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ISSN 1473-9348 VOLUME 10 ISSUE 5 NOVEMBER/DECEMBER 2010ACNRwww.acnr.co.ukADVANCES IN CLINICAL NEUROSCIENCE & REHABILITATIONIn this issueIracema Leroi – Cognitive and Behavioural Complications of Parkinson’s DiseaseChristopher R Sibley, Janine Scholefield and Matthew JA Wood– RNA Interference and Neurological DisordersPaediatric Neurology – Rachel Howells– Headache in Childhood and AdolescenceClinical Dilemmas in Neuropsychiatry – Valerie VoonWhen is an Impulse Control Disorder in Parkinson's Disease a Problem?NEWS REVIEW > CONFERENCE REPORTS > BOOK REVIEWS > JOURNAL REVIEWS > EVENTS DIARY

Make a lasting impressionBy initiating early Azilect monotherapy, you can maintain yourpatients’ overall motor performance. 1,2So make a lasting impression – initiate Azilect monotherapyearly in the course of Parkinson’s disease. 3Simple and effectivewhen it mattersAzilect ® 1mg tabletsPrescribing information (Please refer to the Summary of ProductCharacteristics (SmPC) before prescribing) Presentation: Tabletscontaining 1mg rasagiline (as the mesilate). Indication: Treatmentof idiopathic Parkinson’s disease as monotherapy or as adjunct tolevodopa in patients with end of dose fluctuations. Dosage andadministration: Oral, 1mg once daily taken with or without foodand with or without levodopa. Elderly: No change in dosage required.Children and adolescents (1%: headache, influenza, skin carcinoma, leucopenia,allergy, depression, hallucinations, conjunctivitis, vertigo, anginapectoris, rhinitis, flatulence, dermatitis, musculoskeletal pain, neckpain, arthritis, urinary urgency, fever, malaise. 1%: dyskinesia, decreased appetite, hallucinations,abnormal dreams, dystonia, carpal tunnel syndrome, balance disorder,orthostatic hypotension, abdominal pain, constipation, nausea andvomiting, dry mouth, rash, arthralgia, neck pain, decreased weight,fall.

AWARDS AND APPOINTMENTSEditorial board and contributorsRoger Barker is co-editor of ACNR, and is Honorary Consultant inNeurology 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 usingneural transplants.Alasdair Coles is co-editor of ACNR. He is a University Lecturer inNeuroimmuniology at Cambridge University. He works on experimentalimmunological therapies in multiple sclerosis.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 interests are in neuroimmunology,biomarkers and therapeutics in particular.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 interestsare in prosthetics, orthotics, gait training and neurorehabilitation.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.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 cognitivedisorders. He is also an Honorary Apothecaries' Lecturer in the Historyof Medicine at the University of Liverpool.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 forprogressive multiple sclerosis.Peter Whitfield is ACNR’s Neurosurgery Editor. He is a ConsultantNeurosurgeon at the South West Neurosurgery Centre, Plymouth. His clinicalinterests 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.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.International editorial liaison committeeProfessor 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.Alastair Compston winsKJ Zülch PrizeProfessor Alastair Compston, Head of the Department ofClinical Neurosciences at the University of Cambridge, hasbeen awarded the KJ Zülch Prize for his contributions toresearch on multiple sclerosis. Professor Compston receivedthe award with his co-recipient, Professor Hans Lassman fromthe University of Vienna, for their ‘internationally outstandingachievements in basic neurological research’. The prize, oftenrecognised as one of the most prestigious in the field ofneuroscience, is given annually on behalf of the GertrudReemtsma Foundation by the Max Planck Society for theAdvancement of Science. For over 30 years, ProfessorCompston has been researching the causes and treatments ofmultiple sclerosis. His current research focuses on using theleukaemia drug alemtuzumab to treat multiple sclerosis.WHO acknowledges charity’s workNational Society for Epilepsy (NSE) neurologists are delighted their London base hasbeen redesignated as a World Health Organisation (WHO) collaborating centre forresearch and training in neurosciences. NSE professor, Ley Sander, also a director for thedepartment of clinical and experimental epilepsy at University College London’s (UCL)Institute of Neurology, said: “We are so pleased that our work at UCL which involvesresearch, training and education and information dissemination is recognised and we aredelighted to continue to be a WHO collaborating centre.” NSE’s research programme isclosely allied to the medical services it provides at its Epilepsy Centre in Chalfont StPeter, Buckinghamshire. These services are run in collaboration with UCL to offer anunsurpassed level of care which also means that important findings can quickly betranslated into clinical practice.For more information contact: Tel. 01494 601404, Email: amanda.cleaver@epilepsysociety.org.ukMerck Serono Announces Winner of theReal MS: Your Story CompetitionMerck Serono has announced the winner of the Real MS: Your Story international scriptconcept competition to be Sarah Mead from the UK, as selected by a judging panel. Thewinning script, titled ‘It’s a marathon, not a sprint…’, will now be brought to the screen inan international short film directed by award-winning Director, Robin Sheppard, to showthe world that life with MS can be redefined in a positive and fulfilling way. Real MS: YourStory is the first element of an international campaign that aims to raise global awarenessof MS and demonstrate how life can and could be improved for people living with MS,and their families and carers. The judging panel included global film and MS experts whoselected Sarah’s script concept from over 120 entries. Working with Robin Sheppard, Sarahwill now see her work brought to life as a short film.To find out more about the campaign and life with MS, visit www.realmsvoices.comDementia research receives £1.5 million boostResearch that could take scientists a step closer to discovering the cause ofAlzheimer’s and a study on how to improve care for people with dementia in hospitalsare two of nine research projects that have been announced. The projects have beenmade possible following a £1.5 million grant jointly from Alzheimer’s Society and theBupa Foundation. Top scientists in the UK and Australia are being funded as part of anexciting new partnership between the two charities to boost research into the prevention,diagnosis and treatment of dementia. One of the projects being funded is a studyby Dr Armit Mudher into the role of the tau protein in Alzheimer’s disease. Healthynerve cells produce tau but in Alzheimer’s, an abnormal form of the protein isproduced which does not function correctly. In her most recent research, Dr Mudher -from the University of Southampton - tested the effect of Lithium on tau, a drugcommonly used for bipolar disorder. She found that Lithium not only protects cellsfrom the effects of tau, but also causes the abnormal tau to accumulate in roundedclumps which are then less likely to cause damage to the cell. Dr Mudher will use highpowered microscopy and biochemical techniques to find out exactly what the clumpsare made of, how they are formed, whether they protect nerve cells and whether anyother means can be used to produce them.For more information contact: Tel. 0207 423 3595, Email. joanne.beaney@alzheimers.org.ukENS elects new member to its ExecutiveCommitteeProf Kailash P Bhatia has been elected as new member of the ENS Executive Committee.Prof Bhatia is a Professor of Clinical Neurology in the Sobell Department of MovementNeuroscience at the Institute of Neurology, UCL, Queen Square, London and an HonoraryConsultant Neurologist at the affiliated National Hospital for Neurology, Queen Square.For more information see www.ensinfo.orgACNR > VOLUME 10 NUMBER 5 > NOVEMBER/DECEMBER 2010 > 3

Image: Peter Fraser

MS can make simple, everyday tasks difficult or impossible. Adding Sativex to existingspasticity treatment can improve symptoms like stiffness and spasm, helping to make dailylife easier for people with MS.Instead of leaving the Sativex prescribing informationat the foot of the page, we’ve put it where you can’t miss it.Please take a look. After all, these are the crucial details thatwill help you decide if Sativex can help your MS patients.Sativex ® Oromucosal Spray Prescribing Information(refer to full Summary of Product Characteristics(SmPC) before prescribing). Presentation: 1mL contains:38-44mg and 35-42mg of two extracts from Cannabis sativaL., (Cannabis leaf and flower) corresponding to 27mg delta-9-tetrahydrocannabinol (THC) and 25mg cannabidiol (CBD).Each 100 microlitre spray contains: 2.7mg THC and 2.5mgCBD. Indication(s): as add-on treatment, for symptomimprovement in patients with moderate to severe spasticitydue to multiple sclerosis (MS) who have not respondedadequately to other anti-spasticity medication and whodemonstrate clinically significant improvement in spasticityrelated symptoms during an initial trial of therapy. Posologyand method of administration: oromucosal use only.Treatment must be initiated and supervised by a physicianwith specialist expertise in MS. Direct spray at differentsites on the oromucosal surface, changing site for each useof product. May take up to 2 weeks to find optimal dose,review response after 4 weeks of treatment. Re-evaluatelong term treatment periodically.Adults: titration period necessary; number/timingof sprays will vary between patients. Number of spraysincreased daily according to SmPC table, up to maximum of12 sprays per day with minimum 15 minutes between sprays.Children and adolescents: not recommended. Elderly: nospecific studies but CNS side effects may be more likely (seeWarnings and precautions) Significant hepatic or renalimpairment: no specific studies but effects of Sativex maybe exaggerated or prolonged. Frequent clinical evaluationrecommended. Contra-indications: hypersensitivityto cannabinoids or excipients. Breast feeding. Known/suspected history or family history of schizophrenia/other psychotic illness. History of severe personalitydisorder/other significant psychiatric disorder other thandepression due to underlying condition. Warnings andprecautions: not recommended in patients with seriouscardiovascular disease. Caution in patients with history ofepilepsy/recurrent seizures. THC and CBD are metabolisedin the liver. Several THC metabolites may be psychoactive.Contains approx. 50% v/v ethanol. Risk of falls if spasticity/muscle strength no longer sufficient to maintain posture/gait. CNS side effects e.g. dizziness, somnolence couldimpact personal safety, e.g. hot food and drink preparation.Theoretical risk of additive effect with muscle-relaxingagents, not seen in clinical trials but warn patients riskof falls may increase. No effect seen on fertility butcannabinoids shown to affect spermatogenesis in animals.Female patients of child-bearing potential/male patientswith a partner of child-bearing potential should use reliablecontraception. Patients with a history of substance abusemay be more prone to abuse Sativex. Withdrawal symptomsfollowing abrupt withdrawal of long-term Sativex are likelyto be limited to transient disturbances of sleep, emotion orappetite. No increase in daily dosage observed in long-termuse; self-reported levels of ‘intoxication’ low; dependenceon Sativex unlikely. Interactions: no clinically apparentdrug-drug interactions seen. Co-administration with foodresults in mean increase in C max , AUC and half-life (increaseless than between-subject variability in these parameters).Concomitant ketoconazole increases C max and AUC of THC(and primary metabolite) and CBD. Increase less thanbetween-subject variability. Risk of additive sedation andmuscle relaxing effects with hypnotics, sedatives and drugswith sedating effects. Pregnancy and lactation: do not usein pregnancy unless benefit outweighs potential risks. Donot use if breast feeding. Insufficient experience of effectson reproduction - use reliable contraception during therapyand for 3 months after discontinuation. Effects on ability todrive and use machines: do not drive, operate machineryor engage in any hazardous activity if experiencingsignificant CNS side effects; warn patients may cause lossof consciousness. Side effects: very common – dizziness,fatigue; common – anorexia, decreased or increasedappetite, depression, disorientation, dissociation, euphoria,amnesia, balance disorder, disturbance in attention,dysarthria, dysgeusia, lethargy, memory impairment,somnolence, blurred vision, vertigo, constipation,diarrhoea, dry mouth, glossodynia, mouth ulceration,nausea, oral discomfort/pain, vomiting, applicationsite pain, asthenia, feeling abnormal/ drunk, malaise,fall; uncommon – hallucination, illusion, paranoia,suicidal ideation, delusional perception, syncope,palpitations, tachycardia, hypertension, pharyngitis,throat irritation, upper abdominal pain, oral mucosaldisorders e.g. discolouration, exfoliation, stomatitis,tooth discolouration, application site irritation;unknown frequency – psychiatric symptoms e.g.anxiety and mood changes, transient psychotic reactions,possible leukoplakia (unconfirmed): inspect oral mucosaregularly in long term use.Prescribers should consult the SmPC for furtherinformation on side effects. Overdose: symptomatic andsupportive treatment required. Special precautions forstorage: refrigerate (2 to 8ºC); once opened refrigeration isunnecessary but do not store above 25ºC. Legal Category:POM Package quantities and basic NHS costs: 3 x 10mL£375.00. MA holder: GW Pharma Ltd, Porton Down SciencePark, Salisbury, Wiltshire SP4 0JQ MA number(s): PL18024/0009 Further information available from: BayerSchering Pharma, Bayer plc, Bayer House, Strawberry Hill,Newbury, Berkshire RG14 1JA United Kingdom. Telephone:01635 563000. Date of preparation: March 2010.Sativex ® is a registered trademark of GW Pharma Ltd.Adverse events should be reported. Reporting formsand information can be found at www.yellowcard.gov.uk.Adverse events should also be reported to GW Pharma Ltd.Tel: 01353 616636, Fax: 01353 616638UK.PH.SM.SAT.2010.024. JUNE 2010.

FROM THE EDITOR...In this issue of the ACNR we have two different accounts on the problems oftreating Parkinson’s disease with dopaminergic medication. In the first, IraLeroi discusses the adverse neuropsychiatric effects of dopaminergictherapy in Parkinson’s disease, whilst Valerie Voon discusses a specific scenarioin her contribution to our Neuropsychiatry Series. In both articles the problemsof making the diagnosis are highlighted as such drug induced changes inbehaviour may not be recognised as being abnormal or therapy related by thepatient and family. Of course making the diagnosis is one thing, what you donext, another, as the patients obviously need their dopaminergic medicationfor control of their motor symptoms. Both articles help us negotiate this trickyand emerging area of therapeutics in Parkinson’s disease.RNA interference (RNAi) has become a hot topic in the world of medicineas the potential to use this approach to silence the products of bad genes hasmassive implications for treating certain disorders- e.g. mutant huntingtin inHuntington’s Disease. In our review article from the laboratory of MatthewWood we are guided through the complexities of this topic and how it may beuseful for treating disease. This review is easy to read, and gives a realisticperspective on the strengths and problems of using RNAi as a therapeuticapproach and how it will impact on clinical medicine in the future.Rachel Howells is the author of the next article in our series on PaediatricNeurology and takes as her theme the problem of headache in childhood andadolescence. In this article we learn that much of what we see in the adultclinic with respect to headache also applies to younger patients, but that thereare also important differences, especially with respect to how migraine maypresent. This is a well crafted review that will be of great value to those facedwith the young person with bad heads.The role of the basal ganglia has vexed neuroscientists and neurologists formany years and in the latest in our series on Motor Control, Pietro Mazzoni andMartyn Bracewell discuss this thorny issue. In their article, they explain how ourthinking has evolved since the work of David Marsden and how understandingthe role of the basal ganglia in motor control gives insights into their greaterrole in action selection and reward.Andrew Larner in his latest short piece on neurology and literaturediscusses the use of the word megrim. This word is perhaps not known by most,but has been used in a variety of different ways by authors over the years asAndrew reveals through his close reading of many texts.In a new series, we discuss the relationship between art, artists andneurology. In the first of this series we discuss the work of Willem de Kooning,who late in life developed a dementing illness. This changed his productivityand also raised questions as to the value of what he was painting. We hope thatyou enjoy this new series.Finally, we have our usual collection of book, conference and journalreviews which cover a range of topics including neuroimmunology, epilepsy,functional imaging, neurodegeneration and rating scales and a trial for nonepilepticattacks. lRoger Barker, Co-Editor.Roger Barker, Co-Editor,Email. Rachael@acnr.co.uk6 > ACNR > VOLUME 10 NUMBER 5 > NOVEMBER/DECEMBER 2010

than just a gap bet ween seizuresLife with epilepsy can be much moreIt’s hard to live life to the full if part of you is alwaysexpecting the next seizure. VIMPAT ® is an anti-epilepticdrug with an innovative mode of action. 1,2 In clinicaltrials, VIMPAT ® has shown improved seizure controlwhen added to fi rst and second generation AEDs. 3Prescribe VIMPAT ® when you want your patients to lookforward with the confi dence of additional seizure control. 1,3Confidence, when monotherapy is not enoughPRESCRIBING INFORMATION (Please consult the Summary ofProduct Characteristics (SPC) before prescribing.) Vimpat ®Lacosamide Active Ingredient: Tablets: lacosamide 50 mg, 100mg, 150 mg and 200 mg. Syrup: lacosamide 15 mg/ml. Solution forinfusion: lacosamide 10 mg/ml. Indication: Vimpat is indicated asadjunctive therapy in the treatment of partial-onset seizures with orwithout secondary generalisation in patients with epilepsy aged 16 yearsand older. Dosage and Administration: Adults and adolescentsfrom 16 years: Recommended starting dose is 50 mg twice a day whichshould be increased to an initial therapeutic dose of 100 mg twice a dayafter 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 twicedaily. Can be administered i.v. without further dilution. Elderly: No dosereduction necessary. Age associated decreased renal clearance with anincrease in AUC levels should be considered. Paediatric patients: Notrecommended. Patients with renal impairment: No dose adjustmentnecessary in mild and moderate renal impairment. Dose adjustmentis recommended for patients with severe renal impairment and patientswith end-stage renal disease (see SPC). Dose titration should beperformed with caution. Patients with hepatic impairment: No doseadjustment needed in mild to moderate impairment. In accordance withcurrent clinical practice, if Vimpat has to be discontinued, it isrecommended this be done gradually(e.g. taper the daily dose by 200mg/week). Contraindications,Warnings, etc: Contraindications:Hypersensitivity to lacosamide or to any of the excipients. Known secondorthird-degree atrioventricular block. In addition for tablets,hypersensitivity to peanuts or soya. Precautions: Lacosamide has beenassociated with dizziness. Use with caution in patients with knownconduction problems, severe cardiac disease or in elderly. Excipients inthe syrup may cause allergic reactions (possibly delayed), should not betaken by those with fructose intolerance and may be harmful to patientswith phenylketonuria. Monitor patients for signs of suicidal ideation andbehaviours. Advise patients and carers to seek medical advice shouldsuch signs emerge. Interactions: Prolongations in PR interval withlacosamide have been observed in clinical studies. Use with caution inpatients treated with products associated with PR prolongation and thosetreated with class I antiarrhythmic drugs. Strong enzyme inducers such asrifampicin or St John’s Wort may moderately reduce the systemicexposure of lacosamide. No significant effect on plasma concentrationsof carbamazepine and valproic acid. Lacosamide plasma concentrationswere not affected by carbamazepine and valproic acid. No clinicallyrelevant interaction with ethinylestradiol and levonorgestrel. No effect onpharmacokinetics of digoxin. Pregnancy and Lactation: Should not beused during pregnancy. For precautionary measures, breast feedingshould be discontinued during treatment with lacosamide. Driving etc.:Patients are advised not to drive a car or operate other potentiallyhazardous machinery until they are familiar with the effects of Vimpat ontheir ability to perform such activities. Adverse Effects: Very common(≥10%): Dizziness, headache, diplopia, nausea. Common (between1%-10%): Depression, balance disorder, abnormal coordination,memory impairment, cognitive disorder, somnolence, tremor, nystagmus,blurred vision, vertigo, vomiting, constipation, flatulence, pruritus, gaitdisturbance, asthenia, fatigue, fall, skin laceration. Adverse reactionsassociated with PR prolongation may occur. Consult SPC in relation toother 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. LegalCategory: POM. Marketing Authorisation Number(s): 50 mgx 14 tabs: EU/1/08/470/001; 100 mg x 14 tabs: 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 mgx 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 14tabs: £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, Alléede la Recherche 60, B-1070 Bruxelles, Belgium. Further informationis available from: UCB Pharma Ltd, 208 Bath Road, Slough,Berkshire, SL1 3WE. Tel: 01753 534655. Fax: 01753 536632.Email: medicalinformationuk@ucb.com. Date of Revision: 01/2010(10VPE0010). Vimpat is a registered trademark. References:1. Vimpat Summary of Product Characteristics, 2010. 2. Beyreuther BKet al. CNS Drug Rev 2007; 13(1): 21–42. 3. UCB Data on file.Date of preparation: June 2010. 10VPE0137Adverse 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.

C O N T E N T SCONTENTSNOVEMBER/DECEMBER 201003 Awards & Appointments06 From the Editor...Review Article10 Cognitive and Behavioural Complications of Parkinson’s DiseaseIracema LeroiNeurological literature16 Headache (Part 7): MegrimAndrew J LarnerReview Article17 RNA Interference and Neurological DisordersChristopher R Sibley, Janine Scholefield and Matthew JA WoodMotor Control Series22 The Persistent Mystery of the Basal Ganglia’s Contribution toMotor ControlPietro Mazzoni and Martyn BracewellPaediatric Neurology27 Headache in Childhood and AdolescenceRachel HowellsNeurology in Art30 Neurology And Art: Willem De KooningSebastian Barker and Roger BarkerClinical Dilemmas in Neuropsychiatry32 When is an Impulse Control Disorder in Parkinson's Disease a Problem?Valerie VoonAssociation of British Neurologist Trainees34 The ABN Fellowship Scheme: a new opportunity for neurology traineesBiba StantonBook Reviews35 Immune-Mediated Neuromuscular Diseases;Measurement Scales Used in Elderly Care;A Compendium of Tests, Scales, and Questionnaires The Practitioner’sGuide to Measuring Outcomes after Acquired Brain ImpairmentRegulars36 Journal Reviews40 Conference News43 Events Diary47 News ReviewFor more information & quotes, contact:reprints@whitehousepublishing.co.ukREPRINTS AVAILABLE• Peer reviewed • ABPI compliant• Translations available • Multiple country coordinationdon Hospital said of ife for so many g p g gThe Poseidon statue and fountain is the most well-knownlandmark of Gothenburg. © Kjell Holmner/Gothenburg & Co.ACNRACNRSSN 14 3- 348 O UME 10 SSUE 5 NOVEMBER/D CEMBER 2010www acnr co ukADVANCES N CLIN CAL NEUROSCIENCE & REHABILITAT ONIn this ssueIracema Leroi Cogni ive and Behaviou al Comp ications of Pa kinson’s DiseaseChristopher R S bley Janine Scholefield and Matthew JA WoodRNA In erference and Neurological Diso dersPaediatric Neurology Rachel HowellsHeadache in Ch ldhood and AdolescenceCl nical D lemmas in Neuropsychiatry Dr VoonWhen is an Impulse Con rol Disorder in Pa kinson's Disease a Problem?NEWS REV EW > CONFERENCE REPORTS > BOOK REV EWS > JOURNAL REV EWS > EVENTS DIARYPublished by Whitehouse Publishing,1 The Lynch, Mere, Wiltshire, BA12 6DQ.Publisher. Rachael HansfordE. rachael@acnr.co.ukADVERTISINGRachael HansfordT. 01747 860168 M. 07989 470278E. rachael@acnr.co.ukCOURSE ADVERTISINGRachael Hansford E. rachael@acnr.co.ukEDITORIALJohn Gustar E. editorial@acnr.co.ukDESIGN & PRODUCTION DEPARTMENTE. design.dept@sky.comPRINTED BYManson Group Ltd. Tel. 01727 848 440Copyright: 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, photocopying,recording or otherwise without either the priorwritten 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 orrefraining from action as a result of material in or omittedfrom this magazine. Any new methods and techniquesdescribed involving drug usage should be followed only inconjunction with drug manufacturers' own published literature.This is an independent publication - none of thosecontributing are in any way supported or remunerated by anyof the companies advertising in it, unless otherwise clearlystated. Comments expressed in editorial are those of theauthor(s) and are not necessarily endorsed by the editor,editorial board or publisher. The editor's decision is final andno correspondence will be entered into.8 > ACNR > VOLUME 10 NUMBER 5 > NOVEMBER/DECEMBER 2010

We’re hereto simplifythings...apomorphine hydrochlorideAPO-0210-664(a) Date of preparation: February 2010.APO-GO ® APOMORPHINE HYDROCHLORIDE. ABBREVIATED PRESCRIBINGINFORMATION. Consult Summary of Product Characteristics before prescribing.Uses: The treatment of disabling motor fluctuations (“on-off” phenomena) inpatients with Parkinson’s disease which persist despite individually titratedtreatment with levodopa (with a peripheral decarboxylase inhibitor) and/or otherdopamine agonists. Dosage and Administration: Apomorphine hydrochlorideis administered subcutaneously either as an intermittent bolus injection or bycontinuous 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 duringpatient selection and when establishing a patient’s therapeutic regime. Please referto the Summary of Product Characteristics for full details before initiating therapy.Treatment with domperidone (typical dosage 20mg three times a day) before andduring apomorphine HCl therapy is essential. The optimal dosage of apomorphineHCl has to be determined on an individual patient basis; individual bolus injectionsshould not exceed 10mg and the total daily dose should not exceed 100mg.Contraindications: Children and adolescents (up to 18 years of age). Knownsensitivity to apomorphine or any other ingredients of the product. Respiratorydepression, dementia, psychotic disease or hepatic insufficiency. Intermittentapomorphine HCl treatment is not suitable for patients who have an “on” responseto levodopa which is marred by severe dyskinesia or dystonia. Pregnancy andlactation: 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 ofapomorphine therapy. Particular caution should be given when apomorphine is usedwith other medications that have a narrow therapeutic window. It should be notedthat there is potential for interaction with neuroleptic and antihypertensive agents.It is recommended to avoid the administration of apomorphine with other drugsknown to prolong the QT interval. Precautions: Use with caution in patients withrenal, pulmonary or cardiovascular disease, or who are prone to nausea or vomiting.Extra caution is recommended during initiation of therapy in elderly and/or debilitatedpatients. Since apomorphine may produce hypotension, care should be exercisedin patients with cardiac disease or who are taking vasoactive drugs, particularlywhen pre-existing postural hypotension is present. Neuropsychiatric disturbancesare common in Parkinsonian patients. APO-go should be used with special cautionin these patients. Apomorphine has been associated with somnolence and otherdopamine agonists can be associated with sudden sleep onset episodes, particularlyin patients with Parkinson’s disease. Patients must be informed of this and advisedto exercise caution whilst driving or operating machines during treatment withapomorphine. Haematology tests should be undertaken at regular intervals aswith levodopa with given concomitantly with apomorphine. Pathological gambling,increased libido and hypersexuality have been reported in patients treated withdopamine agonists, including apomorphine. Since apomorphine, especially athigh dose, may have the potential for QT prolongation, caution should be exercisedwhen treating patients at risk for torsades de pointes arrhythmia. Apomorphinehas been associated with local subcutaneous effects that can be reduced byrotation of injection sites or use of ultrasound on areas of nodularity and induration.Side Effects: Local induration and nodules (usually asymptomatic) often developat subcutaneous siteof injection leadingto areas of erythema,tenderness, induration andpanniculitus. Irritation, itching,bruising and pain may also occur.Rarely injection site necrosis andulceration have been reported. Pruritus mayoccur at the site of injection. Drug-induced dyskinesiasduring “on” periods can be severe, and in a few patients may resultin cessation of therapy. Postural hypotension is seen infrequently and is usuallyintransient. Transient sedation following each dose of apomorphine may occurat the start of therapy, but this usually resolves after a few weeks of treatment.Dizziness and lightheadiness have also been reported. Nausea and vomiting mayoccur, particularly when APO-go treatment is initiated, usually as a result of theomission of domperidone. Neuropyschiatric disturbances (including transient mildconfusion and visual hallucinations) have occurred during apomorphine therapyand neuropsychiatric disturbances may be exacerbated by apomorphine. PositiveCoombs’ tests and haemolytic anaemia and thrombocytopenia have been reportedin patients receiving apomorphine and levodopa. Local and generalised rasheshave been reported. Eosinophilia has occurred in only a few patients duringtreatment with apomorphine HCl. Patients treated with dopamine agonists, includingapomorphine, have been reported as exhibiting signs of pathological gambling,increased libido and hypersexuality (especially at high doses). Apomorphine isassociated with somnolence. Yawning and breathing difficulties have been reportedas has peripheral oedema. Prescribers should consult the Summary of ProductCharacteristics 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 (disposablemultiple 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 of5 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 andinformation can be found at www.yellowcard.gov.uk.Adverse events should also be reported to Medical Informationon 0870 851 0207 or drugsafety@britannia-pharm.comVersion Number: APG.API.V11EffectivePd treatment.EffectivePd support.Simple.www.apo-go.co.uk

REVIEW ARTICLECognitive andBehaviouralComplications ofParkinson’s DiseaseDr Iracema Leroi,works as a consultant in Old AgePsychiatry and honorary seniorlecturer in Lancashire CareFoundation Trust/University ofManchester. She trained in Canadaand at Johns Hopkins University.Current interests include themanagement of dementia in PD aswell as behavioural disturbances inboth PD and Alzheimer disease.Correspondence to:Dr Iracema Leroi,MD FRCPC MRCPsychConsultant in Old AgePsychiatry/Honorary SeniorLecturer,Lancashire Care FoundationTrust/University of Manchester,Royal Blackburn HospitalHaslingden Rd, Blackburn, Lancs.BB2 3HH.Email: Iracema.Leroi@lancashirecare.nhs.ukThe most commonly reported neuropsychiatriccomplications in Parkinson’s disease(PD) are symptoms of depression, anxiety,and psychosis. However, some of the most interestingadvances recently have been in the areasof cognitive impairment and behavioural disturbancesin the form of disorders of reward andmotivation, such as apathy and impulse controldisorders (ICDs). These cognitive and behaviouralcomplications, which may interlink witheach other, will be the focus of this article.Cognitive impairment in PDCognitive impairment, particularly in the formof executive dysfunction is common and maymanifest at the same time as the onset of themotor symptoms. More extensive cognitivemanifestations such as dementia in PD (PDD)may also appear and since people are livingwith the disease longer, the prevalence of PDDis increasing. Furthermore, a relatively new areaof inquiry in cognition in PD is gainingincreasing attention, namely, changes inemotionally-dependent decision-making, whichmay be driven by changes in limbic-basedneural pathways.Executive dysfunction or mild cognitiveimpairment in PDEven in the early stages of PD, impairments invarious cognitive domains may be evident in asignificant minority. In one study, 42% of anincident cohort of PD sufferers had cognitiveimpairment on presentation. 1 In particular,executive functions (abstract reasoning, planning,working memory, attention, and temporalsequencing), recall, language, memory, andvisuoperceptual ability may be affected. Ingeneral, these deficits may initially only beevident on detailed neuropsychologicaltesting, however, in some they may becomemore severe or widespread and begin toimpact on non-routine daily activities. At thispoint, the deficits may be considered as a “mildcognitive impairment” (MCI) syndrome,although there is debate about the utility ofusing such a label. 2 MCI may be a precursor toa more severe cognitive syndrome that meetscriteria for dementia (PDD), however, it is morelikely that the neurotransmitter deficits underlyingthese mild cognitive deficits are due todisruptions in dopaminergic pathways,whereas the deficits underlying a more obviousdementia syndrome are cholinergic. 3Dementia in PDIt is now accepted that if someone lives with PDlong enough, they are likely to developdementia. The Sydney Multicentre Study, whichfollowed-up a cohort of 136 PD sufferers overseveral years, found that 83% of the 20-yearsurvivors had developed dementia, togetherwith a constellation of other symptoms ofadvanced PD including excessive daytimesleepiness (EDS), falls, freezing and hallucinations.4 Based on this study, the mean age at diagnosisof dementia was about 70 years old andthe mean time to onset after diagnosis of PD wasabout 11 years. Clinically, PDD is characterisedby an insidious onset and slowly progressiveglobal cognitive decline, usually accompaniedby a variety of behavioural symptoms such asapathy, hallucinations, depression, anxiety, andEDS. PDD differs clinically from dementia withLewy Bodies (DLB) in that the dementiasyndrome in PDD does not generally predate oroccur at the same time as the onset of motorimpairments, and perceptual abnormalitiessuch as visual hallucinations are usually morecommon in DLB. Several factors may predictthe conversion from PD to PDD, suggesting thepresence of a “dementia-prone” subtype of PD.For example, impaired verbal fluency andvisuoperceptual functioning at diagnosis, olderage at disease onset, akinetic-rigid type of PD,depression or psychosis early on in the courseof the illness, orthostatic hypotension, andweight loss may all be predictors of later conversionto PDD. 3,5,6 The underlying pathology ofPDD is heterogeneous and may reflectAlzheimer’s disease-like changes with amyloidplaques and neurofibrillary tangles, the presenceof cortical Lewy bodies, as well as vascularchanges. 4 The extent of cholinergic deficitappears to correlate with the degree of cognitiveimpairment, 7 and this may relate to subcorticalloss of cholinergic neurones and the associatedloss of ascending cortical projections, ratherthan intrinsic cortical neuronal loss. This cholinergicdeficit is the basis for the use ofcholinesterase inhibitor therapy for the pharmacologicalmanagement of PDD. 8,9 The use of the10 > ACNR > VOLUME 10 NUMBER 5 > NOVEMBER/DECEMBER 2010

Focus on concordance in epilepsyDesigned for concordanceOnce-a-day doseSimple evening doseEasy to swallow minitabletsHigh patient acceptabilityConcordance reduces seizure frequencyA“patient friendly”optionEpisenta ®Prolonged Release Sodium ValproateEPISENTA (Prolonged-Release Sodium Valproate)ABBREVIATED PRESCRIBING INFORMATIONSee Full SmPC for Details. Episenta 150mg & 300mg capsules and Episenta 500mg & 1000mg sachets contain prolonged release sodium valproateminitablets. Indication: The treatment of all forms of epilepsy. Dose: Give in 1 2 single doses. Monotherapy: Adults: Start at 600mg daily increasing by150 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 35mg/kg bw/day until control is achieved. Children under 20kg: 20mg/kg bw/day; max 40mg/kg/day. Patients with renal insufficiency: May require decreaseddose. 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 ideationreported. The onset of an acute illness is an indication of the early stages of hepatic failure and requires immediate withdrawal of the drug. Routinely measureliver 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 sodiumvalproate should be gradual. The indigestible cellulose shell of the prolonged release granules, seen as white residue in the stools of the patient, is of noconcern. Interactions, Pregnancy and Lactation: See full SPC. Undesirable Effects: See full SPC. Further information & MA Holder: BeaconPharmaceuticals Ltd. 85 High St., TN1 1YG UK. Presentations & Prices: POM. Episenta 150mg capsule x 100 PL 18157/0021, Episenta 300mg capsulex 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: £7.00,£13.00, £21.00 & £41.00 respectively. Date of text: Mar 2010. Advert prepared March 2010 Ref: ACNR100319Adverse events should be reported. Reporting forms andinformation can be found at www.yellowcard.gov.uk. Adverseevents should also be reported to Beacon Tel: 01892-506958Further information from Beacon85 High St, Tunbridge Wells, TN1 1YG.Tel: 01892 600930

REVIEW ARTICLEuncompetitive antagonist of N-methyl-D-aspartate(NMDA), memantine, may also have a role in managingPDD symptoms 10,11 .Decision-making abnormalities in PDEmotionally-dependent decision-making is ofincreasing interest in PD due to recent studies whichhave shown deficits in such decision-making in peoplewith PD. Moreover, with the relatively recent focus onICDs in PD, this type of decision-making may be ofimportance as a potential basis for the development ofthe impulsive behaviours in the setting of dopaminereplacement therapy (DRT). Broadly, such aspects ofcognitive functioning have been labelled as “hot” decision-making,mediated by limbic areas (includingaspects of self-control and impulsive decision-making)such as the ventral medial prefrontal cortex (VMPC)and orbitofrontal cortex (OFC), as opposed to the more“cool” or rationally-based aspects of executive function,mediated by the dorso-lateral prefrontal cortex (DLFC),all areas which may be affected by PD-relatedpathology. This may result in a reduced ability to interpretnegative consequences or negative feedback, ortake past experience into account when making decisions.Dopamine replacement therapy (DRT) mayfurther impact on this type of cognitive functioning andit has been shown that when “on” DRT, those with PDwere unable to learn to avoid undesirable or negativechoices, as well as over-interpreting positive outcomes,compared to being “off” DRT. 12Behavioural disturbances in PDBehavioural disturbances in PD may manifest as eitherapathy, or loss of motivation and drive, or the ICDs. Thesedisorders may co-occur with depression and anxietyand other neuropsychiatric symptoms and variabledegrees of cognitive change.Apathy in PDApathy in neurodegenerative conditions can be definedas “a lack of interest, emotion and motivation” 13 and isone of the most common neuropsychiatric complicationsin PD, occurring in over 40% of sufferers. 14 Clinicalcorrelates of apathy also include high rates of depression.Cognitive correlates include more impaired executivedysfunction, particularly working memory andverbal fluency, as well as more impaired global cognitivefunctioning. 14 The pathophysiology of PD that mightlead to apathy is linked to impairments in pathways thatunderlie pleasure and reward seeking. 15 This issupported by studies in PD which have demonstratedblunted anticipatory responses to motivationally significantevents or rewards, 16 as well as striatal hypoactivationat the prospect of reward. 17Impulse control disorders in PD“Impulse control disorders” (ICDs) in PD is a looselydefined group of behavioural conditions in PD, whichwas first described in the 1980s when case descriptions ofan addiction to DRT were published. Later, in 2003, Driver-Dunckley described nine cases in a retrospective reviewof 1884 PD sufferers who developed pathologicalgambling (PG) following exposure to dopamine agonists(DAs). 18 Since then, DRT has been considered to play akey, if not causal, role for the development of PG andpossible other ICDs. Now, in the UK, all DAs have warningsabout the risk of developing PG and other ICDs listed intheir Summary of Product Characteristics. ICDs mayCASE REPORTMark Robson, 54, Lives in Royton, near Oldham, Manchester.Mark was working as an engineer when he first noticed a slighttremor and cramping in his right hand when he was trying towrite, and his handwriting seemed to be getting smaller. He wasdiagnosed with Parkinson’s in 1998, and put on Pergolide in theNovember of that year. Mark tried to keep positive, taking upChi-gung and yoga, and trained as a qualified healer. Mark at thistime was married happily to this third wife.When the dosage of Pergolide was increased to combat worseningsymptoms, Mark’s personality began to change. In June2004 the nightmare began. Mark became reclusive and lessoutgoing. His wife noticed things were different. Mark startedto overeat and had no control over the amount of food he waseating. He started gambling, which was totally out of character.At first, it was interactive TV games, then internet casino sites.Mark had five credit cards, and two personal loans. He wasjuggling money on these, plus taking out extra loans. He estimateshe was spending at least 22 hours a day on line gambling.This went on for 18 months.He lost at least £200,000, remortgaging his house to finance hishabit. Up to this point Mark had managed to keep the financialsituation away from his wife. He became increasingly sneaky andconniving, and used to lie to get money to gamble – spendingthe mortgage money, and stealing from his wife’s business –about £20,000 from her account (she was eventually declaredbankrupt in October 2005). His marriage broke up.During this time Mark was seeing his specialist at Oldhamhospital – but as he wasn’t aware of a possible link with medicationhe didn’t mention the gambling addiction. It wasn’t until afriend sent him an article in The Daily Mail about somebody elsewith Parkinson’s who had a gambling habit and was blaming hismedication, that the penny finally dropped. Mark re-contactedhis Parkinson’s specialist and was told him to come in straightaway for a consultation. Then the link with Pergolide andcompulsive behaviours was discussed. Mark was taken offPergolide gradually over about four weeks. The urge to gambledisappeared.Mark was left feeling exhausted, suicidal, and unable to cope.He was admitted to a psychiatric ward where he stayed forseven weeks. In 2006 he got divorced. As his wife had the maritalhome Mark went to live with this father in Fleetwood. Markstruggled to get his life back together. He was on anti-depressants,and lost about three stone. After not having had anycontact with his ex-wife for four years, last year Mark and hisformer wife got back in touch, as Mark had hired a solicitor toprepare a case against the drug manufacturers and needed hersupport. They decided that they should make another go oftheir relationship, and remarried in November 2009. “It was avictory for us as a couple. We had been through hell and backbecause of a tablet no bigger than 2mm in size”. Mark has notbeen able to work since 2000. He is taking part in Parkinson’sfunded research with Dr Iracema Leroi.Mark Robson was part of the research project funded byParkinson's UK12 > ACNR > VOLUME 10 NUMBER 5 > NOVEMBER/DECEMBER 2010

When you want to add tomonotherapy efficacy:Go straight fromA to ZonegranyzonisamideAdd power to your monotherapyZonegran 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 100mg zonisamide. Indication: Adjunctive therapy in adult patientswith partial seizures, with or without secondary generalisation.Dose and administration: Adult: Must be added to existingtherapy. Initial daily dose is 50 mg in two divided doses. Afterone week, increase to 100 mg daily. Then increase at one weeklyintervals in 100 mg increments. Can be taken once or twicedaily after titration. In renal or hepatic impairment and patientsnot receiving CYP3A4-inducing agents consider two weeklyintervals. Withdraw gradually. Elderly and patients with renalor hepatic impairment: Caution (see SmPC). Not recommendedin severe hepatic impairment. Children and adolescentsunder 18 years: Not recommended. Contra-Indications:Hypersensitivity to zonisamide, sulphonamide or any excipient.Pregnancy: Zonegran must not be used during pregnancy unlessclearly necessary in the opinion of the physician, and only ifpotential benefits justify the risks. Specialist advice should begiven to women who are likely to become pregnant. Womenof childbearing potential must use contraception duringtreatment and for one month after discontinuation. Lactation:Excreted into breast milk. A decision must be made to eitherdiscontinue Zonegran or stop breast-feeding. Warnings andPrecautions: Serious rashes occur in association with Zonegrantherapy, including cases of Stevens-Johnson syndrome.Zonegran contains a sulphonamide group which are associatedwith serious immune based adverse reactions. Closely superviseand consider discontinuation in patients with unexplainedrash. Cases of agranulocytosis, thrombocytopenia, leukopenia,aplastic anaemia, pancytopenia and leucocytosis have beenreported. Monitor for signs of suicidal ideation and behavioursand appropriate treatment should be considered. Use withcaution in patients with risk factors for nephrolithiasis, includingprior stone formation, a family history of nephrolithiasis andhypercalcuria. Evaluate and monitor serum bicarbonate levelsin patients who have: underlying conditions which mightincrease the risk of metabolic acidosis; increased risk of adverseconsequences of metabolic acidosis; symptoms suggestive ofmetabolic acidosis. If metabolic acidosis develops and persists,consider reducing the dose, discontinuing or alkali treatment.Use with caution in patients treated with carbonic anhydraseinhibitors, e.g. topiramate. Decreased sweating, elevated bodytemperature and heat stroke have been reported. Patientsshould maintain hydration and avoid excessive temperatures.Monitor pancreatic lipase and amylase levels in patientstaking Zonegran who develop clinical signs and symptomsof pancreatitis, consider discontinuation. In cases of severemuscle pain/weakness with or without fever, assess markersof muscle damage and consider discontinuation. Zonegran 100mg capsules contain E110. Caution in patients less than 40kg. In patients with weight loss consider dietary supplement,increased food intake or discontinuation. Drug Interactions: Noclinically relevant pharmacokinetic effects on carbamazepine,lamotrigine, phenytoin, sodium valproate, oral contraceptives(ethinylestradiol or norethisterone). Insufficient data withcarbonic anhydrase inhibitors, e.g.topiramate. Zonegran wasnot affected by lamotrigine or CYP3A4 inhibitors. Cautionwith drugs which are P-gp substrates. Avoid concomitantadministration with drugs causing urolithiasis. Zonisamideis metabolised partly by CYP3A4, N-acetyl-transferases andconjugation with glucuronic acid; therefore caution withsubstances that can induce or inhibit these enzymes. Sideeffects: The most common adverse reactions in controlledadjunctive-therapy studies were somnolence, dizziness andanorexia. Adverse reactions associated with Zonegran in clinicalstudies 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,

REVIEW ARTICLEoccur in up to 14% of PD sufferers and includePG, hypersexuality, compulsive shopping andbinge eating. 19Pathological gambling (PG) is one of themost commonly reported and clinicallydramatic of the behavioural disturbancesassociated with PD. It characteristicallyarises after the introduction of a DA andmanifests in a change in behaviour thatinvolve seeking out opportunities to gamble,including scratch card or lottery addiction,betting, internet or casino gambling andstock market trading. Such PG behaviour istypically difficult to control by the affectedindividual, progresses to involve largeramounts of money and greater risks, andcontinues despite adverse consequences. Arecent review examined reports of 177 PDsufferers who developed PG and concludedthose affected are more commonly male,young and have psychiatric co-morbidityand use DAs. 20Hypersexuality (HS) in PD, which alsousually occurs with a change in DRT, mayappear in isolation, or in association withother ICDs. It may take the form of anenhanced libido, greater frequency of maleerections, new sexual orientations, practicesand even fetishes and may be accompaniedby changes in mental state such as hypomaniaor disinhibited behaviour.Finally, dopamine addiction, also known as“dopamine dysregulation syndrome” (DDS)involves a progressive dependence on DRT,accompanied by marked dyskinesia, demandsfor more DRT despite being “on” motorically,hoarding behaviours associated with wantingmore DRT, a reluctance to cut back on themedication, and marked irritability and withdrawalsymptoms when denied access to DRT.DDS is often accompanied by purposeless,repetitive and stereotyped behaviours(“punding”), other ICDs and mood changes,and may be more closely linked to the use oflevo-dopa than DAs. There is debate aboutwhether DDS is a separate phenomenon fromthe ICDs since it is more closely related toexcessive dopaminergic doses compared tothe ICDs.Are cognitive changes and behaviourslinked in PD?Since both apathy and the ICDs appear toinvolve reward and decision-making pathways,the question of whether they mayoverlap and how they may be linked tocognitive changes arises. Our own datasuggest that rates of attentional impulsivitymay be higher in those with PD-relatedapathy compared to PD-controls, and thatICD sufferers in PD have higher rates ofapathy compared to PD-controls. 21 In apathyin PD, the predominant cognitive dysfunctioninvolves executive dysfunction, particularlyin set-shifting and verbal fluency, 14supporting the notion that cognitive deficitsmight be driving behaviours. In the ICDs, onthe other hand, executive function may oftenbe intact but here the key “cognitive lesion”may be disruption to emotionally-baseddecision-making, leading to a pattern of“cognitive impulsivity” that may in part driveimpulsive behaviours in the context ofDRT. 22,23While the field of ICD studies in PD is relativelyyoung, a few studies of an experimentalnature have started to emerge and involveexamining PD study participants both “on” and“off” medication while doing specific cognitivetasks. The key overall finding from thesestudies is that neural reward pathways,including the ventral striatum (VS), appear tobe implicated in ICD pathophysiology and thismay be impacted upon by DRT, and thatdopamine is more readily released from the VSduring reward-related tasks. 24 With this model,DRT may precipitate the development ofimpulsivity due to modulation of reward sensitivityby altering the “hot”-limbic/”cool”-executivesystem balance in favour of the “hot”-limbic loop. 25 This, in turn, leads to goaldirected, impulsive behaviour, which maybecome addictive, and, once again, cognitionappears to drive behaviour.ConclusionThe changes in various levels of cognitivefunctioning in PD, as described above, and theputative links to behavioural changes, result ina challenging clinical scenario. In examiningeither behaviour or cognition in neurodegenerativeconditions such as PD, it is important toconsider how they may be interlinked andhow their combined effect may manifest inthe PD sufferer. lDr Leroi has just finished a three year researchproject in this area funded by Parkinson's UK.REFERENCES1. Foltynie T, Brayne CEG, Robbins TW, Barker RA. Thecognitive ability of an incident cohort of Parkinson’spatients in the UK. The CamPaIGN study. Brain 2004.127(3):550-560.2. Dubois B. Is PD-MCI a useful concept? MovementDisorders 2007;22:1215-1216.3. Williams-Gray CH, Foltynie T, Brayne CEG, Robbins TW,Barker RA. Evolution of cognitive dysfunction in an incidentParkinson’s disease cohort. Brain 2007;130(7):1787-1798.4. Hely MA, Reid WGJ, Adena MA, Halliday GM Morris JGL.The Sydney multicenter study of Parkinson’s disease: Theinevitability of dementia at 20 years. Movement Disorders.2008;23(6):837-844.5. Burn DJ, Rowan EN, Allan LM et al. Motor subtype andcognitive decline in Parkinson’s disease, Parkinson’s diseasewith dementia and dementia with Lewy bodies. Journal ofNeurology Neurosurgery and Psychiatry 2006;77:585-589.6. Aarsland D, Anderson K, Larsen JP, Lolk A. Prevalenceand characteristics of dementia in Parkinson disease: an 8-year prospective study. Achives of Neurology 2003;60:387–92.7. Bohnen NI, Kaufer DI, Hendrickson R, Ivanco LS, LoprestiBJ, Constantine GM, Mathis CA, Davis JG, Moore RY,DeKosky ST. Cognitive correlates of cortical cholinergicdenervation in Parkinson’s disease and parkinsoniandementia. Journal of Neurology 2006; 253:242–247.8. Leroi I, Brandt J, Reich SG, Lyketsos CG, Grill S,Thompson R, Marsh L. Randomised placebo-controlledtrial of donepezil in cognitive impairment in Parkinson’sdisease. International Journal of Geriatric Psychiatry2004;19:1-8.9. Emre M, Aarsland D, Albanese A et al. Rivastigmine fordementia associated with Parkinson’s disease. NewEngland Journal of Medicine. 2004 351;24: 2509-251810. Leroi I, Overshott R, Byrne EJ, Daniel E, Burns A. Arandomised controlled trial of memantine in dementia associatedwith Parkinson’s disease (PDD). MovementDisorders 2009; 24:1217-2111. Aarsland D, Ballard C, Walker Z, Bostrom F, Alves G,Kossakowski K, Leroi I et al. Memantine in patients withParkinson’s disease dementia or dementia with Lewybodies: a double-blind, placebo-controlled, multicentretrial. Lancet Neurology 2009;8(7):613-61812. Frank MJ, Seeberger LC, O’Reilly RC. By carrot or by stick:cognitive reinforcement learning in parkinsonism. Science.2004; 306(5703):1940-1943.13. Robert PH, Clairet S, Benoit M, Koutaich J, Bertogliati C,Tible O, Caci H, Borg M, Brocker P, Bedoucha P. TheApathy Inventory: assessment of apathy and awareness inAlzheimer disease, Parkinson’s disease and mild cognitiveimpairment. International Journal of Geriatric Psychiatry2002;7(12):1099-1105.14. Pluck GC, Brown RG. Apathy in Parkinson’s disease.Journal of Neurology, Neurosurgery and Psychiatry 2002;73:636-642.15. Czernecki V, Pillon B, Houeto JL, Pochon JB, Levy RL,Dubois B. Motivation, reward, and Parkinson's disease:influence of dopatherapy. Neuropsychologia. 2002;40:2257–2267.16. Mattox ST, Valle-Inclán F, Hackley SA. Psychophysiologicalevidence for impaired reward anticipation in Parkinson’sdisease. Clinical Neurophysiology 2006; 117(10):2144-53.17. Martin-Soelch C, Leenders KL, Chevalley AF, Missimer J,Kunig G, Magyar S, Mino A, and Schultz W. Rewardmechanisms in the brain and their role in dependence:evidence from neurophysiological and neuroimagingstudies. Brain Research Reviews 2001; 36:139–149.18. Driver-Dunckley E, Samanta J, Stacy M. Pathologicalgambling associated with dopamine agonist therapy inParkinson’s disease. Neurology. 2003; 61:422-42319. Weintraub D, Koester J, Potenza MN, Siderowf AD et al.Impulse control disorders in Parkinson’s disease: a crosssectionalstudy of 3090 patients. Archives of Neurology2010; 67(5):589-95.20. Gallagher DA, O’Sullivan SS, Evans AH, Lees AJ, SchragA. Pathological gambling in Parkinson’s disease: riskfactors and differences from dopamine dysregulation. Ananalysis of published case series. Movement Disorders.2007; 22(12):1757-63.21. Leroi I, Andrews M, McDonald K, Byrne EJ, Burns A. Acomparison of apathy in impulsivity in Parkinson’s disease(abstract). Movement Disorders Society Annual Meeting,Paris June 2009.22. Pagonabarraga J, García-Sánchez C, Llebaria G, Pascual-Sedano B, Gironell A, Kulisevsky J. Controlled study ofdecision-making and cognitive impairment in Parkinson'sdisease. Movement Disorders 2007; 22(10):1430-5.23. Andrews M, Leroi I, McDonald K, Elliott R, Byrne EJ,Burns A. Cognitive functioning in apathy and impulsivityParkinson disease (abstract). WFN World Congress onParkinson’s Disease, Miami 2009.24. Evans AH, Pavese N, Lawrence AD, Tai YF, Appel S, DoderM et al. Compulsive drug use linked to sensitized ventralstriatal dopamine transmission. Annals of Neurology2006;59:852-858.25. Robert G, Drapier D, Verin M, Millet B, Azulay JP, Blin O.Cognitive impulsivity in Parkinson’s disease patients:assessment and pathophysiology. Movement Disorders2009; 24(16):2316-2327.14 > ACNR > VOLUME 10 NUMBER 5 > NOVEMBER/DECEMBER 2010

For some of your patients, chronic migraineis the only thing they can plan forWith the new indication for BOTOX ® , you may beable to help them change their plansBOTOX ® is now licensed for the prophylaxisof headaches in adults with chronic migraineBOTOX ® (botulinum toxin type A)Migraine Abbreviated Prescribing InformationPresentation: Botulinum toxin type A (from Clostridium botulinum), 50 or100 or 200 Allergan Units/vial. Indications: Prophylaxis of headaches inadults with chronic migraine (headaches on at least 15 days per month ofwhich at least 8 days are with migraine). Dosage and Administration:See Summary of Product Characteristics for full information. Reconstitutewith sterile unpreserved normal saline (0.9% sodium chloride for injection).BOTOX ® doses are not interchangeable with other preparations ofbotulinum toxin. Inject using 30 gauge, 0.5 inch needle, or 1 inch needle forthicker muscles in neck region if required. Inject 0.1ml (5U) intramuscularlyto 31 (up to 39) injection sites, divided across seven specific head/neck muscle areas including frontalis, corrugator, procerus, temporalis,trapezius and cervical paraspinal muscles. Inject bilaterally, with theexception of procerus. Total dose 155U–195U. Contra-indications:Known hypersensitivity to any constituent. Pregnancy or lactation.Presence of infection at proposed injection site(s). Warnings/Precautions:Relevant anatomy and changes due to prior surgical procedures must beunderstood prior to administration. Adrenaline and other anti-anaphylacticmeasures should be available. Reports of side effects related to spread oftoxin distant from injection site, sometimes resulting in death. Caution inpatients with underlying neurological disorder and history of dysphagiaand aspiration. Patients should seek medical help if swallowing, speech orrespiratory disorders arise. Clinical fluctuations may occur during repeateduse. Too frequent or excessive dosing can lead to antibody formation andtreatment resistance. The previously sedentary patient should resumeactivities gradually. Caution in the presence of inflammation at injectionsite(s) or when excessive weakness/atrophy is present in target muscle.Caution when used for treatment of patients with peripheral motorneuropathic disease. Use with extreme caution and close supervision inpatients with defective neuromuscular transmission (myasthenia gravis,Eaton Lambert Syndrome). Contains human serum albumin. Procedurerelated injury could occur. Efficacy has not been shown in prophylaxisof episodic migraine (headaches

N E U R O L O G I C A L L I T E R AT U R ENeurological literature:Headache (Part 7): MegrimDr Andrew J Larneris the editor of our Book ReviewSection. He is a ConsultantNeurologist at the Walton Centrefor Neurology and Neurosurgeryin Liverpool, with a particularinterest in dementia and cognitivedisorders. He is also an HonoraryApothecaries' Lecturer in theHistory of Medicine at theUniversity of Liverpool.Correspondence to:AJ Larner,Walton Centre for Neurologyand Neurosurgery,Lower Lane, Fazakerley,Liverpool, L9 7LJ, UK.E. a.larner@thewaltoncentre.nhs.ukREFERENCES1. Harris J (ed.). Samuel Richardson.The History of Sir CharlesGrandison. Oxford: OxfordUniversity Press,1972:III:195.2. Larner AJ. (2010) Jane Austen’s(1775-1817) references to headache:fact and fiction. Journal of MedicalBiography 2010;in press.3. Lane R, Davies P. Migraine. Taylor& Francis: New York, 2006:8.4. Larner AJ. Familial migrainewithout aura with perimenopausalonset. International Journal ofClinical Practice 2010;64:128-9.5. Larner AJ. “Neurological literature”:headache (part 2). Advances inClinical Neuroscience &Rehabilitation 2006;6(2):37-8.6. Liveing E. Observations on megrimor sick-headache. BMJ 1872;1:364-6.7. Pearce JMS. Edward Living’s (1832-1919) theory of nerve-storms inmigraine. In: Rose FC (ed.). A shorthistory of neurology. The Britishcontribution 1660-1910. Oxford:Butterworth Heinemann,1999:192-203.8. Ringer S. Remarks on the action ofhydrate of croton-chloral on megrim.BMJ 1874;2:637.9. Nettleship E. Repeated paroxysmalfailure of sight in connection withheart-disease. BMJ 1879;1:889-91.10. Galezowski X. Ophthalmic megrim.Lancet.1882:1:176-7.AGoogle search for megrim will reveal severaldefinitions, including a species of left-eyedflatfish (the whiff, or Lepidorhombus whiffiagonis),although neurologists will recall that thisword is also an archaic (some would say obsolete)word for migraine. (Pubmed contains no referencesto megrim, as far as I can ascertain.) Otherusages of megrim are reported to include:• a caprice,fancy,whim or fad (often in the plural,megrims); and• depression, melancholy, low spirits or unhappiness.An example of the latter usage is said to be fromSamuel Richardson’s History of Sir CharlesGrandison (1753) wherein Lady G writes to MissByron (volume VI, letter xlv) “If these megrims arethe effect of Love,thank Heaven,I never knew whatit was”. 1 It remains possible, however, that thiscould equally well refer to headaches. Sir CharlesGrandison was the favourite novel of Jane Austen(1775-1817), large passages of which she knew byheart, and it may have been one stimulus, specificallyimitation, for her use of headache as a plotdevice in several of her novels, as well as in otherwritten work. 2Lane & Davies explain that Galen’s term “hemicrania”was translated into low Latin as “hemigranea”,and that through successive transliterationsand abbreviations this evolved by the 16thcentury into megrim in English, denoting sickheadache, blind headache and bilious headache 3(the latter term was still in common usage in thetwentieth century, used for example by mymaternal grandmother 4 ). The Oxford EnglishDictionary has its earliest references to megrim inthe sense of headache dating to the mid-fifteenthcentury,hence postdating the earliest recorded useof headache (ca. 1000AD) by more than fourcenturies. 5 A seventeenth century translation ofthe Chirurgical Works of the French surgeonAmbroise Paré (1510-1590) includes the statement:The Megrim is properly a disease affectingthe one side of the head, right or left.Perhaps most famously in the neurologicalcontext, the word megrim was used by EdwardLiveing in the title of his 1873 work, one of theseminal works in the history of headache, OnMegrim, Sick-Headache, And Some AlliedDisorders: A Contribution To The Pathology OfNerve-Storms 6 which addressed his ideas on thepathophysiology of these headaches. 7 Thefollowing year Sydney Ringer wrote in the BMJ onthe action of hydrate of croton-chloral onmegrim, 8 and later in the same decade, 1879,Edward Nettleship noted that:It is well known that certain of the subjects ofmegrim are liable to a very peculiar affectionof sight, in which a part of the field of visionbecomes obscured by a flickering or wavingcloud, the edges of which in many personsare sharply defined, serrated and brilliantlycoloured. 9Galezowski used the term “ophthalmic megrim” todescribe central retinal vein occlusion associatedwith migraine in 1882. 10Some literary uses of megrim may also be notedhere,some almost contemporaneous with its aforementioneduses in the 19th century medical literature.The word was certainly known to GeorgeEliot, pseudonym of Marian Evans (1819-1880). InAdam Bede (1859),her first major novel,it is said ofone female character:…it was a pity she should take such megrimsinto her head, when she might ha’ stayed wi’us all summer, and eaten twice as much asshe wanted,and it ‘ud niver ha’ been missed.In Felix Holt, the Radical (1866), a character asks:Can’t one work for sheer truth as hard as formegrims?OED records this as an example of megrims in thesense of a whim, fancy or fad. Another examplemay be Dr Tertius Lydgate in Middlemarch (1871-2)who is reported to be:…abrupt but not irritable, taking little noticeof megrims in healthy people.Eliot’s contemporary Wilkie Collins (1824-1889)was also familiar with the word. For example inArmadale (1866), one character asks of another:How did you manage to clear your head ofthose confounded megrims?The context suggests that this may refer to eitherfancies or low spirits,but in The Moonstone (1868),possibly Collins’s best known work,its use certainlysuggests the possibility of headaches:This was the first attack of the megrims that Iremembered in my mistress since the timewhen she was a young girl.Moving to a more contemporary literary use of theword megrim, two examples may be found in theoeuvre of Stephen King (born 1947). In Gerald’sGame (1992) it is used in the sense of fancy, whim,freak, caprice:No, she thought her imagination had morethan earned its right to a few hallucinatorymegrims,but it remained important for her toremember she’d been alone that night.In Desperation (1996),it is used in the sense of lowspirits, unhappiness:He was turning around,zipping his fly,talkingmostly to keep the megrims away (they hadbeen gathering like vultures just lately, thosemegrims), and now he stopped doing everythingat once.One can understand how this word may perhapsappeal to King’s sensibilities.On a final, musical, note, the composer BarryFerguson uses megrim in his song The Ruined Maid(1997), again in the sense of melancholy, from acycle of songs written for Catherine King (listen atwww.catherineking.org). l16 > ACNR > VOLUME 10 NUMBER 5 > NOVEMBER/DECEMBER 2010

R E V I E W A RT I C L ERNA Interference andNeurological DisordersChristopher R Sibley,is a post-doctoral research fellowat the University of Oxford wherehe previously graduated with a BAin Physiological Sciences, an M.Scin Neuroscience and completedhis doctoral thesis. His main interestsare the development of novelgene-silencing strategies forParkinson’s disease and miRNAnetworks.Janine Scholefield,is a Nuffield Medical Fellow at theUniversity of Oxford, having graduatedwith a PhD in HumanGenetics from the University ofCape Town. Her research interestsinclude gene silencing therapiesfor the inherited ataxias.Matthew JA Wood,graduated in Medicine from theUniversity of Cape Town, workingin clinical neuroscience beforegaining a doctorate inPhysiological Sciences from theUniversity of Oxford in 1993. He iscurrently University Lecturer, andFellow and Tutor in Medicine atSomerville College, University ofOxford. The main focus of hisresearch is the study of RNAbiology and therapy for disordersof the nervous system and muscle.Correspondence to:Dr Matthew JA Wood,Department of Physiology,Anatomy and Genetics, Universityof Oxford, South Parks Road,Oxford, OX1 3QX, UKTel: +44 (0)1865 272419Fax: +44 (0)1865 272420Email: matthew.wood@dpag.ox.ac.ukRNA interference (RNAi) is a powerful modeof post-transcriptional gene silencing, thediscovery of which earned Fire and Mello the2006 Nobel Prize in Physiology or Medicine. Sincetheir seminal work published in 1998, which led tothe identification of double-stranded RNAs(dsRNAs) as being responsible for RNAi in asequence-specific manner, 1 it has become clearthat RNAi is an essential and ubiquitous process inall eukaryotic cells and organisms. It is especiallycritical in stem cells and during development, andit is now appreciated that dysregulation of RNAifunction is a central feature of pathologicalprocesses, including cancer and neurologicaldisease. Moreover the powerful ability of RNAi tosilence genes has therapeutic potential.RNAi biologyRNAi refers to the sequence-specific silencing ofmessenger RNA (mRNA) transcripts directed byshort, 21-23 nucleotide antisense RNA species.Thegenes responsible for initiating RNAi are part of anevolutionary conserved cellular pathway thatprocesses endogenous triggers of RNAi, termedmicroRNAs (miRNAs), into mature sequencescapable of directing the silencing of sequencematchedmRNA targets (Figure 1).Over 900 humanmiRNAs have now been identified within thegenome, and several have been shown to silencethe expression of anywhere from tens to hundredsof mRNA transcripts at a time. 2 Thus the naturalRNAi pathway within cells represents a powerfulpost-transcriptional gene regulation network thathelps to maintain and enhance complexity arisingfrom transcription of the genome,whilst the dysregulationof this network can have disease-causingpotential.miRNAs and neurological diseaseGiven their ability to enhance the complexity ofthe transcriptome, it is perhaps no surprise thatthe central nervous system (CNS) is enriched inmiRNA expression. Here they display tight spatialand temporal expression patterns, and have nowbeen shown to have key roles in multiple aspectsof neurobiology including neuronal-lineagedetermination, synaptogenesis and neurogenesisamong others. 3 Further to this, abnormalities atalmost every stage of miRNA processing have nowbeen linked to disease, and several neurologicaldisorders are among those now identified aslinked to miRNA dysregulation. Profiling ofmiRNA expression in post-mortem tissue samplesfrom patients with neurological disorders such asAlzheimer’s disease (AD), 4 6 Huntington’s disease(HD), 7 Parkinson’s disease (PD), 8 schizophrenia, 9and autism 10 have identified miRNAs that demonstrateeither increased or reduced expression relativeto control tissues (Table 1); implicating theirinvolvement in the disease process. Similarly, aplethora of dysregulated miRNAs have also beenidentified in pre-clinical neurological diseasemodels. Importantly, such patterns of miRNAdysregulation may now hold promise as noveldiagnostic or therapeutic biomarkers for neurologicaldiseases, as has already been shown forseveral cancers. However it is unclear at presentwhether alterations in the expression of miRNAsacross these disorders are causative of the diseasephenotypes, or merely consequences of otherprimary defects. This will be important to determinein future since it could reveal novel therapeuticstrategies involving for example the use ofmiRNA inhibitors or mimics to modulate miRNAactivity.In addition, the 3’UTRs of mRNAs typicallycontain target seed-matched sequences formiRNAs and are known to be a common site forgenetic variation. Disease-linked single nucleotidepolymorphisms (SNPs) have now been reported inspecific 3’UTR miRNA target sites in cases ofTourette’s syndrome, 11 PD, 12 TDP43-positive frontaltemporal dementia 13 and even in individualsdisplaying aggressive behavior 14 (Table 1). TheseSNPs can lead to either reduced miRNA silencingof the mutated transcript by the targeting miRNA,or tighter regulation by the miRNA due to strengtheningof the miRNA-binding site. Conversely, SNPsin miRNA transcripts themselves have also beenreported for non-CNS disorders and this could bean additional mechanism found to link miRNAs toneurological disease in future either through directeffects on the processing of the miRNA or directlyon target mRNA silencing.RNA interference is of already centralbiological importance and it promises to makea major clinical impact, particularly in theneurosciencesACNR > VOLUME 10 NUMBER 5 > NOVEMBER/DECEMBER 2010 > 17

REVIEW ARTICLEFigure 1. Mechanism and Exploitation of the RNAi pathway.In the endogenous RNAi pathway, primary miRNA (pri-miRNA) sequences are transcribed from genomic DNA. Complementarybase pairing between separated regions of the pri-miRNA sequence allows characteristic stem-loop secondary structures toform which are subsequently recognised by the ribonuclease enzyme, Drosha. The resulting cleavage within the stem producesa pre-miRNA precursor, with characteristic two nucleotide overhangs at the 3’ end. These overhangs serve as a recognitionsignal for nuclear export by Exportin-5, and then for further processing by Dicer. Removal of the loop-region of the pre-miRNAby Dicer results in production of a dsRNA duplex, or short interfering RNA (siRNA) which initiates the formation of theArgonaute (AGO) protein-containing RNA-induced silencing complex (RISC). Within RISC a thermodynamic selection processselects one of the two siRNA strands as the active guide strand, referred to as the mature miRNA, that will be used to directtarget mRNA silencing whilst the other strand is discarded. RISC subsequently scans the retained mature miRNA across mRNAsequences, and in particular the 3’ untranslated regions (3’UTRs), searching for sequence homology to the mature miRNA. Whenidentified, the AGO proteins within RISC initiate target mRNA silencing through translational repression in the case of incompletehomology, or alternatively through target mRNA degradation if homology to the mature miRNA sequence is complete.Gene silencing based therapy can exploit several points of the endogenous RNAi pathway, including expressed triggers of RNAisuch as pri-miRNAs and shRNAs, as well as siRNA forms.Manipulation of RNAi pathway for neurologicaldisease therapyTherapeutic exploitation of the RNAi mechanismdescribed above is also a prominentfocus of research. For several neurologicaldiseases it is likely that silencing genes that areover-expressed or which harbour pathogenicmutations would be therapeutically beneficial,especially where mutations result in gainof-function.Silencing of pathogenic humantransgenes in mice leads to phenotypicimprovements in both HD 15 and spinocerebellarataxia 1 (SCA1) 16 mouse models. In theHD models, RNAi treatment that reducesmutant human and wild-type mouseHuntington mRNA transcripts concomitantlyby ~60% has been shown to lead to improvedmotor coordination over sham-treated littermates,and importantly to an increase in lifeexpectancy. 15 Similarly, cerebellar degenerationwas reduced and an ataxic behaviouralphenotype improved following RNAi treatmentleading to reduced ataxin-1 in the SCA1mice. 16 However, the non-allele specificsilencing used in these studies would only beapplicable to those diseases in which the functionof the normal wild-type gene is non-essential.For several neurological diseases, a functioningcopy may be important, if not a necessity.In these cases, allele-specific silencing ofthe mutant gene only would be desirable.Though extensive screening is required toidentify RNAi triggers capable of discriminatingbetween wild-type and mutant transcripts,allele-specific therapies have beendemonstrated in neurological disease modelsof SCA3, frontotemporal dementia, SCA7 and17 19HD.The choice of RNAi trigger is also of importance.Gene-specific silencing can beachieved using any of the processed smallRNA species produced in the natural RNAipathway as a method to target a gene ofinterest (Figure 1). Whilst pri-miRNA mimicsand shRNAs can be expressed from DNAencodedplasmids to allow incorporation intoviruses for long-lasting expression, chemicallysynthesised siRNAs are delivered as dsRNAduplexes that are targets for nuclease digestionand rapid clearance from the body,making their effects short-lived. However oneconcern that must be addressed beforeroutine use of RNAi in the clinic is that allthree approaches can direct off-targetsilencing of mRNA transcripts with nearcompletebase-pairing to the antisensespecies. Thus, delivery of the RNAi triggershould ideally be restricted to only the celltypeof interest where possible to limit thisundesirable silencing.The transient nature of a siRNA-basedtherapy lends itself to one-off treatments forinfectious or relapsing diseases. For example,intracranial injections of siRNAs targeting theJapanese encephalitis virus or Nile river virushave prevented a lethal phenotype in viralchallenged mice. 20 In contrast, one-off treatmentsusing an shRNA or pri-miRNA mimicexpressed from within a suitable viral vectorcould lead to long-term gene silencing moresuitable for chronic neurological diseasessuch as PD and HD. 15 However these DNAencodedRNAi triggers should ideally bemodified to allow inducible or even neuronalspecificexpression as these characteristicswould be particularly useful to limit off-targetsilencing of near complete base-paired transcriptsto the RNAi trigger.Finally, one of the biggest challenges indeveloping RNAi-based therapies for neurologicaldisorders is that of delivery to the CNS.The most common viral approaches for RNAidelivery in pre-clinical models are intracranialinjections of integrating lentiviruses or nonintegratingadeno-associated viruses (AAVs).However, it is unclear whether this willbecome a preferred method of administeringtreatment in patients due to the invasivenature of administration. Clearly, identificationof novel methods of traversing the blood-brainbarrier (BBB) following systemic injection arerequired. Encouragingly, transvascular deliveryof a siRNA complexed with a neuronaltargeting-peptide across the BBB to thestriatum, thalamus and cortex has beendemonstrated in vivo. 20 Likewise, the use of18 > ACNR > VOLUME 10 NUMBER 5 > NOVEMBER/DECEMBER 2010

TAKE CONTROLIN ALZHEIMER’S DISEASEProven efficacy across key AD symptom domains – cognition, function and behaviour 1-7No titration required – the only AD treatment with a therapeutic dose from the start 8-15The only AD treatment to offer carers and patients the convenience of an orodispersible formulation 9,16®®RIGHT FROM THE STARTABBREVIATED PRESCRIBING INFORMATIONARICEPT ® (donepezil hydrochloride film-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 orARICEPT EVESS 10 mg. Indication: Symptomatic treatment of mild to moderately severe Alzheimer’sdementia. Dose and administration: Adults/elderly; 5 mg daily which may be increased to 10 mgonce daily after at least one month. Aricept Evess orodispersible tablets should be placed on thetongue and allowed to disintegrate before swallowing with or without water. Aricept film-coatedtablets are taken orally. Treatment with Aricept or Aricept Evess should be initiated and supervisedby a physician with experience of Alzheimer’s dementia. A caregiver should be available to monitorcompliance. Monitor regularly to ensure continued therapeutic benefi t, consider discontinuationwhen evidence of a therapeutic effect ceases. No dose adjustment necessary for patients with renalimpairment. Dose escalation, according to tolerability, should be performed in patients with mild tomoderate hepatic impairment. Children; Not recommended. Contra-Indications: Hypersensitivityto 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 milkunknown. Women on donepezil should not breast feed. Warnings and Precautions: Exaggerationof succinylcholine-type muscle relaxation. Avoid concurrent use of anticholinesterases, cholinergicagonists, cholinergic antagonists. Possibility of vagotonic effect on the heart which may be particularlyimportant with “sick sinus syndrome”, and supraventricular conduction conditions. There have beenreports of syncope and seizures - in such patients the possibility of heart block or long sinusal pausesshould be considered. Careful monitoring of patients at risk of ulcer disease including those receivingNSAIDs. Cholinomimetics may cause bladder outflow obstruction. Seizures occur in Alzheimer’sdisease and cholinomimetics have the potential to cause seizures and they may also have the potentialto exacerbate or induce extrapyramidal symptoms. Care in patients suffering from asthma andobstructive pulmonary disease. No data available for patients with severe hepatic impairment. In three6-month clinical trials in individuals with vascular dementia (VaD), the combined mortality rate wasnumerically higher, in the donepezil group (1.7%) than in the placebo group (1.1%), but this differencewas not statistically significant. In pooled Alzheimer’s disease studies (n=4146), and in Alzheimer’sdisease studies pooled with other dementia studies including vascular dementia studies (totaln=6888), the mortality rate was numerically higher in the placebo group than in the donepezil group.Aricept film-coated tablets containlactose and should not be used in patients withrare hereditary problems of galactose intolerance, the Lapplactase deficiency or glucose-galactose malabsorption. Donepezil has minoror moderate influence on ability to drive/use machines so this should be routinely evaluated.Drug Interactions: Interaction possible with inhibitors or inducers of cytochrome P450; use suchcombinations with care. May interfere with anticholinergic agents. Possible synergistic activitywith succinylcholine-type muscle relaxants, beta-blockers, cholinergic agents. Side effects: Mostcommonly diarrhoea, muscle cramps, fatigue, nausea, vomiting, and insomnia. Very common effects(≥1/10): diarrhoea, nausea, headache. Common effects (≥1/100,

REVIEW ARTICLETable 1. Neurological disorders with reported miRNA abnormalitiesDisease miRNA abnormality Functional effect Ref.Alzheimer’s Disease Decreased expression of miR-29a and miR-29b-1 regulate BACE-1 expression. Loss leads to abnormally 4miR-29a/b-1 clusterhigh BACE-1 levelsAlzheimer’s Disease Decreased expression of miR-107 regulates BACE-1 expression. Loss leads to abnormally high BACE-1 6miR-107levels. Loss seen in early stages of diseaseAlzheimer’s Disease Decreased expression of miR-106b miR-106b regulates APP expression 5Huntington’s Disease Decreased expression of miR-9/9* miR-9/9* is a bidirectional miRNA with one strand, miR-9, regulating the 7transcriptional regulator REST, and the other strand, miR-9*, regulatingCoREST. In turn REST and CoREST negatively regulate miR-9/9* such thatdouble negative feedback loop is seenParkinson’s Disease Decreased expression of miR-133b miR-133b regulates maturation and activity of midbrain dopaminergic 8neurons in subsequent murine models through a negative feedback loopwith transcription factor Pitx3Parkinson’s Disease Polymorphism in fibroblast growth Parkinson’s disease-associated polymorphism leads to reduced miR-433 12factor 20 target site of miR-433 repression of target and subsequent downstream increase inα-synuclein expressionSchizophrenia Decreased expression of miR-26b, Unknown mechanisms. Upto 15 miRNAs decreased and 1 increased with 9miR-92, miR-24 and miR-30emicroarrays. Confirmed 4 to be significant with qPCRAutism Dysregulated expression of 9 miRNAs Unknown mechanisms. Upto 28 miRNAs dysregulated in initial analysis. 10Confirmed 9 to be significant with further analysisTourette’s Syndrome Polymorphism in Slit and Trk-like 1 Tourette’s-associated polymorphism leads to enhanced miR-189 repression 11target site of miR-189of target siteTDP43-frontal Polymorphism in progranulin target Common polymorphism leads to enhanced miR-659 repression of target 13temporal dementia site of miR-659 and is associated with 3-fold increase in susceptibility to diseaseAggressive behaviour Polymorphism in serotonin 1B Common polymorphism leads to enhanced miR-96 repression of target 14receptor target site of miR-96 and is associated with increased aggressionsystemically injected, pegylated immuno-liposomescarrying shRNAs or siRNAs has impressivesite-specific knockdown in induced invivo models of intracranial brain cancer. 21,22 Anew range of nanotechnology vehicles areadditionally showing promise such as goldnanorod nanoplexes incorporating siRNAswhich cross an in vitro BBB model 23 and theuse of self-derived exosomes that have beenmodified with targeting moieties in our laboratory.Finally, certain viruses such as AAV9 havebeen shown to cross the BBB, and it will beimportant to see how these may be harnessedfor RNAi therapeutics in future.ConclusionWithin the last decade our understanding ofRNAi has revealed it to be of central importancein regulating genome activity. Notsurprisingly for a biological process of suchimportance, RNAi dysfunction is now notablein many diseases, including neurologicaldisorders. Moreover, our ability to exploit thepower of RNAi silencing has moved rapidly tothe point where RNAi-based therapeutics arealready in clinical trials, and such approachesare well advanced in numerous pre-clinicalneurological disease models. The future willinevitably reveal much more on the role ofRNAi, and miRNAs in particular, in fundamentalneurological processes and functions.It will also very likely see the first RNAi-basedclinical trials in patients with neurodegenerativedisease in the next five years. lREFERENCES1. Fire A, et al. Potent and specific genetic interference bydouble-stranded RNA in Caenorhabditis elegans. Nature1998;391:806-11.2. Lim LP, et al. Microarray analysis shows that somemicroRNAs downregulate large numbers of target mRNAs.Nature 2005;433:769-73.3. Fineberg SK, Kosik KS & Davidson BL. MicroRNAspotentiate neural development. Neuron 2009;64:303-09.4. Hébert SS, et al. Loss of microRNA cluster miR-29a/b-1 insporadic Alzheimer's disease correlates with increasedBACE1/beta-secretase expression. Proc. Natl. Acad. Sci.U.S.A 2008;105:6415-20.5. Hébert SS, et al. MicroRNA regulation of Alzheimer'sAmyloid precursor protein expression. Neurobiol. Dis2009;33:422-28.6. Wang W, et al. The expression of microRNA miR-107decreases early in Alzheimer's disease and may acceleratedisease progression through regulation of beta-site amyloidprecursor protein-cleaving enzyme 1. J. Neurosci2008;28:1213-23.7. Packer AN, Xing Y, Harper SQ, Jones L & Davidson BL.The bifunctional microRNA miR-9/miR-9* regulates RESTand CoREST and is downregulated in Huntington's disease.J. Neurosci 2008;28:14341-346.8. Kim J, et al. A MicroRNA feedback circuit in midbraindopamine neurons. Science 2007;317:1220-24.9. Perkins DO, et al. microRNA expression in the prefrontalcortex of individuals with schizophrenia and schizoaffectivedisorder. Genome Biol 2007;8:R27.10. Abu-Elneel K, et al. Heterogeneous dysregulation ofmicroRNAs across the autism spectrum. Neurogenetics2008:9:153-61.11. Abelson JF, et al. Sequence variants in SLITRK1 are associatedwith Tourette's syndrome. Science 2005;310:317-20.12. Wang G, et al. Variation in the miRNA-433 binding site ofFGF20 confers risk for Parkinson disease by overexpressionof alpha-synuclein. Am. J. Hum. Genet;82:283-89.13. Rademakers R, et al. Common variation in the miR-659binding-site of GRN is a major risk factor for TDP43-positivefrontotemporal dementia. Hum. Mol. Genet2008;17:3631-42.14. Jensen KP, et al. A common polymorphism in serotoninreceptor 1B mRNA moderates regulation by miR-96 andassociates with aggressive human behaviors. Mol.Psychiatry 2009;14:381-89.15. Boudreau, R.L. et al. Nonallele-specific silencing of mutantand wild-type huntingtin demonstrates therapeutic efficacyin Huntington's disease mice. Mol. Ther2009;17:1053-63.16. Xia H, et al. RNAi suppresses polyglutamine-inducedneurodegeneration in a model of spinocerebellar ataxia.Nat. Med 2004;10:816-20.17. Miller VM, et al. Allele-specific silencing of dominantdisease genes. Proc. Natl. Acad. Sci. U.S.A2003;100:7195-7200.18. Scholefield J, et al. Design of RNAi hairpins for mutationspecificsilencing of ataxin-7 and correction of a SCA7phenotype. PLoS ONE 2009;4:e7232.19. Zhang Y, Engelman J & Friedlander RM. Allele-specificsilencing of mutant Huntington's disease gene.J. Neurochem 2009;108:82-90.20. Kumar P, et al. Transvascular delivery of small interferingRNA to the central nervous system. Nature2007;448:39-43.21. Xia C, Zhang Y, Zhang Y, Boado RJ & Pardridge WM.Intravenous siRNA of brain cancer with receptor targetingand avidin-biotin technology. Pharm. Res2007;24:2309-16.22. Zhang Y, Boado RJ & Pardridge WM. In vivo knockdownof gene expression in brain cancer with intravenous RNAiin adult rats. J Gene Med 2003;5:1039-45.23. Bonoiu AC, et al. Nanotechnology approach for drugaddiction therapy: gene silencing using delivery of goldnanorod-siRNA nanoplex in dopaminergic neurons. Proc.Natl. Acad. Sci. U.S.A 2009;106:5546-50.20 > ACNR > VOLUME 10 NUMBER 5 > NOVEMBER/DECEMBER 2010

16:00A dayof D.I.Y.02:00Sleeping rightthrough the night08:00The early birdcatches the wormWake up readyOnly Neupro ® provides continuous transdermal delivery over 24 hoursin patients with all stages of idiopathic Parkinson’s disease 1Help your patients get up and go with Neupro ®PRESCRIBING INFORMATION(Please consult the Summary of Product Characteristics (SPC) before prescribing.)Neupro ®RotigotineActive Ingredient: Rotigotine. 2 mg/24 h transdermal patch is 10 cm 2 and contains 4.5mg rotigotine, releasing 2 mg rotigotine over 24 hours. 4 mg/24 h transdermal patch is 20cm 2 and contains 9.0 mg rotigotine, releasing 4 mg rotigotine over 24 hours. 6 mg/24 htransdermal patch is 30 cm 2 and contains 13.5 mg rotigotine, releasing 6 mg rotigotine over24 hours. 8 mg/24 h transdermal patch is 40 cm 2 and contains 18.0 mg rotigotine, releasing8 mg rotigotine over 24 hours. Indication:To treat the signs and symptoms of idiopathicParkinson’s disease, either with or without concomitant levodopa therapy. Dosage andAdministration: Neupro is applied to clean, healthy, intact skin once a day. The patchremains on the skin for 24 hours and will then be replaced by a new one at a differentapplication site. Monotherapy: treatment initiated with a single da ly dose of 2 mg/24 h andincreased weekly by 2 mg/24 h until an effective dose is reached. Maximal dose is 8 mg/24h. Adjunctive therapy (with levodopa): treatment initiated with a single daily dose of 4 mg/24h and increased weekly in 2 mg/24 h increments, up to a maximal dose of 16 mg/24 h.Hepatic and renal impairment: Adjustment of the dose is not necessary in patients with mildto moderate hepatic impairment or in patients with mild to severe renal impairmentincluding those requiring dialysis. Caution is advised and dose adjustment may be neededwhen treating patients with severe hepatic impairment. Children and adolescents: Notrecommended. Treatment discontinuation: If treatment is to be withdrawn, it should begradually reduced, in steps of 2 mg/24 h with a dose reductionpreferably every other day, to avoid the possibility of developingneuroleptic malignant syndrome. Contraindications,Warnings, etc: Contraindications: Hypersensitivity torotigotine or to any of the excipients. Neupro should beremoved prior to Magnetic Resonance Imaging (MRI) orcardioversion to avoid burns. Precautions: Switching to anotherdopamine agonist may be beneficial for those patients who are insufficiently controlled byrotigotine. External heat should not be applied to the patch. Dopamine agonists are knownto cause hypotension, and monitoring of blood pressure is recommended. Wheresomnolence or sudden sleep onset occurs, or where there is persistent, spreading or seriousskin rash at the application site, consider dose reduction or termination of therapy. Rotatethe site of patch application to minimise the risk of skin reactions. In case of generalised skinreaction associated with use of Neupro, discontinue treatment. Avoid exposure to directsunlight until the skin is healed. Pathologic gambling, increased libido and hypersexuality havebeen reported in patients treated with dopamine agonists, including Neupro. Hallucinationshave been reported and patients should be informed that hallucinations can occur.Ophthalmologic monitoring is recommended at regular intervals or if vision abnormalitiesoccur. Consideration should be taken when prescribing Neupro in combination withlevodopa as a generally higher incidence of some dopaminergic adverse events have beenobserved.Neupro contains sodium metabisulphite, which may cause allergic-type reactionsincluding anaphylactic symptoms and life threatening or less severe asthmatic episodes incertain susceptible individuals. Interactions: Do not administer neuroleptics or dopamineantagonists to patients taking dopamine agonists. Caution is advised when treating patientstaking sedating medicines or other depressants in combination with rotigotine. Neupro maypotentiate the dopaminergic adverse reaction of levodopa. Co-administration of rotigotine(3 mg/24 h) did not affect the pharmacodynamics and pharmacokinetics of oralcontraceptives (0.03 mg ethinylestradiol, 0.15 mg levonorgestrel). Pregnancy and lactation:Neupro should not be used during pregnancy. Breast-feeding should be discontinued. Drivingetc.: Neupro may have major influence on the ability to drive and use machines. AdverseEffects: Very common (>10%): Somnolence, dizziness, headache, nausea, vomiting,application and insti lation site reactions. Common (between 1%-10%): Perceptiondisturbances, insomnia, sleep disorder, nightmare, abnormal dreams, disturbances inconsciousness, dyskinesia, dizziness postural, lethargy, vertigo, palpitations, orthostatichypotension, hypertension, hiccups, constipation, dry mouth, dyspepsia, erythema,hyperhidrosis, pruritus, oedema peripheral, asthenic conditions, weight decreased, fall.Pharmaceutical Precautions: Store in a refrigerator (2°C - 8°C). Store in theoriginal package. Legal Category: POM. Marketing AuthorisationNumber(s): 2 mg Continuation Pack x 28 patches: EU/1/05/331/002; 4 mg ContinuationPack x 28 patches: EU/1/05/331/005; 6 mg Continuation Pack x 28 patches:EU/1/05/331/008; 8 mg Continuation Pack x 28 patches: EU/1/05/331/011; TreatmentInitiation Pack: EU/1/05/331/013. NHS Cost: 2 mg Continuation Pack x 28 patches:£77.24. 4 mg Continuation Pack x 28 patches: £117.71. 6 mg Continuation Pack x 28patches: £142.79. 8 mg Continuation Pack x 28 patches: £142.79; Treatment Initiation Pack:£142.79. Marketing Authorisation Holder: SCHWARZ PHARMA Ltd, Shannon,Industrial Estate, Co. Clare, Ireland. Further information is available from: UCBPharma Ltd, 208 Bath Road, Slough, Berkshire, SL1 3WE. Tel: 01753 534655. Fax: 01753536632. Ema l: medicalinformationuk@ucb.com. Date of Revision: 03/2010(10NE0100). Neupro is a registered trademark. Reference: 1. Braun M et al. 2005;Poster presented at 9th Congress of the European Federation of Neurological. Societies;September 17 20, Athens, Greece.Adverse events should be reported. Reporting forms andinformation can be found at www.yellowcard.gov.ukAdverse events should also be reported to UCB Pharma10NE0193 Date of preparation: May 2010For their day, their night and their morning

MOTOR CONTROL SERIESThe Persistent Mysteryof the Basal Ganglia’sContribution to MotorControlPietro MazzoniPietro Mazzoni is AssociateProfessor of Neurology andDirector of the Motor PerformanceLaboratory at Columbia Universityin New York. He obtained amedical degree at Harvard and aPhD in Neuroscience at MIT, andhe trained in Neurology,Movement Disorders, and HumanMotor Control at Columbia. Hisresearch interests include the roleof the basal ganglia in motorcontrol and motor learning. Hesteadfastly maintains thatbecoming bald whilst working withhis coauthor during his PhD studieswas pure coincidence.Martyn Bracewellis Senior Lecturer in Neurologyand Neuroscience at BangorUniversity, and honoraryconsultant neurologist to theWalton Centre in Liverpool andthe Betsi Cadwaladhr UniversityHealth Board in North Wales. Hetrained in neurology at Oxford,Queen Square and Birmingham,and did a PhD in neuroscience atMIT. His research interests includesensorimotor integration,non-invasive brain stimulation andnovel approaches to neurorehabilitation.Correspondence to:Pietro Mazzoni, MD PhD710 W. 168th St, Box NI-175The Neurological InstituteNew York, NY, USA.In the second article in our series on motor control, we turn our attention to the persistent mysteryof what the basal ganglia actually do. We present an update on the canonical 'circuit diagram' ofAlexander and colleagues, and discuss some new ideas on the role of the basal ganglia inselection of the parameters of action.Martyn Bracewell, Series editorThe role of the basal ganglia (BG) in motorcontrol has long been mysterious. Thesenuclei were always at a disadvantage, relativeto other motor structures, with regards tohypotheses about their functions. Consider, forexample, the primary motor cortex. It has directprojections to spinal motor neurones; electricalstimulation elicits movement; and lesions causeweakness. It was thus natural to hypothesise thatthe motor cortex encodes motor commands.For the BG, on the other hand, a simple intuitionis elusive. These nuclei receive informationfrom many brain regions and project to brainstructures that drive actions, suggesting a role inmotor control. However, the clinical symptomscaused by BG disorders, such as rigidity, reductionof movement speed and amplitude, involuntarymovements, and abnormal postures, are sovaried and complex that a simple motor hypothesisis difficult to formulate.Marsden synthesised a vast body of knowledgeregarding motor abnormalities due to BG disorders,and hypothesised that the BG “are responsiblefor the automatic execution of learnedmotor tasks.” 1 This hypothesis embodied thefundamental idea that the BG do not simplymake movement possible, but rather that theymake it possible to move in a certain manner.Indeed, early neurophysiologic studies foundneural activity that was frustratingly difficult torelate to simple movement parameters, such asamplitude and direction, and was greatly affectedby non-motor factors. Only years later didevidence emerge of how neural activity mightencode whether a movement is executed automatically2 and whether it is executed as a"learned" motor task. 3A canonical circuit for the BGThese conceptual difficulties did not dissuaderesearchers from a painstaking effort to establishthe anatomical, chemical, and physiologicalconnectivity of the BG. This “bottom-up”approach identified a circuit (the motor loop;Figure 1A) connecting the BG and the motorcortical areas, which became the working modelfor hypotheses about BG function. In addition, thiscircuit was found to be one of several parallelcircuits linking different parts of the basal gangliato different cortical regions. Alexander andcolleagues’ review 4 introduced two ideas thathave fundamentally influenced our notions of BGfunction: the BG’s circuitry is specifically suitedto a particular type of computation (processingsignals from multiple brain structures to influencebehaviour), and this computation is carriedout over multiple functional domains (motor,oculomotor, cognitive, and emotional).The motor circuit is a loop in which motor andother cortical areas project to the BG, which inturn project back to motor cortical areas by wayof the thalamus. In early formulations of this loop 5(Figure 1A), the striatum is the sole inputnucleus, receiving information from motorcortical areas. The striatum projects to theinternal segment of the globus pallidum (GPi) bythe “direct pathway”. GPi is the output nucleus,projecting to thalamus, and thence to motorcortical areas. The remaining nuclei (externalsegment of the globus pallidum, GPe, and subthalamicnucleus, STN) are part of the BG’s internalcircuitry, forming the “indirect pathway.” Thesubstantia nigra pars compacta (SNc) has amodulatory role, via its dopaminergic projectionto the striatum.Major features of this circuit are that thestriatum inhibits GPi (via the direct pathway),and GPi, in turn, inhibits motor cortical areas.These features suggested that the BG tonicallyinhibit movement, and that when a movement isto occur, an excitatory signal from motor corticalareas causes the striatum to briefly inhibit GPi.22 > ACNR > VOLUME 10 NUMBER 5 > NOVEMBER/DECEMBER 2010

Your art,XEOMIN ® scienceNOW approved in post-strokespasticity of the upper limbExtend your treatment optionsAdverse events should be reported. Reporting forms and information can be found atwww.yellowcard.gov.uk. Adverse events should also be reported to Merz Pharma UK Ltd at theabove address or by e-mail to medical.information@merz.com or by calling or on 0333 200 4143.Date of preparation of item: April 2010. 1165/XEO/MAR/2010/JEXEOMIN ® 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 upperlid 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 numberof 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 Botulinumneurotoxin 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 jointaffected by a fixed contracture. Undesirable effects: The followingadverse reactions were reported with Xeomin ® : Frequency byindication defined as: Common (≥1/100,

MOTOR CONTROL SERIESFigure 1: Schematic diagram of the motor cortico-BG loop.A. Early version of the model circuit. 5 The striatum receivescortical signals related to a desired movement, and projectsto GPi via direct and indirect pathways. The GPi projects tothalamus, which in turn projects to motor cortical areas.Projections to brainstem structures are not shown. Excitatory(glutamatergic) synapses are indicated as arrows with "+",inhibitory (GABAergic) synapses as arrows with "-".Dopaminergic synapses (from the SNc) are indicated as filledcircles. Cx, cortex; GPe, external segment of globus pallidum;GPi, internal segment of globus pallidum; SNc, substantianigra pas compacta; STN, subthalamic nucleus; Str, striatum;Th, thalamus.B. Updated version of the cortico-BG loop. In addition tothe connections shown in (A), there is an excitatoryconnection from cortex to STN (hyperdirect pathway) andan excitatory connection from STN to GPe.C. Dynamic model of basal ganglia function explainingactivity changes in thalamus and/or cortex (Th/Cx)caused by sequential inputs through the hyperdirect(top), direct (middle), and indirect (bottom) pathways.Time (t) proceeds from top to bottom. (Adapted, fromNambu et al., 9 with permission from Elsevier).Thus inhibition of motor cortex is temporarilyremoved (disinhibition) and the desiredaction can occur. The indirect pathway(striatum to GPe to STN to GPi) balances theinhibitory effect of the direct pathway.Dopamine from SNc to striatum plays a modulatoryrole by setting the excitability of directand indirect pathways.Dysregulation of this circuit successfullyexplains certain motor abnormalities inParkinson's disease (PD) and other motordisorders. 5,6 In PD, for example, dopaminedepletion in the SNc results in reduced activationof the direct pathway. This pathway istherefore less effective in overcoming the GPi'stonic inhibition of motor cortex, and movementsthus become more difficult to initiate. InHuntington's disease, degeneration of neuronsin the indirect pathway leads to a reduction ofthe GPi’s tonic inhibition of motor cortex, andthus to the occurrence of involuntary movements.These descriptions became the basisfor novel, circuit-based symptomatic treatmentsfor PD and other movement disorders,namely, focal lesions and deep-brain stimulationof the BG. 7The discovery of the cortico-BG loop set thestage for a further major conceptual advance.Mink and Thach proposed that the BG “filter”motor plans, so that neural signals for desiredmovements are enhanced and those for similarbut undesired movements are suppressed. 8They posited a “centre-surround” organisationof projections from striatum to GPi, whichrefines a cortical motor command so that thedesired movement is enabled and othercompeting motor programs are inhibited.A “hyperdirect” pathwayIn the last two decades, there have beenseveral advances in our understanding ofanatomy and physiology of this “canonical” BGcircuitry. In this updated description, 9,10 theSTN joins the striatum as an input nucleusreceiving cortical projections (Figure 1B). TheSTN is now considered part of a “hyperdirect”pathway that contributes to the filtering actionof direct and indirect pathways, helping tofacilitate desired movements and inhibitcompeting motor programs. Recordings fromthese structures suggest a temporal evolutionof this process. 9 The first event associated witha cortical motor signal is activation of the STNvia the “hyperdirect” pathway (cortex-STN-GPi), which causes global excitation of GPiand momentary suppression of all movements.Activation of the direct pathway(cortex-striatum-GPi), a few milliseconds later,inhibits only GPi neurons encoding thedesired movement, and thus activates thedesired motor program through disinhibitionof selected thalamic targets. Finally, a signalthrough the indirect pathway (cortex-striatum-GPe-STN-GPi) puts an end to the motorcommand and terminates the movement.This updated model of the motor circuitintroduced temporal dynamics to signalprocessing in the BG. The pathophysiology ofakinesia in a primate model of PD can now bedescribed in temporal and spatial terms: whena movement is triggered by the cortex, abnormallylarge signals through hyperdirect andindirect pathways suppress larger-than-normalareas of thalamus/cortex, and signals throughthe direct pathway are reduced in amplitudeand duration. Smaller areas of the thalamus/cortexare thus disinhibited for a shorterperiod of time than normal, and the desiredmotor program cannot be released. 11Action selection and reinforcementlearningOur current understanding of BG circuitsoffers a substrate on which to map hypothesesabout action selection, reward-driven behaviour,and reinforcement learning. Theoreticaland behavioural studies of learning had longpredicted the existence of mechanisms forselecting an optimal action among severalchoices, and for learning to do so based onreward and penalty. The convergence ofcortical signals onto the BG, and the adaptivetemporal relationship of striatal dopaminesignals to reward prediction, are ideal candidatesfor implementing reinforcementlearning algorithms. 12,13 At the synaptic level,dopaminergic projections from SNc tostriatum and STN have the power to adjust thestrength of cortical projections to these nuclei,allowing the possibility of precisely fine-tuningthe effect of BG processing of cortical signals. 14These mechanisms for synaptic adjustmentsare well suited to the modification of actionselection mechanisms based on reinforcementlearning, and thus to the development ofautomatic, habit-based behavioural patterns. 3Can such computations help explain clinicalmovement abnormalities? Certain deficits,such as increased delays in movement onsetin PD and abnormal postures of dystonia, canbe related, respectively, to inadequate flow ofsignals through the direct pathway and to24 > ACNR > VOLUME 10 NUMBER 5 > NOVEMBER/DECEMBER 2010

Pure science.At CSL Behring, innovation is in our blood. As with all our plasmaprotein products, the advanced technology behind Privigen helpsto ensure optimal purity. Making Privigen pure science, applied.®Prescribing information is available on the following pageHuman Normal Immunoglobulin, 10% Liquid

PRIVIGEN ® PRESCRIBING INFORMATION(Please refer to the Summary of Product Characteristics beforeprescribing). Privigen ® 100mg/ml solution for infusion.Supplied as a solution for infusion in a 2.5g (25ml), 5g (50ml), 10g(100ml) or 20g (200ml) bottle, containing 100 mg/ml human normalimmunoglobulin (IVIg). The maximum IgA content is 0.025mg/ml.Indications: Replacement therapy in primary immunodeficiencysyndromes such as congenital agammaglobulinaemia andhypogammaglobulinaemia, common variable immunodeficiency,severe combined immunodeficiency and Wiskott-Aldrichsyndrome; myeloma or chronic lymphocytic leukaemia withsevere secondary hypogammaglobulinaemia and recurrentinfections; children with congenital AIDS and recurrent infections.Immunomodulation in immune thrombocytopenic purpura (ITP),in children or adults at high risk of bleeding or prior to surgeryto correct the platelet count; Guillain-Barré syndrome; KawasakiDisease; allogeneic bone marrow transplantation. Dosage: Thedose and dosage regimen is dependent on the indication. Inreplacement therapy the dosage may need to be individualisedfor each patient dependent on the pharmacokinetic and clinicalresponse. Replacement therapy in Primary Immunodeficiencies:dose regimen should achieve trough IgG level at least 4-6g/l.Recommended starting dose is 0.4-0.8g/kg b.w. followed by atleast 0.2g/kg b.w. every three weeks. Replacement therapy inSecondary Immunodeficiencies (including children with AIDS) andrecurrent infections: recommended dose 0.2-0.4g/kg b.w. everythree to four weeks. Immune Thrombocytopenic Purpura: acuteepisodes, 0.8-1g/kg b.w. on day one, which may be repeated oncewithin 3 days, or 0.4 g/kg b.w. daily for 2 to 5 days. Guillain-Barrésyndrome: 0.4g/kg b.w./day for 3 to 7 days. Experience in childrenis limited. Kawasaki Disease: 1.6-2.0g/kg b.w. in divided doses over2 to 5 days or 2.0g/kg as a single dose. Patients should receiveconcomitant treatment with acetylsalicylic acid. Allogeneic BoneMarrow Transplantation: Starting dose is normally 0.5g/kg b.w./week, starting 7 days before transplantation and continued for upto 3 months after transplantation. Method of administration:For intravenous use only. The initial infusion rate is 0.3ml/kgb.w./hr. It may be gradually increased to 4.8ml/kg b.w./hr if welltolerated. Maximum recommended infusion rate in PID is 7.2ml/kg b.w./hr. Privigen may be diluted with 5% glucose solutionto final concentration of 50mg/ml (5%). Contraindications:Hypersensitivity to the active substance or to any of theexcipients. Hypersensitivity to homologous immunoglobulins,especially in the very rare cases of IgA deficiency when the patienthas antibodies against IgA. Patients with hyperprolinaemia.Special warnings, precautions for use: Certain severe adversedrug reactions may be related to high infusion rate such as:hypo- or agammaglobulinaemia with or without IgA deficiency,patients who receive IVIg for the first time, switched therapy orhave not received IVIg for a long period. Haemolytic anaemiacan develop subsequent to IVIg therapy due to enhanced redblood cell sequestration. Monitor for symptoms of haemolysis.Caution should be exercised in obese patients and those with preexistingrisk factors for thrombotic events. Cases of acute renalfailure have been reported in patients receiving IVIg therapy. IVIgadministration requires adequate hydration prior to infusion,monitoring of urine output and serum creatinine levels andavoidance of concomitant use of loop diuretics. In case of adversereaction, either the rate of administration must be reduced or theinfusion stopped. Immunoglobulin administration may impairthe efficacy of live attenuated virus vaccines and may result intransient misleading positive results in serological testing. Usewith caution in pregnant women and breast-feeding mothers.Safety with respect to transmissible agents: Standardmeasures to prevent infections resulting from the use of medicinalproducts prepared from human blood or plasma are consideredeffective for enveloped viruses such as HIV, HBV, and HCV, andfor the non-enveloped viruses HAV and B19V. Despite this, thepossibility of transmitting infective agents cannot be totallyexcluded. This also applies to unknown or emerging viruses andother pathogens. There is reassuring clinical experience regardingthe lack of hepatitis A or B19V transmission with immunoglobulinsand it is also assumed that the antibody content makes animportant contribution to the viral safety. For further informationplease refer to the Summary of Product Characteristics. Sideeffects: Chills, headache, fever, abdominal pain, vomiting,allergic reactions, nausea, arthralgia, fatigue, low blood pressureand moderate low back pain may occur. Rarely, a sudden fall inblood pressure and, in isolated cases, anaphylactic shock may beexperienced. Cases of reversible aseptic meningitis, reversiblehaemolytic anaemia/haemolysis, transient cutaneous reactions,increase in serum creatinine level and/or acute renal failure havebeen observed with IVIg products. Very rarely, thromboembolicevents have been reported. For further information pleaserefer to the Summary of Product Characteristics. MarketingAuthorisation Numbers: 25ml (2.5g): EU/1/08/446/004; 50ml(5g): EU/1/08/446/001; 100ml (10g): EU/1/08/446/002; 200ml (20g):EU/1/08/446/003. Legal Category: POM. Date text last revised:16 September 2010. Legal Category: 25ml vial (2.5g): £135; 50mlvial (5g): £270.00; 100ml vial (10g): £540.00; 200ml vial (20g):£1080.00. Further information is available from: CSL BehringUK Limited, Hayworth House, Market Place, Haywards Heath,West Sussex, RH16 1DB.Adverse events should be reported. Reporting forms andinformation can be found at www.yellowcard.gov.uk.Adverse events should also be reported to CSL BehringUK Ltd. on 01444 447405.UK/PRIV/10-0030MOTOR CONTROL SERIESabnormal balance between GPi excitation and inhibition. 5,8 It is notobvious, on the other hand, how symptoms such as reduced movementspeed and amplitude in PD might result from abnormal movementselection. Moreover, it is not clear how to relate changes indopamine-dependent habit-learning mechanisms to the motor symptomsof PD. While certain types of learning are impaired in PD, 15 thisdisorder’s clinical symptoms affect quotidian, well-rehearsed movementsthat are not thought to require new learning.Part of this difficulty may lie in limitations in our understanding ofnormal motor control, which has traditionally considered kinematicand kinetic parameters, such as speed and force, to be outside thedomain of action selection. Recent work, however, suggests that movementspeed may be subject to selection processes analogous to thoseobserved in motivation-driven action selection, and that bradykinesiain PD results from faulty speed selection policies, rather than from aninability to move at normal speeds. 16 This interpretation suggests thatmovement kinematics are governed by selection processes with theirown optimality policies, response to reinforcement, and susceptibilityto habit development. Thus the initiation, speed, amplitude, and timecourse of movements may require circuitry specialised for optimalselection of parameters, similar to the mechanisms that guide actionselection and habit learning. The reinforcement signals and optimalitypolicies relevant to motor control may be distinct from those thatguide action selection and more complex behaviour, but there maybe computational analogies between the selection of how to performa movement (e.g., how soon, how fast, how long) and the selection ofwhat movement to perform. Such considerations may extend ourunderstanding of clinical motor symptoms of BG disease that are notexplained by current models, and may provide new insights into theBG’s more mysterious motor functions. lREFERENCES1. Marsden CD. What do the basal ganglia tell premotor cortical areas? Ciba FoundSymp 1987;132:282-300.2. Wu T, Kansaku K, Hallett M. How self-initiated memorized movements becomeautomatic: a functional MRI study. J Neurophysiol 2004;91(4):1690-8.3. Graybiel AM. The basal ganglia: learning new tricks and loving it. Curr OpinNeurobiol 2005;15(6):638-644.4. Alexander GE, DeLong MR, Strick PL. Parallel organization of functionallysegregated circuits linking basal ganglia and cortex. Annu Rev Neurosci1986;9:357-81.5. Albin RL, Young AB, Penney JB. The functional anatomy of disorders of the basalganglia. Trends Neurosci 1995;18(2):63-4.6. DeLong MR. Primate models of movement disorders of basal ganglia origin. TrendsNeurosci 1990;13(7):281-5.7. Wichmann T, Delong MR. Deep brain stimulation for neurologic andneuropsychiatric disorders. Neuron 2006;52(1):197-204.8. Mink JW. The basal ganglia: focused selection and inhibition of competing motorprograms. Progress in neurobiology 1996;50(4):381-425.9. Nambu A, Shigemi Mori DGS, Mario W. A new dynamic model of theortico-basal ganglia loop. In: Prog Brain Res: Elsevier, 2004:461-6.10. Obeso JA, Marin C, Rodriguez-Oroz C, et al. The basal ganglia in Parkinson's disease:current concepts and unexplained observations. Ann Neurol2008;64 Suppl 2:S30-46.11. Nambu A. A new approach to understand the pathophysiology of Parkinson’s disease.J Neurol 2005;252(0):iv1-4.12. Balleine BW, Delgado MR, Hikosaka O. The role of the dorsal striatum in reward anddecision-making. J Neurosci 2007;27(31):8161-5.13. Dayan P, Niv Y. Reinforcement learning: the good, the bad and the ugly.Curr Opin Neurobiol 2008;18(2):185-96.14. Surmeier DJ, Plotkin J, Shen W. Dopamine and synaptic plasticity in dorsalstriatal circuits controlling action selection. Curr Opin Neurobiol2009;19(6):621-8.15. Muslimovic D, Post B, Speelman JD, Schmand B. Motor procedural learning inParkinson's disease. Brain 2007;130(Pt 11):2887-97.16. Mazzoni P, Hristova A, Krakauer JW. Why don't we move faster? Parkinson's disease,movement vigor, and implicit motivation. J Neurosci 2007;27(27):7105-16.26 > ACNR > VOLUME 10 NUMBER 5 > NOVEMBER/DECEMBER 2010

PAEDIATRIC NEUROLOGYHeadache in Childhoodand AdolescenceRachel Howellsis a consultant paediatrician inPlymouth, Devon. Followingundergraduate studies atClare College, Cambridge shetrained in paediatrics andpaediatric neurology in London,the South West and East Anglia.She now runs a busy headacheservice for children andadolescents.Correspondence to:Dr Rachel Howells,Consultant Paediatrician,Plymouth Hospitals NHS Trust,Plymouth, Devon, UK.Email: rachel.howells@phnt.swest.nhs.ukThe aim of this review article is to equip youwith a paediatric perspective of headache:the commonalities and differences betweenthat seen in childhood and adulthood in terms ofpresentation, diagnosis and management.Headache is extremely common in childhoodand adolescence. By the age of seven, half of allchildren will have experienced a headache ofone sort or another. Almost all young people willhave by the age of 15. The burden of paediatricheadache is huge. A recent study showed that020% of young adolescents suffered fromheadache which reduced their ability to functionfor more than 12 days in a three month periodand which was associated with reduction inquality of life greater than that of teenagers withdiabetes or asthma. Despite this, most youngchronic headache sufferers never get to see aheadache specialist. 1History (Figure 1)Most children and adolescents will attend aconsultation with their parents. Involve even thevery young patient in the information-gatheringpart of the visit; a child as young as five can giveyou a history of pulsating headache aggravatedby movement. Parents can provide a perspectiveon their child’s personality, ambitions andworries, all of which can influence the prevalenceand experience of headache. 2ExaminationIn the first article in this series on paediatricneurology Anna Maw discussed the approach topaediatric neurology examination. A detailedneurological assessment by confrontation can besuccessfully performed in most school-age children,can avoid the need for brain imaging whennormal and offer reassurance for patients andparents 3 . Include:• Assessment of growth (plot on UK standardgrowth chart, to include head circumferencein a child VOLUME 10 NUMBER 5 > NOVEMBER/DECEMBER 2010 > 27

PAEDIATRIC NEUROLOGYFigure 2: Important considerations when screening for secondary headaches inchildhood / adolescenceAcute severe headache• Infection eg meningitis - the younger the patient the less specific signs of meningism are formeningitis.• Venous thrombosis - headache quality is variable in quality and site with no relationshipbetween site of headache and location of the thrombus save in sigmoid sinus thrombosis.Consider in childhood especially where otitis media / mastoiditis / dehydration arepresent, or in the presence of hypercoagulable states such as inflammatory bowel diseaseand nephrotic syndrome. Cranial neuropathies including hemianopia, deafness, oculomotorand abducens palsies are common, with acute raised intracranial pressure signs in lateralsinus thrombosis.• Intracranial haemorrhage - more likely due to bleed into tumour or venous infarct, or fromAVM rather than from a berry aneurysm'Acute recurrent headache• Idiopathic or symptomatic occipital epilepsy – post-ictal headache (2/3 of patients) may beindistinguishable from migraine. Unlike migraine, seizures may occur several times a day. Acareful history of visual phenomena accompanying headache will be discriminating. With orwithout blindness, visual hallucinations of occipital seizures usually last 1-3 minutes, arenon-progressive, multi-coloured and circular vs the linear, zigzag and dichromatic features ofmigraine aura. May involve other non-occipital ictal phenomena eg those arising frominvolvement of temporal lobe.• Chiari malformation-related headache – symptoms attributable to brain protrusion throughthe foramen magnum include headache, ataxia, vertigo, hearing loss, neck pain anddysarthria aggravated by coughing and Valsalva manoeuvre. Surgical decompression isrequired for truly symptomatic cases.Chronic progressive headache• Brain tumour (98% accompanied by other neurology eg eye movement disorder, ataxia).• VP shunt blockage / failure – acute or chronic headache, drowsiness and vomiting alloverlap with other common paediatric diagnoses, but a combination of all three in a childwith a shunt makes blockage highly likely. An unchanged CT scan does not rule out shuntblockage.• Idiopathic intracranial hypertension – post-pubertal IIH is similar to ‘adult’ IIH with femalesex and obesity predominating. In prepubertal children obesity is uncommon; strabismusand a stiff neck may accompany or occur without headache. Opening CSF pressure of>18cmH2O (age25cmH2O (age>8 or less than 8 withoutpapilloedema) should suggest IIH in prepubertal children.Primary headache in childhood andadolescenceMigraineThe most prevalent primary headache in childhoodand adolescence, prior to pubertymigraine shows early male predominance with3-11% prevalence. Migraine is more commonafter puberty (up to a quarter of adolescents)and girls catch up with boys in terms of prevalence.Migraine has been reported in toddlers,behaviour change and vomiting being thepredominant symptoms at this age.Spontaneous remission does occur in a largeminority of adolescents, with a much reducedchance if migraine is still occurring after 18years of age. Catamenial migraine is rare in thepaediatric population.IHS criteria for paediatric migraine aredifferent to adult migraine (Figure 3) but the 2-72 hour duration limit is thought to be restrictiveas some childhood migraine attacks arevery short indeed. Childhood migraine is morelikely to be bilateral (bitemporal / bifrontal)compared to adult migraine. Aura occurs in15%, most commonly visual. Vagal phenomenaare often prominent.Acute confusional migraine is uncommon,with confusion and dysarthria dominatingattacks encountered after minor head injury orexercise. This migraine variant, associated withfocal slowing on EEG and hypoperfusion onSPECT imaging, can cause considerable diagnosticdifficulty at first presentation.Figure 3: IHS criteria for childhoodmigraine without auraFive or more headaches lasting 1-72hours with at least two of the followingcharacteristics• Unilateral or bilateral pain• Throbbing pain• Moderate or severe pain• Pain aggravated by routine physicalactivityand at least one of the following• Nausea / vomiting• Photophobia / phonophobiaThe paediatric migraineur may have ahistory of one or more ‘childhood periodicsyndromes’ thought to be migraine variantsalthough there is no clear predictive relationshipbetween many of these and later migraineheadache:• Benign paroxysmal torticollis of infancy(regular attacks of acute agitation, vomiting,pallor and torticollis lasting a few minutes ina toddler). 4• Benign paroxysmal vertigo (acute vertigo,nystagmus lasting a few minutes, usually in apre-adolescent child) – the commonestcause of recurrent childhood vertigo otherthan recurrent otitis media. The latter is easyto spot by identifying conductive hearingloss and visualising the inflamed eardrum. 5• Cyclical vomiting syndrome (incapacitatingrecurrent vomiting lasting several dayssometimes needing hospital admission forfluid support) – strong association withmigraine headache and often precipitatedby travel, not to be confused with metabolicconditions or Panayiotopoulos seizures. 6,7• Abdominal migraine (periodic headache,pallor and abdominal pain which may beassociated with other GI symptoms andfever) – the relationship between this andrecurrent abdominal pain of childhood isunclear although they can be delineated byapplication of the Rome III criteria. 8• Recurrent short-lived limb pain in childhood(usually lower limb pain sufficient toprevent usual activities, lasting VOLUME 10 NUMBER 5 > NOVEMBER/DECEMBER 2010

PAEDIATRIC NEUROLOGYUse of complementary therapies for paediatricheadache is widespread, and mostparents want their clinicians to be able toadvise on such therapies even when they donot prescribe them. 15 Despite this, there are norandomised controlled trials for herb-basedremedies showing any benefit in childhoodmigraine. There is no convincing evidence of alink between biogenic amines and migrainebut an oligoantigenic diet may benefitseverely affected paediatric migraineursresistant to other treatments. The importanceof good sleep hygiene should be emphasisedand may be enough for some children’smigraines to be prevented without recourse tomedication, especially in pre-adolescents.Obesity, like migraine prevalent within thepaediatric population, is thought to be a riskfactor for chronic migraine but there are nostudies as yet which determine the impact ofweight loss on migraine frequency in thepaediatric population.Tension type headacheThis is a poorly researched primary headachein childhood and adolescence but is probablymore common than and at least as debilitatingas migraine 16 (Figure 4). Epidemiologicalevidence from large populations of adolescentswith tension-type headache suggestbehavioural phenotypes different tomigraineurs: a high incidence of anxiety anddepression, a tendency to derive stress fromacademic achievements, 17,18 association withother somatic symptoms and difficulties withfamily relationships. 19 Opinion is divided as towhether migraine and tension type headachesrepresent distinct entities.Figure 4: IHS criteria fortension-type headacheAt least 10 headaches lasting 30 minutesto 7 days with at least two of thefollowing:• Pressing / tightening quality• Bilateral location• Mild or moderate pain (may inhibitbut does not prevent daily activity)• Pain not aggravated by routine physicalactivityand both of the following• No nausea or vomiting• No photophobia / phonophobia, orone but not the other is presentPrevention and treatment of paediatrictension-type headacheThere is no evidence for pharmacologicaltreatment or prophylaxis for childhoodtension-type headache although the followingmay help:• Limiting analgesic only to the most incapacitatingheadaches, to avoid medicationoveruse.• Cognitive behavioural therapies, for whichthere is a large evidence base, especially forbiofeedback methods. Group therapies maywork.• Maintain healthy physical exercise andsleep routines.• Offering to write to a patient’s school toencourage a staff response to mild-moderateheadache whereby the patient takes promptanalgesia and remains in lessons rather thanbeing sent home. This stops children andadolescents from falling behind socially andacademically.• Manual therapies eg stretching, trigger pointrelease, TENS machine use.• Topical peppermint / menthol derivatives(4Head, TigerBalm) – no evidence in childhoodbut a blinded study of adult patientssuggests benefit over placebo and similarlevel of efficacy when compared with paracetamol.20• Amitriptylline – no evidence for use specificallyin this headache type but commonlyused where pharmacotherapy sought.Medication overuse headacheThis commonly encountered headache in childrenand adolescents should always be consideredas a potential cause of chronic dailyheadache. It can occur with almost anyheadache attack treatment including tryptans,the latter tending to cause medication overusemore quickly than analgesics. 21 Children andadolescents with medication-overusefrequently respond to medication withdrawalwithin a month. 22Short duration headachesRecurrent headache, lasting seconds tominutes are rare in childhood, and can be difficultto classify according to IHS criteria asfeatures are variable. There is no robustevidence base for management of short durationheadache in childhood. Idiopathic stabbingheadache is the most widely reported,and in childhood is less likely to be associatedwith other primary headaches than in adulthood.23,24 Like episodic and chronic paroxysmalhemicrania, idiopathic stabbingheadache should respond to indomethacin.Cluster headache is rarer still, but as in adulthoodappears to be responsive to a range oftreatments including oxygen, tryptans, verapamiland dihydroergotamine. 25SummaryThis synopsis of paediatric headache showshow much is common to both childhood andadult headaches, but how they differ in presentation,differential diagnosis and treatment.Paediatric headache is the Cinderella of paediatricneurology specialties, but it is worthy ofmore attention and research, being so commonand yet so disruptive to young people’s lives. Notbefore time, the National Institute for ClinicalExcellence is now consulting on guidance fornew onset headache in adults and adolescents,with guidance for headache in younger childrenfollowing on in the next few years.Follow progress athttp://guidance.nice.org.uk/CG/Wave23/2. lREFERENCES1. Kernick D, Reinhold D, Campbell JL. Impact ofheadache on young people in a school population. Br JGen Pract 2009;59:678-81.2. Torelli P, Abrignani G, Castellini P, Lambru G, ManzoniGC. Human psyche and headache: tension-typeheadache. Neurol Sci;29:Suppl 1,S93-5.3. Lewis DW, Ashwal S, Dahl G, Dorbad D, Hirtz D,Prensky A, Jarjour I. Practice parameter: evaluation ofchildren and adolescents with recurrent headaches:report of the Quality Standards Subcommittee of theAmerican Academy of Neurology and the PracticeCommittee of the Child Neurology Society. Neurology2002;59:490-8.4. Rosman NP, Douglass LM, Sharif UM, Paolini J. Theneurology of benign paroxysmal torticollis of infancy:report of 10 new cases and review of the literature. JChild Neurol 2009;24:155-60.5. Batson G. Benign paroxysmal vertigo of childhood: Areview of the literature. Paediatr Child Health2004;9:31-4.6. Abu-Arafeh I, Russell G. Cyclical vomiting syndrome inchildren: a population-based study. J PediatrGastroenterol Nutr 1995;21:454-8.7. Covanis A. Panayiotopoulos syndrome: a benign childhoodautonomic epilepsy frequently imitatingencephalitis, syncope, migraine, sleep disorder, orgastroenteritis. Pediatrics 2006;118:e1237-43.8. Rasquin A, Di Lorenzo C, Forbes D, et al. Childhoodfunctional gastrointestinal disorders: child/adolescent.Gastroenterology 2006;130: 1527-37.9. Abu-Arafeh I, Russell G. Recurrent limb pain in schoolchildren.Arch Dis Child 1996;74:336-9.10. de Vries B, Freilinger T, Vanmolkot KR, Koenderink JB,et al. Systematic analysis of three FHM genes in 39sporadic patients with hemiplegic migraine. Neurology2007;69:2170-6.11. Lance JW. Is alternating hemiplegia of childhood (AHC)a variant of migraine? Cephalalgia 2000;20:685.12. Silver S, Gano D, Gerretsen P. Acute treatment of paediatricmigraine: a meta-analysis of efficacy. J PaediatrChild Health 2008;44:3-9.13. Ahonen K, Hamalainen ML, Eerola M, Hoppu K. Arandomized trial of rizatriptan in migraine attacks inchildren. Neurology 2006;67:1135-40.14. Victor S, Ryan SW. Drugs for preventing migraineheadaches in children. Cochrane Database Syst Rev2003;CD002761.15. Vlieger AM, van de Putte EM, Hoeksma H. The use ofcomplementary and alternative medicine in children at ageneral paediatric clinic and parental reasons for use.Ned Tijdschr Geneeskd 2006;150:625-30.16. Schwartz BS, Stewart WF, Simon D, Lipton RB.Epidemiology of tension-type headache. JAMA1998;279:381-3.17. Sarioglu B, Erhan E, Serdaroglu G, Doering BG, et al.Tension-type headache in children: a clinical evaluation.Pediatr Int 2003;45:186-9.18. Battistutta S, Aliverti R, Montico M, Zin R, Carrozzi M.Chronic tension-type headache in adolescents. Clinicaland psychological characteristics analyzed through selfandparent-report questionnaires. J Pediatr Psychol2009;34:697-70619. Anttila P, Sourander A, Metsahonkala L, et al.Psychiatric symptoms in children with primaryheadache. J Am Acad Child Adolesc Psychiatry2004;43:412-920. Gobel H, Fresenius J, Heinze A, Dworschak M, SoykaD. [Effectiveness of Oleum menthae piperitae and paracetamolin therapy of headache of the tension type].Nervenarzt 1996;67:672-81.21. Limmroth V, Katsarava Z, Fritsche G, Przywara S,Diener HC. Features of medication overuse headachefollowing overuse of different acute headache drugs.Neurology 2002;59:1011-4.22. Kossoff EH, Mankad DN. Medication-overuse headachein children: is initial preventive therapy necessary? JChild Neurol 2006;21:45-8.23. Fusco C, Pisani F, Faienza C. Idiopathic stabbingheadache: clinical characteristics of children and adolescents.Brain Dev 2003;25:237-40.24. Soriani S, Battistella PA, Arnaldi C, De Carlo L, et al.Juvenile idiopathic stabbing headache. Headache1996;36:565-7.25. Majumdar A, Ahmed MA, Benton S. Cluster headachein children--experience from a specialist headache clinic.Eur J Paediatr Neurol 2009;13:524-9.ACNR > VOLUME 10 NUMBER 5 > NOVEMBER/DECEMBER 2010 > 29

NEUROLOGY AND ARTNeurology And Art:Willem De KooningSebastian BarkerAfter graduating from theUniversity of Leeds with a degreein History of Art, Sebastian is nowstudying a Masters in Art Businessat Sotheby’s Institute of Art inLondon.Roger Barkeris co-editor of ACNR, and isHonorary Consultant in Neurologyat The Cambridge Centre for BrainRepair. His main area of research isinto neurodegenerative and movementdisorders, in particularparkinson's and Huntington'sdisease. He is also the universitylecturer in Neurology at Cambridgewhere he continues to develop hisclinical research into these diseasesalong with his basic research intobrain repair using neural transplants.Correspondence to:Dr Roger A Barker,Cambridge Centre for Brain Repair,Forvie Site,Robinson Way,Cambridge CB2 0PY.Email: rab46@cam.ac.ukThe extent to which disease interacts withartistic abilities has always been a topic ofgreat interest and in this new series weexplore this in the world of art. Many famousartists have suffered from neurological conditions,which in some way have altered their work,whether it be through some alteration in endorgan function (e.g. Monet and his eyes) or somemore central cause (e.g. Goya). In all cases thereis a fascinating and unique insight into the effectsof diseases of the nervous system on an individual,and their expression through the evolvingand changing visual works produced. In the firstarticle in this new series we consider Willem deKooning and his work and the effects that his lateonset dementia had on this.Throughout the mid-twentieth century, Americabecame a locus of global cultural activity. Europe,which had previously housed and nurtured theavant-garde within the bohemian setting ofmodern Paris, had become socially ruptured byWorld War Two. The Nazi occupation of Paris hadleft a culture fractured by political disparity, withdifferent facets fighting a philosophical battleover questions surrounding social responsibility.America, meanwhile, was experiencing unprecedentedlevels of strength. An economic boomimpelled the growing consumer society, and capitalistideology began to lead the world into a newera of commoditisation.Contemporary culture found itself disorientatedby the rapidly changing bureaucratic structures.The preceding artistic styles of Cubism andSurrealism were underpinned by political ideologiesveering on the far-left. In the wake of the war,hope of a communist nirvana had shattered, withStalin’s Russia exemplifying the potential evil ofthe left wing. For Willem De Kooning and hiscontemporaries, among them Jackson Pollock,Barnett Newman and Robert Motherwell, art hadits most obvious avenues of progression blockedoff. These artists, later categorised as the AbstractExpressionists’, responded by internalising theirartistic concerns, with a privileged emphasisplaced on painterly abstraction as the rarifiedexpression of the self. Their aspiration was toenact an unabated interaction with the canvas,sourcing a universal creative drive latent withinhuman consciousness. Motherwell conciselysummarised the idea with his assertion that‘painting is…the mind realising itself in colourand space’; 1 Newman augmenting this with hisuse of shape as a ‘vehicle for an abstract thoughtcomplex, a carrier of… awesome feelings’. 2Stylistically, this led the artists to work on expansivecanvases, characterised by a dynamic use ofcolour. De Kooning was to become the figureheadof Abstract Expressionism par excellence,his popularity in the forties paving the way forothers and forming the erudite counterpart to thebohemian explosiveness of Pollock.Much of the early work of AbstractExpressionism grapples with the transition of theavant-garde from Europe to America, and DeKooning was no exception. Pink Angels (1945)with its biomorphic shapes and fluid compositionreveals an artist heavily under the influence ofSurrealist painter Yves Tanguy. After a series ofblack and white abstractions, it was in the workExcavation (1950) that De Kooning most clearlyestablished a more idiosyncratic style for himself.The work is hardly free of a European andmodernistic approach to art; the modulated structureof Excavation is highly reminiscent of Cubismwhilst the attempt to manifest unconsciousthought through unrestrained spontaneity nods tothe popularity of Surrealism. Here, however, DeKooning has fused the two into somethingunique, with the catalyst being a distinctlyAmerican sensibility. The title references the newbuilding work undertaken by a newly moneyedIf the brain cannot remember simple events nor holdcoherent conversations of thoughts, then how canthe art it generates have anything to say?America, with the piece alluding to the symbiosisof emotion between the urban environment ofNew York and De Kooning’s personal response toit. Excavation was to galvanise the AbstractExpressionist movement and lead De Kooning toswiftly become one of the premier artists of theday. From this position, we can see how his subsequentreturn to figurative painting was confusingfor people at the time. Nevertheless, it was to yieldsome of his most celebrated works.Woman I (1950-1952) took De Kooning twoyears to complete, having started work on it immediatelyafter the completion of Excavation. Thefinal work De Kooning produced was a visceraland disquieting rendering of the female figure, inwhich a violent use of colour deforms the subjectinto a snarling animal. Instead of using the urbanenvironment as inspiration, De Kooning focuseson one part of it: the use of the female figure inadvertising. Originally starting the piece bypainting around teeth from a cigarette advertise-30 > ACNR > VOLUME 10 NUMBER 5 > NOVEMBER/DECEMBER 2010

NEUROLOGY AND ARTWillem de Kooning in his studio. Copyright statement: Sam Abell/National Geographic/Getty Imagesment, De Kooning pictorially describes therelationship between the objectified figure andthe painter, a subject implicitly framed by theobjectification of femininity throughoutcommercial America. De Kooning’s semioticsmake explicit the shared unconscious forces atwork in each scenario; that of a physicallonging overwrought with sexual anxiety, anidea possibly gleaned from the current popularityof Sigmund Freud at that time. In abroader sense, De Kooning’s Woman decriedthe end of modernist painting, taking a subjectof perennial artistic interest, and imploding itacross the canvas. A new era was beingushered in and art was swept along with it,moving away from exhausted conventions andtowards pure abstraction. De Kooning,however, mercilessly forged a new identity fortraditional painting, the Woman seriesproviding the highly charged response to thedilemma faced by art and serving as the nail inthe coffin for modernism.Whilst De Kooning’s early abstractions lie at apivotal point within the vicissitudes of arthistory, his later works form indexical referencepoints to an artist clinging to his fading mentalfaculties. The progression of the artist’sAlzheimer’s throughout the eighties accompaniedabrupt changes in style, raising questionson the extent to which the new works should beconsidered ‘authentic’ De Koonings. At the startof the decade, the artist had moved away fromsome early experimentation with sculpture, topainting untitled abstractions that blended naturalistichues of colour, seemingly inspired by hisnew surroundings of East Hampton. Here wasan artist staying true to his attempt of ‘[slipping]into a glimpse’, 3 taking Monet as a point ofdeparture and dissolving recognisable shapesinto an immersive experience of organic colour.In 1982, De Kooning suddenly began rapidlyreducing his style, painting smaller works withfar fewer brush strokes. An artist who had takentwo years to finish his first Woman paintingbegan producing a worryingly high number ofworks, doubling his work rate in 1983 bycompleting fifty-four works in just one year.Incidents such as an infamous encounter withthe president in which De Kooning did notrecognize the American leader (and on beingtold who he had met afterwards, merelyremarked ‘geez, I knew he looked familiar’)revealed the full severity of his condition. Thenew work began to garner uniformly badreviews, with Time magazine describing them as‘a lot of banality and parody, conscious or not’. 4Yet, De Kooning had not completely lost controlof his aesthetic judgment. In 1983 the artist’swife, Elaine, worried that his palette wasbecoming too limited throughout the proliferationof new works, bought new tubes of paint,which she surreptitiously left with his favouredcolours, only to find them unused several weekslater. In some ways then, late paintings by DeKooning exhibit the ultimate extension of theartist’s aesthetic theory. The contact with a deeprooted creative force that survived beyond acoherent understanding of the external world,demonstrate the unconscious forces DeKooning contrived to harness in his early life.Critically lauded or not, his last works stand as atestament to the enduring presence of one ofthe last century’s great artists and the creativewill of the individual triumphing over its owndestitution.This last phase of his life with its greatlyincreased output has drawn comments fromothers, 5 8 not only as to whether he truly hadAlzheimer’s disease (AD) (as opposed todepression, Wernicke’s encephalopathy, etc)but also as to the extent to which a brainundergoing a neurodegenerative process cancontinue to generate meaningful works. If thebrain cannot remember simple events norhold coherent conversations or thoughts, thenhow can the art it generates have anything tosay? Art that takes as its origins some sort ofsocial context for its content cannot surely beregarded as making any profound statement ifthe author of it has an advancing dementia. Ofcourse disease and its treatment can bring outcreativity, 8 9 but they can also rob it of itscontent. Does this describe the later works ofDe Kooning or does his art not require theconscious, cognitive processes stored in thoseparts of the brain affected by the evolving ADprocess? We will return to this theme in thisseries as we consider the lives and neurologicalconditions of other famous artists. lREFERENCES1. Robert Motherwell quoted in: Dore Ashton The NewYork School (Berkeley: University of California Press,1972) P. 162.2. Barnett Newman quoted in: Armin Zweite BarnettNewman, (Ostfildern-Ruit: Hatje Cantz, 1999) P. 16.3. Interview with the artist: Robert Hughes The Shock of theNew, Episode 6: the view from the edge (London: BBC,1980).4. Mark Stevens and Annalyn Swan de Kooning: AnAmerican Master (New York: Alfred A. Knopf Inc.,2006) P.606.5. Espinel CH. de Kooning’s late colours and forms:dementia, creativity and the healing power of art. Lancet1996;347:1096-8.6. Meulenberg F. de Kooning’s dementia. Lancet1996;347:1838.7. Gibson PH. de Kooning’s dementia. Lancet1996;347:1838.8. Gordon N. Unexpected development of artistic talents.Postgrad.Med. J 2005;81;753-5.9. Kulisevsky J, Pagonabarraga J, Corral-Martinez M.Changes in artistic style and behaviour in Parkinson’sdisease: dopamine and creativity. J Neurol2009;256:816-19.ACNR > VOLUME 10 NUMBER 5 > NOVEMBER/DECEMBER 2010 > 31

CLINICAL DILEMMAS IN NEUROPSYCHIATRYSeries EditorAlan CarsonSeries editor Alan Carson is a Consultant Neuropsychiatristand Part-time Senior Lecturer. He works between theNeurorehabiltation units of the Astley Ainslie Hospital andthe Department of Clinical Neurosciences at the WesternGeneral Hospital in Edinburgh. He has a widespread interestsin neuropsychiatry including brain injury, HIV andstroke. He has longstanding research and teaching collaborationwith Jon Stone on functional symptoms inneurology.Series EditorJon StoneSeries editor Jon Stone is a Consultant Neurologist andHonorary Senior Lecturer in the Department of ClinicalNeurosciences in Edinburgh. Since 1999 he has developed aresearch and clinical interest in functional symptoms withinneurology, especially the symptom of weakness. He writesregularly on this topic in scientific papers and for textbooksof neurology and psychiatry.Correspondence to: Email: Jon.Stone@ed.ac.ukWelcome to the third in a series of articles in ACNR exploringclinical dilemmas in neuropsychiatry. In this series of articleswe have asked neurologists and psychiatrists workingat the interface of those two specialties to write shortpieces in response to everyday case-based clinical dilemmas. We haveasked the authors to use evidence but were also interested in their ownpersonal views on topics. We would welcome feedback on these articles,particularly from readers with an alternative viewpoint.AuthorDr Valerie Voonis a neuropsychiatrist and currentlythe Associate Clinical Director ofthe Behavioural and ClinicalNeurosciences Institute at theUniversity of Cambridge. She haspublished widely in theneuropsychiatric aspects ofmovement disorders. Her researchfocuses on mechanisms underlyingthe impulsive and compulsivebehaviours.Correspondence to:Behavioural and ClinicalNeurosciences Institute,Department of ExperimentalPsychology,University of Cambridge,Downing Site,Cambridge,CB2 3EB, UK.Email: vv247@cam.ac.ukWhen is an Impulse ControlDisorder in Parkinson'sDisease a Problem?CaseA wealthy 61-year-old man has been seen in your clinic for the last seven years with a diagnosis ofidiopathic Parkinson’s disease. His motor symptoms are well controlled on Ropinirole. At the mostrecent appointment his wife confides that for the last year she has been distressed by a change in hissexuality. Their sex life had been on the wane but he now had a much higher libido and wasrequesting sex four or five times a week. He had also uncharacteristically started to buy lottery scratchcardsand was spending around £60 a week on these. The patient explained that he enjoyed hisscratchcards and his renewed sexual vigour, although was aware that the changes in his behaviourdistressed his wife. What do you do?This case illustrates the intriguing issues thatarise from the dopamine agonist (DA)-related impulse control disorders (ICD)reported with Parkinson’s disease (PD) 1and restless legs syndrome. 2 The ICD behavioursincluding pathological gambling (5.0%), hypersexuality(3.5%), compulsive eating (4.3%) andcompulsive shopping (5.7%) are reported in 13.6%of PD patients in a large North American multicenterstudy. 1 The ICDs overlap with substance usedisorders and are also known as a behaviouraladdictions. 3 These behaviours are associated withDA use, Levodopa presence and higher Levodopadose. 1 The related behaviours of compulsivedopaminergic medication use are reported in 3% 4and punding or hobbyism in 1.5 to 14% 5,6 and areassociated with Levodopa dose.When is a behaviour consideredpathological?The association between Levodopa and increasedsexual drive has long been recognised. 7 Anincrease in libido associated with dopaminergicmedications, like any other behaviour, exists on acontinuum and can be a positive side effect at oneend but defined as pathological when it is both achange from baseline and persistently interfereswith social or occupational functioning or is timeconsuming or distressing. 8 Hypersexualitycommonly presents as excessive requests to thespouse for sex or internet pornography use, lesscommonly as increased use of prostitutes, andmore rarely, paraphilias such as transvesticfetishism. The symptom is commonly discoveredon complaint by the patient’s spouse to thetreating clinicians thus highlighting the hiddennature of the behaviour and the role of familymembers in diagnosis and management. Notably,hypersexuality in women may be under-recognizedas male spouses may be less likely tocomplain of changes in sexual desire.Is the patient fully aware of this symptom?Unlike obsessive compulsive disorder in whichsymptoms are experienced as excessive orabnormal, 9 the urge or desire for sex, to eat, gambleor shop associated with DA is commonly experiencedas consistent with ones underlying selfimageor personality. This experience is moreconsistent with that of substance use disorders.Hence, insight that the symptom is a problem maybe impaired. This lack of insight in substance use32 > ACNR > VOLUME 10 NUMBER 5 > NOVEMBER/DECEMBER 2010

C L I N I C A L D I L E M M A S I N N E U R O P S YC H I AT RYdisorders has been suggested to have underlyingneurobiological correlates (reviewed in 10).Is the patient responsible for hisbehaviour?In the context of a psychiatric evaluation in theemergency room,a patient presenting with mania(with euphoric or irritable affect, grandiosity,impaired sleep, excessive energy and excessiveharmful behaviours including gambling or hypersexuality),would be considered to have diminishedresponsibility if they did not understand thefull consequences of their actions in the contextof their illness. Hence, an interim judgment offinancial incapacity or treatment incompetencemay be relevant.A similar case of impaired judgementand diminished responsibility can also bemade for DA-induced pathological gambling. Thisraises intriguing ethical questions. Primary pathologicalgambling, unrelated to DA, is not a sufficientcondition for consideration of impairedresponsibility. The issue can become furtherconfusing. What if an individual has a history ofpathological gambling which had been undercontrol prior to the introduction of the DA? DAinducedparaphilias have also been described.Cases of new onset paedophilic behaviour in thecontext of DA have also been anecdotallydescribed. Is this a disinhibition of a premorbidtendency and if so, is the patient responsible fortheir behaviour?Why do some patients develop thisbehaviour?DA interacting with an underlying susceptibility(leading to a greater drive towards these behaviours)along with impaired inhibition have beensuggested to be the key factors in the pathophysiologyof these behaviours. We have shown thatspecific factors are associated with ICDs in PD.For instance, a family history of gambling problems1 or alcohol use disorders 11 is associated withICDs, suggesting a potential genetic or socialdiathesis. A greater association with smoking 1suggests potential overlaps in neural substratesunderlying smoking behaviours and ICDs. Thatthe behaviours are more frequent in unmarriedindividuals 1 and in the United States ascompared to Canada 1 suggests potential culturalor environmental factors.There are gender differences,with hypersexuality more commonlyexpressed by men and compulsive eating andshopping more commonly expressed by women.A greater association with novelty seeking,impulsivity11,12 and faster reward learning 14 suggestingunderlying cognitive traits may be similarlyaffected by DA or play a role in the pathophysiologyof the behaviours. Pathological gamblingand compulsive medication use in PD may becharacterised by greater dopamine release tochallenges such as a gambling task, 13 unexpectedreward 14 and Levodopa use. 4 Imaging studies onhypersexuality have not yet been reported.Should this be treated?Patients and their caregivers should be warnedabout these behaviours as potential medicationside effects and actively questioned or administeredscreening questionnaires 15 during clinicvisits. The behaviours can be presented in thecontext of other potential side effects thusnormalising and increasing the patient’s comfortlevel. Treatment is based on clinical judgmenton discussion with the patient and caregiver anddepends on balancing the consequences interms of distress to the patient, spouse or caregiver,other social/occupational dysfunction andtime consumed with the tolerance of lower DAdoses and motor efficacy of the dopaminergicmedications. A high index of suspicion and acareful history is warranted given that the extentof the problem is commonly minimised. A trialof a decrease of DA may be indicated in uncertaincases.How should this be treated?Decreasing or discontinuing DA with a concomitantincrease in Levodopa appears to be effectivewith many patients. 16 In patients withcomorbid dementia, cholinesterase inhibitors,which can be effective for behavioural symptomsassociated with dementia, have also beenanecdotally reported to be effective. 17 In patientswith comorbid depression, an antidepressantmay possibly decrease the obsessional sexualurges. 8 A family history or a personal history ofbipolar disorder may warrant a trial of a moodstabiliser. In severe cases,anti-androgens may beconsidered. 18 Deep brain stimulation targetingthe subthalamic nucleus with a postoperativerapid decrease in dopaminergic dose and DAdiscontinuation along with active follow up hasbeen reported to be effective for refractoryICDs. 19,20 Whether this holds for hypersexuality isnot clear as post-operative new onset hypersexualityhas been clearly reported and ICDs are alsoassociated with an increase in post-operative21 22suicide risk.How should this particular patient betreated?Based on the available information in this case,the behaviour is not clearly pathological andmay represent a general increase in motivationand libido. However,given the likelihood that thebehaviour and degree of distress or conflict islikely minimised, the patient and spouse shouldbe carefully interviewed both separately andtogether to ascertain the full range of behaviours,frequency, duration, degree of distress andrelationship conflict, attempts by the patient tocontrol the behaviour and assessment of otherpsychiatric symptoms. Careful follow-up, documentationand warnings should be institutedgiven the risk of escalation of behaviours. Ifindeed the behaviour and distress is very mild,there is no single correct approach and shouldbe guided by the patient and wife.Understanding that the change in behaviourmay simply reflect changes in medication andan improvement back to a pre-Parkinsonianstatus of motivation and libido along with anincrease in communication may be sufficient toalleviate distress. A reasonable approach wouldbe to attempt to behaviourally manage the symptomsin a manner suitable for the couplefollowed by a trial of a decrease in DA dose ifineffective. lREFERENCES1. Weintraub D, Koester J, Potenza MN, Siderowf AD,Stacy M, Voon V, et al. Impulse control disorders inParkinson disease: a cross-sectional study of 3090patients. Arch Neurol. May;67(5):589-95.2. Driver-Dunckley ED, Noble BN, Hentz JG, Evidente VG,Caviness JN, Parish J, et al. Gambling and increasedsexual desire with dopaminergic medications in restlesslegs syndrome. Clin Neuropharmacol. 2007 Sep-Oct;30(5):249-55.3. Potenza MN. Non-substance and substance addictions.Addiction. 2009 Jun;104(6):1016-7.4. Evans AH, Lees AJ. Dopamine dysregulation syndromein Parkinson's disease. Curr Opin Neurol. 2004Aug;17(4):393-8.5. Miyasaki JM, Al Hassan K, Lang AE, Voon V. Pundingprevalence in Parkinson's disease. Mov Disord. 2007 Jun15;22(8):1179-81.6. Evans AH, Katzenschlager R, Paviour D, O'Sullivan JD,Appel S, Lawrence AD, et al. Punding in Parkinson'sdisease: its relation to the dopamine dysregulationsyndrome. Mov Disord. 2004 Apr;19(4):397-405.7. Uitti RJ, Tanner CM, Rajput AH, Goetz CG, KlawansHL, Thiessen B. Hypersexuality with antiparkinsoniantherapy. Clin Neuropharmacol. 1989 Oct;12(5):375-83.8. Voon V, Hassan K, Zurowski M, de Souza M, ThomsenT, Fox S, et al. Prevalence of repetitive and rewardseekingbehaviors in Parkinson disease. Neurology. 2006Oct 10;67(7):1254-7.9. Diagnostic and Statistical Manual of Mental Disorders,4th ed. Washington, DC: American PsychiatricAssociation; 1994.10. Goldstein RZ, Craig AD, Bechara A, Garavan H,Childress AR, Paulus MP, et al. The neurocircuitry ofimpaired insight in drug addiction. Trends Cogn Sci.2009 Sep;13(9):372-80.11. Voon V, Thomsen T, Miyasaki JM, de Souza M, ShafroA, Fox SH, et al. Factors associated with dopaminergicdrug-related pathological gambling in Parkinson disease.Arch Neurol. 2007 Feb;64(2):212-6.12. Voon V, Reynolds B, Brezing C, Gallea C, Skaljic M,Ekanayake V, et al. Impulsive choice and response indopamine agonist-related impulse control behaviors.Psychopharmacology (Berl). Jan;207(4):645-59.13. Steeves TD, Miyasaki J, Zurowski M, Lang AE,Pellecchia G, Van Eimeren T et al. Increased striataldopamine release in Parkinsonian patients with pathologicalgambling: a [11C] raclopride PET study. Brain.2009 May;132(Pt 5):1376-85. Epub 2009 Apr 3.14. Voon V, Pessiglione M, Brezing C, Gallea C, FernandezHH, Dolan RJ, et al. Mechanisms underlying dopaminemediatedreward bias in compulsive behaviors. Neuron.Jan 14;65(1):135-42.15. Weintraub D, Hoops S, Shea JA, Lyons KE, Pahwa R,Driver-Dunckley ED, et al. Validation of the questionnairefor impulsive-compulsive disorders in Parkinson'sdisease. Mov Disord. 2009 Jul 30;24(10):1461-7.16. Mamikonyan E, Siderowf AD, Duda JE, Potenza MN,Horn S, Stern MB, et al. Long-term follow-up of impulsecontrol disorders in Parkinson's disease. Mov Disord.2008 Jan;23(1):75-80.17. Ivanco LS, Bohnen NI. Effects of donepezil on compulsivehypersexual behavior in Parkinson disease: a singlecase study. Am J Ther. 2005 Sep-Oct;12(5):467-8.18. Guay DR. Drug treatment of paraphilic and nonparaphilicsexual disorders. Clin Ther. 2009 Jan;31(1):1-31.19. Ardouin C, Voon V, Worbe Y, Abouazar N, Czernecki V,Hosseini H, et al. Pathological gambling in Parkinson'sdisease improves on chronic subthalamic nucleus stimulation.Mov Disord. 2006 Nov;21(11):1941-6.20. Thobois S, Ardouin C, Lhommee E, Klinger H, LagrangeC, Xie J, et al. Non-motor dopamine withdrawalsyndrome after surgery for Parkinson's disease: predictorsand underlying mesolimbic denervation. Brain.Apr;133(Pt 4):1111-27.21. Lim SY, O'Sullivan SS, Kotschet K, Gallagher DA, LaceyC, Lawrence AD, et al. Dopamine dysregulationsyndrome, impulse control disorders and punding afterdeep brain stimulation surgery for Parkinson's disease. JClin Neurosci. 2009 Sep;16(9):1148-52.22. Voon V, Krack P, Lang AE, Lozano AM, Dujardin K,Schupbach M, et al. A multicentre study on suicideoutcomes following subthalamic stimulation forParkinson's disease. Brain. 2008 Oct;131(Pt 10):2720-8.ACNR > VOLUME 10 NUMBER 5 > NOVEMBER/DECEMBER 2010 > 33

A S S O C I AT I O N O F B R I T I S H N E U RO LO G I ST T R A I N E E SThe ABN FellowshipScheme: a newopportunity forneurology traineesBiba Stanton,Chair, ABNT.Correspondence to:Dr Biba Stanton,Chair, ABNT,Ormond House,27 Boswell Street,London WC1N 3JZ, UK.Key Facts on theABN Clinical ResearchTraining Fellowships• Open to clinicallyqualified trainees inneurology and relateddisciplines• Provide three yearclinical research trainingfellowships in anyneurological discipline• Additional fundingopportunities areavailable in specificdisease areas• A single application andinterview process for allthe fellowships• Salary, university fees,travel costs andlaboratory consumablescan be funded• Details of theapplication process areavailable atwww.theabn.orgWhy a new fellowship scheme?British neurology has a strong academic tradition.Aperiod of time spent in research remains avery valuable part of training for many registrarsin neurology. A clinical training fellowshipproviding up to three years of research funding isthe ideal way for trainees to undertake an MD orPhD, which is essential for those considering anacademic career. The Medical Research Counciland Wellcome Trust offer prestigious fellowships,but these are limited in number and extremelycompetitive. A number of other charities havetraditionally funded training fellowships, butcharities have reported increasing difficulties inrecruiting suitable candidates and administeringthe selection process. Some had even considereddiverting these funds to other uses. From atrainee’s perspective, finding suitable options forfunding their research can be a bewilderingprocess, and making multiple applications wasextremely time-consuming. Against this background,the Association of British Neurologistsrecently established a new scheme to coordinateand manage the award of prestigious clinicaltraining fellowships available to neurologytrainees from a variety of charitable sources.How does the scheme work?The ABN fellowship scheme brings together anumber of existing charitable fellowships as wellas new funding from the Guarantors of Brainunder a single umbrella. This scheme will takeplace annually and offers opportunities either forfellowships in a non-specified neurological discipline(from the Guarantors of Brain and thePatrick Berthoud Charitable Foundation),or additionalopportunities in disease areas sponsoredby specific disease-orientated charities. The ABNsupports and administers the scheme, includingthe application, peer review and interviewprocess, but individual charities continue tomake the final decisions on which candidate(s)they will fund. A single application form allowsapplicants to apply for one or more of the fellowshipsbeing offered at any one time, dependingon their own area of interest, and a single set ofinterviews is held. The interview panel isappointed by the Clinical Research andAcademic Committee of the ABN, chaired byPatrick Chinnery, and includes a member of theAssociation of British Neurological Trainees(ABNT) and representatives from each charityoffering funding. The process aims to be efficientand streamlined, with a timeline of only 3-4months between applications and funding decisions.Salary, university fees, reasonable travelcosts, and laboratory consumables may befunded, although the resources available fromeach sponsor differ.The first round of applications took place insummer 2010,with five fellowships being offered,including disease specific funding from the MSSociety, Ataxia UK and the Parkinsons UK. Thedeadline for applications was the end of May,withinterviews held at the end of July and finalfunding offers made by September. The aim is torepeat the process at a similar time each year, ormore frequently if resources become availablemeanwhile. Full details, including informationabout the specific fellowships to be offered, areavailable on the ABN website (www.theabn.org).How can I make a successful application?It can take some time to develop a fellowshipproposal, so trainees thinking about undertakingresearch should already be beginning discussionswith potential supervisors in time to applyfor a fellowship in 2011.As with the MRC and Wellcome fellowships,the“three Ps” - Person, Project and Place - are allimportant in the selection process, but a strongemphasis is placed on supporting the careerdevelopment of the most promising potentialacademic neurologists. The charities’responsibilitiesto their trustees means that projects withclear potential benefit to patients are also morelikely to be supported. Being well prepared forthe interview is essential: candidates need todemonstrate a clear understanding of both thescientific basis of their project and how thefellowship fits into their longer term career plans.Unsuccessful candidates are offered personalfeedback at the end of the process with the aimof helping them to make other successful fundingapplications in future.In summary, the new ABN Fellowship Schemeshould make it easier for neurology trainees toaccess funding opportunities for research, andaims to offer awards as prestigious as thoseprovided by MRC and the Wellcome Trust. Lookout for details of next year’s application processon the ABN website. l34 > ACNR > VOLUME 10 NUMBER 5 > NOVEMBER/DECEMBER 2010

BOOK REVIEWSImmune-Mediated Neuromuscular DiseasesThis 16-authored (14 USA, 2 UK) 165page hardback offering sets out toprovide “the latest updates in treatableautoimmune neuromusculardisorders. Due to page limitations,other autoimmune neuromusculardiseases are not discussed. This bookcontains information about the morecommon and well-known diseases.”Is it just me being unkind butwould you have been happy with thatas the key introductory text on thefirst page of your book? Putting thataside, does it deliver?Chapter One: Acute Neuropathies –GBS – five pages including one paragraph(no tables, no graphs, nopictures) devoted to treatment. Fivefurther pages on acute plexopathies,both commenting that there are noRCTs to inform treatment, completethe first chapter.Let us move swiftly on to ChapterTwo Chronic Neuropathies – CIDPand its Variants. Ten pages of text andthree pages of references here withtwo tables bringing a little welcomerelief to the eye. Perhaps a page and ahalf on treatment at most (againwithout graphs, tables, or any pictorialimagery) makes this, well, rather dullI’m afraid, which is a pity becausewithin a pretty didactic chapter thethorny issue of how to reconcile thespecificity and sensitivity of diagnosisis explored, briefly. The issue of howmuch or how little clinical or electrophysiologicalsuspicion of CIDP isenough to justify a trial of immunosupressionis touched upon. Anevidence-based section on clinicallymeaningful treatment responsewould have been a helpful addition.One gets a more expansive and overlappinglook at chronic neuropathiesand paraproteins, myeloma,Waldenstroms, and POEMS in achapter on Dysimmune Neuropathy.Castleman’s gets a mention but from apractical point of view an approach to“treatment–resistant CIDP” is notablyabsent from either chapter.The section on nonsystemicvasculitic neuropathy (40 pages, ofwhich 10 are references) at leastcontains some attractive photoslidesof the pathology. The pages overflowwith more immunopathology thanmy addled brain can cope with but totheir credit the authors do justice towhat evidence exists (with referencesspanning 1914-2009!) regarding treatment(over nine pages) and producea useful end of chapter summary.Further topics include autoimmuneautonomic ganglionopathy (think Imay have see one once but will bemore vigilant now!), myasthenia –AChR and MuskR positive and(double) seronegative, LEMS, idiopathicinflammatory myopathies, andstiff person syndrome.What does this book have that alarge text book or a series of reviewarticles copied or downloaded fromjournals doesn’t? Convenienceperhaps, up-to-date-edness probably,digestibility ‘fraid not.Aspiring neurologists more drawnto the periphery of the neurologicallandscape who prefer books withwords to journals and computerscreens with pictures will like this. Notsure how big that tribe might be… lEditor: R PourmandPublished by: Karger 2009Price: £97.91ISBN: 9783805591416Reviewed by:John Bowen,Lincoln County HospitalMeasurement Scales Used in Elderly CareA Compendium of Tests, Scales, and QuestionnairesThe Practitioner’s Guide to Measuring Outcomes after Acquired Brain ImpairmentMeasurement scales are now ubiquitous inclinical practice, and several compendia ofsuch scales are available. Two recent additionsto the market are considered here.Gupta aimed to write a “handy book foruse by a busy clinician”, and to my way ofthinking has succeeded. The volume islight, portable, and reproduces most of thescales described. Although aimed principallyat geriatricians, there is material hereof interest to neurologists and neurorehabilitationists,with scales for coma (GCS),cognition (AMTS, MMSE), stroke,Parkinson’s disease, activities of daily living,and physical disability, amongst others.Tate’s book is a much more ambitiousaffair, attempting to map instruments to thecomponents and domains of the 2001WHO International Classification ofFunctioning, Disability and Health (ICF)framework, not always an easy task due tothe overlap of categories. This mappingmay be of more direct relevance toneurorehabilitationists than neurologists;the latter will presumably just pick-and-mixthe scales they want according to clinicalcircumstance. Test descriptions are structured(source, purpose, item description,scale development, administration procedures,psychometric properties, derivatives,comment, and key references) andconcise; these are certainly not exhaustivereviews of common tests. For neurologists,the sections on general and specific cognitivefunctions will probably be of most use.For the dedicated scale user, meaningsome cognitive neurologists, Tate is anextremely valuable and desirable additionto the library, alongside other compendia(e.g. Burns et al., Assessment Scales in OldAge Psychiatry 2nd edition, London: MartinDunitz, 2004), and many neurorehabilitationistswill also want to have access to thisbook as well. For a one-off additional fee(£100), online access to many of the testscan be purchased. lAuthor: A GuptaPublished by: RadcliffePublishing (2008)Price: £24.95ISBN: 9781846192661Author: R L TatePublished by: PsychologyPress (2010)Price: £100.00ISBN: 9781841695617Reviewed by:AJ Larner, Cognitive Function Clinic, WCNN, Liverpool, UK.ACNR > VOLUME 10 NUMBER 5 > NOVEMBER/DECEMBER 2010 > 35

JOURNAL REVIEWSEDITOR’S CHOICEAtaxin 2 ‘premutation’may contribute to ALSEvidence is accumulating that TDP-43, the hallmark protein ofpathological inclusions in ALS, has a direct pathogenic role inmotor neurone degeneration. In a recent paper in Nature,Elden et al. appear to have identified a protein that may beimportant in promoting TDP-43 toxicity, and which may influenceALS susceptibility. Beginning with a library of 5,500yeast genes they characterised 13 genes that suppressed and27 genes that enhanced TDP-43 toxicity. RNA metabolismappeared to be strongly represented (unsurprising given thatTDP-43 has important roles in RNA processing). Although coyabout naming these genes, the one candidate they domention, PBP1, is intriguing as it’s human orthologue is ataxin2 (ATXN2), which is mutated in spinocerebellar ataxia 2(SCA2). Elden et al then show that the human protein, ATXN2,interacts in vitro with TDP-43 and that this interaction isdependent on RNA. Furthermore, post mortem spinal cordexamination demonstrated altered distribution of ATXN2 inALS cases, with the formation of cytoplasmic inclusions.However, TDP-43 and ATXN2 did not appear to colocalise inthe spinal cord.ATXN2 contains a polyglutamine sequence of 22 repeats.Expansions greater than 34 repeats cause SCA2. In a geneticscreen Elden et al found that an intermediate repeat numberof 27-33 repeats was associated with ALS (24/980 controls hada single allele with such an expansion, while 50/915 ALS caseshad this allele). In vitro studies demonstrated that longerrepeat lengths increased the stability of ATXN2 and promoteda stronger interaction with TDP-43. Presumably this wouldincrease toxicity. In support of this theory, ALS cases with theexpanded repeat length had an earlier age of disease onset(mean age 47.8y) than those with a normal length (59.4y).However, the number of cases that they had sufficient clinicaldetail to do this analysis on was, curiously, rather small at just65. As ever, further work is necessary by other groups to replicatethese findings.The search for common genetic variants that contribute tosporadic ALS has been disappointing with conflicting resultscoming out of most large scale genome wide associationstudies (GWAS). Chromosome 9p21 has provided the mostpromising polymorphisms to date, but no mutation has yetbeen identified (Shatunov et al 2010). Rare genetic variants(immune to analysis by conventional GWAS approaches) areprobably more likely to contribute to disease. In identifyingand characterising ATXN2 polyglutamine expansions, Eldenet al have unearthed what appears to be a very important rarevariant. Their toxicity studies in yeast and drosophila suggestthat modulation of ATXN2 expression in humans could be apotential therapeutic approach. Research will continue toidentify other rare genetic variants associated with sporadicALS. We are another step closer to the day when we can geneticallyfingerprint individuals and predict future risk of ALS.– Jemeen Sreedharan, Guy’s and St Thomas’ NHS Trust,London.Elsen AC et al. Ataxin-2 intermediate-length polyglutamineexpansions are associated with increased risk for ALS.NATURE 2010 Aug 26;466(7310):1069-75.Shatunov A, et al. Chromosome 9p21 in sporadicamyotrophic lateral sclerosis in the UK and seven other countries:a genome-wide association study. LANCET NEUROL.2010Oct;9(10):986-94.Shining light of what it means to beBOLDThere are now a number of techniques to study brain activityin vivo in patients and normal volunteers including PET scanning,MEG and fMRI. The latter technique relies on the assumptionthat what is being detected truly reflects neuronal activity,as measured using changes in blood oxygenation leveldependent (BOLD) signals. However it is not known whetherthis is the case, namely exactly what type of local activitycauses and accounts for the change in BOLD signal and morespecifically can local excitatory neurons give positive BOLDsignals. In a recent study this has now been shown using highfield fMRI coupled to another new technology which involvesactivating specific cells using engineered light sensitive ionchannels which have been transfected into specific cell types(in this case local CaMKIIalpha-expressing excitatory cells inthe primary motor cortex or thalamus) (optogenetics). Thistechnique, called ofMRI, allows for selective cells to be activatedwhen light is shone on them. By looking at the fMRIsignal in response to that activation, one can show that e fMRIdoes equate to neuronal activity in excitatory neurons, andthat this activation is pathway specific.This study is important given that much of what we havelearnt from fMRI relies on this assumption and once moredemonstrates that our ability to probe neuronal activity in vivohas come a long way since the neurophysiologicalapproaches of the 1960s which defined the beginning of themodern neuroscientific age. Furthermore this new approachnot only helps us better understand what changes in BOLDsignals actually mean, but ofMRI offers the potential for “globalmapping of the causal connectivity of defined neurons inspecific brain regions” (p792). As such it may greatly enhanceour abilities to dissect the complex circuitry of the brainunder a whole host of normal and modelled diseased states.– Roger BarkerLee JH, et al. Global and local fMRI signals driven by neuronsdefined optogenetically by type and wiring. NATURE2010;465:788-92.Therapeutic trial for non-epilepticattacks a start at leastNon-epileptic attack disorder is a very common and importantclinical problem, and there is little good evidence on how tobest manage these patients (confirmed by the most recentCochrane review on the subject). These authors havepublished a pilot study, with a view to establishing numbers fora larger, powered trial. The pilot was a randomised, doubleblind, intention to treat comparison of sertraline versusplacebo in patients with non-epileptic attacks in a tertiarycentre. The inclusion criteria were: patients aged 18-65, withtelemetry evidence of non-epileptic attacks (includingpatients who also had epilepsy but that could clearly distinguishbetween attacks). Exclusion criteria were those withsubjective sensory attacks, MAOIs, sertraline greater than100mg, severe psychiatric issues (psychosis, suicidality,substance abuse), litigation or disability application, and thosebeginning new psychotherapy treatment. Patients wereassessed for two weeks and filled in a daily seizure calendarand an assessment battery (including depression anddisability scales). Sertraline or placebo was commenced onday 15 and increased bi-weekly to a maximum of 200mg astolerated. Subjects were reviewed in six bi-weekly sessions andassessed at the end of the study (12 weeks). 128 subjects wereassessed for inclusion, 90 excluded, 38 randomised (19 tosertraline, 19 to placebo) with 17 and 16, respectively, analysed.Drop-outs were largely due to patients’ concerns about receipt36 > ACNR > VOLUME 10 NUMBER 5 > NOVEMBER/DECEMBER 2010

JOURNAL REVIEWSof placebo rather than active drug. The primary outcomewas relative change in seizure rates: those in the setralinegroup had a 45% reduction in seizures (placebo 8%increase) and 8/17 had a 50% reduction in seizurefrequency (placebo, 3 of 16) (NNT 3.53). The statisticalcomparisons were non-significant. There were no differencesin secondary outcomes, including depression.The authors concluded that sertraline was producing itseffect directly through serotonergic modulation ratherthan via an antidepressant effect. An antidepressant effectshould probably be seen at 12 weeks, but a longer followup may be more informative. The numbers were too smallto be able to make such inferences. The authors felt thatsince even low doses of sertraline produced improvementin seizure control, patients with non-epileptic attacks havea lower serotonin response threshold; yet, 50% of subjectswere taking antidepressants (no information was providedon which types) before enrolment and the authors felt thatincreasing the dose would produce a therapeutic effect.There were also some patients taking anti-epileptics butthe patients were clear they were taking them for otherindications such as mood stabilisation or migraine.The authors found that most participants had morethan one Axis 1 psychiatric disorder, so suggested notexcluding patients with psychiatric disorders from suchtrials but instead stratifying according to personality disorders.I would agree with this given that patients withpersonality disorders have a higher rate of factitiousdisorder (as opposed to functional disorders). This paperprovides useful information to guide further trials in nonepilepticattacks, an area sorely in need of further study,and the disorder is certainly common enough to allowcomprehensive trials to take place.– Wendy Phillips, Neurology Unit, Addenbrooke’sHospital, Cambridge, UK.LaFrance et al. Pilot pharmaceutical randomisedcontrolled trial forpsychcogenic nonepileptic seizures. NEUROLOGY2010;75:1166-73(epub Aug 25)When is an AED not an AED?The ups and downs of inhibitionin epilepsyIt has been known for some years that the behaviour ofGABA receptors changes during maturation, because ofdifferences in subunit composition. In mature neurons, thereceptor allows influx of chloride ions, causing hyperpolarisationand reducing excitation of the post-synapticcell. However, in immature neurons, higher levels of chlorideand different properties of the receptor mean thatthey cause efflux of chloride resulting in excitation, whichhas a role in neuronal migration and synapse development.Clearly, this has implications for the use of antiepilepticdrugs acting via GABA receptors, such as benzodiazepines,in early life. In this study the authors looked atthe property of neurons removed at epilepsy surgery in 25children with areas of cortical developmental abnormalityand the properties of neurons, mostly removed atpost-mortem from 20 children without epilepsy. In normalindividuals, the expression of GABAA α1 and γ2 subunitexpression increased over the first five years of life beforereaching a plateau. The normal brains also exhibitedchanges in the relative proportions of chloride transporters,NKCC1 (decreases after birth) and KCC2(increases from low levels with maturation). In theEDITOR’S CHOICEMultiple Sclerosis: treating withanti-hypertensive drugsTraditionally viewed as being pivotal for blood pressure regulationand fluid homeostasis, the renin-angiotensin-aldosterone system(RAAS) and specifically the angiotensin-converting enzyme (ACE) -angiotensin II - angiotensin II type 1 (AT1) receptor axis have nowalso been suggested to play an important role in tissue inflammationand fibrosis. T-cell expression of the AT1 receptor has been suggestedto contribute to both inflammatory events and the development ofhypertension. Moreover, activated T cells themselves generateangiotensin II to influence cell function in an auto- and paracrinefashion, and ACE inhibitors suppress inflammatory CD4+ T cell subsetdevelopment (Th1 and Th17 cells) and induce regulatory immunosuppressiveT cell subsets (Treg). In the animal model of MS, experimentalautoimmune encephalomyelitis (EAE), AT1 expression in theCNS is increased and subsequent AT1 receptor blockade usingcandesartan or losartan or by ACE inhibition using lisinopril amelioratesthe autoimmune inflammation. Similarly, proteomics analyses ofMS plaques indicates a presence of proteins related to the RAAS(Platten et al PNAS 2009). However, the explanation for the antiinflammatoryproperties of AT1 receptor or ACE inhibitors remainedlargely unknown.In a recent paper, also from Larry Steinman’s group, an intriguingnetwork of regulations was unravelled, suggesting an explanation forthe pro-inflammatory properties of angiotensin II. The researcherswere able to show in EAE that angiotensin II acts on CNS-residentastrocytes and microglia, which respond by an increase in secretionof the cytokine transforming-growth factor beta (TGF-beta) and itsactivating enzyme thrombospondin-1. This connection betweenangiotensin II and TGF-beta was not entirely unknown, as angiotensinII-dependent induction of TGF-beta is pathophysiologicallyconnected with pulmonary, cardiac and renal fibrosis. An increase inTGF-beta can have pleiotropic functions in the immune system, withsometimes opposite outcomes; it is able to suppress inflammationbut in different situations it can also exacerbate inflammation. Thefunction seems to be dependent on the surrounding tissue and theinterplay between different mediators. In respect to the entireorganism, systemic applications of TGF-beta show immunosuppressivefunctions. However, paradoxically, the blockade of the TGF-betaproduction in the CNS leads to an amelioration of inflammatory reactionsand a clinical remission in the MS animal model. Lanz et alwere able to show that AT1 receptor blockade by losartan is able toinhibit the inflammatory-induced elevated TGF-beta concentrationswithin the CNS, which contribute to uphold neuroinflammation.However, TGF-beta basal levels, which are continuously produced inthe brain, were not changed. This suggests that interventions into theRAAS do not alter basic immune responses but rather inhibit harmfulelevations of TGF-beta. So far no increase in risk of opportunisticinfections under RAAS interventions has been reported.Although this and previous studies advocate the possible beneficialrole of the antihypertensive and licensed AT1 receptor or ACEinhibitors for the treatment of MS, the situation in humans might beconsiderably different from that seen in the experimental mousemodels. Here, the therapy was only effective in mice when the treatmentwas started before the animals developed any paresis: anunlikely clinical situation. While there remain concerns about theeffectiveness of these drugs in human MS the long standing clinicalexperience and their well described side effects do, in my opinion,justify clinical studies using AT1 receptor or ACE inhibitors in MS.– Manuel A Friese, University Medical Centre, Hamburg, Germany,Lanz TV, et al. Angiotensin II sustains brain inflammation in micevia TGF-beta. JOURNAL OF CLINICAL INVESTIGATION2010Aug2;120(8):2782-94.ACNR > VOLUME 10 NUMBER 5 > NOVEMBER/DECEMBER 2010 > 37

JOURNAL REVIEWSepileptic cortex, the maturation of GABAA subunit types was not seen butinstead there were patterns of expansion unique to each patient. Similarlythere was not the normal maturation of chloride transporters in epilepticbrains. What does this mean? Firstly, it may be one explanation of interpatientvariability in the anti-epileptic effect of AED, not only in paediatricepilepsy, but if these patterns are maintained, also in adult epilepsy. Thechallenge now is to identify these patients and predict AED response,without having to do a biopsy.– Mark Manford, Neurology Unit, Addenbrooke’s Hospital, Cambridge,and Bedford Hospital, Bedford, UK.Jansen LA, et al. Impaired GABA maturation of cortical GABAA receptorEpilepsy: not just seizuresOver the years, a number of studies have compared epilepsy with otherchronic conditions with respect to the impact of the condition onpsychosocial status and broader health-related outcomes. This largestudy looked at the Canadian population, using the CanadianCommunity Health Survey (CCHS), which is administered to a largerepresentative sample of the population. Certain individuals areexcluded; the armed forces, those living in Indian Reserves and some inremote regions. In this study the characteristics of patients with epilepsy(prevalence 0.6%), diabetes (prevalence 3.6%) and migraine (prevalence8.4%) were compared. Numerous variables were studied and therelevant ones, which showed some differences between groups, are inthe table below. The diabetes data are the least comparable because ofthe difference in the age of patients and the specific nature of the riskfactors for diabetes, e.g. BMI. The social disadvantage of patients withepilepsy is striking. The study does not tell us who was in employmentor whether some of the low income amongst epilepsy patient may havebeen benefits rather than earned income, and potentially an even morestriking disparity. Although patients with epilepsy were more likely to besmokers than the general population (28.1% v 23.6%), this differencedisappeared when the data were adjusted for age, income, gender andeducation. Alcohol consumption appeared bimodal in all groups withover half of patients never drinking and the second largest groupconsuming over 12 units per week; 25% of epilepsy sufferers, comparedwith 18.2% of the general population. The association of epilepsy withthyroid disease and with colitis is unexplained.General Epilepsy Migraine Diabetespopn400,000 2,555 37,797 22,432Median age 44 43 40 64Female 50.7% 50.9% 71.4% 46.9%Married/partner 58.4% 48% 59.7% 67.6%Single 29.9% 38.4% 28.2% 9.8%University education 36.6% 26.9% 32.9% 30.2%Income (Canadian Dollars) 32,857 22,807 28,353 27,706BMI > 30 15.4% 20% 18% 37%Physical inactivity 50% 60% 50%Thyroid disease 5.3% 9.1% 7.6% 10.8%Arthritis 16.2% 23.9% 22.7% 37.8%Stroke 1.1% 5.6% 1.5% 5%Crohn’s disease/colitis 2.8% 5.5% 6.1% 4.4%Asthma 8.4% 12.3% 14.8% 10.1%– Mark Manford, Neurology Unit, Addenbrooke’s Hospital, Cambridge,and Bedford Hospital, Bedford, UK.Hinnell C et al. Health status and health-related behaviors in epilepsycompared to other chronic conditions – a nation population-based study.EPILEPSIA 2010;51:853-61.Cognition in PSP and MSAThe Neuroprotection and Natural History in Parkinson Plus Syndromes(NNIPPS) study represents the largest prospective cohort of PSP and MSApatients (> 750) yet evaluated, with high overall clinical diagnostic accuracy(94%) compared to pathological examination (n = 112; see alsoBrain 2009; 132:156-171). This cohort has therefore provided an opportunityto examine the cognitive phenotype of these conditions, assessedusing the MMSE, Frontal Assessment Battery (FAB), and Mattis DementiaRating Scale (DRS) in 372 MSA patients and 311 PSP patients, most (>80%) receiving levodopa preparations. MMSE and FAB scores were higherin the MSA group. On the DRS, PSP patients were worse on all global andage-scaled subscale scores, with the means for the MSA group beingclose to the population average for each subscale. Overall, 57% of PSPpatients and 20% of MSA patients were judged impaired, with an identicalcognitive profile, the main impairment being in the Initiation andPerseveration subscale, especially for the verbal fluency item. Only aboutone-fifth of PSP patients but two-thirds of MSA patients showed no impairmentin any cognitive domain.My education, dating to the last century, was to the effect that cognitiveimpairment was extremely rare in MSA, and indeed some suggested diagnosticcriteria have regarded cognitive impairment as an exclusion criterionfor the diagnosis. This large prospective cohort study clearly showsthis to be an error, which will need to be addressed in future clinical diagnosticcriteria. Moreover, cognitive as well as motor endpoints might nowbe regarded as reasonable outcome measures in any future therapeutictrials of disease-modifying agents in these conditions.– AJ Larner, Cognitive Function Clinic, Walton Centre for Neurologyand Neurosurgery, Liverpool, UK.Brown RG, et al.Cognitive impairment in patients with multiple system atrophy andprogressive supranuclear palsy.BRAIN 2010;133(8):2382-93.Valproate, levetiracetam or both forDown syndrome with cognitive declineand myoclonusThese authors reviewed the records of all patients referred to theircentres with Down syndrome. They found 18 patients with adult onset ofmyoclonic jerks. The age of onset of cognitive decline as described bycarers ranged from 36-59 years (mean 48). Massive myoclonic jerks wereinitially prominent in all patients soon after waking and sometimes theypresented with falls as a result. As the dementia progressed, the jerksbecame prevalent throughout the day. Fourteen patients also had tonicclonic seizures, mostly after, but sometimes before the onset ofmyoclonus. EEG’s showed widespread slowing in all and generalisedspike and wave in ten of the patients. Treatment with valproate or levetiracetamor both together seemed to have the best effect. Other agentswere also tried in more refractory patients with variable success. Thesepatients crop up from time to time in all our clinics; it is good to know ofothers’ experiences.– Mark Manford, Neurology Unit, Addenbrooke’s Hospital, Cambridge,and Bedford Hospital, Bedford, UK.De Simone R, et al.Senile myoclonic epilepsy: delineation of a common condition associatedwith Alzheimer’s Disease in Down syndrome.SEIZURE 2010;19:383-9.Can I smoke dope Doc?The MS doctors have been grappling with this question for a number ofyears and it does come up in the epilepsy clinic from time to time. Myusual response of: “not in the waiting area”, is perhaps not the mostconstructive but it does highlight the illegality of these drugs. There is ofcourse the broader philosophical question around cannabinoids in asociety that enjoys alcohol to the point where one in five male admissionsto hospital is alcohol related, and where doctors dish out opiateslike Smarties ® , but perhaps I should come off my hustings and look at38 > ACNR > VOLUME 10 NUMBER 5 > NOVEMBER/DECEMBER 2010

JOURNAL REVIEWSsome science. This is one of a series of studies which has looked atcannabinoids over the years. Most have looked at the hippocampus inpartial epilepsy and have found that changes in cannabinoids are generallyconsistent with them having an anti-epileptic role. These authorsstudied a genetic model of absence epilepsy, in which rats developabsence seizures at three months of age. Various brain regions wereanalysed for cannabinoid CB1 and animals were also analysed with EEG.Data showed a reduction in CB1 receptor mRNA and protein levels ascontrol rats matured in a range of brain areas, with the most markeddifference between control and epileptic rats being a much greaterreduction in the thalamic reticular nucleus, believed to be involved inthalamocortical circuits, important in absence epilepsy. Injecting ratswith an agonist at this receptor had complex effects on spike-wavedischarges but the most significant was a reduction in discharges in thefirst two hours, which was blocked by an antagonist at the same receptor.So when my patients tell me that dope is the only thing that helps theirseizures, do I believe them? Of course I do. When they ask if it is OK forthem to smoke it, I mumble something vaguely disapproving yet permissive.Will we ever prescribe cannabinoids for epilepsy? Perhaps, if theclinical evidence is good enough. We are lucky that in MS, the evidenceis sufficiently poor that it plays into public prejudices and political priorities.It will take a brave pharma to try and bring a cannabinoid to marketin a climate where politics and scientific evidence combine in decisionmakinglike oil and water.– Mark Manford, Neurology Unit, Addenbrooke’s Hospital, Cambridge,and Bedford Hospital, Bedford, UK.Van Rijn C et al.WAG/Tij rats show a reduced expression of CB1 receptors in thalamicnuclei and respond to the CB1 receptor agonist, R9+) WIN55,212-2, with areduced incidence of spike-wave discharges.EPILEPSIA 2010;51:1511-21.MS: glutamatergic neuroprotection?Glutamate mediated excitotoxicity has long been thought a mechanism ofneuronal damage in MS, demonstrated for example by the amelioration ofEAE with an AMPAR antagonist by Cedric Raine’s group (Pitt et al NatureMedicine 2000), correlation of glutaminase with axonal damage in MSlesions (Werner et al Ann Neurol 2001), and MR spectroscopic measures ofraised glutamate in acute MS lesions and normal appearing white matter(Srinivasan et al. Brain 2005). Looking for associations of polymorphisms ingenetic regions which control glutamate processing has already proveninteresting, and favours the established view that raised glutamate overall isassociated with accelerated neuronal loss, as measured by brain volume(Baranzini et al. Brain 2010). So it is with interest to see a report that asks usto think of glutamate’s potential for good. The model is thus: glutamateencourages dendritic cells in an inflammatory environment to produce acytokine milieu that pushes T cells away from a pro-inflammatory lineage(Th17) towards a protective one (Treg). The mechanism is through activationon dendritic cells of the type III metabotropic glutamate receptor,mGluR4, erstwhile known to be predominantly presynaptic and highlyexpressed in cerebellum and olfactory bulb (Pekhletski et al. J Neurosci1996). Here, mGluR4 knockout mice exhibit earlier onset and more severeMOG35-55-induced EAE than wild type, with a greater influx of inflammatorycells on histology, and an mGluR4 positive allosteric modulator (PAM)rescues EAE in wildtype mice but not in the knockouts. The implementationof all this, through trials of specific PAMs of mGluR4 and therefore ensuringa highly selective action, may be tricky, and if the effect is just on inflammation,then why develop another anti-inflammatory drug for MS at all? As anadjunct with immediate efficacy is one possible answer.– Mike Zandi. Fallarino et al. Metabotropic glutamate receptor-4 modulatesadaptive immunity and restrains neuroinflammation. NATURE MEDICINE2010Aug;16(8):897-902. And editorial by Hansen and Caspi, page 856-8.Organised by8th national conferenceBipolar Disorder‘What is it – how to treat it’3rd December 2010 London13th national conferenceDementias 2011A review and update on current developments in the dementias; in the fields of research,investigations, clinical care and service and policy issues10th & 11th February 2011 London10th London InternationalEating Disorders29th, 30th & 31st March 2011 LondonFor further information and/or to book your place please visitwww.mahealthcareevents.co.ukAlternatively call our booking hotline on 020 7501 676240 YEARS OF MEDICAL EDUCATIONACNR > VOLUME 10 NUMBER 5 > NOVEMBER/DECEMBER 2010 > 39

CONFERENCE REPORTSEuropean Committee for Treatment and Research inMultiple Sclerosis (ECTRIMS) Annual MeetingConference details: 13-16 October; Gothenburg, Sweden. Reviewed by: Susan Mayor, Freelance Medical JournalistEncouraging findings from clinical trialswith new oral disease-modifying agentsbeing developed to treat multiple sclerosis(MS), further evidence from epidemiologicalstudies on the role of vitamin D status inthe risk of developing MS and a greateremphasis on understanding MS in childrenwere key themes emerging at this year’sEuropean Committee for Treatment andResearch in Multiple Sclerosis (ECTRIMS)annual meeting.Swedish study confirms MS link with lowexposure to ultraviolet radiationLow exposure to ultraviolet (UV) radiation isassociated with increased risk of developingMS among both women and men, according tolatest results from the ongoing EpidemiologicalInvestigation of MS (EIMS). This is a populationbasedcase-control including the general populationaged 16-70 years in defined areas ofSweden.Results based on 1231 incident cases of MSand 2682 controls showed that people with thelowest previous UV exposure had nearly twicethe risk of developing MS compared to thosereporting the highest exposure (odds ratio 2.0,95% confidence interval 1.4-2.7). There was astatistically significant inverse trend – thelower UV exposure, the higher risk of MS.Vitamin D levels were significantly loweramong cases than controls (p=0.04), with asignificant inverse trend between levels ofvitamin D and MS. The research group foundno association between exposure to UV radiationand vitamin D levels and HLA-DRB1*15.Reporting the findings, the group from theKarolinska Institute, Stockholm, said, “Lowexposure to ultraviolet radiation is associatedwith an increased risk of developing MSamong both women and men. Together withthe observed association between vitamin Dand MS, these findings support the hypothesisthat vitamin D is causally related to risk of MS.Canadian study in children with acutedemyelination reveals MS risk factorsVitamin D levels and the HLA-DRB1*15 alleleare independent risk factors for MS in children,show new results from the Canadian PediatricDemyelinating Disease Network. The studyincluded 332 children (aged under 16 years)with acute demyelination recruited from 23 sitesacross Canada and monitored prospectivelywith serial clinical and MRI visits. During followup,MS was diagnosed in 63 children (19%).Results revealed that children carrying atleast one copy of the HLA-DRB1*15 allele hadnearly three times the risk of developing MSthan those without (hazard ratio 2.84).Children of European ancestry showed particularlyhigh risk of developing MS if they carriedthe allele. In a preliminary subgroup of 83 children,in which 19 (23%) were diagnosed withMS; DRB1*15 carriers had more than a ten-foldrisk (HR 10.57) compared to noncarriers.Increasing levels of serum 25-dehydroxyvitamin D were associated with reduced riskof MS, with a hazard ratio of 0.87 for each10nmol/l increase. Mean 25-(OH) D levelswithin 40 days of the onset of symptoms werelower in children that went on to develop MS(mean 52 nmol/l) than in those that did not(66.2noml/l) (p=0.004).Heather Hanwell, from the University ofToronto, told the meeting, “Paediatric MS is notnearly as rare as we thought; three to ten percent of MS cases begin to experience clinicalsigns and symptoms in childhood and adolescence.”She added, “The HLA-DRB1*15 alleleand circulating 25-dehydroxy vitamin D levelsare independently associated with MS diagnosisfollowing acute demyelination in children.Further study is justified to determine whetherimproving vitamin D status from conceptionthrough childhood will reduce MS risk.”Five year follow-up data showalemtuzumab achieves sustainedreduction in relapses and disability inmultiple sclerosisPatients with multiple sclerosis (MS) treatedwith alemtuzumab show sustained reduction inrelapses and disability after five years, accordingto results reported at ECTRIMS. The CAMMS223study randomised 334 patients with early, activerelapsing remitting MS to alemtuzumab (atdoses of either 12mg/day or 24mg/day) for up tofive days in two or three cycles, or to interferonbeta-1a (44mcg, three times/week).Results after five years of follow-up showedconsistently lower annualised relapse rates inpatients treated with alemtuzumab (0.11)compared with those randomised to interferonbeta-1a (0.35). Only 13% of patients inthe alemtuzumab group demonstratedsustained increase in disability, compared with38% of those taking interferon beta-1a.“These long-term follow-up data suggest thatalemtuzumab may have a significant diseasemodifying effect in patients with early, active,relapsing-remitting MS,” said Dr Alasdair Coles,Senior Lecturer, University of Cambridge, UK,and lead investigator of the study. He added,“The efficacy after five years is as good as wesaw after three years, despite patients beinggiven no more treatment with alemtuzumab, sowe are seeing a durable effect.”Further results for patients with highly activerelapsing remitting MS in the study (just overhalf of those taking part) showed the annualisedrelapse rate was reduced by 81% in thosetreated with alemtuzumab (0.09) compared tothose treated with interferon beta-1a (0.47),after three years’ follow-up. 91% of alemtuzumab-treatedpatients were free of sustainedaccumulation of disability, compared to 75% ofthose in the comparator group. These patientsall had highly active disease, with at least tworelapses in the year before treatment in the trial,and at least one gadolinium enhancing brainlesions identified by magnetic resonanceimaging.Two phase 3 trials are currently further evaluatingalemtuzumab in the treatment of MS,with results expected in 2011.Global study confirms increase in MS inwomenThe ratio of women developing MS comparedto men has increased over the last 60 years,revealed results from the MSBase Registry.Researchers identified cases of definite MSwith birth years ranging from 1930 to 1989through the international registry and calculatedthe female to male sex ratios. Figureswere adjusted to take account of any differencesin the birth rates for each country, usingnational birth registers.Results for the whole population of 11,028patients showed a progressive increase in theadjusted female/male sex ratio from the first tothe last decade, from 1.78 to 2.96 (p VOLUME 10 NUMBER 5 > NOVEMBER/DECEMBER 2010

Rebif ® : established,effective treatmentfor people with RRMS 1,2Delivered through innovationto help address adherenceRebif ® is available in multidosecartridges for use with the RebiSmart electronic autoinjector deviceUp to 70% of RRMS patients treatedwith DMDs are non-adherentwith therapy* 3RebiSmart is the only device inMS which allows adherence tobe reviewed* Retrospective analysis of 1606 RRMS patients treated with interferon-ß-1a(44µg sc tiw or 30µg im qw) or interferon-ß-1b; adherence was defi ned asa medication possession ratio of ≥85% over a period of 360 days.RRMS: relapsing–remitting multiple sclerosis. DMD: disease-modifying drug.sc: subcutaneous. tiw: three times weekly. im: intramuscular. qw: once weekly.Prescribing information can be found overleaf.Merck Serono is adivision of Merck

CONFERENCE REPORTSPRESCRIBING INFORMATION – UK AND ROIREBIF ® 8.8 MICROGRAMS AND 22 MICROGRAMS SOLUTION FOR INJECTIONIN PRE-FILLED SYRINGEREBIF ® 22 MICROGRAMS SOLUTION FOR INJECTION IN PRE-FILLED SYRINGEREBIF ® 44 MICROGRAMS SOLUTION FOR INJECTION IN PRE-FILLED SYRINGEREBIF ® 8.8 MICROGRAMS AND 22 MICROGRAMS SOLUTION FOR INJECTIONIN PRE-FILLED PENREBIF ® 22 MICROGRAMS SOLUTION FOR INJECTION IN PRE-FILLED PENREBIF ® 44 MICROGRAMS SOLUTION FOR INJECTION IN PRE-FILLED PENREBIF ® 8.8 MICROGRAMS/0.1ML AND REBIF ® 22 MICROGRAMS/0.25MLSOLUTION FOR INJECTION IN CARTRIDGEREBIF ® 22 MICROGRAMS/0.5ML SOLUTION FOR INJECTION IN CARTRIDGEREBIF ® 44 MICROGRAMS/0.5ML SOLUTION FOR INJECTION IN CARTRIDGEInterferon beta-1aPresentation Rebif 8.8μg and 22μg: Pre-filled glass syringe containing 8.8μg or 22μg ofInterferon beta-1a in respectively 0.2 or 0.5ml. Rebif 22μg or 44μg: Pre-filled glass syringecontaining 22μg or 44μg Interferon beta-1a in 0.5ml. Rebif 8.8μg and 22μg: Disposablepre-filled pen injector (RebiDose) containing 8.8μg or 22μg of Interferon beta-1a inrespectively 0.2 or 0.5ml. Rebif 22μg or 44μg: Disposable pre-filled pen injector (RebiDose)containing 22μg or 44μg Interferon beta-1a in 0.5ml. Rebif 8.8μg/0.1ml and Rebif22μg/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 or132μg of Interferon beta-1a in 1.5ml. Indication Treatment of relapsing multiple sclerosis.Efficacy has not been demonstrated in patients with secondary progressive multiple sclerosiswithout ongoing relapse activity. Dosage and administration Initiate under supervision ofa physician experienced in the treatment of multiple sclerosis. Administer by subcutaneousinjection. Recommended dose: Weeks 1 and 2: 8.8μg three times per week (TIW); weeks 3and 4: 22μg TIW; week 5 onwards: 44μg TIW (22μg TIW if patients cannot tolerate higherdose). RebiDose pre-filled pen is for single use and should only be used following adequatetraining of the patient and/or carer. Follow the instructions provided in the package leaflet.Rebif solution for injection in cartridge is for multidose use and should only be used withthe RebiSmart autoinjector device following adequate training of the patient and/or carer.Follow the instructions provided with the RebiSmart device. Limited published data suggestthat the safety profile in adolescents aged 12–16 years receiving Rebif 22μg TIW is similarto that in adults. Do not use in patients under 12 years of age. Prior to injection and for24h afterwards, an antipyretic analgesic is advised to decrease flu-like symptoms. Evaluatepatients at least every second year of the treatment period. Contraindications History ofhypersensitivity to natural or recombinant interferon beta, or to any of the excipients; treatmentinitiation in pregnancy; current severe depression and/or suicidal ideation. PrecautionsInform patients of most common adverse reactions. Use with caution in patients withprevious 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 oftherapy. Administer with caution in patients with a history of seizures and those receivinganti-epileptics, particularly if epilepsy is not adequately controlled. Closely monitor patientswith cardiac disease for worsening of their condition during initiation of therapy. Patientsshould use an aseptic injection technique and rotate injection sites to minimise risk of injectionsite necrosis. If breaks in skin occur, patients should consult their doctor before continuinginjections. If multiple lesions occur, discontinue Rebif until healed. Use with caution in patientswith history of significant liver disease, active liver disease, alcohol abuse or increased serumALT. Monitor serum ALT prior to the start of therapy, at months 1, 3 and 6 and periodicallythereafter. Stop treatment if icterus or symptoms of liver dysfunction appear. Treatment haspotential to cause severe liver injury including acute hepatic failure. Full haematologicalmonitoring is recommended at months 1, 3 and 6 and periodically thereafter. All monitoringshould be more frequent when initiating Rebif 44μg. New or worsening thyroid abnormalitiesmay occur. Thyroid function testing is recommended at baseline and if abnormal every 6–12months. Use with caution in, and closely monitor patients with, severe renal and hepatic failureor severe myelosuppression. Serum neutralising antibodies may develop and are associatedwith reduced efficacy. If a patient responds poorly and has neutralising antibodies, reassesstreatment. Use with caution in patients receiving medicines with a narrow therapeuticindex cleared by cytochrome P450. Women of childbearing potential should use effectivecontraception. Limited data suggest a possible increased risk of spontaneous abortion. Duringlactation, either discontinue Rebif or nursing. If overdose occurs, hospitalise patient and givesupportive treatment. Side effects In the case of severe or persistent undesirable effects,consider temporarily lowering or interrupting dose. Very common: flu-like symptoms, injectionsite 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 sideeffects include: injection site necrosis, hepatic failure, hepatitis with or without icterus, severeliver injury, anaphylactic reactions, angioedema, erythema multiforme, erythema multiformelikeskin reactions, seizures, thromboembolic events, thrombotic thrombocytopenicpurpura/haemolytic uremic syndrome, suicide attempt, Stevens–Johnson syndrome,dyspnoea, retinal vascular disorders. Consult the Summary of Product Characteristicsfor more information relating to side effects. Legal category POM. Price Rebif 8.8μgand 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 and 22μg: 6 (0.2ml) +6 (0.5ml) pens – £552.19. Rebif 22μg: 12 pens (0.5ml) – £624.77. Rebif 44μg: 12 pens(0.5ml) – £813.21. Rebif 8.8μg/0.1ml and 22μg/0.25ml: 2 cartridges – £406.61. Rebif22μg/0.5ml: 4 cartridges – £624.77. Rebif 44μg/0.5ml: 4 cartridges – £813.21. Forprices in Ireland, consult distributors Allphar Services Ltd. Marketing AuthorisationHolder and Numbers Merck Serono Europe Ltd, 56 Marsh Wall, London, E149TP; EU/1/98/063/007; 003; 006; 017; 013; 016; 010; 008; 009. For furtherinformation contact: UK: Merck Serono Ltd, Bedfont Cross, Stanwell Road, Feltham,Middlesex, TW14 8NX. Tel: 020 8818 7373. Republic of Ireland: Merck Serono,4045 Kingswood Road, Citywest Business Campus, Dublin 24. Tel: 01 4687590.Date of Preparation July 2010.Adverse events should be reported. Reporting forms andinformation can be found at www.yellowcard.gov.uk. In theRepublic 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: medinfo.uk@merckserono.net.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.Date of Preparation: August 2010REB10–0231Teriflunomide blocks de novopyrimidine synthesis, which inhibitsthe replication and function of activated,but not resting, lymphocytes.The study randomised 1,088 patientswith relapsing MS to teriflunomide(7mg or 14mg) or placebo, once dailyfor 108 weeks.Results showed that both doses ofteriflunomide reduced the primaryendpoint of annualised relapse rate(ARR) by 31.2%, from 0.539 withplacebo to 0.37 with the 7mg doseand to 0.369 with the 14mg dose.There was also a significant increasein the time to first relapse of 29.8%with the higher dose of teriflunomide,and a 30% reduction in disabilityprogression. In addition, MRI showssignificant reduction in diseaseactivity with active treatment.“This is somewhat happy news,”said Paul O’Connor, from theUniversity of Toronto, Canada, as hereported the findings. He noted thatteriflunomide was well tolerated witha similar number of patients reportingadverse events as with placebo.Nausea, diarrhoea and minor hairthinning were more common withactive therapy. “Altogether, these observationsindicate that teriflunomide isa safe and effective new oralmonotherapy for relapsing MS,” heconcluded.Study confirms anti-JCV antibodiesin natalizumab-treatedpatients developing PMLAround half of MS patients treatedwith natalizumab have antibodies toJC virus (JCV), according to resultsfrom the largest cohort yet to look atthis issue. JCV infection is one of thekey factors necessary for the developmentof PML, so detection of anti-JCVantibodies in blood may be a usefultool to identify previous or ongoingJCV infection in order to stratify PMLrisk in MS patients treated with natalizumab.A novel two-step enzyme-linkedimmunosorbent assay (ELISA) wasused to detect anti-JCV antibodies inblood from natalizumab-treatedpatients enrolled in TYSABRI safetystudies. A chi-square test was used toassess associations between factorsand prevalence of anti-JCV antibodies.Results showed a seropositivity rateof 48.0%. There was an increasingprevalence of anti-JCV antibodies inmen compared to women. There wasalso an increasing prevalence withage, regardless of gender. Treatmentwith natalizumab and prior treatmentwith immunosuppressants did notappear to affect the prevalence ofanti-JCV antibodies.Reporting the findings, MeenaSubramanyam, from Biogen Idec,said, “Together, these data representone of the largest cohorts of MSpatients evaluated for the presence ofanti-JCV antibodies, demonstratingan overall prevalence of anti-JCV antibodiesof approximately 50 to 60%and delineating the prevalence byfactors such as age and gender.”He noted that large, prospectiveclinical studies are underway toexpand on previous observationsthat antibodies to JCV weredetected in all 17 of 17 MS patientsprior to being diagnosed withprogressive multifocal leukoencephalopathy(PML), to determinethe potential utility of the ELISA testto stratify PML risk in natalizumabtreatedpatients.Survey suggests healthcareprofessionals may underestimatemobility loss in MS patientsHealthcare professionals mayunderestimate the extent of mobilityimpairment in patients with MS,according to a new survey. Thesurvey, commissioned by BiogenIdec, of 180 healthcare professionalsfrom Canada, France, Germany,Spain, Sweden and the UK showedthat 56% considered that their MSpatients experience some loss ofmobility, which is lower thanpublished data which suggest up to85% of people with MS sufferimpaired mobility.A second survey of 436 MS patientsillustrated the impact of impairedmobility. Almost three-quarters (72%)said their mobility problems had hadsignificant impact on their workinglives and nearly two-thirds (64%) hadlost earnings due to MS-relatedmobility issues.Professor Shibeshih Belachew,from the University of Liege, Belgium,said, “Loss of mobility can have ahuge impact on all aspects of life forpatients living with MS. It has physicaland psychological effects that candrastically reduce patients’ ability towork.” He suggested that the surveyfindings indicate the need for greaterdialogue about mobility issuesbetween patients and healthcareprofessionals. Mobility impairmentcan start early in MS, with the surveyshowing that 45% of patients reportedmobility issues within the first monthafter being diagnosed.Early identification and managementof mobility issues, includingexercise and physical therapy, canhelp to improve quality of life forpeople with MS, Professor Belachewconcluded. l42 > ACNR > VOLUME 10 NUMBER 5 > NOVEMBER/DECEMBER 2010

EVENTS DIARYTo list your event in this diary, email brief details to John Gustar at editorial@acnr.co.uk by 6th December, 20102010NovemberMotivating the Unmotivated1 November, 2010; Derby, UKT. 01332 254679www.ncore.org.ukManagement of Adult Central Nervous SystemTumours3 November, 2010; London, UKwww.bir.org.ukParkinson's Study day3 November, 2010; Derby, UKT. 01332 254679www.ncore.org.ukInternational Symposium on Nitric Oxide-CyclicSignal Transduction in Brain4-6 November, 2010; Valencia, SpainE. catedrasg@cac.eswww.fundacioncac.es/catedrasgClinical Reasoning in Soft Tissue Repair:Using the evidence to maximise recovery usingmanual therapy, exercise and electrotherapy6 November, 2010; Edinburgh, Scotlandwww.physiouk.co.ukMS Trust Annual Conference 20107-9 November, 2010; Kenilworth, UKT. 01462 476700F. 01462 476710E. info@mstrust.org.ukPosture & Balance in Neurological Conditions– Upper Limb Assistant10 November, 2010; Derby, UKT. 01332 254679www.ncore.org.ukOZC – Communication, Assessment andRehabilitation11 November, 2010; Ely, UKT. 01353 652173E. Rachel.everett@ozc.nhs.ukUKABIF Annual Conference11 November, 2010; London, UKT. 01752 601318E. ukabif@btconnect.comAn Introduction to Bobath Concept (Module 3)11-12 November, 2010; Derby, UKT. 01332 254679www.ncore.org.ukHow to do Cognitive Rehabilitation13 November, 2010; Gatwick Airport, UKE. enquiries@braintreetraining.co.ukwww.braintreetraining.co.ukClinical update of sleep disorder and the brain15 November, 2010; London, UKT. 020 7290 2984E. sleep.disorders@rsm.ac.ukwww.rsm.ac.uk/academ/slb01.phpwww.rsm.ac.uk/sleepNanoBioTech-Montreux 201015-17 November, 2010; Montreux, Switzerlandwww.nanotech-montreux.comThe West of England Seminars in AdvancedNeurology (WESAN)18-19 November, 2010; Exeter, UKE. cgardnerthorpe@doctors.org.uk3rd International Conference on FixedCombination in the Treatment of Hypertension,Dyslipidemia and Diabetes Mellitus18-20 November, 2010; Brisbane, AustraliaT. +41 (0)22 5330 948F. +41 (0)22 5802 953E. fixed2010@fixedcombination.com1st Rio International Eating Disorders andObesity Conference19-20 November, 2010; Rio de Janeiro, BrazilE. anne.haylock@markallengroup.comElectrotherapy Update: Current Concepts inElectrical Stimulation (Study Day 1)20 November, 2010; Farnborough, UKwww.physiouk.co.ukElectrotherapy Update: Current Concepts inTissue Repair (Study Day 2)21 November, 2010; Farnborough, UKwww.physiouk.co.ukCervical Auscultation23 November, 2010; Derby, UKT. 01332 254679www.ncore.org.ukMotivational Interviewing25 November, 2010; Derby, UKT. 01332 254679www.ncore.org.ukEvolving MS Services26 November, 2010; Liverpool, UKT. 0208 438 0809E. pcrossman@mssociety.org.ukParkinson’s Disease Consultants Masterclass24-26 November, 2010; Bristol/Bath, UKT. 01872 225552E. info@redpublish.co.ukwww.redpublish.co.uk/courses6th Essential Neuro MRI Course27 November, 2010; Liverpool, UKT. 0151 5295416/5552E. essentialneuromri@hotmail.co.ukSpR Forum: Neurology28-29 November, 2010; Manchester, UKT. 01202 201223Encephalitis Professional Seminar:Some Solutions and Emerging Changes29 November, 2010; London, UKT. 01635 692583E. alina@encephalitis.infowww.encephalitis.info/Community/NewsEvants/Events.aspxPosture & Balance in Neurological Conditions– Upper Limb, Qualified29 November, 2010T. 01332 254679www.ncore.org.ukThe Birmingham Neurosurgery Meeting30 November – 1 December 2010;Birmingham, UKT. 0114 225 9057E. academia.bbmuk@bbraun.comwww.aesculap-academia.co.uk5th UK Stroke Forum Conference30 November – 2 December 2010;Glasgow, ScotlandE. sally.atkinson@stroke.org.ukwww.ukstrokeforum.orgDecemberAnatomy & Mobilisation of Hands & Feet forAssistants1 December, 2010; Derby, UKT. 01332 254679www.ncore.org.ukUniversity Classes in Multiple Sclerosis VII1 December, 2010; Fiuggi, ItalyE. m.friedrichs@charcot-ms.eduwww.charcot-ms.eduPractitioner on Trial2 December, 2010; Derby, UKT. 01332 254679www.ncore.org.ukThe maternal embryonic interface2-3 December, 2010; Valencia, SpainE. catedrasg@cac.eswww.fundacioncac.es/catedrasgEuropean Charcot Foundation Lecture2-4 December, 2010; Fiuggi, ItalyE. m.friedrichs@charcot-ms.eduwww.charcot-ms.eduOZC – Understanding Brain Injury3 December, 2010; Ely, UKT. 01353 652173E. Rachel.everett@ozc.nhs.ukMA Healthcare 8th Bipolar Disorder Conference3 December, 2010; London, UKT. 020 7501 6762www.mahealthcareevents.co.ukAttention & Information Processing:Advanced Cognitive Rehabilitation Workshop3-4 December, 2010;Gatwick Airport, London, UKE. enquiries@braintreetraining.co.ukwww.braintreetraining.co.uk3rd National Sleep Disorders Conference7 December, 2010; London, UKE. anne.haylock@markallengroup.comKinetic Contol: Theory & Concepts7-8 December, 2010; Derby, UKT. 01332 254679www.ncore.org.ukBritish Institute of Radiology: Imaging in Stroke–Update8 December, 2010; London, UKE. British_Institute_of_Radiology@mail.vresp.comThe 7th International Congress on MentalDysfunctions & Other Non-Motor features inParkinson's Disease (MDPD 2010)9-12 December, 2010; Barcelona, SpainT. 41 229 080 488, F. 41 229 069 140E. msaragosti@kenes.comwww.kenes.comBiochemical Society Conference:Models of dementia16-17 December, 2010; Cambridge, UKE. elizabeth.faircliffe@biochemistry.orgwww.biochemistry.org/MeetingNo/SA120/view/Conference2011JanuaryCognitive Rehabilitation Workshop14-15 January, 2011; Gatwick Airport, London, UKE. enquiries@braintreetraining.co.ukwww.braintreetraining.co.ukBritish Paediatric Neurology AssociationConference26-28 January, 2011; Bolton, UKT. 01204 492888E. info@bpna.org.ukSpecialist Rehabilitation Course27-28 January, 2011; Derby, UKT. 01332 724735E. Amy.Harte@nottingham.ac.ukHow to do Cognitive Rehabilitation29 January, 2011; Gatwick Airport, London, UKE. enquiries@braintreetraining.co.ukwww.braintreetraining.co.ukFebruaryElectrotherapy Update: Current Concepts inElectrical Stimulation (Study Day 1)5 February, 2011, Elstree, UKwww.physiouk.co.ukElectrotherapy Update: Current Concepts inTissue Repair (Study Day 2)6 February, 2011; Elstree, UKwww.physiouk.co.uk112th Meeting of theBritish Neuropathological SocietySymposium:Organiser:Speakers:January 5-7th 2011Institute of Child Health, Guilford Street,London WC1N 1EH“New Perspectives in Multiple Sclerosis”Professor Kenneth Smith, London, UKProfessor Richard Reynolds, London, UKDr Klaus Schmierer, London, UKDr Don Mahad, Newcastle, UKProfessor Kenneth Smith, London, UKProfessor Robin Franklin, Cambridge, UKAlfred Meyer Memorial Lecture: Professor Hans Lassmann,Brain Research Institute, Vienna, Austria• Full programme of talks and posters• The Society Dinner to be held at The Worshipful Company ofButchers, Butchers' HallWe welcome Neuropathologists, Neurologists andNeuroscientists to a meeting attracting a wide range of speakersfrom the UK and abroad. Trainees in Neuropathology andNeurology are particularly encouraged to attend. Join us for a fullacademic programme with an excellent opportunity to meet anddiscuss professional and academic matters.Full details:http://www.bns.org.uk/http://www.ich.ucl.ac.uk/education/short courses/courses/2T 79ACNR > VOLUME 10 NUMBER 5 > NOVEMBER/DECEMBER 2010 > 43

CONFERENCE REPORTSWorld Parkinson CongressConference details: 28 September-1 October, 2010; Glasgow, UK. Reviewed by: Patrick Lewis, UCL Institute of Neurology.The second World Parkinson Congresstook place at the Scottish Exhibition andConference Centre in Glasgow from the28 September to 1 October, in a venue madefamous by the likeness of its main hall to ametal armadillo. The World ParkinsonCongress brings together several thousandresearchers, clinicians, care givers and patients,providing a distinct forum where all the peoplestudying and impacted by Parkinson’s canexchange experiences, ideas and the latestresearch. This is by no means an easy task, asthe different constituencies have very differentexpectations of a conference such as this but,having attended both of the Congresses held todate (the last one was in Washington DC in2006), I have been impressed by how well theWPC achieves this.The Congress, co-chaired by Andrew Lees(UCL Institute of Neurology, London UK) andStanley Fahn (Columbia University, New YorkUSA) opened, on the Tuesday, with a plenarysession that emphasised the range of participantsat the meeting. This included an introduction byGavin Hastings, former captain of the Scottishand British Lions rugby teams, during which hegave a touching description of his wife developingand living with Parkinson’s.On to the conference itself and, as is clearfollowing a cursory glance at the academicliterature over the last 12 months, we live inexciting times with regard to research into thegenetic and cellular basis of Parkinson’s, withmajor advances occurring, most notably in thegenetic definition of this disorder. This wasunderlined by a presentation from HaydehPayami (Wadsworth Center, New York USA)following on from her recent Nature Geneticspaper (Hamza et alia) describing a genomewide association study for idiopathicParkinson’s disease. Her team are interrogatingthe data generated for this study, and claim tohave discovered a possible gene locus for theprotective impact of caffeine in someParkinson’s patients. Although this was verymuch a preliminary report, and much morework is needed to confirm the finding, itoffered an intriguing glimpse of what pharmacogeneticscan offer.A highlight of the first morning was a superbpresentation by David Iverson, a journalist fromSan Francisco who has been diagnosed withParkinson’s, and whose father and brother bothdeveloped the disease. He has made a documentaryabout his experiences of Parkinson’swhich is available on the PBS website(http://www.pbs.org/wgbh/pages/frontline/parkinsons/), and I would encourage readers tovisit this. It was particularly interesting to hearhow someone deals with the probability thathe or she has an inherited form of the disease,and the decisions that they face in terms ofwhether or not to try and identify what iscausing the disease in their family.Continuing the genetics theme, there weresome fascinating talks on altered rates ofcancer in patients with mutations in LRRK2, themost common genetic cause of Parkinson’sdisease. Susan Bressman at the Beth IsrealMedical Center in New York and RivkaInzelberg of the Meir Hospital in Haifa bothpresented data showing that the commonG2019S mutation of LRRK2 is linked to anincreased rate in cancer (the New York study,by Saunders-Pullman and co-workers, has justbeen published). The balancing act betweencell death, manifesting as neurodegeneration,and cell proliferation, manifesting as cancer,and their links to monogenic forms of diseaseis one that is of increasing interest to cell biologistsresearching PD, and this will onlyencourage them to redouble their efforts.Another hot topic that was the subject ofseveral talks in Glasgow was the possibility thatalpha synuclein pathology in Parkinson’s maybe spreading via a prion-like mechanism.Research into this exploded following thedescription of Lewy body pathology spreadinginto fetal grafts implanted into the brains ofpatients (see the review by Brundin et alia fordetails), with a number of researchers usingcell and animal models to try to dissect themechanism of propagation. Again, this is anaspect of Parkinson’s that we are only justbeginning to understand, but it is encouragingto see some really outstanding work inprogress.Stem cells, and their potential to be used asreplacement therapy for human disease, are anemotive subject for patients, for clinicians, forresearchers and for society. There were severalvery impressive reports, on the clinical use offoetal transplants, the future use of stem cells inParkinson’s and on the basic biology of stemcells. Patrick Brundin from the University ofLund, Sweden, gave a comprehensive report onwhere transplants stand as a clinical treatmentnow, highlighting their benefits and some of thepitfalls that have been encountered. OleIsaacson (Harvard University, Boston USA) andLorenz Studer (Sloan-Kettering MemorialCentre, New York USA) gave a pair of inspirationalpresentations on stem biology,describing the derivation of dopaminergicneurons for replacement and for modeling thedisease process in cell culture (see Kriks andStuder, 2009 for a review of this). These wereparticularly timely presentations as the FDAhave just licensed the first stem cell trial inhumans, to be carried out on spinal cord injurypatients(seehttp://www.bbc.co.uk/news/health-11517680),and it is only a matter of time before similarapproaches are applied to neurodegenerativediseases such as Parkinson’s.In addition to all the research and patientnews, there was a strong presence from theleading charities involved in funding researchinto Parkinson’s and patient support groups.Parkinson’s UK, The Michael J. Fox Foundation,and the Cure Parkinson’s Trust all had verygood and informative stalls. As for the research,the Congress provided a very useful forum fordiscovering where the charities are focusingtheir efforts and what funding mechanisms areavailable.In summary, I found the Congress bothenlightening and satisfyingly different from themajority of conferences on Parkinson’s. Fromthe point of view of basic researcher, the interactionbetween the patients, the clinicians andresearchers is both a valuable and humblingexperience, bringing into clear focus thehuman faces of the disease you areresearching and I am looking forward to thenext Congress, to be held in Quebec, Canada, in2013. lAcknowledgementsThe author would like to thank Julia Fitzgerald for criticalcomments.Dr Lewis is a Parkinson’s UK research fellow, and is fundedby Parkinson’s UK, the Michael J. Fox Foundation and theBrain Research Trust.ReferencesBrundin P, Li JY, Holton JL, Lindvall O, Revesz T. Research inmotion: the enigma of Parkinson's disease pathologyspread. Nat Rev Neurosci. 2008 Oct;9(10):741-5.Hamza TH, Zabetian CP, Tenesa A, Laederach A,Montimurro J, Yearout D, Kay DM, Doheny KF, Paschall J,Pugh E, Kusel VI, Collura R, Roberts J, Griffith A, Samii A,Scott WK, Nutt J, Factor SA, Payami H. Common geneticvariation in the HLA region is associated with late-onsetsporadic Parkinson's disease. Nat Genet. 2010Sep;42(9):781-5Kriks S, Studer L. Protocols for generating ES cell-deriveddopamine neurons. Adv Exp Med Biol. 2009;651:101-11Saunders-Pullman R, Barrett MJ, Stanley KM, Luciano MS,Shanker V, Severt L, Hunt A, Raymond D, Ozelius LJ,Bressman SB. LRRK2 G2019S mutations are associatedwith an increased cancer risk in Parkinson disease. MovDisord. 2010 Sep 3. [Epub ahead of print]Image – Clyde Auditorium, freely available image fromWikipedia44 > ACNR > VOLUME 10 NUMBER 5 > NOVEMBER/DECEMBER 2010

CONFERENCE REPORTS20th Congress of the European Neurological SocietyConference details: 19-23 June, 2010; Berlin, Germany.It was towards the end of June, whensummer finally arrived in Central Europetoo and the European Neurological Societygathered for their 20th anniversary meeting inBerlin, Germany. More than 3000 participantsattended the meeting which again not onlyoffered lectures held by the best experts intheir respective fields of neurology during officialsymposia, but also high-quality educationin the form of teaching courses, workshopsand practical sessions. From the nearly 900abstracts submitted, 125 were selected for anoral presentation. As in the past, the postersexhibited were highlighted by the popularposter walks, with an expert leading thediscussion.The topics treated during the meetingencompassed all fields in the neurologicalscience and ranged from scientific researchto clinical treatments. How rich thepresented content was, is shown by thefollowing summary.PathogenesisMicro(mi)RNAs involved in the differentiationand regulation of CD4+ cells have been shownto play a role in relapsing remitting multiplesclerosis (RRMS); this might contribute tofinding new therapeutic targets. On thecontrary, the search for genetic risk factorsinvolved in the susceptibility to progressivecourse of MS remains inconclusive.Nevertheless, novel targets have been identified,such as the HLA class II region, and representpotential candidates for further studies.Calcitonin gene-related peptide (CGRP),which is a key molecule in the pathogenesis ofmigraine, has been shown to trigger migrainelikeattacks in migraine patients with andwithout aura.Gelatinase matrix metalloproteinases(MMP)-2 and 9 provide a link betweenneuronal degeneration and skin alteration inpatients with amyotrophic lateral sclerosis(ALS). Another study showed a mitochondrialimpairment in skin fibroblasts of patients withALS, which is likely related to oxidative stress.These findings suggest that the skin abnormalitiesmay be a biomarker for monitoring ALS inthe context of neuroprotective treatment trials.Clinical findingsIn myoclonus-dystonia, the clinical spectrumof DYT11 mutations includes patients with anon classical phenotype (i.e., lower limbonset, generalized distribution, and absence offamily history).The clinical characteristics of 1241 ALSpatients included in an Italian prospectiveepidemiological register have been presented.Pyramidal and flail arm phenotypes had thebetter prognosis, while bulbar and respiratoryphenotypes had the worst one. A smaller studyshowed that a more rapid progression wasassociated with a later onset of symptoms inpatients with primary lateral sclerosis (PLS).Compared with patients with Alzheimer’sdisease (AD), patients with frontotemporallobar degeneration (FTLD) are characterisedby a faster cognitive decline, which is independentlyassociated with the languagesubtype and an early memory impairment.In FTLD patients carrying exon 8 delCACTmutation of Progranulin (GRN) gene, cerebrospinalfluid (CSF) levels of total tauprotein, phosphorylated-tau, and β-amyloid 1-42 were normal. This suggests that normal CSFbiomarker may be consistent with a diagnosisof FTLD caused by GRN mutations.NeuroimagingThe assessment of the regional distribution ofdamage to the normal-appearing white matter(NAWM) and gray matter (GM), using quantitativemagnetic resonance (MR) techniques, maycontribute to a phenotypic characterization ofdifferent neurological diseases, including MS,migraine, Leber’s hereditary optic neuropathy(LHON), Parkinson’s disease and atypicalparkinsonisms, Alzheimer’s disease (AD) andother dementias. Furthermore, it may improvethe understanding of specific disease-relatedsymptoms, such as fatigue in MS. The study ofWM damage in AD patients also contributed tothe understanding of atypical forms of earlyonset AD, such as posterior cortical atrophy andlogopenic/phonological progressive aphasia.MR imaging studies have identified objectivemarkers of long-term clinical worsening inpatients with different neurological conditions,such as thalamic damage in patientswith MS and corticospinal tract damage inthose with ALS.ALS patients with mild disability have beenshown to experience a dysfunction of restingstate (RS) connectivity of the sensorimotornetwork. RS fMRI revealed also abnormalitiesof the visual network in LHON patients, whichwere correlated with structural damage alongthe visual pathways and disease duration.ACNR > VOLUME 10 NUMBER 5 > NOVEMBER/DECEMBER 2010 > 45

CONFERENCE REPORTSTreatmentA substantial proportion of relapsing/remittingmultiple sclerosis (RRMS) patients treated withcladribine were free from clinical and radiologicaldisease activity over a short-course treatment(96 weeks). Fingolimod significantlyreduced the annualized relapse rate comparedwith placebo regardless of prior disease-modifyingtherapies. In these patients, interferon β-1b affected the development of permanentblack holes, which is a marker of permanenttissue destruction, at year 2 from active lesionsat year 1, to a similar or better extent than glatirameracetate. Data from the “TYSABRI observationalprogram” showed that MS patientsunder natalizumab exhibit a very low level ofdisease activity and the safety profile is consistentwith that from the preregistration trials.In patients with atrial fibrillation who havealready suffered from a stroke or TIA, dabigatran110 mg was as effective as warfarin, while dabigatran150 mg bid was superior to warfarin.Both dosages of dabigatran also resulted in arelatively low rate of cerebral haemorrhages.Bevacizumab in combination with fotemustineis a promising treatment for recurrent highgrade gliomas with acceptable toxicity.Apart from this excellent opportunity foreducation in cutting-edge neurological scienceand exchange of knowledge and experiences,the meeting’s various social events also offeredthe possibility for more personal conversationsand for meeting colleagues in a relaxed atmosphere.The dinosaurs in the Museum of NaturalHistory watched as leading neurologists fromall over the world mingled with residents andstudents at the occasion of the WelcomeReception. The banquet in the famous TIPI Tentoffered the right ambience for the last eveningof this meeting, which ended the next day againwith high-quality workshops, teaching coursesand two highlight symposia treating hot topicsin neurology. lProf. Massimo Filippi,Neuroimaging Research Unit,Institute of Experimental Neurology,Division of Neuroscience,San Raffaele Scientific Institute and University,Milan, Italy.7th FENS Forum of European NeuroscienceConference details: 3-7 July, 2010; Amsterdam, The Netherlands. Reviewed by: Bauke M. de Jong, MD.PhD.On Saturday July 3rd, neuroscientistsfrom all over Europe, as well ascolleagues from more distant continents,gathered in the RAI Congress Centre inAmsterdam to participate in the openingsceremony of the FENS Forum 2010, the 7thbiannual conference of the Federation ofEuropean Neuroscience Societies. Attendeesthus started to familiarise both with each otherand the conference venue. The latter was characterisedby a spacy atmosphere, not in theleast due to an excellent ordering of posterboards surrounding the exhibition area with alarge central meeting point. Weather was fineand rented bikes were widely used, next topublic transportation. The oral forum presentationscomprised 9 plenary sessions, 10 speciallectures and 7 blocks of 8 parallel 90 minsymposia with 4 speakers each. Seven workshopswere given before the opening. Themesreflected the wide scope of topics at molecular,cellular, neuronal network and behaviourallevels, aimed at understanding bothnormal brain function and brains affected bydisease. In this respect, the symposium was ofinterest for basic neuroscientists as well asneurological and psychiatric disciplines.In particular the synergy of the four presentationsin the symposia provided an excellentforum for enhancing synergy and generatingnovel points of view. As a symposium organiser,I personally experienced such positiveinteraction between contributing speakers inthe symposium ‘Prefrontal and parietalpremotorcontributions to free choice selection’.Our symposium illustrated research on afundamental level, providing a balancedperspective on a hierarchy in action selection,reaching from response freedom of singleneurons at early sensorimotor processingstages to action selection experienced as theresult of free will. Sensing a free will is closelyrelated to the feeling of ownership of one’sbody. In the symposium of Henrik Ehrsson onthis topic, the illusion of feeling an observedrubber hand provided a starting point forfuture perspectives on practical applicationsto enhance the sense of prosthetic limbs asbeing a ‘real’ part of one’s own body.The fMRI work of Maurizio Corbetta instroke patients can also be placed at the interfacesof basic neuroscience, clinicalneurology and rehabilitation. Identifying sitesof interaction between separate resting statenetworks involved in attention and controllingarm movement, respectively, distant fromthe lesion location, helped to predict recoveryand functional outcome. Such new brain scantechnology may thus offer new approaches intreatment and targeted strategies for rehabilitation.With regard to molecular aspects ofstroke treatment, Denis Vivien presentedresults from animal experiments demonstratingthat immunotherapy with antibodiesmight prevent secondary brain damagefollowing stroke, including side-effects ofacute trombolysis.Advances at molecular level of neuronalfunctioning were addressed in plenarylectures concerning, for example, the role ofadhesion molecules in synaptic plasticity andregeneration (Melitta Schachner), and taupathology in neurodegenerative disorders(Maria Spillantini). In a symposium onmicroRNAs, new data on their role in finetuningsynaptic development and the consequenceof deregulation for the emergence ofneurodegeneration in Alzheimer’s andParkinson’s disease were addressed.Clearly, given the quality of presentedresearch, an increasing number of neuroscientistsfrom outside Europe can also beexpected to attend future FENS conferences.http://forum.fens.org/2010. l46 > ACNR > VOLUME 10 NUMBER 5 > NOVEMBER/DECEMBER 2010

NEWS REVIEWMerck Serono to Appeal CHMP Opinion onCladribine Tablets in MSMerck Serono has notified the European MedicinesAgency (EMA) of its intention to request a reexaminationof the opinion issued by theCommittee for Medicinal Products for Human Use(CHMP) in September regarding Cladribine Tabletsas a treatment for relapsing-remitting multiplesclerosis (MS).“We are committed to the potential of CladribineTablets to meet an unmet medical need and tomake this treatment option available to patientswho could benefit from it,” said Elmar Schnee,President of Merck Serono. “We will continueworking closely with the CHMP to address thecommittee’s concerns and pursue a way forward.”In accordance with European regulations,applicants may appeal a CHMP opinion providedthey notify the EMA in writing of their intention toappeal within 15 days of receipt of the opinion. Theapplicant must provide to the agency with detailedThe government has decided not to make genericprescription of NHS drugs compulsory.Supporters of The National Society forEpilepsy’s (NSE’s) ‘Count Epilepsy Out’ campaignsent campaign postcards and letters, earlier thisyear, to the Minister of State for Health saying thatcutting costs on epilepsy drugs doesn’t add up. Itcould provoke seizures or side effects – with ahigh cost to both the NHS and the person withepilepsy. The NSE also submitted an in-depthresponse to the consultation laying out thepotential dangers of generic substitution topeople with epilepsy. This backed up an earlierreport that was formative in the government’sdecision to consult on their plan.This campaign contributed to the government’srejection of the scheme. In the Department ofHealth press release Health Minister Lord Howesays, ‘We have listened to the concerns from thepublic, patients and other interested parties… It isgrounds for a re-examination of the opinion within60 days after receipt of the opinion.Cladribine Approved in AustraliaOn 3rd September, The Australian TherapeuticGoods Administration (TGA) approved CladribineTablets for the treatment of relapsing-remittingmultiple sclerosis. Cladribine Tablets will beregistered in Australia under the trade nameMovectro®.Cladribine Tablets, also under the trade nameMovectro, became the first oral MS treatment in theworld to gain marketing authorisation when healthauthorities in Russia approved it in July 2010.For further information contact Merck Serono onE. medinfo.uk@merckserono.net orT. +44 (0)20 8818 7373.Government Listens to Epilepsy Campaignersnot clear whether the proposals would haveprovided a substantial benefit to the NHS.’People with epilepsy have been nervous aboutthe long wait since the Department of Health’sconsultation closed in March 2010. Breakthroughseizures can be caused if their drug is swapped fornon-clinical reasons. One breakthrough seizure isdevastating and could cause serious injury andharm, rob someone of their driving licence andaffect their job.“Thank you to all our supporters who sent apostcard and wrote to the Minister of State,” saidNSE chief executive Graham Faulkner. “Workingtogether we have made a big contribution to agreat result for people with epilepsy. This doesshow that we can make a difference.”For the full guidance, seehttp://guidance.nice.org.uk/Type/TA/PublishedMilestone Ruling forAlzheimer's DiseasePatients AnnouncedThe National Institute for Health and ClinicalExcellence (NICE) has announced new draftguidance which represents a significant steptowards ensuring patients with Alzheimer's diseasein England and Wales receive treatment for theircondition, from the early stages of disease.New draft NICE guidance recommends thatacetylcholinesterase inhibitors, includingAricept(R) (donepezil), should be made availableto patients in England and Wales as options formanaging mild to moderate disease. This is asignificant change to an earlier 2006 NICE rulingwhich restricted access to these medicines forpatients with moderate disease only."This provisional decision by NICE is animportant milestone for the thousands ofAlzheimer's patients currently unable toreceive treatment for their condition. Earlydiagnosis and access to medication is criticalto help reduce both the short and long-termimpact of this devastating condition onpatients, families and carers." says ProfessorRoy Jones from The Research Institute for theCare of Older People (RICE) Centre, RoyalUnited Hospital, Bath, UK.The announcement supports the Departmentof Health's National Dementia Strategy (NDS).The NDS encourages the active management ofAlzheimer's disease from its earlier stages tominimise the burden of the condition onpatients, their carers and society. In addition, theneed for greater access to dementia-specifictreatments is in line with the recent Alzheimer'sDisease International report which calls forgovernments to make dementia a higher healthpriority, to help tackle the huge burden of thedisease. The draft NICE recommendations onAlzheimer's disease treatment will now go intoconsultation, with final guidance expected inearly 2011.For the full guidance, seehttp://guidance.nice.org.uk/Type/TA/PublishedAdvancing Scientific Understanding of AutismThe Wales Autism Research Centre at the Schoolof Psychology, Cardiff University, has beenestablished with support from the charitiesAutism Cymru and Autistica, and from the WelshAssembly Government.Autism affects up to one child in every 100.Those affected have difficulties incommunicating, forming relationships andmaking sense of the world. The new Centre willresearch new areas in identification, diagnosis,development and intervention.Director of the Centre, Professor SusanLeekam said, “The launch of the Wales AutismResearch Centre marks the beginning of anexceptional opportunity to advance scientificresearch. We will not only be carrying outinternationally competitive research projects butalso helping to build evidence-based policy andpractice. This mission is supported bypartnerships between scientists, practitionersand government policy makers, and makes thepurpose of this research centre unique in theUK”.The Centre already has a number of newprojects underway. These include research onsensory processing using neuroimagingtechniques, research on clinical symptoms anddiagnostic tools and research on the effects ofinterventions. The team has also beencontributing to a schools training programme,evaluating diagnosis services, assisting withawareness-raising materials and investigating thepotential for new databases of information.Researchers at the Centre have also set upnew collaborations and networks with theUniversity’s pioneering Cardiff University BrainResearch Imaging Centre (CUBRIC) and CardiffNeurosciences Centre.The Welsh Assembly Government’s StrategicAction Plan for Autism Spectrum Disorder isbelieved to be the first of its kind anywhere inthe world. Uniquely, the Centre works withpractitioners and government policy makerswithin this action plan to integrate researchevidence with policy and practice. It also aimsto raise public and professional awareness ofautism research, highlighting the importance ofreliable, scientific evidence and breaking downsome of the myths surrounding it.For more information T. 02920 879074ACNR > VOLUME 10 NUMBER 5 > NOVEMBER/DECEMBER 2010 > 47

Confidence to takeConfidenceactionto takeeveryday● Copaxone has similar efficacy to high dose interferon-betaaction everyday1-3● Copaxone is simple and convenient● Copaxone can help patients maintain a working life 4COPAXONE® (glatiramer acetate)PRE-FILLED SYRINGE PRESCRIBING INFORMATIONPresentation – Glatiramer acetate 20mg solution for injectionin 1ml pre-filled Syringe. Indication – Treatment of patientswho have experienced a well-defined first clinical episodeand are determined to be at high risk of developing clinicallydefinite multiple sclerosis (MS). Reduction of frequency ofrelapses in relapsing-remitting MS in ambulatory patients. Inclinical trials this was characterised by at least two attacks ofneurological dysfunction over the preceding two-year period.Dosage and administration – 20mg of glatiramer acetate (onepre-filled syringe) administered sub-cutaneously once daily.Children (12 - 18 years) no specific studies. Limited publisheddata suggest the safety profile of 20mg administered subcutaneouslyonce daily is similar to that seen in adults.Children (2/100) higher incidence in the Copaxonetreatment group than in the placebo group: nausea, anxiety,rash, back pain, chills, face oedema, vomiting, skin disorder,lymphadenopathy, tremor, eye disorder, vaginal candidiasis,weight increased. Rarely: anaphylactoid reactions. pleaserefer to the SpC for a full list of adverse effects. Overdose –Monitor, treat symptomatically. Pharmaceutical Precautions– Store Copaxone in refrigerator (2ºC to 8ºC). If the prefilledsyringes cannot be stored in a refrigerator, they canbe stored at room temperature (15ºC to 25ºC) once for up toone month. Do not freeze. Legal Category – poM. PackageQuantity and Basic NHS Cost – 28 pre-filled syringes ofCopaxone: £513.95. Product Licence Number – 10921/0023Further Information – Further medical information availableon request from Teva pharmaceuticals Limited, The GateHouse, Gatehouse Way, aylesbury, Bucks, Hp19 8DB. Date ofPreparation – December 2009.Adverse events should be reported.Reporting forms and information can befound at www.yellowcard.gov.uk.Adverse events should also be reported toTeva Pharmaceuticals Ltd ontelephone number: 01296 719768.Date of preparation: May 2010C0210/610aStanding up to RRMS everyday