisations, each with its own procedures active
New Opportunities for ClinicalResearch Training in Neurology
The ABN Research Networkand the Second Annual ABNResearch ForumThe Clinical Research and Academic Committee(CRAC) has recently introduced two long-lastingresources for those interested in advancing theircareer in neurological research. The first is aninteractive database of information, the ‘ABNResearch Network’, to be found on the ABN web-site; the second is the Annual ABN ResearchForum, which will take place at the ABN Meetingin Bournemouth in May 2010. These resourceswill benefit trainees embarking on their careersin research, clinical academics who are lookingto recruit new trainees or colleagues and moresenior Principal Investigators seeking to extendtheir time in research or dovetail research withtheir clinical work.
The ABN Research Network on the ABNwebsiteThe aim of this network is to assist neurologytrainees and consultants to find their idealresearch opportunity. The Network will consist ofthree main sections:
• a guide to getting involved in research (withlinks to the articles in this ACNR series oncareers in research)
• a database of funding opportunities
• an electronic compendium of UK academicneurology departments, including links to cur-rent vacancies
This network will be an easily accessible, one-stop source of information, where people canfind all the information necessary to move theircareer in research forward.
More than 85% of the research centres invitedto be represented in the compendium have
responded and we hope that the remainder willdo so once they see the site up and running! Inorder to keep the network straightforward andeasily navigable, information for each departmenthas been standardised: browsers are directed todepartmental websites for more detailed infor-mation.
It is envisaged that the network will ‘go live’before May 2010, and will be clearly sign-postedon the ABN website.
The Annual ABN Research ForumIn 2010, the Annual ABN Research Forum will bein the form of a poster fair. This will take placealongside the main poster session, allowing thoseinterested in research to browse posters, illustrat-ing what is happening in neurology across theUK. Perhaps more importantly, it creates an idealopportunity for informal discussions with thosepresenting the posters. Trainees interested inresearch are specifically invited to attend (withtheir CVs), in order to take full advantage of thisunique opportunity to meet key investigators in arelaxed environment. l
Further information, including posterabstracts, about this year’s Research Forum
will be available in the ABN MeetingWelcome Packs.
If you would like any further informationabout becoming involved with either of the
Patrick Chinneryis chair of the Clinical Research andAcademic Committee of theAssociation of British Neurologists.As a Wellcome Trust Senior Fellowin Clinical Science and Professor ofNeurogenetics in Newcastle uponTyne, he runs the clinical neuroge-netics service closely linked to atranslational research programme ingenetic neurology, with a particularinterest in mitochondrial disorders.
Patrick Chinneryis chair of the Clinical Research andAcademic Committee of theAssociation of British Neurologists.As a Wellcome Trust Senior Fellowin Clinical Science and Professor ofNeurogenetics in Newcastle uponTyne, he runs the clinical neuroge-netics service closely linked to atranslational research programme ingenetic neurology, with a particularinterest in mitochondrial disorders.
Beth Mallamis the ABNT ResearchRepresentative. She is currentlyworking towards a PhD withProfessor Scolding’s team atFrenchay Hospital, Bristol. Herresearch is looking at the potentialof mesenchymal stem cells as atherapy for Multiple Sclerosis.
at different times of the year. Each charity has toorganise and co-ordinate an expert panel. Thisin itself is challenging, and there is usually littlein the way of feedback to unsuccessful appli-cants. Anecdotally, the quality of the proposalssubmitted to disease-specific charities can be ofa lower standard that that seen at MRC orWellcome Trust review panels, giving the percep-tion of a reduced kudos, despite the often high-ly productive research training programme inan excellent environment.
There is also a group of clinical traineeswho do not initially aspire to an academiccareer, but do seek a more limited period ofresearch exposure. At present these individualsusually join a local research group on ‘soft’funding, often engage in routine clinical trialswork, and do not study for a higher degree(PhD, MPhil, or MRes). This arrangement offerslittle in the way of research experience, and it
is likely that some clinical academics of thefuture will be lost to the system through suchexposure. More generally, without developing agenuine understanding of the researchprocess, future clinical neurologists are lesslikely to be effective contributors to theincreasingly numerous and important localand national research networks which arenow firmly part of the NHS fabric.
In response to these concerns, the ClinicalResearch and Academic Committee (CRAC)of the Association of British Neurologists(ABN) approached the major UK neurologicalcharities and charitable trusts to offer assis-tance in co-ordinating a centralised ClinicalResearch Fellowship Application process. Theinitiative was designed to benefit applicantsand charities alike, allowing shared fundingbetween generic and disease-specific sources,and providing a simple “one point of entry” for
applicants. The proposal was very wellreceived, and as a result, a number of charitieshave committed substantial funds to thescheme, including Ataxia UK, The PatrickBerthoud Trust, The Guarantors of Brain, TheMultiple Sclerosis Society and The Parkinson’sDisease Society.
In the spring of 2010, applications will beinvited for fully-supported Clinical ResearchTraining Fellowships of up to three years dura-tion, with a closing date of 31st May 2010.Shortlisted candidates will be interviewed on29th July 2010, with final confirmation of fund-ing in early September 2010. l
Alastair Compstonis Professor of Neurology and Headof the Department of ClinicalNeurosciences in Cambridge; President of the Association ofBritish Neurologists (2009-2010);and Editor of Brain (from 2004). Heis a foundation Fellow of theAcademy of Medical Sciences, andForeign Member of the NationalAcademy of Sciences of Germany.His research on the clinical scienceof human demyelinating disease hasbeen recognised by award of theSobek Foundation InternationalResearch Prize (2002), the CharcotAward of Multiple SclerosisInternational Federation (2007), andthe Zülch Prize of the Max-PlanckSociety (2010).
Interested in finding research fellows and collaborators?The ABNT is collating information tocreate an interactive research networking database on the ABNwebsite. This will include cross-referenced lists of AcademicNeurologists, research groups andresearch posts available in the UK.
If you would like to find out more,or ensure that your group is represented, please contact theABNT Research Rep, Beth Mallam:[email protected].
Training as a specialist serves several purposes. Itensures that the quality of care provided to anymember of the public through the National HealthService (NHS) is excellent. It establishes in thetrainee the means for life-long learning that sustainsinterest in the subject, keeps us safe and addressesissues of clinical governance. And it reduces the riskof professional arrogance by making doctors sensi-tive to our limitations, responsive to the challengesof not knowing enough and, through research, moti-vated to advance the subject. In short, training servesnot only the vocational principles of medicine as aprofession, but it also imprints the ethic and stan-dards to which we aspire.
Neurological training in the UKLike the Norfolk countryman asked for directions(“if I was going to Norwich, I wouldn’t start fromhere”), trainees suffer a system that they did notdesign and may wish to change for themselves andtheir successors. Once, neurology was patrician. Itspractitioners considered the laying-on of diagnosisto be a sufficient activity, ideally delivered as fleetingvisits from Harley Street whilst the Rolls Royce waskept gently purring in the hospital car-park. Later,and especially following the NHS reforms of theearly 1990s, establishment improved, commitmentincreased and regional deployment became moreevenly distributed. Although the model remainedessentially centre-based, networks of care devel-oped in response to the imperative of deliveringcare close to where people live and become ill. Forneurology, the impact of this expanded infrastruc-ture was mainly reflected by increased out-patientactivity and participation in the management ofchronic neurological disorders. Now, neurologistsare also negotiating more active involvement inacute care. However, the facilities and expertiseneeded to practice neurology at the highest levelcannot sensibly be reproduced in each and everyhospital where neurology has a presence. Therefore,
tomorrow’s service must allow rapid access for thepatient at any point along the continuum of com-munity, district hospital and tertiary centre; andthereafter to permit traffic effortlessly in either direc-tion according to need. That basic principle requiresthe service to be well led, coordinated and fully inte-grated within any one geographical region or city,and delivered by a team that includes staff trainedin professions allied to medicine.
One size will not fit all. Neurology needs toaccommodate several styles in response to themodel of responsibility and care distributed acrossa spectrum that ranges from primary care to ivorytower. The generalist in the district retaining mean-ingful links to the centre; the sub-specialist who isnonetheless competent in general neurology; thesuper-specialist who rarely strays outside a particu-lar area of expertise (previously parked safelythrough placement on the Specialist Register butwithout a Certificate of Specialist Training); and themedically qualified full-time research scientist whooccasionally sees patients. It follows that trainingmust adapt to reflect these changing patterns ofneurological practice, and the need to work effi-ciently and comfortably at the various locationswhere services are to be delivered.
The reverberations on training of the notoriousproposals for Modernising Medical Careers (MMC)can still be felt. Is it overly cynical to conclude thatMMC was designed entirely to support a politicalmanifesto that promised no more absentee consult-ants doing private practice or out on the golf coursewhilst trainees did all the work; now, medicine wasto be led and delivered by consultants? No-onewould challenge the merits of that principle. Sincespecialists, including neurologists, could not becloned overnight, and expansion within medicalschools would take a generation to increase thenumber of consultants trained according to existingstructures, the only medium-term solution was todesignate doctors as specialists at the earliest possi-
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ble stage in their careers. Therefore, the dura-tion of training had to be curtailed; and luxuri-ous items such as grounding in general medi-cine and experience of research rapidly side-lined. Concerns were expressed by trainersand trainees alike with respect to whether thiscut-price system would equip newly appoint-ed consultants to manage the diversity of neu-rological illness confidently and without hav-ing to learn a great deal ‘on-the-hoof’. Patientsunderstand that doctors need to ‘practice’ butpreferably not on them. Furthermore, sincemost clinical research is carried out bytrainees on behalf of consultant supervisors,academic neurology was particularly chal-lenged by these and related changes to thecareer pathway. Those threats were real notperceived and, despite the apparent demise ofMMC, have had profound influences on train-ing in neurology.
The changing face of academic neurologyAs others in this series have commented, untilrecently a period of research was a non-nego-tiable rite of passage for higher training as aspecialist registrar. The aspiring neurologistwas stacked for a few years, carrying outresearch for which not every individual neces-sarily had an appetite, pending clearance toland for clinical training in a given deanery. Atthe same time, the academic aspirations ofmedical schools submitting to the ResearchAssessment Exercises (RAE), needing a portfo-lio in which neurology and all the other mainmedical specialities were represented,became too dependent on support from thepharmaceutical industry given the stiff compe-tition for grants awarded by the ResearchCouncils or major Charities. But with muchtighter pharmaceutical regulation, realisationthat the dividend for knowledge from theseinvestments was often small, and changingmodels of industry research and developmentstrategy, the support from Big Pharma has con-tracted, leaving some vulnerable researchactive neurology (and other) departmentsbadly exposed. Trainees in research wereunevenly distributed when MMC, proposingalterations not only in the schedule for train-ing but also placing restrictions on geographi-cal migration between deaneries, was intro-duced; and many were caught out when theshutters came down. Centres that had over-loaded the system with researchers who couldnot subsequently be placed in local trainingposts were seen to have acted irresponsibly byinflating the research market. With this newlyacquired pariah status, we hung our heads inshame at having wantonly promoted research.Articles in the present series reiterate theadvice to avoid expanding the pre-specialistregistrar (ST3) post-core medical training(ST2) cohort merely to suit ‘professors lookingfor research fellows’.
Were these changes altogether a bad thing?In the main ‘yes’; for the simple reason that, inmedicine, academic is an adjective not anoun. It reflects a style and interest in acquir-ing new knowledge, and is fundamental toclinical education. The exposure to uncertain-
ty equips the trainee to sift the available infor-mation and make judicious decisions in situa-tions where the evidence is ambiguous orincomplete. Therefore, over and above thepotential for acquisition of new knowledge –an uncertain dividend – the academic compo-nent matters purely from the training perspec-tive. It creates the sense of confidence neededto challenge the subject throughout the neu-rologist’s career without feeling daunted; tomanage complex situations decisively withoutresorting to the protective armour of endlessand repeated investigation; to know what arethe strategic directions for our subject, throughbeing able to assess the significance for clini-cal practice of emerging discoveries; and - notnecessarily a bad thing – it does indeed serveas rite of passage to appointment as a consult-ant neurologist in a competitive environment.
In the run-up to MMC and its aftermath,some organisations responded to the threatsfor academic medicine with initiatives thatprovided complementary or alternativeroutes to training. By way of example, theGuarantors of Brain introduced a flexibleentry scholarship scheme that continues tosupport clinical trainees across transitionalcareer gaps at stages where the next step onthe ladder is competitive, success unpre-dictable, and opportunity limited by avail-ability. The Eastern Deanery established 7year Clinical Neuroscience TrainingFellowships with (4 year) clinical traininglinked to a fully funded (3 year) period ofresearch. Later this year, the Association ofBritish Neurologists will introduce ‘ABNFellowships’. These fellowships will bringtogether the resources of several Charitieswho feel that the interests of their donors arebest served by a generic clinical research fel-lowships scheme, which enables trainees towork on the right project for the trainee andin the most suitable place, ensuring highquality and careful assessment of applica-tions and thereby matching the ‘3Ps’ (Person,Place and Project) in the interests of all con-cerned. But these domestic activities, intro-duced on the small scale, are merely paper-ing over the cracks. On a grander scale, newAcademic Training Fellowships and ClinicalLectureships have been introduced; theDepartment of Health and the Academy ofMedical Sciences have supported ClinicianScientist Fellowships; and the HigherEducation Funding Council for Englandawards Senior Lectureships through theNational Institute for Health Research and itsIntegrated Academic Training Pathway.Recognition that the interest of potentialcareer academics needs to be captured earlyled to the introduction of academicFoundation Year programmes that include aresearch attachment as a taster for longer-term commitment to research. To someextent, these initiatives have been targeted atsubjects that seemed especially threatenedby the changing landscape and neurologywas not perceived to be a particular casualtyof the system. One stricture on theseschemes is the requirement for the host insti-
tution to contribute between 25% and 75% ofthe salary costs. Therefore it has proved diffi-cult to integrate these parallel track positionswithin programmes without sacrificing exist-ing training posts or finding alternativesources of collateral funding; and somedepartments elected not to bid for addition-al academic posts, sensing that their abilityto recruit and keep the wheels of theresearch engine well oiled would continueundiminished.
Overall, however, the perceived threats haveproved to be real. It would astonish our prede-cessors to learn that training posts in neurolo-gy are unfilled; and that the Association ofBritish Neurologists is organising the first road-show for medical students and FoundationYear doctors designed to capture interest inthe specialty. Expectations on trainees havechanged. Being on call no longer replaysscenes from Doctor in the House: propping upthe bar in the hospital mess and wanderingdown to casualty at closing time. More activeinvolvement in acute medicine, includingstroke, means routine management of acutethrombolysis. Many hospitals now organiseacute triage systems requiring early input fromspecialists including neurologists so that, right-ly, patients are managed quickly and by themost appropriate teams. Complying withEuropean Working Time Directives threatensthe specialist registrar grade with the same fatethat befell senior house officers required towork shifts. Under-staffing and the lack of indi-viduals wanting locum appointments for train-ing (LATS) makes it much more difficult toarrange out of programme experience. Andthe attrition on research training posts hasbeen especially noticeable. Topics that offer apredictable dividend from time in researchremain popular, as do posts in those regionswhere the number of training posts is high andentry into clinical training beyond researchmore predictable. But the take-up of morechallenging experimental laboratory studies islow. One senses a growing feeling amongsttrainees that the interest in research must bedeclared early. Not to obtain an academicFoundation Year post is to distance oneselffrom research. Subsequent de-differentiationdown an academic track, if so desired, is thenconsidered something of a reversal of tacticand a retrograde step. As a result, researchactivity is again starting to be mal-distributed –geographically and by topic; and trainees areforced to commit to a research style training,or not, at too early a stage in their careers.These trends will shape the development ofneurology in terms of the topics that receivemost attention - emphases that may not suitsociety or the long-term professional interestsof the future neurologist, nor ones that leavethe discipline alert and responsive to unex-pected developments.
Finding the path for tomorrow’s academic neurologistQuite what tomorrow’s neuroscience and itsclinical applications will bring remains specu-lative. Self evidently global changes in demog-
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raphy and economics will impinge on neurol-ogy. Epidemics of novel infectious diseaseswill continue. Neurodegenerative diseaseswill become more prevalent as the popula-tion ages. That much is obvious. More general-ly, descriptions of disease will change aseponymous nosology is replaced by classifi-cations that reflect disease mechanisms -Parkinson’s disease and fronto-temporaldementia being examples of the alpha-synu-cleinopathies and tauopathies, respectively.Empirical therapeutics will be refined bytreatments that target defined molecular path-ways. Diagnosis will be anticipated on thebasis of biomarkers derived from the many‘–omics’ that screening provides, shifting theconcept of disease from pathology to risk.Behaviour will no longer be studied exclusive-ly in the individual nervous system, but ratheras interactions that form social neurosciencenetworks, and impact on decision-makingand cultural activity in all realms of humanendeavour and social organisation. How willthese trends affect the training needs oftomorrow’s neurologists?
Because opportunities are narrowed yetthe number of trainees who aspire to medi-um- or long-term academic posts alsoreduced, that market is currently neither abuyer’s nor seller’s, but generally in reces-sion. For those who are attracted toresearch, timing can be problematic.Establishing a relationship with a depart-ment known to be experienced and havinga reasonable track record in mentoringsooner rather than later makes good sense,even if these provisional arrangementsrequire research interests to be shapedslightly earlier than is ideal. After all, with adynamic subject such as neurology, thelonger the interval between committing to aparticular research topic and developing aclinical sub-specialty interest, the greaterthe risk that the two will end up not closelyaligned. This is the down-side of the earlyhigher degree such as that embodied in MBPhD programmes that are common in theUnited States and increasingly adopted byUniversities in the United Kingdom.Because the MB PhD student has recentlybeen exposed to basic neuroscience, thesubject matter for research that appeals maybe clinically remote and this can widen thegap between skills acquired early and theeventual clinical sub-specialty focus.Therefore, whilst a basic neuroscience proj-ect may provide an excellent grounding inlaboratory methods, that choice makes it allthe more sensible for the potential clinicianscientist to establish a relationship, maintaincontinuity and negotiate re-entry links to ahost department well in advance of clinicaltraining. For those who come to researchlater, looking around in terms of place andtopic of interest and acquiring clinicalexperience as a specialist registrar beforeembarking on research is sensible and mostcertainly does not thwart the process. Often,this is an appropriate caution, so that onemay sample enough of the subject to sense
what will prove to be a specialist area oflasting interest. And although it should beremembered that research is time consum-ing and the commitment relatively inflexi-ble towards the end of training, when thepriority may be appointment to a consultantpost, once the right opportunity arises, it isalmost never too late to start.
Choosing where to do research involvesassessing the extent to which the preferreddepartment is capable of accommodatingindividuals who are clinically inactive at timesduring their attachment and used to movingtrainees on and off the wards without encour-aging two cultures – research fellows and realdoctors – who do not interact. Having a poolof clinical trainees based either in research orclinically active at any one time, and all ofwhom experience both aspects of trainingduring their attachment, offers an ideal envi-ronment in which academic (the ‘adjective’and the ‘noun’) neurologists are nurtured andcan flourish. Furthermore, programmes thatare regionally coordinated and offer diversityof clinical training both in the district andcentre, with supervision when needed andfreedom when wanted, best equip the traineeto work in the future health service.
Can one map the ideal training today fortomorrow’s world, especially for neurologistswith an interest in research? It makes goodsense to sample research and perhaps makeinitial overtures with a future sponsor throughan academic Foundation Year appointment.But this is of less importance than obtainingexperience in the general medical disciplinesthat impinge on neurological practice. AnAcademic Training Fellowship provides rightof access to a training programme, if theintended transition to a Clinical TrainingFellowship does not materialise. Protectedtime for research and the default position ofclinical training are clearly advantageous tothe trainee, but they do not remove the needto be in the right place, with experience of theright research topic. Appointed before entryto specialist training, the Academic TrainingFellowship endorses the run-through princi-ple that neurology has otherwise arguedagainst – the discipline preferring to filterapplicants through competitive entry at ST3with a further curriculum of five years in train-ing (with one off for good behaviour if time isspent in research). Even so, choosing the mostappropriate academic environment shouldcount for more than merely obtaining one ofthese early-career Fellowships. For the remain-der, because the channel through which theacademically-minded trainee must subse-quently pass at ST3 is relatively narrow andcompetitive, any opportunity to decorate thecurriculum vitae with something that standsout and distinguishes one from another isbound to help. This matters more in a systemwhere applications are increasingly anony-mous and centralised making personalknowledge and preference somewhat moredifficult to manage, both for the trainee andhost department. The current arrangement forappointing specialist registrars, with and with-
out research experience, will – until the nextinvention supervenes – involve national appli-cation for a single annual round of regionalappointments, specifying two preferred loca-tions and ranking the remainder. Short-listingand interview will be local but standardisedand scored so that, in the event of unfilledposts and individuals whose applications arenot successful, a clearing system can operatethat is calibrated and does not require re-application or re-interview. Local interviewpanels may add questions that reflect the styleand flavour of their programmes but mustfocus on the structured components. It isrumoured that only one deanery has indicat-ed that it will ask about research interests aspart of this bolt-on menu to the standardisedinterview. Appointments are timed for theautumn, with much of the year a closed sea-son for local recruitment in order to protectposts for the national round. Only for a coupleof months in the pre-Christmas period maydeaneries manage their own affairs outsidethe national recruitment scheme. Presumably,with only a single annual round of appoint-ments, gaps will appear in rotations pendingarrival of the national juggernaut. These willnot be filled by LATS, for there are none; andresearch staff may find themselves frog-marched on to the wards at crucial periods intheir research. Although this ritualised systemmay prove efficient during the clearing phase,it disadvantages the applicant who has devel-oped a career strategy early, based on a specif-ic vision for training in a place that suits thatperson’s interests and abilities. The cynicalview is that once again, the motivation seemsnot to be protection of those for whom dis-crimination and disadvantage were perceivedto exist but rather the need to move traineesthrough the system fast and with built-indelays avoided so that each person graduatesas a clinical consultant at the earliest possibleopportunity. In neurology at least, trainers andtrainees do not support this arrangement forappointment and it seems that enormoustrouble has been taken to fix something thatwas not bust. Beyond the acquisition of clini-cal experience as a specialist registrar, for thetrainee seeking a long-term academic post,the secondary phase of research is the defin-ing period. Here, an independent profile andexperience of writing successful grant appli-cations are established, work is delegated andled within a group, and the curriculum vitaeacquires all the characteristics predictinglong-term and sustained success. All thatremains is to become a professor and join thelocal golf club.
Even in the present climate, the only thingthat stops someone realising ambitions for acareer in neurology is uncertainty about whatyou want. That applies equally to a purely clin-ical post and one that carries research respon-sibilities. The pathway for training in each maydiverge in the years ahead so it is worth givingthe matter careful thought at a relatively earlystage in your career. Clinical activity is impor-tant and rewarding; discovering new things issustaining and thrilling. l
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As neurologists, at least in the UK, we tend to approach thepatient with a probable inherited neurological disease in a fair-ly structured way. Following a careful history and examination,the search for the precise genetic abnormality begins. For certainmonogenic neurological conditions, the likelihood of achievinga genetic diagnosis is favourable; for example, Huntington’s dis-ease in a patient with chorea, dementia and a relevant family his-tory. However, we now know that many neurological conditionscan present with identical phenotypes but be caused by a widevariety of underlying genetic defects. Charcot-Marie-Tooth dis-ease (CMT), the commonest inherited neuromuscular disorder,is a familiar example. While a number of excellent clinical andneurophysiological algorithms exist to help request the appropri-ate gene test in CMT, logistical reasons dictate that most patientswill have the commonest mutations tested first, leaving manywithout a precise underlying genetic diagnosis. This may changefollowing the publication of a paper by Lupski et al. describingtheir approach to genetic diagnosis in a patient with demyelinat-ing CMT, deemed to be autosomal recessive.
Instead of taking the traditional ‘one gene at a time’approach, Lupski et al. decided to take advantage of theadvances seen in DNA sequencing in the past 10 years andsequence the whole genome of their patient and extendedfamily members. This included both coding and non-codingregions of DNA. Using reference genome sequences and thesequences obtained from unaffected family members, the pre-cise genetic mutations in the known CMT-associated gene,
SH3TC2, were identified. While one could argue that the clini-cal details, family history and neurophysiological data avail-able would have pointed towards the SH3TC2 gene using thetraditional approach to genetic diagnosis, Lupski et al. showthat whole-genome sequencing is now not only possible, butcan also be applied to the clinical setting. The impressiveadvance that whole-genome sequencing provides is its abilityto identify all DNA changes in each haplotype (exons, intronsand copy-number variants), making it a potential powerful toolwhen applied to diseases with complex genetic aetiologies.
Nevertheless, there remain a number of cautionary notes.First, the diagnosis was possible due to the fact that the SH3TC2gene was already known and characterised. Second, the accu-racy of the genetic disease databases is questioned as thepatient also displayed a mutation in the ABCD1 gene reportedto cause X-linked adrenoleukodystrophy, without showing anyclinical features of this disease. And the price? Lupski et al. esti-mate that their whole experiment would now cost less than$50,000. In comparison, a clinical-testing panel looking at thecopy number variant that commonly causes CMT along withmutations in 15 other genes associated with CMT currentlycosts $15,000. We should not put away our tendon hammersand tuning forks just yet.– Rhys Roberts, Cambridge University. Lupski JR, et al. Whole-Genome Sequencing in a Patient withCharcot-Marie-Tooth Neuropathy. THE NEW ENGLAND JOURNAL OF MEDICINE 2010 Apr 1;362(13):1181-91. Epub 2010 Mar 10.
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Neurogenetics: Making a diagnosis by whole-genomesequencing
The frontotemporal lobar dementias (FTLDs) are a clinically,pathologically and genetically heterogeneous group of diseases.Although frequently described as “the second commonest causeof presenile dementia”, FTLD remains an uncommon disease(incidence 3.5, prevalence 4-15, cases per 100,000 in 45-64 yearolds; Mercy et al 2008). It has therefore taken a large collabora-tive study using samples from North America, Europe andAustralia to identify the first association of common genetic vari-ants with FTLD. Van Deerlin et al identified association with sin-gle nucleotide polymorphisms on chr 7p21 surrounding theTMEM106B gene, which encodes an uncharacterised 274 aminoacid transmembrane protein. Functional studies suggested thatrisk alleles could result in increased brain expression ofTMEM106B and a more aggressive disease course.
Genome-wide association studies (GWAS) in general are usedto identify association in common diseases, such as diabetes,and require many thousands of cases to generate the power todetermine true associations. Nevertheless, Van Deerlin et alappear to have succeeded with an n of just 515. Their successstems partly from preparation of a homogeneous group of casesmade up only of patients with TDP-43 pathology (FTLD-TDP). Byexcluding those with tau inclusions and other less commonpathological subtypes of FTLD, they appear to have distilled the
genetic pool under scrutiny, reducing the chances that a trueassociation would be lost. It must be noted, however, that themajority of the chr 7p21 association appears to be due to a sub-population of their cohort already identified to have autosomaldominant FTLD due to GRN mutations. A further interestingobservation is that the most significant SNPs Van Deerlin et alidentified on chromosome 9 are in a region of great interest inanother ‘TDP-43 proteinopathy’, amyotrophic lateral sclerosis(Van Es et al 2009, Vance et al 2006). – Jemeen Sreedharan, Guy's and St Thomas'NHS Trust, London.Van Deerlin VM et al. Common variants at 7p21 are associatedwith frontotemporal lobar degeneration with TDP-43 inclusions. NATURE GENETICS 2010 Mar;42(3):234-9. Epub 2010 Feb 14.Mercy L, et al. Incidence of early-onset dementias inCambridgeshire, United Kingdom. NEUROLOGY 2008 Nov 4;71(19):1496-9.van Es MA, et al.Genome-wide association study identifies19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadicamyotrophic lateral sclerosis. NAT GENET. 2009 Oct;41(10):1083-7.Vance C, et al.Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome9p13.2-21.3. BRAIN 2006;129(Pt 4):868-76.
FTLD genetics: progress through collaborative splitting
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Memory: A name for forgettingWhen considering memory it is easy to neglect forgetting. Over the cen-turies, forgetting has continued to represent the dark side of memory, oftenportrayed as a passive process of memory fading, or an ‘overwriting’ by com-peting memories. Modern science too has dwelled more on the mecha-nisms of memory than on those of forgetting. The authors in this study nowtake steps to redress this deficiency by directly examining the molecularmechanisms of forgetting. They define a molecular pathway which, whenactivated, causes memories to fade faster; conversely, inhibiting the pathwaymakes memories more lasting and more resistant to change. The study usesfruit flies expressing mutated versions of a molecule called Rac in definedadult neurones, analysing them with standard behavioural memory tests.The authors firstly demonstrate that memory fades more rapidly in the pres-ence of a constitutively active version of Rac, and less rapidly if an inactiveversion is used (crucially, they also confirm that the differences are notbecause of an alteration in the strength of the initial memory). They go onto look at reversal learning, where the conditioned stimulus in a learningtask is reversed on a second trial, forcing the flies to relearn; the reversalturns out to be easier in the presence of active Rac, showing that the initialmemory is now less durable. Conversely, in the presence of inactive Rac theflies stick more stubbornly to their original memory, relearning the newassociation less readily. Finally, the authors show in wild type flies that levelsof active Rac fall as learning is consolidated by repeated trials, but areraised in reversal learning paradigms, correlating with an increased need to‘remove’ or overwrite inappropriate associations.
That active Rac seems to promote forgetting comes as something of asurprise. Conventional understanding has it that memories, and molecu-lar correlates such as long-term potentiation, rely on glutamate receptorclustering and increases in polymerised actin within strengthenedsynapses; both of these changes are driven by active Rac (and its down-stream target PAK1). On this background, the idea that Rac activity pro-motes forgetting seems counter-intuitive. One solution to the paradoxmay be that Rac is key to a forgetting mechanism that is effectively inte-gral, ‘built in as standard’, to each new memory, and which wanes as thememory matures with repeat exposure. Rac activity then becomes amarker of the recency of memories, with newer memories being moresusceptible to forgetting than consolidated ones – a useful feature incase fresh memories need to be overwritten before they become tooestablished. Such insights are clearly relevant to diseases such asAlzheimer’s, where forgetting is the rule, and where dysregulation of Racpathways may well be involved. These questions are not directlyaddressed in this paper, but a central message stands out: forgetting hasa mechanism, and it needs to be understood.
– Philip Buttery, Cambridge Centre for Brain Repair and QueenElizabeth Hospital, King’s Lynn.Shuai et al. Forgetting Is Regulated through Rac Activity in Drosophila. CELL 2010;140(4):579-89.
Stimulating the brainstem in Parkinson’sDisease a step in the right direction? The use of deep brain stimulation (DBS) to treat patients with movementdisorders is now well established and this is perhaps most obvious inadvanced Parkinson's Disease (PD) with DBS of the subthalamic nuclei.However, whilst this treatment works well for many features of PD, it doesnot improve all aspects of the disorder, especially those that involve moreaxial features and this includes gait. As a result modifications have beensought that can help this disabling aspect of PD, and one approach hasbeen to target brainstem nuclei involved with locomotion such as thepedunculopontine nucleus (PPN).
The PPN is a small structure within the brainstem that has widespreadconnections throughout the CNS, receives from the basal ganglia outputnuclei, and has been thought for many years to be a vital relay station inthe initiation and generation of gait. It has been found to be affected inPD, having pathology itself as well as being in receipt of a disorderedbasal ganglia output. As such it became the target for the stimulatingelectrode of curious neurosurgeons! The initial open label studies sug-
gested that benefits could be seen using low frequency stimulation of thePPN in patients with PD. However, such studies are hard to interpret giventhe placebo problems inherent in small open label studies and the dif-ferent criteria used to select patients for this treatment in these trials. Thusbetter controlled studies are needed although what constitutes a goodcontrol arm is difficult when the treatment under scrutiny involves inva-sive neurosurgery. Nevertheless with DBS, one does have the opportunityto switch on or off DBS without the patient knowing the activation statusof their stimulator. This strategy has now been exploited in two recentstudies reported in Brain.
First, Ferraye et al took 6 patients with PD and severe freezing of gaitthat was unresponsive to L-dopa or DBS of the subthalamic nucleus.These patients all had bilateral electrodes placed in the PPN with the pri-mary outcome being the improvement in gait, freezing episodes and fallsat 1 year. There was a period between 4-6 months when a double blindcross over study was done with the stimulator being on or off. The mainfinding was that at one year the number of freezing episodes and fallswas reduced, although none of the other outcomes were improved norwas there any clear consistent effect seen in the double blind period. Inthe second study by Moro et al, 6 patients with advanced PD and signifi-cant gait and postural abnormalities were recruited and treated using aunilateral PPN stimulator (the side chosen for stimulation being con-tralateral to the most severely affected side of the body). In this case thepatients had to have failed medical therapy but had not had DBS of thesubthalamic nucleus. These patients were then subject to a double blindtreatment with the stimulator being either switched on or off, and againsome benefit was seen with respect to falls but no other measures usingsubsections of the UPDRS motor examination.
So what are we to make of all this? I think the studies have suggestedthat the PPN may be a useful target in helping treat axial features of PD -especially issues of gait and falls. This is important because these featuresare often resistant to L-dopa therapies and carry significant morbiditiesand impact on quality of life. Thus being able to offer something usefulin this domain is worth pursuing, but bigger studies are needed to knowthe extent to which this stimulating approach really works and benefitspatients with PD.
– Roger BarkerFerraye MU et al. Effects of pedunculopontine nucleus area stimulation ongait disorders in Parkinson's disease. BRAIN 2010; 133: 205-214. Moro E et al. Unilateral pedunculopontine stimulation improves falls inParkinson's disease. BRAIN 2010; 133:215-224.
Parkinson’s Disease: earliest diagnosisNeurologists strive to differentiate early idiopathic Parkinson’s disease(PD) from its mimics in order to properly advise patients about progno-sis and treatment options. Clinical diagnosis alone will get it wrong about15% of the time, and accuracy improves as disease progresses. Tang andcolleagues at The Feinstein Institute for Medical Research in New Yorkused fluorine-18-labelled-fluorodeoxyglucose-PET to differentiate idio-pathic PD, multiple system atrophy and progressive supranuclear palsy in167 patients with parkinsonism of unknown cause. They used an auto-mated voxel-based classification procedure to map characteristic patternabnormalities in these three conditions. The patients were scanned at anearly stage of their disease, and followed-up for a mean of 2.6 years by ablinded movement disorder specialist to ascertain the final diagnosis.When the accuracy of the initial image-based classification was com-pared with the final diagnosis, the positive predictive value was greaterthan 90% for each condition. The imaging categorisation was repro-ducible on repeat scanning and confirmed in nine patients on post-mortem examination.
The fact that 32 patients had to be excluded at the outset because thefinal clinical diagnosis was unclear should not be forgotten, as this wasthe gold standard in the study. Further, patients with structural brainabnormalities that could potentially account for their symptoms (includ-ing white matter and ischaemic lesions which are commonly seen in theclinic) were excluded. The utility and cost-effectiveness of PET in theearly differential diagnosis of parkinsonism needs to be proven further,but the desire to identify suitable candidates for novel drug trials and sur-
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gical procedures (such as stem cell transplantation) means that there isbound to be considerable interest in this approach.
– David Breen, Cambridge University Centre for Brain Repair.Tang CC et al. Differential diagnosis of parkinonsim: a metabolic imagingstudy using pattern analysis. LANCET NEUROLOGY 2010;9(2):149-58.
Parkinson’s Disease: Reckless GenerosityHere is another phenomenon to add to the growing collection of impulsecontrol disorders (ICDs) in Parkinson’s disease. O’Sullivan et al describethree cases of “excessive and inappropriate philanthropy”. All three weretaking dopamine agonists and the behaviour improved or ceased whenthe agonist was reduced or discontinued. The authors speculate as to the pathophysiological basis in dysfunction-al dopaminergic reward pathway stimulation, an interaction betweenincreased oxytocin release and dopaminergic reward systems, andimpaired decision making, with an insensitivity to the negative conse-quences of a particular action. As with all impulse control disorders, theirpresence should be screened at each clinic visit, and patients warned. Asone can imagine, the behaviours may be associated with profound con-sequences for the patients and carers, both financially and socially. – Wendy Phillips, Norfolk and Norwich University Hospitals NHS TrustO'Sullivan S et al. Reckless generosity in Parkinson's disease. MOVEMENT DISORDERS 2010;9999.
Rehabilitation: the importance of priordepression in surgical outcomeAlthough the relationship between disability, depression and pain is acomplex one, is there a case to be made for attempting to optimise psy-chological as well as physical health prior to complex surgical proce-dures? The existence of the term “failed back syndrome” to describepatients who have had poor outcomes from spinal surgery illustrates thechronic and disabling consequences of adverse results for this interven-tion. It is obvious that optimising general health improves outcome, andhigh risk patients will be assessed from an anaesthetic perspective well inadvance to minimise their physical co-morbidities. This paper looksspecifically at outcomes following lumber spinal stenosis surgery in rela-tion to depressive symptoms in the pre-operative and post-operative peri-od. Rather than focussing solely on pre-operative depressive symptoms,the authors have looked at “depressive burden” across the pre-operative,post-operative and late (3 and 6 months) periods. Depressive symptomswere evaluated with the Beck Depression Inventory and disability wasassessed by walking capacity, back and leg pain, and the OswestryDisability Index. Perhaps not surprisingly, late depression had a strongassociation with pre-operative depression although depressive symptomsgenerally improved following surgery. There is a clear relationshipbetween pre-operative depression and post-operative outcome, in termsof disability, however. This is true for both younger and older patients.There are serious clinical, economic and social consequences of a “failedback” and whether these could be attenuated by rigorous pre-operativescreening and intervention for psychological issues remains to be seen.– Lloyd Bradley, Western Sussex Hospitals TrustSinikallo S et al. Depressive symptoms predict postoperative disabilityamong patients with lumbar spinal stenosis: A two-year prospective studycomparing two age groups. DISABILITY AND REHABILITATION 2010;32(6):426-68.
Dementia: motor predictionsMild parkinsonian signs (MPS) are common in the elderly, and two previ-ous studies (including the Washington Heights Inwood Columbia AgeingProject, WHICAP) have suggested that MPS is a risk factor for developingdementia. The authors of this paper have studied a new cohort from 1999-2001, an extension of the original WHICAP cohort (1992-1996). Again,these prospective population based data show that MPS in elderly people
(>65 years) is associated with a greater than two-fold risk of developingdementia, mainly (86.4%) Alzheimer’s disease (AD). A cohort of 1851 ran-domly sampled elderly people underwent a neurological examination,abbreviated unified Parkinson’s disease rating scale (UPDRS) evaluationand a standard neuropsychological battery; mean follow up was 3.7years. MPS was defined as ≥ 2 UPDRS rating of 1 or one rating of ≥ 2 (PDwas defined as ≥ 2 UPDRS rating of ≥ 2). People with MPS were morethan twice as likely to develop dementia as those without MPS, particu-larly in the domains of language and memory. Furthermore, with eachpoint increase in the UPDRS score, the risk of dementia increased by 15%.Patients with MPS were older and more had diabetes and stroke- but theincreased risk of dementia still held after adjusting for these confounders(hazard ratio, HR = 1.98), and also when the 408 participants with mildcognitive impairment (MCI) were removed from the analysis. Those withaxial dysfunction and tremor (rather than rigidity) were more likely todevelop dementia. The risk of dementia with MPS was not compoundedby other known risk factors (including education, family history, stroke,apoE). There was no interaction between MCI and MPS - so MPS cannotbe used as a predictor of MCI progression. MPS have been thought to be relatively benign, but this study underlinesa substantial risk of dementia. Although the majority of patients devel-oped AD, it would have been interesting to know what other dementiaswere diagnosed - particularly PD dementia, vascular dementia and Lewybody disease; and, the progression of MPS to frank Parkinsonism. This isparticularly relevant given that the distinction between MPS and PD is rel-atively subjective (only one point on the UPDRS could make the differ-ence). The basis for MPS as a risk factor for dementia is unknown but onepossibility is that MPS represents basal ganglia tangles (and patients withAD often have MPS). It is perhaps surprising that those with tremor, ratherthan rigidity, were more likely to develop dementia given that tremulousPD is relatively benign. Neurologists do not tend to see the very frail eld-erly, so it is helpful to have a reminder that MPS are very common amongthis population, and that MPS are not necessarily ‘normal for age’. – Wendy Phillips, Norfolk and Norwich University Hospitals NHS TrustLouis E et al. Mild parkinsonian signs are associated with increased risk ofdementia in a prospective, population-based study of elders. MOVEMENT DISORDERS 2010;25:172.
Cognition: finding where we keep trackof whenIt has been established for a long time that temporal perception, the abili-ty to perceive the passage of time, is influenced by attention, and thus theneural systems underlying temporal perception and attention mightinclude similar structures. This study used repetitive transcranial magneticstimulation (rTMS) to test the a priori hypothesis that the right parietallobe plays an important role in both orientation of attention and tempo-ral perception. Previous studies using rTMS have established the role of theangular gyrus (AG) in temporal perception but the role of the supra mar-ginal gyrus (SMG) had not previously been tested. A two stage experimentwas designed in which healthy volunteers had to compare the duration ofa visual stimulus presented in different durations with and with out rTMSto three brain areas (Right SMG, left SMG and vertex). The differencebetween the two stages of the experiment was in rTMS timing. In the firststage, rTMS was delivered during presentation of the first sensory stimuluswhereas in the second stage this happened during presentation of the sec-ond stimulus. This was to establish whether memory and decision makingprocesses, which are more prominent in the latter part of the test, imposeany significant effect on the temporal perception. Analysis of the resultsrevealed that rTMS delivery to the right SMG consistently led to increasedtemporal perception compared to the left SMG, vertex stimulation and norTMS delivery. These findings reinforce the existing theories regardingimportance of the right parietal lobe in temporal perception, and for thefirst time highlight the particular role of right SMG in this process. – Seyed Sajjadi, Herchel Smith building and Neurology Unit,Addenbrooke’s Hospital.Wiener et al. Fast Forward: Supramarginal Gyrus Stimulation Alters TimeMeasurement. J COG NEUROSCI. 2010 Jan
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The role of neurology in our ever-changinghealth service is uncertain. Evidence sup-ports the importance of neurologists, particu-
larly in the acute treatment of patients. In Britain,neurological involvement in acute care, includingstroke, continues to be low, despite the fact that 15-20% of acute medical admissions are neurological,and of these, stroke constitutes one-quarter. Earlyinvolvement of neurologists impacts on diagnosisand management, this effect occurring no matterthe ratio of neurologists to population.1 This worksboth ways – neurologists reduce overdiagnosis aswell as highlighting life-threatening diseases. Forexample, one study found significant misdiagnosisof seizure and stroke; in benign conditions such asmigraine, syncope or peripheral vertigo.2 In pre-sentations with possible epilepsy, neurological con-sultation increased the diagnostic rate by 50%,3
while absence of neurological input led to signifi-cant misdiagnosis of epilepsy in both communityand hospital based groups. The view that neurolo-gists should focus largely on outpatients under-mines some of the proven strengths of neurology.
This has major implications for neurologists atall stages of our careers. We need to continueattracting keen medical students to neurology.Trainees need a broad base of medicine and adiversity of experience if they are to be good atdealing with emergency care. ‘Jobbing’ neurolo-gists working hard in busy general hospitals musthave the protected time to keep up-to-date andinspired. Probably most crucial, we need to per-suade others in Britain of the importance of a par-adigm shift in thinking about neurological servic-es. This will take considerable energy and drive, asin cash-strapped times, we may be seen to be fight-ing for scarce resources, and in competition withother specialties.
And what is the Association of BritishNeurologists (ABN) doing about this? We haveadded the first roadshow to the ABN Meeting inBournemouth, to pass on the excitement of neurol-ogy to medical students. We are thinking aboutfuture directions of the ABN, and how to protecthigh standards of training, with enough flexibilityto allow people to come to neurology from differ-ent angles. As for all of us, the domestics of life takeup a huge amount of energy for the ABN. We wantto make sure we are using our time wisely (whichis the membership’s time). The membership atlarge; as well as Charles Warlow, our Non-Executive
Officer; the President, Officers and Council, all putin a massive effort to meet tight deadlines for com-ment on a variety of neurological topics. We willbe auditing the huge number of guidelines andcommentaries requested from us. We need toknow whether the effort we put into these is heed-ed. The ABN must have a role in protecting valu-able supporting activities which are vital to excel-lence in practice; and academic and teaching con-tacts; just as important for clinicians as for academ-ics. There has been a focus on broader ethicalissues in medicine of particular importance toneurology, and how to draw commentary and con-sensus from our members on these.
Almost all neurologists in Britain, from trainingonwards, are members of the ABN. This is the great-est strength of the organisation. We are diverse, andshould reject stereotypes which never fitted any-way. If we are going to make the most of our organ-isation, then members’ views on the political roleof the ABN are crucial and we want your voice ona variety of day to day and large scale ethicalissues. And most importantly, on the shape of ourpolitical involvement. Should the ABN be a politi-cally neutral organisation? There is a strong argu-ment that political neutrality is a misnomer, thatneutrality means acceptance of the status quowithout question. When we exercise our politicalmuscle, life is more complex. Many issues will raisehackles, as well as lively and constructive debate.An organisation that says anything of vigour willtread on toes, even with the most robust attemptsat consultation and balance.
My bias is obvious. I think that the ABN should beactively involved in politics, and making a noise. Butthe ABN is all of our members, and decisions aboutour political profile need to come from the member-ship. The Annual General Meeting, next atBournemouth in May, is a forum for the views ofmembership. Council want, and need, your activeinvolvement and your opinions. l
1. Ali E, Chaila E, Hutchinson M, Turbridy N. The “hiddenwork” of a hospital neurologist: 1000 consults later. Eur JNeurol, 2009, Epub ahead of publication.
2. Moeller JJ, Kuniawan J et al. Diagnostic accuracy of neurologi-cal problems in the emergency department. Can J Neurol Sci2008;35:335-341.
3. Angus-Leppan H. Diagnosing epilepsy in neurology clinics: aprospective study. Seizure 2008;17:431-436.
Challenges Ahead
Heather Angus-Leppan MSc (Ep), MD,FRACP, FRCP was born in South Africa, trainedin Australia and won aScholarship as VisitingAustralasian Registrar to theRadcliffe Infirmary, Oxford, in1993. She is Head of theNeurology Department at BarnetHospital and ConsultantNeurologist, Honorary SeniorLecturer and Epilepsy Lead at theRoyal Free Hospital, London, UK.She is the Honorary AssistantSecretary of the Association ofBritish Neurologists, HonorarySecretary of the NeurosciencesSection of the Royal Society ofMedicine and current Chair ofthe Map of Medicine EpilepsyGroup, UK.
T H E A S S O C I AT I O N O F B R I T I S H N E U R O L O G I S T S
Are you looking for a Training Post in Neurology?
Do you have a vacancy to fill?
See www.acnr.co.uk/recruitment.htm for details of training posts aroundthe UK, sourced directly from Training Course Directors and Deaneries.There is no charge for using this service.To list a vacancy on the recruitment page free of charge, or for more information, Email. [email protected] or Tel. 01747 860168.
REFERENCES
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MSologists vs Neurologists:who is best placed to treat MS?
Disease Improvement in MS: a real possibility?
Join the debate...
CURRENT CONTROVERSIES IN MULTIPLE SCLEROSIS
A debate at the Association of British Neurologists Annual Meeting, BIC, Bournemouth
13.00 - 14.00 hours Tuesday 11th May 2010
In the rapidly evolving area of MS, new issues relating to patient management and treatmentexpectations are the subject of discussion. Join the experts in considering two core issues,in this debate chaired by Dr Eli Silber:
■ MSologists vs Neurologists: who is best placed to treat MS effectively?Dr Peter Brex vs Dr Chris Clough
■ Disease Improvement in MS: a real possibility?Prof Gavin Giovannoni vs Dr Giles Elrington
Date of preparation: April 2010 Code No: BI-GBR-0048b The debate is sponsored by Biogen Idec Ltd
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CO -
SPO
NSO
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ST Organised in co-operation with the Swiss Neurological Society
Co-sponsored by the World Federation of Neurology (WFN)
Co-sponsored by the European Section of the Movement Disorder Society (MDS-ES)
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aN
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EFNS EUROPEAN FEDERATION OFNEUROLOGICAL SOCIETIES
eFNS 2010 c/o Kenes International Global Congress Organisers and Association Management Services1 3 rue de Chantepoulet, P.O. Box 1726 1211 Geneva 1, Switzerland
Warwick University Short Course.Techniquesand Applications of Molecular Biology: ACourse for Medical Practitioners12-15 July, 2010; Warwick, UKT. 024 7652 3540E. [email protected]/go/bioscienceshortcourses
XII International Congress on NeuromuscularDiseases17-22 July, 2010; Naples, Italywww.icnmd2010.naples.org
15th World Congress of Psychophysiology - theOlympics of the Brain - IOP2010 30 August – 4 October, 2010; Budapest, HungaryMark Molnar, T. 61 350 1854E. [email protected]
SEPTEMBER3rd International Congress Biotechnologies forSpinal surgery1-4 September, 2010; Amsterdam, NetherlandsE. [email protected]
Understanding and Dealing with BehaviourProblems following ABI17-18 September, 2010; Gatwick Airport, London,UKE. [email protected]
Clinical Reasoning in Soft Tissue Repair: Usingthe evidence to maximise recovery using manu-al therapy, exercise and electrotherapy18 September, 2010; Bath, UKwww.physiouk.co.uk
Second Meetingof the European Societies ofNeuropsychology22-24 September, 2010; London, UKE. [email protected]
14th Congress of the European Federation ofNeurological Societies (EFNS 2010)25-28 September, 2010; Geneva, SwitzerlandT. 41 229 080 488E. [email protected]
To list your event in this diary, email brief details to John Gustar at [email protected] by 8th June, 2010
E V E N T S D I A RY
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Fifth Meeting of the UK PD Non Motor Group:Non Motor Symptoms of PD: Treatment & Quality of LifeConference details: 20 March 2010, Royal Society of Medicine, London, UK. Reviewed by: Miss Chandni Chandiramani, Kings College and Institute of Psychiatry,London, UK and Mr Kartik Logishetty, Kings College, London, UK,
The fifth meeting of the Parkinson diseaseNon-Motor Group (PDNMG) was held atthe Royal Society of Medicine, London.
This year the international faculty sought tolook deeper into issues surrounding treatmentand quality of life in Parkinson’s disease (PD).
Professor K Ray Chaudhuri (UK), thePDNMG chairman and meeting organiser, wel-comed the delegates by presenting anoverview regarding the recognition and preva-lence of non motor symptoms (NMS) of PD.Professor AHV Schaipra (UK), formally beganthe meeting by shedding light on neuroprotec-tion approaches for PD. He discussed recentevidence which encourages early initiation oftreatment, highlighting the results from ADA-GIO, TEMPO and DATATOP trials which suggestthat PD patients who started on early treat-ment had better outcomes with more sympto-matic relief. He postulated that drugs such asselegiline, rasagiline and levodopa are able topromote brain plasticity and compensation.Prof Schapira emphasised preclinical non-motor markers of PD, including olfaction andconstipation. He concluded that the decisionof starting treatment should be based uponweighing treatment side effects and effects onquality of life with symptom control and dis-ease progression. However, with questions sur-rounding the conclusiveness of the data andthe power of the studies, further robust trialsare required to further understand the possi-ble disease-modifying properties of PD drugs.
Next, Prof DJ Brooks (UK) discussed therole of neuroinflammation in PD. He exploredthe evidence suggesting a pathogenic role ofmicroglia in PD. Microglia are most highly con-centrated in the substantia nigra, and mosthighly active and clustered around dystrophicdopaminergic neurones. Cytokine releaseleads to microglial and macrophage activationand subsequent dopaminergic and choliner-gic cell death and brain remodelling. ProfBrooks outlined the uses of FDG-PET, FP-SPECT, F-Dopa PET, acetylcholinesterase imag-ing and PET amyloid plaque imaging in PD.These neuroimaging strategies provide bio-markers of the ongoing disease activity. Finally,he examined the correlation between Braak-staging of PD with clinical manifestations,imaging the substantia nigra and the nonmotor symptoms including olfactory distur-bances, autonomic symptoms and disordersin the cognitive domain.
Prof Chaudhuri provided a succinct reviewof pain in PD. As well as outlining a classifica-tion of pain in PD (symptomatically groupedinto musculoskeletal, radicular/neuropathic,dystonic, central or primary pain, and
akathisia) he highlighted that depression maycontribute to the intractability of a chronicpain syndrome. Orofacial pain is a poorlyunderstood NMS but highly detrimental toquality of life. It encompasses headaches, burn-ing mouth syndrome, temporomandibular jointpain and compromised trigeminal reflexes. Heemphasised that most painful symptoms couldoccur during ‘off periods’, particularly early inthe morning. Prof Chaudhuri discussed thegeneric pain evaluation tool - McGill PainQuestionnaire (MPQ) . The MPQ, used judi-ciously, is useful for defining the prevalanceand characteristics of pain according to itslocation, intensity and temporal pattern, thusenabling a pain specialist to tailor manage-ment plans and monitor treatment response.
Professors P Martinez-Martin (Spain) and POdin (Germany) discussed the impact of NMSon quality of life, and non-declaration of NMSin PD, respectively. Particular NMS includingdepression and autonomic, sexual and gas-trointestinal dysfunction are under-reportedby patients and as a result under-treated byhealth care professionals. This could be attrib-uted to patients’ lack of awareness betweentheir NMS and PD or perhaps a reluctance toreveal embarrassing problems to a stranger.The recently published study recommends the
use of the patient-completed ‘Non-MotorSymptom Questionnaire’ (NMSQuest) to pro-vide an early screen of NMS.
Professor A Antonini (Italy) offered anappraisal of drug therapy for motor and non-motor symptoms. He began with reviewingresults from the recent PRIAMO study – a largeItalian cross-sectional observational studywhich described epidemiology and evolutionof NMS. NMS in the psychiatric domain weremost frequent, with apathy being most associ-ated with reduced quality of life scores. NMSare closely associated with cognitive impair-ment, with the number of NMS per patientincreasing with age and disease severity.Finally, the PRIAMO study highlighted the highprevalence of NMS in the PD population(98.6%). For the treatment of NMS, ProfAntonini went on to discuss pramipexole,which has negative effects on daytime sleepi-ness but may significantly alleviate depres-sion. The clinical benefit of DBS in NMS is rel-atively much higher than that of apomorphine.However, while DBS may improve dyskinesiasin late PD, it does not seem to have any effectson sexual aspect of NMS in PD. Lastly, intrajeju-nal infusion of levodopa is a more invasivetreatment than apomorphine. Levodopa infu-sion not only replaces oral medication butalso helps in avoiding swallowing problemsthat may be commonly experienced in PD.
In recent years, dementia has been recog-nized as a common albeit highly variable fea-ture of PD. Professor D Aarsland (Norway) out-lined the clinical and neuropathological dif-ferences between PD dementia (PDD) andAlzheimer’s disease (AD) pathology with or
Per Odin, Alexandra Rizos, K Ray Chaudhuri, Dag Aarsland,Pablo Martinez-Martin.
Standing: Graham Macphee, Pablo Martinez-Martin, Peter Fletcher, Per Odin, Kieran BreenSeated: Alison Forbes, Fabrizio Stocchi, K Ray Chaudhuri,Cristian Falup-Precariu.
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DAY 1:• COGNITIVE OUTCOMES FOLLOWING EPILEPSY IN PREGNANCY• EPILEPSY IN METABOLIC DISORDERS AND NEUROCUTANEOUS SYNDROMES• EXCELLENCE IN EPILEPSY AWARD• ANNUAL GENERAL MEETING
Day 2: PARALLEL SESSIONSA. BASIC SCIENCE PLATFORM SESSIONS (jointly with Epilepsy Research UK)B. TRANSITION: MIND THE GAP (jointly with the ILAE UK Chapter Primary Care Society)
Transition of epilepsy care in adolescenceEpilepsy in the elderly: Who does what?
• RISK REDUCTION IN EPILEPSY• EXPERT-LED POSTER SESSIONS• CASE PRESENTATION COMPETITION• GENETICS LECTURE• PLATFORM PRESENTATIONS
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The programme will provide up-to-date and cutting edge talks on infectious and inflammatory diseases of the nervous system from some of the country’s leading experts. This course will be of interest to consultant neurologists, trainee neurologists at all levels,infectious diseases physicians and trainees, general physicians, immunologistsand microbiologists.
Symposium OrganiserProfessor Peter Kennedy CBE, Glasgow University.Tuesday 2 November 2010
RCPSG232-244 St Vincent StreetGlasgowG2 5RJ
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Symposium on Neuroinflammation and NeuroinfectionTuesday 2 November 2010
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Global Symposium on the Dietary Treatments for Epilepsy andother Neurological Disorders5-8th October 2010 • Sheraton Hotel, Edinburgh, Scotland, UK
To book visit www.matthewsfriends.org - email [email protected] or call 07748800438Registered Charity No. 1108016
Although the ketogenic diet has been used in the treatment of epilepsyfor almost 100 years, it is now 15 years since the story of Charlie, who,after failing numerous anti-epileptic drugs became seizure free anddrug free on the ketogenic diet and brought awareness of the possibleeffects of the diet to a wider population. There is now no question ofagreement to its efficacy, not only in epilepsy but also now widening toother neurological conditions. Research into basic mechanisms ofaction and implementation has also escalated and it was agreed thatprogress would be sufficient to bring individuals together once againin 2010 following the first Symposium held in Phoenix, Arizona in April2008. As you can see from the programme, available atwww.matthewsfriends.org, we have no doubt this is true.
I sincerely hope that you are able to attend and we lookforward to welcoming you to Edinburgh in October.
J Helen Cross - Chair Scientific Organising CommitteeThe Prince of Wales’s Chair of Childhood Epilepsy, UCL-ICH, Great Ormond Street Hospital for Children, London & the National Centre for YoungPeople with Epilepsy, Lingfield, UK.
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without dementia. Old age, visual hallucina-tions, and more marked motor symptoms areestablished risk factors for PDD, with at least75% of PD patients developing dementia with-in 10 years. Differentiating PDD withAlzheimer’s disease (AD) pathology remainsdifficult, since half of dementia patients haveenough pathology to be diagnosed with ADwhile PDD can develop without any ADpathology at all. However, a shorter duration ofPD symptoms before onset of dementia in anolder patient may suggest PDD+AD pathology.Sufferers are prone to experience cognitiveimpairment, psychiatric fluctuations andsleep disturbances. There are a wide range oftreatment approaches for dementia in PD. ProfAarsland reviewed cholinesterase inhibitorsand memantine (specifically licensed for AD)as possible treatments for PDD. Statins, antiamyloid strategies, anti inflammatory treat-ments and anti psychotic therapies were alsobriefly discussed .
Dystonia is not classically regarded as oneof the non motor symptoms of PD but it seemsto share analogous features with NMS in PD.Like NMS, dystonia is under-recognised as wellas under-treated. Professor T Warner (UK) dis-cussed the multiple factors which may inducedystonia before reviewing the diverse treat-ment strategies for dystonia in PD. Purportedlinks between dopa-responsive dystonia andexercise-induced dystonia with PD remainunclear. Dystonia in PD seems to have a genet-ic connection - autosomal recessive inheri-
tance, involving mutations in PARK2 andPARK6 genes. He recommended anti-dyskinet-ic drugs like amantadine, continuous lev-odopa infusions, botulinum toxin to treat thistroublesome, albeit rare, problem in PD.
Professor F Stocchi (Italy) examined thecorrelation between gastrointestinal problemsin PD and quality of life. Dribbling of saliva,swallowing abnormalities, nausea, vomitingand constipation are some of the most com-mon NMS seen in PD. Prof Stocchi outlinedthat constipation could precede the motorsymptoms and be regarded as one of the pre-clinical markers of PD. There are many thera-pies that have been advocated for the treat-ment of gastrointestinal symptoms in PD,including botulinum toxin as a solution fordribbling of saliva and even constipation.
Dr Graeme MacPhee (UK) examined theaetiology, prevalance and the various assess-ment tools and treatment strategies for depres-sion in PD. Depression is a key neuropsychi-atric NMS and can affect up to 45% of PDpatients. Dysfunctions of dopaminergic, sero-tonergic and noradrenergic pathways in thelimbic system of depressed PD patients havebeen implicated. He recommended the use ofthe Hamilton depression scale (HAD Scale) toidentify depression. The treatment should betailored to symptom severity, in addition,recent SIGN guidelines examining the treat-ment of depression in PD identified that tri-cyclic antidepressants showed the best effica-cy but that these agents often came at the
expense of adverse effects. SSRIs are oftenused in routine practice.
The meeting ended with video case presen-tations of PD patients facilitated by ProfChaudhuri, Prof Stocchi and Professor GMacphee (UK). The interactive session exam-ined the sometimes puzzling and atypicalpresentation of parkinsonism and was buoyedby enthusiastic audience contribution.
Non motor symptoms have a significantimpact on quality of life – more so than theirmotor counterparts. The search for a therapythat adequately addresses motor and non-motor symptoms continues. In the meantime,clinicians must adopt a holistic approach totheir treatment, and place the patient’s individ-ual perception of their symptoms at the coreof any management strategy. On reflection, it isclear that since its genesis 6 years ago, thePDNMG has gone some way in achieving itsinitial mission statement. Thanks in part to thewidespread use of the group’s internationallyvalidated assessment tools, non motor symp-toms are now a widely recognised feature ofPD. It is likely that from 2011 onwards, meetingswill take place under the banner of 'EU-ROPAR', a group dedicated to the advance-ment of non-motor research in PD.
The organisers acknowledge the support ofthe meeting’s sponsors, Boehringer IngelheimLtd, Solvay and Britannia Pharmaceuticals,Teva & Lundbeck Ltd and IpsenPharmaceuticals, without whom the meetingwould not have been possible. l
Sixth World Congress for Neurorehabilitation 2010Conference details: 21-25 March 2010, Vienna, Austria Reviewed by: Louise Blakeborough, on behalf of the World Federation for Neurological Rehabilitation.
The 6th World Congress for Neurorehabili-tation was held between the 21st and 25thMarch in Vienna. Over 1600 health profes-
sionals from 71 countries met in the historicalCongress Centre in the Hofburg, Vienna’s for-mer imperial palace.
There was an extensive programme of work-shops, lectures and symposia on clinical prac-tice and research covering topics from basic
science to practical applications. The breadthof content attracted neurorehabilitation clini-cians and therapists from all disciplines. Just afew highlights follow.
In the Opening Ceremony, Heinrich Binder,President of the Austrian Society ofNeurorehabilitation welcomed delegates toVienna. The President of the World Federationfor Neurorehabilitation (WFNR), Michael
Selzer, then introduced the first Michael PBarnes Lecturer in Neurorehabilitation, givenby the eminent Alberto Juan Aguayo. ThisLecture will now be the highlight of eachWFNR World Congress, in recognition of thevisionary leadership of the WFNR’s founder,Michael P Barnes.
Alberto Aguayo gave an historical overviewof axon regeneration in the central nervous sys-
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tem (CNS), beginning with Santiago Ramón yCajal’s ‘Degeneration and Regeneration of theNervous System,’ which was published in 1914and anticipated many of the current ideas in thefield. Beginning in the 1980’s, Dr Aquayo and hiscolleagues at McGill University carried out pio-neering studies that showed injured axons ofthe central nervous system were not intrinsical-ly incapable of regenerating after injury, as hadbeen assumed. Aguayo rediscovered an oldfinding by Cajal and his students that theseaxons could grow for long distances into graftsof peripheral nerve. In a long series of elegantexperiments in the spinal cord, brain and opticnerve, Aguayo showed that the extracellularenvironment of the CNS is an important factorin limiting the regenerative ability of axons.These studies laid the groundwork for the subse-quent discovery of molecules found in the CNSthat are inhibitors of axon regeneration.
Later in the congress, Dr Selzer introducedtwo of the most prominent scientists in thefield, who focused on the molecular mecha-nisms that underlie Aguayo’s findings. DrJames Fawcett of Cambridge Universitydescribed how perineuronal nets containingchondroitin sulphate proteoglycans and otherinhibitory molecules suppress axon regenera-tion and sprouting, a form of plasticity, in thebrains and spinal cords of rats. Enzymaticdigestion of chondroitin sulphate proteogly-cans increased sprouting in the injured spinalcord, but this did not automatically result infunctional improvement, unless the treatmentwas combined with behavioural reinforce-ment (physical therapy). This demonstrateswhat neurorehabilitation researchers havelong suspected, that restored anatomical con-nections will have to be sculpted by physicaltherapy in order to achieve optimal restorationof function. Dr Marie Filbin of the CityUniversity of New York focused on anothergroup of inhibitory molecules, those con-tained in CNS myelin. These molecules bindto the Nogo receptor, part of a receptor com-plex present in the membranes of axons thattriggers inhibition of their growth. Dr Filbinhas discovered many of the steps in the intra-neuronal signalling cascade that leads frombinding to the Nogo receptor to shut-down ofaxon growth. Clinical trials still ongoing areaimed at neutralising these inhibitory mole-cules in patients with spinal cord injury.
Although actual cures for serious nerveinjuries have not yet been achieved and thereare many challenges ahead, multiple strategiesare now converging to manipulate the nerv-ous system at many levels in order to promoteaxon sprouting and regeneration.
A session entitled Cell Therapies: Hope orIllusion? introduced by Dr Bruce Dobkinencapsulated the acceleration of neurologicalresearch in the field of stem cells for condi-tions such as stroke, multiple sclerosis,Parkinson’s and Huntington’s disease. The ses-sion began with an audience vote on whetherthey believed that cell therapy interventionswould eventually improve life for the mostseverely impaired patients. The majority of the
audience voted yes. However, Dr Dobkin cau-tioned against the selling of hope to vulnera-ble people and families by ‘for-profit stem cellorganisations’ and strongly advocated the con-duct of prospective, randomised, multicentrecontrolled trials as ethically and scientificallynecessary.
A very encouraging development was report-ed by Dr Wise Young, who has worked withresearch communities around the world, includ-ing the Peoples Republic of China, to adopt theuse of standardised frameworks to guide futurepre-clinical and clinical research. This sessionwas attended by several disabled young peoplewho asked the speakers and audience toencourage “partnerships with the spinal cordinjury community” and ensure that patientsunderstand the basics of this exciting science.
As with any meeting about neurorehabilita-tion, the use of robotics provided lively discus-sion and debate. There is no doubt that reha-bilitation robotics is a highly promising tech-nology that has demonstrated benefit in sever-al disabling neurological illnesses. DrHermano Igo Krebs reported results of aprospective, randomised, multicentre con-trolled trial of robotic-assisted physical therapyfor upper limb recovery after stroke, carried outin the US Department of Veterans Affairs. Whileconventional physical therapy resulted inalmost as good recovery, this was only true ifthe intensity of therapy was equal. It is possiblethat robotics will allow a greater intensity oftherapy.
The key problem faced by this technology isour uncertainty about the appropriate way touse these devices and their potential limita-tions. Maybe, as Dr William Rymer said “theproblem is not with robotics but with us andour way of using them”. The key to successfuluse of robotics may be their simplification andadaptation to home use.
Another symposium focused on the poten-tial use of brain-computer interfaces to permittotally paralyzed patients to control assistivedevices and even their own paralyzed mus-cles. Dr John Donoghue explained that evi-dence from multielectrode microchipsimplanted in paralysed human patients showsthat command neurons in the cerebral cortexsurvive despite the neurodegenerative natureof amyotrophic lateral sclerosis and trauma toaxons in spinal cord injury.
But with all the high-tech advances in regen-erative medicine and robotics, perhaps themost interesting theme of the congress relatedto the notion of simplicity in research design.A poster by Dr Bruce Dobkin and colleaguespresented the results of a clinical trialdesigned to allow participation by investiga-tors who have no access to specialised equip-ment. In the SIRROWS study, providing inpa-tients recovering from stroke with feedback onhow quickly they walked improved their ulti-mate walking speed over ten metres and howfar they could walk in three minutes. Theimprovement persisted at least as long as athree month follow-up.
Several sessions addressed evidence-based
neurorehabilitation, an area that has been slowto progress, partly due to the constraints of ran-domised controlled trials. Matching the rightintervention for a patient’s deficits can prove tobe extremely difficult, with a lack of treatmentprotocols available. An overview of guidelinepreparation was presented by Dr Lynne Turner-Stokes and Dr Thomas Platz who outlinedguidelines for arm treatment after stroke.
Recent neuroscience research suggests thatthe neural systems underlying music alsoserve non-musical functions, such as linguisticprocessing, motor control, attention, memoryand other functions. Dr Michael Thaut postu-lated that music can affect general cognitiveand motor functions subserved by these brainsystems via mechanisms of neural plasticity.There is now a new treatment model ofNeurologic Music Therapy with considerableevidence for its effectiveness in rehabilitatingdisorders of the human nervous system.
When do you start neurorehabilitation?This key question was discussed by DrHeinrich Binder and followed by Dr AnthonyWard who showed that the outcomes of braininjured patients were improved by interven-tions that took place in the intensive care unitrather than waiting until the patient has beentransferred onto a rehabilitation ward. Butperhaps the most impressive example of theapplication of simplicity to research designwas given by Dr Gert Kwakkel of theNetherlands. Using multivariate analysis heshowed that within a few days after a stroke,recovery of hand and arm coordination couldbe almost perfectly predicted by two findingson very simple bedside tests; a small amountof finger extension, and a small amount ofshoulder abduction. Similarly, recovery ofwalking could be predicted by whether thepatient could sit up over the side of the bed.
There were over 400 interesting and diverseposter presentations throughout the week. Theprize for the best poster by a student or fellowwent to Dr Johan Gaverth of Sweden for devel-oping a biomechanical model that can quan-tify spasticity and distinguish it from contrac-ture. The prize for the overall best poster wentto Dr D Cinteza of Romania for a study thatshowed the superiority of training to step overobstacles over treadmill training for recoveryof gait after stroke.
The meeting ended with a special lectureby Dr Henry Markram of Lausanne,Switzerland. He gave a spectacular demon-stration of the Blue Brain Project, a combina-tion of experimental work and computer mod-elling that is developing an accurate represen-tation of the cerebral cortex down to the finestdetails of synaptic connectivity and molecularmechanisms.
The next World Congress forNeurorehabilitation in 2012 will take place
in Melbourne, Australia.
For further information please visit theWFNR website www.wfnr.co.uk
C O N F E R E N C E R E P O RT S
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Positive Steps in Parkinson’s DiseaseConference details: 5-6 March 2010, London UK Reviewed by: David Burn, Professor in Movement Disorder Neurology, Newcastle University and Dr Doug MacMahon, Consultant Physician, Camborne-Redruth Hospital, Cornwall.
The third Positive Steps in Parkinson’sDisease meeting, sponsored by TevaPharmaceuticals Ltd and Lundbeck Ltd,
was held on March 5th-6th in London. The pre-sentations and discussions covered both cut-ting edge clinical research and aspects of dailypractice that, although sometimes overlooked,have significant impact on patient quality oflife. Although the presentations were varied incontent, it was striking that a common themewas the recognition that Parkinson’s disease(PD) is no longer considered solely a motordisorder, and that treatments and researchstrategies need to address the issues of non-motor problems suffered by the majority ofpeople with PD.
Dr Doug MacMahon began the programmeby giving an update on clinical trials reported inthe past year. New genome-wide associationstudies have recently shown two strong associ-ation signals in genes coding for alpha-synucle-in and Tau proteins. Importantly, these new stud-ies were not conducted in relatively small pop-ulations with familial PD, but in patients with“sporadic” idiopathic PD, thus demonstrating aclear role for common genetic variants in theaetiology of this disease, and also recent specu-lation of the possible role of prions. DrMacMahon highlighted that recent researchhas tended to focus on the recognition andtreatment of early disease in the hope of a treat-ment that will slow or halt the inexorable pro-gression of PD. The recognition that non-motorsymptoms (such as hyposmia and constipa-tion) can often emerge before motor symptomsor signs has given rise to the notion of diagnos-ing prodromal PD. Dr MacMahon stressed thatthe early recognition of PD becomes more cru-cial as we begin to review the role of early treat-ment. Last year saw the publication or release ofdata from a number of large clinical trials inearly disease and although some of the resultswere disappointing, some have indicated thatmore strategic use of currently available drugsmay help maintain patient function for longer.While discussing the results of the ADAGIO(rasagiline) and PROUD (pramipexole)delayed-start studies, Dr MacMahon noted thatphysicians must now be able to interpret datafrom complex trial designs and understand therationale that effects of drugs given in early dis-ease may not always be clinically obvious asthe patients only display mild symptoms, butmay modify the progress thereafter.
A hot topic in PD is the association ofdopaminergic therapy with impulse controldisorders (ICDs) and Dr Graeme Macpheegave a presentation covering the large amountof work recently conducted in this area.Although they have only been recognised rel-atively recently, ICDs (including compulsivebuying, pathological gambling, binge eating,
hypersexuality) are not uncommon. A recentlarge observational study conducted in theUnited States and Canada found that 13.6% ofpatients with PD had at least one ICD, and 36%of these had more than one disorder. ICDs areoften associated with dopamine agonists, butpatients receiving both levodopa and adopamine agonist appear to be at highest risk.Dr Macphee suggested that ICDs can beviewed as a continuum of reward-basedbehaviours; the earliest signs being the emer-gence of atypical behaviours that the patientsoften try to hide. Notably, there is often a lackof pleasure associated with the behaviours, thepatient needing rather than liking the feelingsassociated with the activities. Pathologically, itappears that degeneration in the ventral stria-tum and nucleus accumbens is more closelyassociated with problems with impulse con-trol than degeneration in the dorsal striatum.Dr Macphee suggested that non-physiologicalstimulation of dopamine receptors in the ven-tral striatum might underlie the developmentof ICDs; the analogy later suggested by thepanel was that ICDs may be regarded as aform of ‘limbic dyskinesia’.
Dr Peter Fletcher continued the theme, look-ing at non-motor problems in elderly patientswith PD. People in the western world are nowfitter and living longer, so more people are sur-viving other diseases to achieve older age,when PD becomes more prevalent. Added tothis, improvements in the care of patients withPD mean that they are now surviving longerand this brings a new aspect to care; the elder-ly PD patient is no longer just the patient whodeveloped PD in later life, but also includespatients who have lived with PD for a longtime. In addition to the core motor symptoms,the typical elderly patient with PD will sufferfrom a multitude of non-motor symptoms, par-ticularly autonomic dysfunction, sleep disor-ders, dementia and depression – often withconsiderable impact on caregivers and family.The risk of falls and associated fractures canstart early, but the average time to first fractureis 9 years from diagnosis and is the numberone cause for admission of people with PD toA&E. As more patients are surviving longer inthe complex and palliative care phases of PDmanagement, Dr Fletcher stressed that physi-cians need to take the long view and that treat-
ment should target the needs of the wholepatient and not just motor symptoms and thatour training and support systems need tochange in recognition of this.
The problems of dementia were reviewed infurther detail by Professor David Burn whohighlighted the high cumulative incidence ofPD dementia (PDD) and its significant neu-ropsychiatric burden (including psychotic fea-tures and mood disturbances). The peoplemost at risk for PDD are older with moresevere disease. They will often have the PIGDphenotype and might have REM sleep behav-iour disorder. Professor Burn discussed thatdiagnosing cognitive impairment is not alwayseasy and that a collateral history from care-givers and relatives is essential in teasing outthe slow progression of cognitive decline thatis associated with PDD. Though a wide varietyof cognitive tests are available for daily prac-tice, physicians should no longer rely on theMMSE for assessing PDD. Tests such as theMontreal Cognitive Assessment (MoCA) andthe Addenbrooke’s Cognitive Examination(ACE-R) are relatively short and are better forpicking up problems with executive function.Treatment with cholinesterase inhibitorsremains the mainstay of treatment (onlyrivastigmine is licensed for PDD), andalthough the atypical antipsychotics can beuseful they are not licensed for the treatmentof PDD. Despite the association ofcholinesterase inhibitors with increasedtremor in the titration phase, this doesn'tappear to be troublesome enough for thepatients to withdraw from treatment. However,physicians should be aware of the increasedrisks of fractures and bradycardia before giv-ing a cholinesterase inhibitor. In addition,Professor Burn stressed that if onecholinesterase inhibitor doesn't work, it isalways worth trying another as they each havespecific efficacy and tolerability profiles thatmay suit different patients.
Another problem associated with PD ispoor oral health, and Dr Helen Roberts sur-prised the audience by giving one of the firsttalks on this topic at a national meeting.Although physicians who treat PD are veryfamiliar with the problems of drooling anddysphasia, most are less aware of the problemsof xerostomia (dry mouth), burning mouth
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and dental caries. Dr Roberts pointed out thatthe common practice of reducing salivaryflow (by atropine or botox) to control droolinghas the adverse effect of impairing the normalbuffering role of saliva, leading to an acidicenvironment, demineralisation of the teethand ultimately tooth decay. Similarly xerosto-mia, which can be caused by treatments suchas levodopa, can affect up to 55% of the PDpopulation and also carries an increased riskof dental caries and periodontal disease. Thefew dental studies which have been carriedout have all shown that PD patients have moremissing teeth, swollen gums and denture dis-comfort, all of which can impact on thepatient’s ability to eat. Dr Roberts urged allattendees to question their patients about theiroral health, and to coordinate care with den-tists where possible to give advice on the spe-cific dental problems associated with PD.
The question of who is a good candidate forneurosurgery was tackled by Dr Tom Foltynie,who stressed that patient selection is the key toa successful outcome. Accepted indicationsinclude severe motor fluctuations, dyskinesiaand tremor, and more recently patients whoare intolerant to medication (for example dueto ICDs) are increasingly being considered.The benefits of deep brain stimulation (DBS)can be dramatic and studies have shown thatthe effects are relatively long lasting, but the ‘fit-ness’ of the patient should always be consid-ered, as surgery is not without risk. Aside from
the immediate risks of an invasive procedure(the overall rate of surgical complications is3%), patients should be cognitively intact andhave good speech as DBS can affect verbal flu-ency. Weight gain can also be a problem forsome patients. Advances in the technologyinclude changes in the electrode, for flexibilityin targeting, and rechargeable batteries. Thereis also evidence that although earlier ratherthan later DBS treatment may optimise its ben-efits, there are logistical and financial obsta-cles to adopting this theoretical approach.
Looking to the future, Dr Roger Barker dis-cussed the role of stem cells as a neurorestora-tive treatment. Recent advances in developingInduced Pluripotent Stem (IPS) cells nowallow the generation of stem cells from thepatient’s own skin, thus avoiding many of theethical problems of embryonic stem cells.Indeed, it has been reported this year that it isnow possible to convert fibroblasts directly toneurones by using appropriate growth factors.However, numerous technical problems havemeant that this technology is currently bestused as a way to model the disease rather thanas a treatment. Furthermore, experience withfoetal grafts into the striatum tells us that weshould again pay close attention to patientselection and timing of the graft. Youngerpatients with localised nigral pathology havebeen reported to do extremely well, whereasolder patients who suffered from posturalinstability and gait dysfunction tended to have
a more widespread pathology throughout theCNS and experienced minimal benefit anddyskinesia. Similarly, significant benefits motorfunction were only seen in patients with aUPDRS score of <49.
Professor Peter Jenner closed the meetingby looking at upcoming drugs in the PDpipeline. A number of potential non-dopamin-ergic drugs have recently failed in Phase IIIstudies, although a few candidates such as theadenosine A2A antagonists remain in clinicaldevelopment as adjunct therapies. Similarly,research into neuroprotective and neu-rorestorative therapies have yet to produce anyreal candidates for treatment. However, theintroduction of new delivery systems for olderdrugs (including levodopa and a number ofdopamine agonists) and revised treatmentalgorithms have already made a significantimpact on patient care. For example, evidenceis now accumulating that early interventionmay increase the amount of time that thepatient remains stable and delay the onset ofmotor complications. Professor Jenner endedthe meeting by stressing that in order to meetthe developing needs of people with PD, physi-cians should take a long-term strategicapproach to treatment.
The lively discussions and debate were allsupplemented with workshops and interactivesessions and participants left eagerly lookingforward to the next meeting planned for 4-5March 2011 in Newcastle upon Tyne.
Review of the Third Biennial Meeting of the UK SwallowingResearch GroupConference details: 4-5 February 2010, London, UK. Reviewed by: Sophie Puritz CT1, Medicine, University Hospital of Wales and Tom Hughes Consultant Neurologist,University Hospital of Wales.
The UK Swallowing Research Group held a conference onThursday 4th & Friday 5th February 2010 in UCL Institute of ChildHealth, London. This was the third meeting of the group fol-lowing its first meeting in Manchester four years ago. Theattendees were from a range of backgrounds but speech thera-py was the best represented profession. Although it may seemanomalous to some to arrange a conference around a singlefunction or ability, the relevance of a clinical appreciation ofswallowing problems and the complications of defective swal-lowing soon became apparent during the presentations.
Swallowing was the subject of some of Sherrington’s reveal-ing experiments in the early 1900s. In 1916 he demonstrated thedeglutition apnoea and the expiration that (usually) precedesand follows it. He described various phagetic agents and theireffectiveness in eliciting reflex swallowing in decerebrate cats;whiskey was the most effective and viscous oily liquids theleast.. His insights into the basics of swallowing are still the sub-ject of discussion today as reflected in presentations in thisconference about the integration of respiration and deglutitionin health and disease and the differences in opinion regardingthe extent to which swallowing is voluntary or reflex.
The conference started with a comprehensive review of dys-phagia research (Dr. Paula Leslie, University of Pittsburg USA),demonstrating how far the field has expanded over the pasttwenty years. The future of dysphagia research was also consid-ered, serving as a reminder of the need for clinically relevantresearch to inform the development of evidence based practice.
Following on seamlessly from this opening was a series of talksdemonstrating the effect of dysphagia research on clinical prac-tice, including the use of fibreoptic endoscopic evaluation ofswallowing (FEES) in adult and paediatric patients (Ms SarahWallace, Manchester, Ms Sophie Frey, Germany, Ms RebeccaHarris and Ms Martina Ryan, London.)
Towards the end of the morning, we heard about swallowingproblems in two very different populations of patients; thosewith neuromuscular disorders such as Duchenne muscular dys-trophy and patients who have suffered a stroke (Dr.AnitaSimonds, London). It became apparent how ideas are changingabout the mechanism and management of dysphagia in thesepatients and how different approaches are required to reducemorbidity and mortality. The relationship between swallowingand breathing was explored (Dr. Katie Ward, London), offering afurther opportunity to consider dysphagia in a different context.
During the lunch break, while we all checked the integrity ofour own swallowing mechanisms, there was a display of highquality posters, some of which were also platform presentationsduring the afternoons. Some of the notable presentationsincluded: Promoting the recovery of swallowing after stroke bystimulation of the motor cortex (Dr Andrew Barritt, Kent,);Reduction in rates of aspiration pneumonia after stroke (Dr.Soenke Stanschus, Germany); and a pilot study into the effec-tiveness of thickened fluids in preventing pneumonia (Dr. SuePownall, Sheffield), which won the prize for the best free paper.
The following day, there was an emphasis on assessment
tools and rating scales, starting with an in-depth five-yearresearch project carried out in the USA (Prof. Bonnie MartinHarris) using the modified barium swallowing study. We werealso introduced to the pitfalls of rating scales (Dr. Stefan Cano,Plymouth), many of which, although commonly used, are basedon weak scientific theory and questionable arithmetic.
Later in the afternoon, we had our focus brought back topatients with an overview of the holistic approach to swallow-ing problems and a reminder to view dysphagia in context, as an‘oral feeding’ problem (Dr. Tom Hughes, Cardiff). The conferencewas closed with two talks concerning the regeneration of voiceand swallowing using various methods including tissue replace-ment and neuromuscular electrical stimulation (Prof. MartinBirchall, UCL, Ms Emilia Michou, Salford) .
After such a variety of topics within this highly specialisedfield had been covered, I (SP) certainly felt that my knowledgeof the swallowing mechanism and related pathology hadincreased. The importance of the multidisciplinary team wasmade more apparent to me; complex problems require inputfrom several different sources. I was also amazed by the volumeand depth of dysphagia related research that has been going onworldwide over the past few years, and the different approach-es to the dysphagic patient it has opened up. A highly spe-cialised, niche field it may be, but as the third meeting of theUKSRG has shown, dysphagia research continues to influenceand guide the management of our patients with the commonaim of improving quality of life.
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Training future physiotherapists with SonoSite MicroMaxx® ultrasound systems
In discussions with those that treatepilepsy we often find a general beliefthat their patients adhere to theprescribed regimen of AED’s. Furtherdiscussion often reveals that this beliefis not based on careful questioning ofthe patient. It therefore raises thequestion as to whether it is safer toassume that patients’ adherence ispoor rather than good. Indeed, non-adherence has been shown to be acommon problem with several studiesshowing that adherence to AED’stypically ranges from 27% to 59%. It isnot surprising that this can be animportant factor in the effectivenessof the medication and studies reportthat seizure frequency is higher when adherence is poor. It is clear that amedication cannot be expected to work if the patient does not take it. Otherstudies show a preference towards a simpler once daily regimen. NICE suggestthat, where appropriate, clinicians should consider the preferences of thepatient and/or carers when individualising AED regimens. Once dailycontrolled release versions of valproate have, for example, been shown to bepreferred by patients, improve adherence, reduce seizure frequency andimprove clinical outcomes. There is an argument that to get the most out ofan AED the prescriber should aim for a convenient presentation that makes itas easy as possible to gain concordance in order to help ensure an effectiveoutcome.
For more information contact Beacon Pharmaceuticals on T. 01892-600930
Epilepsy – I think my patients taketheir medication!
Carl Zeiss is setting new standards forimage quality in fluorescence microscopywith the launch of the LSM 780. The newmicroscope features radical, high quantumefficiency, GaAsP detector technology,which increases sensitivity by 100%compared to the class-leading ZeissLSM710.
The LSM 780 will be of particular valueto cell- and neuro-biologists, enablingweakly fluorescent or bleach-sensitivespecimens or specimens with finestructures to be visualised more rapidly and withhigher image quality. It also permits specimens thatcould not be satisfactorily examined in the past tobe imaged at high resolution for the first time.
Zeiss offers three versionsof the GaAsP detector technology: a 32-channeldetector in the LSM 780 laser scanningmicroscope, an internal detector upgrade for
existing LSM 710 systems and an externalLSM BiG upgrade module. All versions of the32-channel GaAsP array permit traditionalspectral imaging, photon counting withmaximum sensitivity, and single moleculevisualisation through fluorescencecorrelation spectroscopy (FCS) with one tosix signal channels. The LSM BiG modulegives LSM users a substantial increase in theflexibility of their imaging system and is aconsiderable advantage in multiphotonmicroscopy when fitted to the LSM 780 NLO
Carl Zeiss increases Fluorescence Sensitivity by 100%
Deciding on drug treatments and how to manage the life of a personwith Parkinson's (PWP) is not easy. Choosing the best way to live withthe disease – in terms of both mental attitude and physical health –can be confusing for both the person with Parkinson's (PWP) and theirhealthcare professional. It requires excellent communication betweenboth parties.
As a result, the EPDA and the Parkinson's Association of Ireland (PAI)have worked together to launch the Parkinson’s Decision Aid (PDA), anonline educational toolkit that seeks to put the PWP in the bestpossible position to make the right choices so they themselves canactively work with their healthcare professional to improve their qualityof life and make informed choices together.
It is hoped the PDA will be rolled out in other parts of Europe overthe next few years. It provides a wealth of up-to-date information aboutParkinson’s that has been researched and reviewed by EuropeanParkinson’s experts, and has been written in an easy-to-understand stylefor everyone.The website has three core sections:PD Essentials: Questions a PWP can ask their doctor and otherhealthcare professionals that will enable them to receive the rightanswers.PD In depth: A huge library of researched and reviewed information tohelp PWPs live a better life as well as providing answers to the manyquestions they might have.Later in Life: This section provides information for people who havelived with Parkinson’s for some considerable time. The informationprovides answers to many complex issues they may have experienced,for example surrounding palliative care, end-of-life issues and a differentlife.
For more information see www.parkinsonsdecisionaid.eu.com
EPDA and PAI launchParkinson’s Decision Aid
The SonoSite MicroMaxx point-of-care ultrasound systemis being used for musculoskeletal visualisation to trainundergraduate and postgraduate physiotherapists in theSchool of Health and Rehabilitation at Keele University.
Kim Major, a clinical physiotherapist and lecturer at theschool, said, “We chose the MicroMaxx system toillustrate our lectures, showing muscles and soft tissue inaction and how everything interrelates inside the body,instead of relying on two-dimensional textbooks. For ourpurposes, being able to delineate muscle is the keyelement and the MicroMaxx’s image quality has allowed usto see almost everything we need. Its portability is a realboon because we need to be able to move the systemfrom room to room, and it is easy to set up. We now use
the MicroMaxx in several undergraduate research projectswhen we effectively hand it over to the students, and thesystem’s fairly indestructible nature is very reassuring. Thefive-year warranty is important in that respect, too. Theimage storage facilities have also been very useful for theseprojects.” Kim concluded, “Ultrasound gives the students amuch better understanding and it really speeds up thelearning process for many of them.”
For information and to register on SonoSite structured trainingcourses, log on to www.sonositeeducation.co.ukFor more information about SonoSite products T. 01462 444 800, E. [email protected]
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Optical sectioning is the technique of choice forfluorescence imaging of biological specimens,providing highly-resolved, contrast-rich imageseven from thick living cells. However, its appealhas been limited by the cost and complexity ofthe systems and the sophisticated software andtime-consuming processing required.
VivaTome, from Carl Zeiss, cuts through thesebarriers, combining the imaging speed of aspinning disk system with the light efficiency ofstructured illumination, pioneered by Zeiss withthe award-winning ApoTome. Designed for lifescience applications where temporal resolution isa priority, VivaTome provides developmental andcell biologists with a fast, cost-effective tool toexamine the dynamics of living specimenswithout extensive prior knowledge of opticalsectioning.
VivaTome’s structured illumination technique isone of the easiest and most efficient ways toimplement optical sectioning capabilities into awhite-light widefield system. Fast frame rates ofup to 30 frames a second capture highly-dynamicprocesses in living samples, something onlypossible until now with advanced microscopesystems.
For more information see http://bit.ly/cSUcqr
Carl Zeiss VivaTomemakes Optical SectioningFast and EasyNikon has added the high speed DS-Vi1 colour
camera to its market-leading range of Digital Sightcameras for microscopic imaging. The DS-Vi1offers high frame rates and increased sensitivityfor both multiple live image and sharp still imagecapture, making it ideal for high end biologicalresearch, clinical analysis and documentation aswell as medical teaching use.
The DS-Vi1 features a 2-megapixel colour CCDwith outstanding SXGA video display rates of upto 27 frames per second possible and effortlessfast focusing. In addition, the DS-Vi1 offers highsensitivity and a wide dynamic range of more than600:1, enabling the capture of clear, sharp images.
The DS-Vi1 can be combined, via a USB 2.0interface, with either the stand-alone Nikon DS-L2control unit or the DS-U2 PC control-based unit.The DS-L2 features a large 8.4 inch high-definitionLCD monitor and allows live observation, cameracontrol and image capture via simple on-screenmenus without connection to a PC. In addition,
the DS-Vi1 can be controlled by Nikon’s NIS-elements software. With the DS-U2 PC controlunit, live images can be viewed, recorded,measured, processed, and analysed withintegrated control of the camera and microscopeperipherals.
For further information contact Nikon InstrumentsEurope, T. 0208 247 1718, E. [email protected]
Nikon introduces new colour camera to DigitalSight series
N E W S R E V I E W
Vision Source has announced the release of a newultra sensitive high colour fidelity CCD scientificcamera from Lumenera Corporation. This newest USB2.0 offering from the popular INFINITY family ofmicroscopy cameras is an ideal solution for low lightapplications such as fluorescence, and where precisecolor reproduction is needed.
The INFINITY3-1U offers large 6.45µ x 6.45µ pixels ina 2/3” format with a maximum resolution of 1392 x1040. It employs the Sony ICX285 1.4 megapixel CCDsensor – the market leader for fluorescence and otherchallenging low light applications. In addition, thecameras near-perfect colour rendition makes it anexcellent addition to any clinical laboratory. Suitablefor both fluorescent and brightfield imaging, thiscamera offers an excellent price-to-performance ratio.
The camera’s adaptability to vary resolution andframe rate requirements, combined with low noiseperformance and 8- or 12-bit pixel data mode, makethe INFINITY3-1U an ideal camera for both live andfixed cell imaging. Live video preview allows for real-time focus; while auto exposure and auto/manualwhite balance efficiently capture your optimal image.This complete solution includes Lumenera’s INFINITYCAPTURE and INFINITY ANALYZE software, and isoffered with both colour and monochrome capability.Advanced camera control is available through aSoftware Developers Kit, while TWAIN and DIRECTXdrivers ensure integration and compatibility with avariety of 3rd party software applications.
For more information see www.visionsource.co.uk
The new INFINITY 1.4 Megapixel Ultra-Sensitive CCD Microscopy Camerafrom Lumenera Corporation
The South West Regional Anaesthesia (SoWRA)Group runs a popular regional anaesthesiacourse, and is supported by SonoSite through theloan of equipment and training aids. Thisinitiative is helping Trusts in Devon and Cornwallto expand their use of ultrasound for regionalnerve blocks, as Dr Matthew Grayling, aconsultant in anaesthesia at the Royal Devon andExeter Hospital and secretary of SoWRA,explained, “Our aim is to promote local interestin regional anaesthesia techniques, using localexpertise to provide cost-effective training andestablish a good foundation in high qualityanaesthesia care in the region. SonoSite andother manufacturers have been very generous byloaning equipment and teaching us to use theirinstruments, helping us to invest more indeveloping the course and providing a forum toimprove regional nerve blocks in the SouthWest.”
For information and to register on SonoSitestructured training courses, log on towww.sonositeeducation.co.uk For more information about Sonosite products T. 01462 444 800.
SonoSite supports regional anaesthesia training in the South West
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We’re here to simplify things...
apomorphine hydrochloride
Effective Pd treatment.
Effective Pd support.
Simple.
APO-gO® APOmOrPhine hydrOchlOride. ABBreViATed PreScriBinginFOrmATiOn. Consult Summary of Product Characteristics before prescribing. Uses: The treatment of disabling motor fluctuations (“on-off” phenomena) in patients with Parkinson’s disease which persist despite individually titrated treatment with levodopa (with a peripheral decarboxylase inhibitor) and/or other dopamine agonists. dosage and Administration: Apomorphine hydrochloride is administered subcutaneously either as an intermittent bolus injection or by continuous subcutaneous infusion. Its rapid onset (5-10 mins) and duration of action (about 1 hour) may prevent an “off” episode which is refractory to other treatments. Hospital admission under appropriate specialist supervision is necessary during patient selection and when establishing a patient’s therapeutic regime. Please refer to the Summary of Product Characteristics for full details before initiating therapy. Treatment with domperidone (typical dosage 20mg three times a day) before and during apomorphine HCl therapy is essential. The optimal dosage of apomorphine HCl has to be determined on an individual patient basis; individual bolus injections should not exceed 10mg and the total daily dose should not exceed 100mg. contraindications: Children and adolescents (up to 18 years of age). Known sensitivity to apomorphine or any other ingredients of the product. Respiratory depression, dementia, psychotic disease or hepatic insufficiency. Intermittent apomorphine HCl treatment is not suitable for patients who have an “on” response to levodopa which is marred by severe dyskinesia or dystonia. Pregnancy and lactation: Apomorphine should not be used in pregnancy unless clearly necessary. Breast-feeding should be avoided during apomorphine HCl therapy. interactions: Patients should be monitored for potential interactions during initial stages of apomorphine therapy. Particular caution should be given when apomorphine is used with other medications that have a narrow therapeutic window. It should be noted that there is potential for interaction with neuroleptic and antihypertensive agents.It is recommended to avoid the administration of apomorphine with other drugs known to prolong the QT interval. Precautions: Use with caution in patients with renal, pulmonary or cardiovascular disease, or who are prone to nausea or vomiting. Extra caution is recommended during initiation of therapy in elderly and/or debilitated patients. Since apomorphine may produce hypotension, care should be exercised in patients with cardiac disease or who are taking vasoactive drugs, particularly when pre-existing postural hypotension is present. Neuropsychiatric disturbances are common in Parkinsonian patients. APO-go should be used with special caution in these patients. Apomorphine has been associated with somnolence and other dopamine agonists can be associated with sudden sleep onset episodes, particularly in patients with Parkinson’s disease. Patients must be informed of this and advised to exercise caution whilst driving or operating machines during treatment with apomorphine. Haematology tests should be undertaken at regular intervals as with levodopa with given concomitantly with apomorphine. Pathological gambling, increased libido and hypersexuality have been reported in patients treated with dopamine agonists, including apomorphine. Since apomorphine, especially at high dose, may have the potential for QT prolongation, caution should be exercised when treating patients at risk for torsades de pointes arrhythmia. Apomorphine has been associated with local subcutaneous effects that can be reduced by rotation of injection sites or use of ultrasound on areas of nodularity and induration.Side effects: Local induration and nodules (usually asymptomatic) often develop
at subcutaneous site of injection leading to areas of erythema, tenderness, induration and panniculitus. Irritation, itching, bruising and pain may also occur. Rarely injection site necrosis and ulceration have been reported. Pruritus may occur at the site of injection. Drug-induced dyskinesias during “on” periods can be severe, and in a few patients may result in cessation of therapy. Postural hypotension is seen infrequently and is usually intransient. Transient sedation following each dose of apomorphine may occur at the start of therapy, but this usually resolves after a few weeks of treatment. Dizziness and lightheadiness have also been reported. Nausea and vomiting may occur, particularly when APO-go treatment is initiated, usually as a result of the omission of domperidone. Neuropyschiatric disturbances (including transient mild confusion and visual hallucinations) have occurred during apomorphine therapy and neuropsychiatric disturbances may be exacerbated by apomorphine. Positive Coombs’ tests and haemolytic anaemia and thrombocytopenia have been reported in patients receiving apomorphine and levodopa. Local and generalised rashes have been reported. Eosinophilia has occurred in only a few patients during treatment with apomorphine HCl. Patients treated with dopamine agonists, including apomorphine, have been reported as exhibiting signs of pathological gambling, increased libido and hypersexuality (especially at high doses). Apomorphine is associated with somnolence. Yawning and breathing difficulties have been reported as has peripheral oedema. Prescribers should consult the Summary of Product Characteristics in relation to other side effects. Presentation and Basic nhS cost:Apo-go ampoules contain apomorphine hydrochloride 10mg/ml, as follows:20mg in 2ml – basic NHS cost £37.96 per carton of 5 ampoules. 50mg in 5ml – basic NHS cost £73.11 per carton of 5 ampoules. APO-go pens (disposable multiple dosage injector system) contain apomorphine hydrochloride 10mg/ml, as follows: 30mg in 3ml – basic NHS cost £123.91 per carton of 5 pens.APO-go Pre-filled syringes contain apomorphine hydrochloride 5mg/ml, as follows: 50mg in 10ml – basic NHS cost £73.11 per carton of 5 syringes. marketing Authorisation numbers: APO-go Ampoules:PL 06831/0245. APO-go Pens: PL 06831/0246. APO-go Pre filled syringes:PL 06831/0247. legal category: POM. date of last revision: February 2010.For further information please contact: Genus Pharmaceuticals, Park View House, 65 London Road, Newbury, Berkshire, RG14 1JN, UK.
Adverse events should be reported. reporting forms and information can be found at www.yellowcard.gov.uk.
Adverse events should also be reported to medical information on 0870 851 0207 or [email protected]
Version Number: APG.API.V11APO-
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