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Make a lasting impression...…when adjusting therapyThe 24-hour clinical effect of once-daily Azilect gives patientsimproved motor control first thing in the morning, evenbefore their first dose of levodopa – an effect that was notseen with multi-dose entacapone. 1,2For more information visit www.azilect.co.ukSimple 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 adjunctto levodopa in patients with end of dose fluctuations. Dosageand administration: Oral, 1mg once daily taken with or withoutfood and with or without levodopa. Elderly: No change in dosagerequired. Children and adolescents (1%: headache, influenza, skin carcinoma, leucopenia, allergy,depression, hallucinations, conjunctivitis, vertigo, angina pectoris,rhinitis, flatulence, dermatitis, musculoskeletal pain, neck pain,arthritis, urinary urgency, fever, malaise. 1%: 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 a Specialist Registrar in Neurologyat the National Hospital for Neurology and Neurosurgery, Queen Square,London. He is interested in clinical and experimental neuroimmunology.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.Boyd Ghosh is the Editor of our Conference News section. He is currentlya Specialist Registrar in Southampton having completed a PhD in Cambridgein cognitive neuroscience. His special interests are cognition and movementdisorders, with a particular interest in progressive supranuclear palsy. He iscurrently secretary for the ABN trainees committee.Rhys Davies is the editor of our Book Review Section. He is a consultantneurologist at the Walton Centre for Neurology and Neurosurgery inLiverpool and at Ysbyty Gwynedd in Bangor, North Wales. He has a clinicaland research interest in cognitive neurology.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.Alzheimer’s Society supporter Sir TerryPratchett recognised as a Champion ofAlzheimer’s diseaseAward-winning author and Alzheimer’s Society supporter,Sir Terry Pratchett, has been named Health Champion ofthe Year by the UK’s leading health experts andjournalists. The award, presented at the MedicalJournalists’ Association (MJA) Summer Awards,acknowledges Sir Terry’s tireless campaigning andawareness-raising of dementia-related issues.Sir Terry, who has a rare form of dementia calledPosterior Cortical Atrophy (PCA), said of his award: “I am,of course, very pleased to have won this award but mustpoint out that all I had to do, some years ago, was find out that I had thiswretched disease. It took no courage to freely talk about it in public, indeed,it would have taken more courage to do nothing.” In addition to Sir Terry’saward, Alzheimer’s Society’s national media team beat off strong competitionto be presented with the ‘Health Charity of the Year’ award.Alzheimer’s Society’s Chief Executive, Jeremy Hughes, said: “These twoawards are a testament to the hard work of everyone involved. Theydemonstrate just how far we have come in terms of public awareness ofdementia. There are 750,000 people with dementia in the UK, and it is acondition that is likely to affect all of us in some way. We now need toensure the spotlight is kept on dementia-related issues.’For more information contact: press@alzheimers.org.ukAwards for Innovation and Inspiration inAcquired Brain Injury 2011The United Kingdom Acquired Brain Injury Forum Awards for Innovation andInspiration 2011 in the field of acquired brain injury are now open and thisyear there are new categories to extend the range of work which needs to berecognised in the sector. This years categories are:Innovation by a lawyer/law firm in the field of ABIInnovation by a clinician in the field of ABIInnovation by a care provider in the field of ABIInnovation by a social care worker in the field of ABIInnovation by a educational person or provider in the field of ABIInnovation by a voluntary sector provider or registered charity in the field of ABIThe Stephen McAleese Award for Inspiration by an individual in the field of ABIThe awards were launched last year and the judging panel wereoverwhelmed by the quality and quantity of entries. ‘It goes to show thatalthough you may think that you know what is happening in the sector, thereis a tremendous amount which is not shared – and we hope that theseawards remedy that.’ said Professor Mike Barnes, UKABIF Chair.Nominations may be made by those involved in or benefiting from aproject or piece of work. There is an application form which must becompleted with each nomination and the deadline for submission is 30thSeptember 2011. The awards will be presented at the UKABIF AnnualConference which takes place on 10th November 2011 at The NationalMotorcycle Museum in Birmingham and shortlisted entrants will be offered afree place at this event.Full details and application forms are available on the UKABIF website.– see http://www.ukabif.org.uk/news/3-newsflash/167-ukabif-awards-for-innovation-and-inspiration-2011-Prof Ray Dolan nominated for 2012Santiago Grisolia Chair AwardProfessor Ray Dolan, Director of the Wellcome Trust Centre for Neuroimaginghas been nominated by the Cátedra Santiago Grisolía for the 2012 PrizeSantiago Grisolía Chair. The Santiago Grisolía Chair is awarded to outstandingresearchers and scientists in the field of Biomedicine and Neuroscience.Professor Ray Dolan will give three lectures on a topic related to theneurobiology of cognition, emotion and behaviour and be awarded a silvermedal in the presence of the Highest Authorities of the ValencianCommunity in Spain next year. Professor Dolan said upon receiving the prize:“I am delighted to receive this prestigious award, and all the more so in lightof the illustrious prior recipients.”ACNR > VOLUME 11 NUMBER 4 > SEPTEMBER/OCTOBER 2011 > 3

Image by: 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 Cannabissativa L., (Cannabis leaf and flower) corresponding to 27mgdelta-9-tetrahydrocannabinol (THC) and 25mg cannabidiol(CBD). Each 100 microlitre spray contains: 2.7mg THCand 2.5mg CBD. Indication(s): as add-on treatment, forsymptom improvement in patients with moderate to severespasticity due to multiple sclerosis (MS) who have notresponded adequately to other anti-spasticity medicationand who demonstrate clinically significant improvement inspasticity related symptoms during an initial trial of therapy.Posology and method of administration: oromucosaluse only. Treatment must be initiated and supervised by aphysician with specialist expertise in MS. Direct spray atdifferent sites on the oromucosal surface, changing sitefor each use of product. May take up to 2 weeks to findoptimal dose, review response after 4 weeks of treatment.Re-evaluate long 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:no specific studies but CNS side effects may be morelikely (see Warnings and precautions) Significant hepaticor renal impairment: no specific studies but effectsof Sativex may be exaggerated or prolonged. Frequentclinical evaluation recommended. Contra-indications:hypersensitivity to cannabinoids or excipients. Breastfeeding. Known/suspected history or family history ofschizophrenia/other psychotic illness. History of severepersonality disorder/other significant psychiatric disorderother than depression due to underlying condition.Warnings and precautions: not recommended in patientswith serious cardiovascular disease. Caution in patientswith history of epilepsy/recurrent seizures. THC and CBDare metabolised in the liver. Several THC metabolites maybe psychoactive. Contains approx. 50% v/v ethanol. Riskof falls if spasticity/muscle strength no longer sufficientto maintain posture/gait. CNS side effects e.g. dizziness,somnolence could impact personal safety, e.g. hot foodand drink preparation. Theoretical risk of additive effectwith muscle-relaxing agents, not seen in clinical trials butwarn patients risk of falls may increase. No effect seen onfertility but cannabinoids shown to affect spermatogenesisin animals. Female patients of child-bearing potential/malepatients with a partner of child-bearing potential should usereliable contraception. Patients with a history of substanceabuse may be more prone to abuse Sativex. Withdrawalsymptoms following abrupt withdrawal of long-term Sativexare likely to be limited to transient disturbances of sleep,emotion or appetite. No increase in daily dosage observedin long-term use; self-reported levels of ‘intoxication’ low;dependence on Sativex unlikely. Interactions: no clinicallyapparent drug-drug interactions seen. Co-administrationwith food results in mean increase in C max, AUC and half-life(increase less than between-subject variability in theseparameters). Concomitant ketoconazole increases C maxandAUC of THC (and primary metabolite) and CBD. Increase lessthan between-subject variability. Risk of additive sedationand muscle relaxing effects with hypnotics, sedatives anddrugs with sedating effects. Pregnancy and lactation: donot use in pregnancy unless benefit outweighs potentialrisks. Do not use if breast feeding. Insufficient experience ofeffects on reproduction - use reliable contraception duringtherapy and for 3 months after discontinuation. Effectson ability to drive and use machines: do not drive,operate machinery or engage in any hazardousactivity if experiencing significant CNS side effects;warn patients may cause loss of consciousness.Side effects: very common – dizziness, fatigue;common – anorexia, decreased or increasedappetite, depression, disorientation, dissociation,euphoria, amnesia, balance disorder, disturbance inattention, dysarthria, dysgeusia, lethargy, memoryimpairment, somnolence, blurred vision, vertigo,constipation, diarrhoea, dry mouth, glossodynia,mouth ulceration, nausea, oral discomfort/pain, vomiting,application site pain, asthenia, feeling abnormal/drunk,malaise, fall; uncommon – hallucination, illusion, paranoia,suicidal ideation, delusional perception, syncope,palpitations, tachycardia, hypertension, pharyngitis, throatirritation, upper abdominal pain, oral mucosal disorders e.g.discolouration, exfoliation, stomatitis, tooth discolouration,application site irritation; unknown frequency – psychiatricsymptoms e.g. anxiety and mood changes, transientpsychotic reactions, possible leukoplakia (unconfirmed):inspect oral mucosa regularly 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.2011.05. February 2011.

FROM THE EDITOR...In a very stimulating article, Boris Kotchoubey and colleagues discussdisorders of consciousness and how concepts about this have changed withthe advent of better diagnostic procedures using functional imaging andevoked potentials. They argue that the presence or absence of higher cognitivefunctions should not be seen as the only definition for human consciousness,because lower order systems exist which can remain intact even in the absenceof these higher order functions. Furthermore these lower order systems will stillallow a level of communication to be established and used and as such we maybe missing ways to better treat patients in minimally conscious states.The power of Genome Wide Association Studies (GWAS) to better define theplayers involved in complex genetic disorders is now being realised and in theirarticle Hanne Harbo and Maria Ban discuss this with respect to MS. They showhow international collaborations have managed to find the major genetic riskfactors for MS with the latest instalment in this story being published in theAugust issue of Nature this year. This impressive work has highlighted thosecritical aspects of the immune system that have a role in MS, although as theauthors comment, the next challenge for the consortia is to find the missinghereditability that is still out there.You know that feeling of not being able to quite remember something followedby moments of anxiety that this is the harbinger of a dementing process? In hiscontribution to the ‘Clinical Dilemmas in Neuropsychiatry’, Alex Mitchelldiscusses this topic of subjective memory complaints and its relationship to mildcognitive impairment and dementia. This is a very helpful distillation of asomewhat under-researched area but generally gives me comfort.You know that feeling of not being able...sorry.One of the common misconceptions in the world of medicine is that raisedblood pressure causes headaches, or at least that is what many of my patients tellme. In the article from the Norwegian team of Lars Jacob Stovner, Knut Hagen andErling Tronvik we learn a lot about how higher blood pressures seem to beassociated with less pain and what may underlie this relationship.Neurobehavioural disability (NBD) following head injury is common andoften hard to manage. Nick Alderman describes his experiences of managingsuch patients based on his huge expertise through his work at the National BrainInjury Centre. In his article he not only describes the nature of NBD and itsdestructive force at the individual, family and society level but also how it canbest be assessed and managed.In the Motor Control Series, Leonardo Fogassi and Francesca Roda discussmirror neurons - neurons that were originally described because of their capacityto not only discharge when an animal performs a motor act but also when theyobserve that same act being performed by another animal. The discovery of thesecells has generated much debate and in this article we have an excellentoverview of how this field has developed by a team that has contributed much tothis fascinating area of neurobiology.Heather Angus-Leppan in the ABN section takes us through what may happenif primary care had direct access to MRI for the investigation of headache as wellas discussing the problems of taking on acute neurology with the current numberof UK neurologists. This short article not only highlights the problems but alsosuggests some solutions.We have our usual collection of journal, book and conference reviews - thelatter containing a particularly interesting account by Dr Rosemary Fricker of arecent meeting discussing the different animal models of Parkinson’s Disease. lRoger Barker, Co-Editor.Roger Barker, Co-Editor,Email. Rachael@acnr.co.uk6 > ACNR > VOLUME 11 NUMBER 4 > SEPTEMBER/OCTOBER 2011

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 of ProductCharacteristics (SPC) before prescribing). Vimpat ® Lacosamide ActiveIngredient: Tablets: lacosamide 50 mg, 100 mg, 150 mg and 200 mg.Syrup: lacosamide 15 mg/ml. Solution for infusion: lacosamide 10 mg/ml. Indication: Vimpat is indicated as adjunctive therapy in the treatmentof partial-onset seizures with or without secondary generalisation in patientswith epilepsy aged 16 years and older. Dosage and Administration:Adults and adolescents from 16 years: Recommended starting dose is 50mg twice a day which should be increased to an initial therapeutic dose of100 mg twice a day after 1 week. Maximum daily dose of 400 mg (in two200 mg doses). For solution for infusion: Infused over a period of 15 to 60minutes twice daily. Can be administered i.v. without further dilution. Elderly:No dose reduction necessary. Age associated decreased renal clearancewith an increase in AUC levels should be considered. Paediatric patients: Notrecommended. Patients with renal impairment: No dose adjustment necessaryin mild and moderate renal impairment. Dose adjustment is recommendedfor patients with severe renal impairment and patients with end-stage renaldisease (see SPC). Dose titration should be performed with caution. Patientswith hepatic impairment: No dose adjustment needed in mild to moderateimpairment. In accordance with current clinical practice, if Vimpat has tobe discontinued, it is recommended this be done gradually (e.g. taper thedaily dose by 200 mg/week). Contraindications, Warnings, etc:Contraindications: Hypersensitivity to lacosamide or to any of the excipients.Known second- or third-degree atrioventricular block. Precautions: Lacosamidehas been associated with dizziness.Use with caution in patients with knownconduction problems, severe cardiacdisease or in elderly. Second degreeor higher AV block has been reportedin post-marketing experience. Atrial fibrillation or flutter have been reported inopen-label trials and in post-marketing experience. Patients should be madeaware of the symptoms of second-degree or higher AV block and of thesymptoms of atrial fibrillation and flutter. Patients should be counseled to seekmedical advice should any of these symptoms occur. Excipients in the syrupmay cause allergic reactions (possibly delayed), should not be taken by thosewith fructose intolerance and may be harmful to patients with phenylketonuria.Monitor patients for signs of suicidal ideation and behaviours. Advise patientsand carers to seek medical advice should such signs emerge. Interactions:Prolongations in PR interval with lacosamide have been observed in clinicalstudies. Use with caution in patients treated with products associated withPR prolongation and those treated with class I antiarrhythmic drugs. Strongenzyme inducers such as rifampicin or St John’s Wort may moderatelyreduce the systemic exposure of lacosamide. No significant effect on plasmaconcentrations of carbamazepine and valproic acid. Lacosamide plasmaconcentrations were not affected by carbamazepine and valproic acid.No clinically relevant interaction with ethinylestradiol and levonorgestrel.No effect on pharmacokinetics of digoxin. Pregnancy and Lactation: Shouldnot be used 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 potentially hazardousmachinery until they are familiar with the effects of Vimpat on their ability toperform such activities. Adverse Effects: Very common (≥10%): Dizziness,headache, diplopia, nausea. Common (between 1%-10%): Depression,confusional state, insomnia, balance disorder, abnormal coordination,memory impairment, cognitive disorder, somnolence, tremor, nystagmus,hypoesthesia, dysarthia, disturbance in attention, blurred vision, vertigo,tinnitus, vomiting, constipation, flatulence, dyspepsia, dry mouth, pruritus,rash, muscle spasms, gait disturbance, asthenia, fatigue, irritability, injectionsite pain or discomfort, irritation, fall, skin laceration. The use of lacosamideis associated with dose-related increase in the PR interval. Adversereactions associated with PR prolongation may occur. Please consultSPC in relation to other side effects. Pharmaceutical Precautions:Tablets: None. Syrup: Do not store above 30°C. Use within 4 weeksof first opening. Solution for infusion: Do not store above 25°C. Useimmediately. Legal Category: POM Marketing AuthorisationNumber(s): 50 mg x 14 tabs: EU/1/08/470/001; 100 mg x 14tabs: EU/1/08/470/004; 100 mg x 56 tabs: EU/1/08/470/005;150 mg x 14 tabs: EU/1/08/470/007; 150 mg x 56 tabs:EU/1/08/470/008; 200 mg x 56 tabs: EU/1/08/470/011; Syrup(15 mg/ml) x 200 ml: EU/1/08/470/014; Solution for Infusion(10 mg/ml) x 20 ml: EU/1/08/470/016. NHS Cost: 50 mg x 14tabs: £10.81; 100 mg x 14 tabs: £21.62; 100 mg x 56 tabs: £86.50;150 mg x 14 tabs: £32.44; 150 mg x 56 tabs: £129.74; 200 mgx 56 tabs: £144.16; Syrup (15 mg/ml) x 200 ml: £38.61; Solution forInfusion (10 mg/ml) x 20 ml: £29.70. Marketing AuthorisationHolder: UCB Pharma SA, Allée de la Recherche 60, B-1070 Brussels,Belgium. Further information is available from: UCB PharmaLtd, 208 Bath Road, Slough, Berkshire, SL1 3WE. Tel: 01753 534655.Fax: 01753 536632. Email: medicalinformationuk@ucb.com.Date of Revision: 05/2011 (UK/11VPE0072). Vimpat is a registeredtrademark.References:1. Vimpat Summary of Product Characteristics.2. Beyreuther BK et al. CNS Drug Rev 2007; 13(1): 21–42.3. Chung S et al. CNS Drugs 2010; 24(12): 1041–1054.Date of preparation: June 2011. UK/11VPE0083aAdverse 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 SCONTENTSSEPTEMBER/OCTOBER 201103 Awards & Appointments06 From the Editor...Review Article10 On the Way to the Deep Layers of ConsciousnessBoris Kotchoubey, Tao Yu, Alexandra Markl, Dominik Vogel, Friedemann Müller, Simone LangReview Article14 From GWAS to Molecules in MSHanne F Harbo, Maria BanClinical Dilemmas in Neuropsychiatry20 Are People with Subjective but no ObjectiveMemory Complaints at Increased Risk of Dementia?Alex J MitchellThe Association of British Neurologists22 Avoiding VOMITs and Improving CareHeather Angus-LeppanMotor Control Series23 The Premotor Cortex and Mirror NeuronsLeonardo Fogassi, Francesca RodàRehabilitation Article26 Effectiveness of Neurobehavioural Rehabilitation for YoungPeople and Adults with Traumatic Brain Injury andChallenging BehaviourNick AldermanNorwegian Leading Discoveries28 The Relationship Between BP and Pain:The Nord-Trøndelag Health SurveyLars Jacob Stovner, Knut Hagen, Erling TronvikSponsored Conference Report36 Evolving Strategies for the Management of Patients with MS– Biogen Idec Nurse Academy 2011Association of British Neurologists38 Annual Meeting PreviewRegulars18 Book Reviews31 Conference News42 Diary44 Journal Reviews47 News ReviewCover picture: Courtesy of Modine Photography.Turn to page 31 for the XXth World Congress ofNeurology Preview In Marrakesh.ACNRACNRSSN 47 -9 48 VOLUME 11 SSUE 4 SE TEMBER/OCTOBER 20 1www acnr co ukADVANCES IN CL NICAL NEUROSCIENCE & REHABILITATIONInside > Conference PreviewWCN 2011 Neurologists fromall over the wo ld to meet inmagical Marrakesh P31In this issueBoris Kotchoubey Tao Yu Alexandra Ma kl Dominik VogelFriedemann Müller Simone Lang– On the Way to he Deep Layers of Consciousne sHanne F Harbo Maria Ban– From GWAS to Mo ecu es n MSMotor Control Series Leonardo Fogassi Francesca Rodà– The Premotor Cor ex and M rror NeuronsRehabi itation Ar icle Nick Alderman– Ef ectiveness of Neu obehav oural Rehabi ita ion or Young Peop e and Adu tsw th T auma ic B ain njury and Chal eng ng Behav ourNorwegian Leading DiscoveriesLars Jacob Stovner Knut Hagen Erling Tronvik– The Relat onsh p Between BP and Pa n The Nord Trønde ag Health Su veyNEWS REVI W > CON ER NCE RE ORTS > BOOK REVI WS > JOURNAL REVIEWS > VENTS D ARYPublished 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 BYBuxton Press T. 01298 21 2000Copyright: 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 11 NUMBER 4 > SEPTEMBER/OCTOBER 2011

Thinkbeyondefficacy...…when looking for additional seizure controlZonegran is indicated as adjunctive therapy in the treatment of adult patients with partial seizures, with or without secondary generalisation.PRESCRIBING INFORMATIONZonegran ® (zonisamide)Please refer to the SPC before prescribing.Presentation: Hard capsules: 25 mg, 50 mg, 100 mgzonisamide. Indication: Adjunctive therapy in adultpatients with partial seizures, with or without secondarygeneralisation. Dose and administration: Adults: Startingdose is 50 mg in two divided doses. After one 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 andpatients not receiving CYP3A4-inducing agents considertwo weekly intervals. Withdraw gradually. Elderly andpatients with renal or hepatic impairment: Caution. Notrecommended in severe hepatic impairment. Childrenand adolescents under 18 years: Not recommended.Contra-indications: Hypersensitivity to zonisamide,sulphonamide or any excipient. Pregnancy: Do notuse during pregnancy unless potential benefits justifythe risks. Women of childbearing potential must usecontraception during treatment and for one month afterdiscontinuation. Lactation: Excreted into breast milk.Either discontinue Zonegran or stop breast-feeding.Warnings and precautions: Serious rashes occur,including cases of Stevens-Johnson syndrome. Containsa sulphonamide group which is associated with seriousimmune-based adverse reactions. Closely supervise andconsider discontinuation in patients with unexplainedrash. Cases of agranulocytosis, thrombocytopenia,leukopenia, aplastic anaemia, pancytopenia andleucocytosis have been reported. Monitor for signs ofsuicidal ideation and behaviours and consider appropriatetreatment. Use with caution in patients with risk factorsfor nephrolithiasis, including prior stone formation,family history of nephrolithiasis and hypercalcuria.Evaluate and monitor serum bicarbonate levels inpatients who are at risk of metabolic acidosis. If metabolicacidosis develops and persists, consider reducingZonegran dose, discontinuing Zonegran treatment oradding alkali treatment with Zonegran as osteopeniamay develop. Use with caution in patients treatedwith carbonic anhydrase inhibitors, e.g. topiramate.Decreased sweating, elevated body temperature andheat stroke have been reported. Patients should maintainhydration and avoid excessive temperatures. Monitorpancreatic lipase and amylase levels in patients takingZonegran who develop clinical signs and symptoms ofpancreatitis, consider discontinuation. In cases of severemuscle pain/weakness with or without fever, assessmarkers of muscle damage and consider discontinuation.Zonegran 100 mg capsules contain E110. Caution inpatients less than 40 kg. In patients with weight lossconsider dietary supplement, increased food intake ordiscontinuation. Drug interactions: No clinically relevantpharmacokinetic effects on carbamazepine, lamotrigine,phenytoin, sodium valproate, oral contraceptives(ethinylestradiol or norethisterone). Insufficient datawith carbonic anhydrase inhibitors, e.g. topiramate.Zonegran was not affected by lamotrigine or CYP3A4inhibitors. Caution with drugs which are P-gp substrates.Avoid concomitant administration with drugs causingurolithiasis. Zonisamide is metabolised partly byCYP3A4, N-acetyl-transferases and conjugation withglucuronic acid; therefore caution with substances thatcan induce or inhibit these enzymes. Side effects: Mostcommon adverse reactions in controlled adjunctivetherapy studies were somnolence, dizziness and anorexia.Refer to SPC for all side effects. Very common effects(≥1/10): anorexia, agitation, irritability, confusionalstate, depression, ataxia, dizziness, memory impairment,somnolence, diplopia, decreased bicarbonate. Commoneffects (≥1/100,

REVIEW ARTICLESex/age Aetiology Months since Imagery paradigm Language paradigm Trace conditioning “Empathy” paradigm Pain paradigmaccident results results paradigm results results resultsM56 anoxia 38 1 0 2 3 2(s)M47 vascular 64 1 0 0 1 3F56 vascular 33 0 0 0 2(s) 3M29 anoxia 34 1 2 0 1 3M54 vascular 60 0 no data 0 2(a) 0F54 anoxia 93 1 0 2 3 2(s)F62 vascular 66 1 1 2 1 1F45 anoxia 287 0 0 0 0 0M59 anoxia 88 0 0 0 2(s) 1F16 anoxia 20 2 1 0 2(s) 3F38 anoxia 2 no data no data 0 0 1M35 vascular 3 1 1 2 0 1F64 anoxia 104 0 2 2 2(a) 3F69 vascular 39 1 0 0 3 1F71 vascular 2 1 0 0 2(s) 3M75 vascular 20 2 1 0 3 3M19 anoxia 4 1 no data 0 1 1F62 anoxia 4 2 no data 2 1 2(s)F30 anoxia 1 1 2 2 2(s) 3M44 herpes 50 0 1 0 1 1M47 anoxia 18 0 0 2 2(s) 1Notes: M, male; F, female. The results patterns are coded as follows: 0 = no significant activation; 1 = random activations in unexpected brain areas; 2 = activation of a part of the networkexpected on the basis of the literature or the own experiments with healthy individuals; 3 = activation in the entire network, comparable with typical activation patterns of healthy individuals;(s) = activations primarily in the sensory portion of the pain matrix (e.g., thalamus, primary sensorymotor cortex); (a) = activations primarily in the affective portion of the pain matrix(e.g., insula, anterior cingulate cortex).prognosis of the outcome. In contrast, in VSand MCS the diagnosis is very difficult, as itrequires the subtle differentiation betweensimple reflex movements and voluntaryactions. The former are compatible with bothVS and MCS, the latter contradict the diagnosisof VS in any case, and to the diagnosis MCS ifthey occur systematically.Both subjective experience and consciousintention are first-person phenomena thatcannot be checked for in a completely objectiveway. Not surprising, therefore, the rate ofdiagnostic errors is about 40%, and, evenworse, this rate has not decreased for at leastfifteen years despite considerable progress inthe development of assessment techniques 13 15 .The majority of these errors are the confusionbetween VS and MCS; however, a proportion ofthem are also erroneous diagnosis of DoC inpatients who are fully conscious. Patients withsevere paralysis, global aphasia, vision disorders(i.e., lacking a response to light), and inparticular with a combination of these disordersare in danger of being labelled as VS orMCS while they are conscious. 14Apparently, the high diagnostic error ratedoes not simply result from insufficient qualificationor limited practice of the neurologists,but is deeply rooted in the impossibility ofjudging the state of consciousness on the basisof behaviour. This gave rise to the idea that thediagnostics might be improved if, in additionto behavioural assessment, techniques ofmodern neuroscience are applied to “lookinto the patient’s brain”. At the transition of themillenia, two such techniques were activelyused: event-related brain potentials 16,17 andpositron-emission tomography. 18,19 The twomethods are as different as they could be. Theformer is characterised by perfect temporalbut poor spatial resolution, which additionallydecreases with the depth of the source; thelatter has a good spatial resolution and canrepresent subcortical activity, but its temporalresolution is bad. Yet the results of the twoapproaches were similar: in many VS patientsneural activities exist that indicate complexcognitive processing of various stimulus qualitiesincluding word meaning.Since, however, the DoC are defined in termsof the lack (VS) or limitation (MCS) ofconsciousness, the question arises whether theobserved cognitive processes can be regardedas indicators of consciousness. The answer israther negative, because there is vast evidencethat each function, including semanticprocessing, can also be performed withoutconscious awareness. The obtained braininformation processing operations can benecessary for conscious perception or action,but they may not be sufficient.At this point the research stagnated for awhile, but then Owen et al. 20 made a breakthrough.The researches asked a young patientwho exactly fulfilled the clinical criteria for VSafter a head injury to imagine either playingtennis or navigation in their own apartment. Inaccord with the instructions, the two taskselicited two distinct patterns of brain activity(as measured using functional magnetic resonanceimaging, fMRI), quite similar to thepatterns obtained in healthy individuals withthe same instructions.However, an analysis of Owen’s method indicatesits high false negative rate. The authorsdemonstrated in several control experimentsthat a positive finding in such a test wouldprove the patient’s awareness (i.e., the abilityto understand and follow a verbal instruction)independently of behavior. However, a negativefinding would not prove anything. There isboth theoretical and empirical evidence thateven fully conscious patients with neurologicaldiseases can fail in Owen’s test. 21 This isbecause the test aims at the higher-orderlanguage-related awareness. If there are (seethe first paragraph) other, language-unrelatedlayers of subjective experience such aspleasant-unpleasant, pain, or elementarysensations, these layers are not addressed.However, just these elementary aspects ofconsciousness are of vital importance fromthe practical point of view. Not the ability tothink clearly or problem solving decideswhether the patient is a human person or justa mindless body, but the ability to experienceACNR > VOLUME 11 NUMBER 4 > SEPTEMBER/OCTOBER 2011 > 11

REVIEW ARTICLEpain and suffer. Furthermore, only a smallportion of the diagnostic errors concerned thepatients who were in full possession of HOC.Therefore, a method capable of assessing thefull-blown, ‘normal’ awareness would onlymoderately decrease the error rate.Thus, the aim of the present project was thedevelopment of a set of stimulation paradigmsdesigned to investigate different levels ofconscious experience without the patient’sability to demonstrate overt behavior. LikeOwen et al., we use fMRI as the recording techniquewhose relative slowness (as comparedto the EEG) is more than compensated for byits ability to reveal the activity of various brainstructures including those related to “primary”emotional processes.The battery needed to fulfil several criteria.Firstly, it should address the different levels ofcognitive functions that could possiblyremain. Secondly, these functions should berelated to consciousness, which is not trivialgiven that even very complex cognitiveprocesses (e.g., learning) can run unconsciously.Thirdly, the patients’ ability to appropriatelyrespond to the stimuli should be manifestedin their fMRI responses. Last but notleast, the overall examination time should belimited because DoC patients quickly becometired, and the probability of severe movementartefacts increases with time of testing.For this reason, our project included thefollowing hierarchical procedure.1. The mental imagery paradigm was anexact replication of 20 and addressed HOCincluding its important components, selectiveattention and working memory. 222. Patients who cannot follow verbal instructionscan nevertheless understandlanguage. In the language paradigm shortcorrect (e.g., May is the month that followsApril) and incorrect sentences (e.g., Marchis the month that follows April) werepresented. The paradigm was based on theidea that whereas semantic associations(e.g., cat-dog) can be processedadequately at an automatic level, theunderstanding of the factual correctness ofsentence requires its conscious apprehension.On the basis of the literature, weexpected a larger activation in the classicallanguage areas to false than correctsentences as a neurophysiological sign ofsentence understanding.3. Patients who do not understand languagecan nevertheless retain the ability toconsciously learn. The simplest form ofconscious learning is trace conditioning. 23We used a trace conditioning procedurein which two tones were randomlypresented 30 times each. One of them (aconditional stimulus, CS) was followed 15times by a weak electric shock (unconditionalstimulus), whose intensity twiceexceeded the average pain threshold in acomparable control group. The intervalbetween the CS and the shock was 3 s. TheBOLD-contrast was that between the CSnot followed by the shock and the othertone, which was never accompanied by ashock.4. Patients who lost the ability to build newexplicit associations can neverthelessretain emotional responses to affectivestimuli. Whereas the processes depictedabove are learning-related and probablybelong to HOC, at least some kinds ofemotional experience might be speculatedto be inborn and to belong to LOC (ofcourse, we do not know exactly which kindof consciousness is simpler than anotherkind, because the criteria of simplicity/complexity are highly controversial in thisrespect). Brain responses to exclamations(screams) expressing pain and sufferingwere compared with the responses to othersounds of human voice, both positive (e.g.,laughing) and negative (e.g., snoring). Inhealthy individuals, such pain-relatedsounds elicit activation of the whole painmatrix of the brain even though they arenot nociceptive. 245. Finally, the fifth paradigm was simply thepresentation of nociceptive stimuli, i.e.,electrical shocks to the index finger. Here,again, the activation of the pain matrix (ascompared with rest) was expected. It isalso worth noticing that while severalcomponents of this matrix (e.g., thesomatosensory cortex) are mainly relatedto sensory aspects of pain, other components(e.g., the insula and the cingulategyrus) are closely related to its subjective,emotional aspects.To avoid the unnecessary patient transportation,two different Siemens MRT devices (1.5 Tand 3 T) were used for examinations. In theformer, in which fourteen patients were examined,T2* weighted MR signal was measuredusing a gradient echo-planar imagingsequence (TR = 3.41 s, TE = 50 ms, FoV = 192mm, flip angle = 90°, 64 x 64, 36 slices coveringthe whole brain, slice thickness 3mm, no gap,voxel size 3x3x3mm). In the latter (sevenpatients), the corresponding parameters wereTR = 2.38 s, TE = 25 ms, FoV = 210mm, 40 slices,voxel size 3.3x3.3x3mm. Individual T1weighted anatomical images served as anunderlay for the activation pictures. The datawere processed using SPM8.Figure 1. Top row: group average brain activation patterns in healthy participants. Bottom row:examples of brain activations in selected VS patients. For a better comparison, the same sliceis shown for patients and controls. Leftmost column: the contrast between pain stimulationand rest. Note the activation in the structures (i.e., ACC and insula) related to the emotionalrather than sensory aspects of pain. Middle left column: empathy paradigm, the contrastbetween pain-related and pain-unrelated sounds of human voice. Middle right column: traceconditioning paradigm, the contrast between CS+ and CS-. Rightmost column: language paradigm,the contrast between correct and wrong sentences. According to [26], the activationthreshold for individual patients (p ACNR > VOLUME 11 NUMBER 4 > SEPTEMBER/OCTOBER 2011

REVIEW ARTICLEA total of twenty-one patients (aged 16-75;11 females) carefully diagnosed as VS tookpart in the study after the approval of theEthics Commission of the University ofTübingen and the informed consent of eachpatient’s legal representative. The characteristicsof the patients are described in the Tableabove.In the imagery paradigm, three of the 21patients showed responses similar to those ofcontrol individuals. In the language paradigm,activations in some of the expected brainstructures were found in three of 17 patients(the language paradigm was not performed infour patients with a different mother tongue).In trace conditioning, similar positive findingswere obtained in eight patients. However, noneof the patients displayed a pattern of activitythat would entirely correspond to that ofhealthy individuals in any of these paradigm.Different results were obtained in the othertwo paradigms. In response to emotionalsounds, four patients demonstrated significantactivations of the entire pain matrix of thebrain including both sensory and affectivecomponents, nine patients showed activity inseveral (but not all) regions of this network,and eight patients showed no response orresponses inconsistent with the expectedones. During pain stimulation, eight patientsdemonstrated activations in the entire painmatrix, practically identical to the responses ofhealthy controls, and three further patientsshowed a widespread activity in the componentsof this matrix related to sensory aspectsof pain (thalamus, putamen, cerebellum,somatosensory cortex).Clearly, these data do not strongly prove thepatients’ real experience of negative emotionsrelated to pain and emotional cries. However,the opposite thesis that an unresponsivepatient has no subjective experience at all isdifficult to defend when significant activity isobserved in the entire brain network, or even aconsiderable part of it, which is known tostrongly correlate with such subjective experience.Also, the exact quantitative data reportedabove should be treated with caution. Thereare numerous reasons as to why a particularfMRI test may yield a negative result even if thecorresponding function in the given patient ispreserved. However, the general qualitativetrend in the data is unequivocal. Whereasneural correlates of cognitive (presumablyconscious) processes are rare findings in VS,correlates of emotional processes are wellexpressed in many patients. This is in line withthe hypothesis 11 that emotional consciousnesscan remain even despite the nearly completeloss of cognitive awareness. It is furthermoreworth noting, that our previous experiment 25has indicated that patients in acute non-traumaticcoma can consistently respond toemotional screams like those used in the paradigm4 of the present study.From a theoretical viewpoint, the data indicatethat the essential cognitive functionsconstituting our everyday awareness, such asexplicit learning ability, biographical memoryand language comprehension, do not makethe whole of human subjectivity. There may beeven more basic and probably simpler functions,which include not only feeling pain andpleasure, but also feeling pain (and perhapspleasure) of others. However simple, thesefunctions importantly contribute to beinghuman. From a practical viewpoint, the datasuggest that emotional contact with caregivers(e.g., using affective prosodic cues, music asaffective stimulus, or touch) can be establishedeven in patients with a complete loss ofall major cognitive functions. People havingpets, and parents of young children, know thatthe lack of HOC does not completely precludecommunication. For many patients fulfillingthe diagnostic criteria of VS the same mayhold true as well. lEmotional contact with caregivers (e.g., using affective prosodic cues,music, or touch) can probably be established even in patients with acomplete loss of all major cognitive functionsREFERENCES1. Baars BJ. In the Theater of Consciousness. New York - Oxford: Oxford University Press1997.2. Damasio AR. The Feeling of What Happens: Body and Emotion in the Making ofConsciousness. San Diego: Harcourt 1999.3. Block N. Consciousness, accesibility, and the mesh between psychology and neuroscience.Behav Brain Sci 2007;30:481-499.4. Edelman DB, Baars BJ, Seth AK. Identifying hallmarks of consciousness in non-mammalianspecies. Cons Cogn 2005;14:99-118.5. Edelman G. Consciousness: The remembered present. Ann NY Acad Sci 2001;929:111-122.6. Rosenthal DM. State consciousness and transitive consciousness. Cons Cogn 1993;2:355-363.7. Searle JR. Consciousness. Ann Rev Neurosci 2000;23:557-578.8. Bennett MR, Hacker PMS. Philosophical Foundations of Neuroscience. Oxford: Blackwell,2003.9. Humphrey NA. History of the Mind. Evolution and the Birth of Consciousness. New York -London - Toronto - Sydney: Simon & Schuster 1992.10. Panksepp J. Affective consciousness: Core emotional feelings in animals and humans. ConsCogn 2005;14:30-80.11. Panksepp J, Fuchs T, Garcia VA, Lesiak A. Does any aspect of mind survive brain damagethat typically leads to a persistent vegetative state? Ethical considerations. Philos EthicsHumanities Med 2007;2(32): doi:10.1186/1747-5341-2-32.12. Kotchoubey B. Vegetative state. In: Squire L, ed. Encyclopedia of Neuroscience. Vol. 10.Amsterdam: Elsevier, 2009:61-66.13. Childs NL, Mercer WN, Childs HW. Accuracy of diagnosis of persistent vegetative state.Neurology 1993;43:1465-1467.14. Andrews K, Murphy L, Munday R, Littlewood C Misdiagnosis of the vegetative state:Retrospective study in a rehabilitation unit. BMJ 1996;313:13-16.15. Schnakers C, Vanhaudenhuyse A, Giacino J, Ventura M, Boly M, Majerus S, et al.Diagnostic accuracy of the vegetative and minimally conscious state: Clinical consensusversus standardized neurobehavioral assessment. BMC Neurology 2009;9:Article 35.16. Kotchoubey B, Lang S, Bostanov V, Birbaumer N. Is there a mind? Psychophysiology ofunconscious patients. News Physiol Sci 2002;17:38-42.17. Kotchoubey B, Lang S, Mezger G, Schmalohr D, Schneck M, Semmler A, et al. Informationprocessing in severe disorders of consciousness: Vegetative state and minimally consciousstate. Clin Neurophysiol 2005;116:2441-2453.18. Laureys S, Antoine S, Boly M, Elincx S, Faymonville ME, Berre J, et al. Brain function in thevegetative state. Acta Neurol Belg 2002;102:177-185.19. Owen AM, Menon DK, Johnsrude IS, Bor D, Scott SK, Manly T, et al. Detecting residualcognitive function in persistent vegetative state. Neurocase 2002;8:394-403.20. Owen AM, Coleman MR, Boly M, Davis MH, Laureys S, Pickard JD. Detecting awareness inthe vegetative state. Science 2006; 313: 1402.21. Bardin JC, Fins JJ, Katz DI, Hersh J, Heier LA, et al. Dissociations between behavioral andfunctional magnetic resonance imaging-based evaluations of cognitive function after braininjury. Brain 2011;134:769-782.22. Tulving E. How many memory systems are there? Amer Psychol 1985;40:385-398.23. Bekinschtein T, Shalom F, Herrera M. Classical conditioning in the vegetative and minimallyconscious state. Nature Neurosci 2009;12:1343-1349.24. Lang S, Yu T, Markl A, Müller F, Kotchoubey B. Hearing others' pain: Neural activity relatedto empathy. (in press). Cogn Affect Behav Neurosci 2011: doi 10.3758/s13415-011-0035-0.25. Daltrozzo J, Wioland N, Mutschler V, Lutun P, Calon B, Meyer A, et al. Emotional electrodermalresponse in coma and other low-responsive patients. Neurosci Lett 2010;425:44-47.26. Lieberman MD, Cunnigham W Type I and Type II error concerns in fMRI research: Rebalancingthe scale. SCAN 2009;4:423-428.ACNR > VOLUME 11 NUMBER 4 > SEPTEMBER/OCTOBER 2011 > 13

REVIEW ARTICLEHanne F Harbo,MD, PhDis Professor of Neurology at OsloUniversity Hospital, Oslo, Norway.She is the leader of the Oslo MSGenetics Group and theNorwegian lead member inNordic MS Genetic Network andIMSGC, and was the leader of theEFNS scientist panel of neurogeneticsfrom 2007-2010. Her focusof interest is MS treatment andresearch, in particular immunogeneticstudies of MS.Maria Ban, PhDis a postdoctoral researcher in theDepartment of ClinicalNeurosciences, CambridgeUniversity, UK. Her researchinterest is in identifying thegenetic factors involved insusceptibility to multiplesclerosis.Correspondence to:Hanne F HarboProfessor, dr. med (MD, PhD)Department of Neurology,Oslo University Hospital, Ullevåland University of Oslo0407 Oslo, NorwayEmail: h.f.harbo@medisin.uio.noAcknowledgement:We thank all our collaboratorsworld-wide in the IMSGC andWTCCC. Stephen Sawcer iswarmly thanked for comments tothis manuscript.Disclosures:HF Harbo has received research grantsfrom the Norwegian Research Council,South-East Regional Norwegian HealthAuthorities, Oslo University Hospital,Norwegian and Oslo MS association,Odd Fellow MS society, diverse otherNorwegian research funds, Sanofi-Aventis, Novartis, Biogen-Idec, BayerSchering, as well as Wellcome Trust, UKthrough the IMSGC grant for genotypingof Norwegian samples in theIMSGC-WTCCC MS GWAS.Maria Ban is supported by a grant fromthe Wellcome Trust.From GWAS toMolecules in MSMultiple sclerosis (MS) is one of the mostfrequent causes of neurological disability inyoung adults in western countries. Despiteextensive efforts, little is known about events thattrigger the disease or factors that control its highlyvariable course and severity.Given its unpredictable nature, alongside theaccumulation of significant disability in a largeproportion of patients, MS is a feared disease, oftenleading to a severe impact on patients and theirfamilies as well as a large cost for society. Theestablished immune modulation MS therapies areonly indicated for the relapsing remitting forms ofMS and are often only partly effective, some withserious side effects. The development of moresuccessful treatments is limited by our poor understandingof pathogenesis and disease mechanisms.Through genetic and molecular studies ofMS, guidance to ‘personalised medicine’ andestablishment of new therapies can hopefully beachieved.Familial clustering is a firmly established featurein MS, with 15-20% of affected individuals having afamily history of the disease, epidemiologicalstudies showing this is primarily a result of sharedgenes rather than a shared environment. 1 The importanceof genetic factors in determining susceptibilityto the disease prompted efforts towards identifyingresponsible genes in the expectation that thisknowledge will provide invaluable informationabout pathogenesis and inform future research intoeffective treatments.Candidate gene studies identified the importanceof HLA genes in MSEarly genetic research efforts quickly establishedassociation with the human leukocyte antigen(HLA) region in the major histocompatibilitycomplex (MHC) on chromosome 6p21. 2Subsequent research efforts have refined this associationand confirmed that in virtually every populationtested, risk is primarily determined by the classII allele HLA-DRB1*15:01. 3 Carriers of this risk alleletypically have a three-fold increased risk of developingMS, making this the largest genetic factorpredisposing an individual to MS yet identified.Considerable progress in fine mapping anddissecting this important signal has providedgrowing evidence supporting the involvement ofgenes within the class I region with MS, independentof the 15:01 association. 4 Much work still needs to beundertaken to completely understand the role ofthis complex region in the development of MS.In the years following the HLA discovery, despitethe heritable nature of susceptibility to MS, candidategene studies made remarkably little progress inidentifying the genes involved in MS. The invariableuse of inadequate sample sizes coupled with thelimited probability that a relevant gene might beselected for study have been prominent amongstthe reasons for the limited success of this approach.Genome screening identified the firstnon-HLA gene associations in MSAs such the momentum shifted towards screeningthe genome, an advantageous method as no priorknowledge of the pathogenesis of disease isrequired as genetic variants are screenedthroughout the genome in the hope that they will becorrelated with the disease causing allele. The firstgenome screens were performed by linkage analysisgenotyping microsatellite markers in affected sibpairfamilies in the mid-1990s in the UK 5 , US 6 andCanadian 7 population and have since beencompleted in several other populations.Disappointingly no region of genome wide significancewas identified in any study and little overlapin the results between studies was found. In 2005, adefinitive linkage screen was completed by theInternational Multiple Sclerosis GeneticsConsortium (IMSGC), by whom 4506 singlenucleotide polymorphisms (SNPs) were typed in730 multiplex families. 8 While the only region toreach genome wide significance was the alreadyestablished HLA region, this linkage study did establishthat outside the HLA region, common susceptibilityalleles (frequency >10%) are unlikely toincrease the risk of disease by a factor of more thantwo and therefore association screening is a morepowerful method to establish these small geneticeffects in MS.It was only as the understanding of the nature andextent of human genetic variation increased and thetechnology to screen hundreds of thousands ofsingle nucleotide polymorphisms (SNPs) in thehuman genome in a cost and time efficient mannerbecome available, that the ability to completegenome-wide association screens (GWAS) wasmade possible. The first high-density genome wideassociation screen in MS was published in 2007. 9Close to 1000 trio families (an affected individualand both of their parents) were screened for over300,000 SNPs and implicated the IL7RA and IL2RAgenes in MS susceptibility, which was successfullyreplicated and confirmed in other populations. 10Since then more than 10 GWAS and meta-analysisstudies have been completed and alongside replicationstudies have confirmed a growing list of genesinvolved in MS susceptibility (see Figure 1). 9 20 Theseare the first genuine associations to be identified inmultiple sclerosis since the long established associationwithin the HLA region. As indicated by the MSlinkage studies, 9 no other MS loci have been identifiedwith a higher risk than the HLA region, reflectedin odds ratios typically around 1.2 for the now establishednon-HLA MS risk loci (Figure 1).Interestingly these associations have uncovered agrowing overlap in susceptibility loci between MS14 > ACNR > VOLUME 11 NUMBER 4 > SEPTEMBER/OCTOBER 2011

REVIEW ARTICLEand other autoimmune diseases, including forexample the IL7R, IL2RA, CLEC16A and CD22611, 21genes. This result is not surprising asepidemiological studies have identified anincreased frequency of autoimmune diseasein the family members of MS patients,suggesting shared disease mechanisms basedon a common genetic background.Acknowledging the crucial importance ofthe sample size for well-powered geneticstudies, the IMSGC decided to perform thelargest and most well powered MS GWAS. Incollaboration with the Wellcome Trust CaseControl Consortium 2 (WTCCC2) close to10,000 MS samples and 20,000 controls wereanalysed using a 660K SNP chip, providing oneof the largest and statistically most complexGWAS studies performed both due to thenumber of samples included as well as thelarge number of populations represented inthe screen. This screen will identify an additionallist of MS associated loci. 22 The resultsfrom this screen will be published in the nearfuture.Moving into the post GWAS area ofmolecular characterisation in MSMuch work still remains to understand the fullgenetic architecture of susceptibly to MS. As thevariants typed in a GWAS are only a small fractionof variants that co-segregate, causal variantsfor disease will only occasionally bedirectly typed in GWAS. Fine mapping studies, inwhich the regions that are found to be associatedwith disease in GWAS are followed up andextensively mapped to identify the causal variants,are essential and are currently beingcompleted. These studies will further define thecausative associations, and lead to molecularstudies aimed at characterising the functionaleffects of the identified MS associated loci.The figure shows the MS associated risk loci as identified from published GWAS and replication studies in MS (references 9-20)and the odds ratios for the risk variants identified at each loci. A large proportion of the associated genes in MS are identifiedas being involved in immune system processes (as identified from the Gene Ontology database) and are shown in green in thefigure, while those not involved in immune system processes are shown in blue.Analyses of cellular pathways as well as genegeneand gene-environment interaction studiesof the established MS loci are further needed tofully comprehend the mechanisms of disease.So far, there does not appear to be a geneticdifference between the different clinicalsubgroups of MS. This may merely be a reflectionof the lack of clearly defined subgroups.Careful genotype-phenotype studies,comparing the clinical and paraclinicalexpression of the disease (for example as evaluatedby detailed MRI examinations), areneeded in order to define if the mechanismsof disease development varies betweendifferent MS patient groups.Future of genetic analysis in MSDespite the success of the recent GWAS in MS,the variations associated with MS to dateaccount for only a moderate proportion of theinheritable risk of MS. This “missing heritability”is a feature not only in MS but also othercomplex genetic diseases. Factors that cancontribute to this missing heritability includemissed or rare genetic variants, allelic heterogeneity(where more than one allele at a singlelocus is associated with disease) and epigeneticeffects. Identification of the missing heritabilityis one of the next challenges in MS genetics.In conclusion, genetic studies have thepotential to identify molecules of importanceto MS aetiology through systematic wellpowered scientific studies, most successfullyapplied by recent GWAS studies madepossible by large international collaborativeprojects. Genetic research of MS susceptibilityis therefore now quickly moving into anotherphase, characterising the full genomic architectureof disease susceptibility alleles as wellas focusing on characterisation of the moleculesinvolved in MS development. lREFERENCES1. Compston A, Coles A. Multiple sclerosis. Lancet 2002;359:1221-31.2. Jersild C, Svejgaard A, Fog T. HL-A antigens and multiple sclerosis. Lancet 1972;1:1240-1.3. Compston A, Confavreux C, Lassmann H, McDonald I, Miller D, Noseworthy J, et al.McAlpine's Multiple Sclerosis. 4th edition ed. London: Churchill Livingstone; 2006.4. Bergamaschi L, Ban M, Barizzone N, Leone M, Ferrante D, Fasano ME, et al. Association ofHLA class I markers with multiple sclerosis in the Italian and UK population: evidence of twoindependent protective effects. J Med Genet 2011.5. Sawcer S, Jones HB, Feakes R, Gray J, Smaldon N, Chataway J, et al. A genome screen inmultiple sclerosis reveals susceptibility loci on chromosome 6p21 and 17q22. Nature genetics1996;13:464-8.6. Haines JL, Ter-Minassian M, Bazyk A, Gusella JF, Kim DJ, Terwedow H, et al. A completegenomic screen for multiple sclerosis underscores a role for the major histocompatabilitycomplex. The Multiple Sclerosis Genetics Group. Nat Genet 1996;13:469-71.7. Ebers GC, Kukay K, Bulman DE, Sadovnick AD, Rice G, Anderson C, et al. A full genomesearch in multiple sclerosis. Nat Genet 1996;13:472-6.8. Sawcer S, Ban M, Maranian M, Yeo TW, Compston A, Kirby A, et al. A high-density screenfor linkage in multiple sclerosis. Am J Hum Genet 2005;77:454-67.9. The International Multiple Sclerosis Genetics Consortium. Risk alleles for multiple sclerosisidentified by a genomewide study. N Engl J Med 2007;357:851-62.10. The International Multiple Sclerosis Genetics Consortium. Refining genetic associations inmultiple sclerosis. Lancet Neurol 2008;7:567-9.11. The International Multiple Sclerosis Genetics Consortium. The expanding genetic overlapbetween multiple sclerosis and type I diabetes. Genes Immun 2009;10:11-4.12. The International Multiple Sclerosis Genetics Consortium. Comprehensive follow-up of thefirst genome-wide association study of multiple sclerosis identifies KIF21B and TMEM39A assusceptibility loci. Hum Mol Genet 2010;19:953-62.13. Zuvich RL, McCauley JL, Oksenberg JR, Sawcer SJ, De Jager PL, Aubin C, et al. Genetic variationin the IL7RA/IL7 pathway increases multiple sclerosis susceptibility. Hum Genet2010;127:525-35.14. Sanna S, Pitzalis M, Zoledziewska M, Zara I, Sidore C, Murru R, et al. Variants within theimmunoregulatory CBLB gene are associated with multiple sclerosis. Nat Genet 2010;42:495-7.15. Ban M, Goris A, Lorentzen AR, Baker A, Mihalova T, Ingram G, et al. Replication analysisidentifies TYK2 as a multiple sclerosis susceptibility factor. Eur J Hum Genet 2009;17:1309-13.16. Baranzini SE, Wang J, Gibson RA, Galwey N, Naegelin Y, Barkhof F, et al. Genome-wide associationanalysis of susceptibility and clinical phenotype in multiple sclerosis. Hum Mol Genet2009;18:767-78.17. ANZgene. Genome-wide association study identifies new multiple sclerosis susceptibility locion chromosomes 12 and 20. Nat Genet 2009;41:824-8.18. Burton PR, Clayton DG, Cardon LR, Craddock N, Deloukas P, Duncanson A, et al.Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunityvariants. Nat Genet 2007;39:1329-37.19. De Jager PL, Jia X, Wang J, de Bakker PI, Ottoboni L, Aggarwal NT, et al. Meta-analysis ofgenome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosissusceptibility loci. Nat Genet 2009;41:776-82.20. Jakkula E, Leppa V, Sulonen AM, Varilo T, Kallio S, Kemppinen A, et al. Genome-wide associationstudy in a high-risk isolate for multiple sclerosis reveals associated variants in STAT3gene. Am J Hum Genet 2010;86:285-91.21. Zhernakova A, van Diemen CC, Wijmenga C. Detecting shared pathogenesis from the sharedgenetics of immune-related diseases. Nat Rev Genet 2009;10:43-55.22. The International Multiple Sclerosis Genetics Consortium. The new MS gene list - wholegenome association studies in MS. ECTRIMS; 2010 14 October 2010; Gothenburg, Sweden;2010.ACNR > VOLUME 11 NUMBER 4 > SEPTEMBER/OCTOBER 2011 > 15

New – Gilenyaan MS treatment that’s oralPrior IFNtreatmentFailed responseto full andadequate courseRelapseUnchanged orincreased rate, orongoing severerelapsesPrescribeGilenyaOnce dailyoral MS therapyAbbreviated Prescribing Information: GILENYA ® (fingolimod)Important note: Before prescribing, consult Summary of Product Characteristics (SmPC). Presentation: Hard capsule containing0.5 mg fingolimod (as hydrochloride). Indications: Gilenya is indicated as single disease modifying therapy in highly activerelapsing remitting multiple sclerosis for the following adult patient groups:- Patients with high disease activity despite treatment with a beta-interferon. These patients may be defined as: those who havefailed to respond to a full and adequate course (normally at least one year of treatment) of beta-interferon. Patients should havehad at least 1 relapse in the previous year while on therapy, and have at least 9 T2-hyperintense lesions in cranial MRI or at least1 Gadolinium-enhancing lesion. A “non-responder” could also be defined as a patient with an unchanged or increased relapserate or ongoing severe relapses, as compared to the previous year.- Patients with rapidly evolving severe relapsing remitting multiple sclerosis defined by 2 or more disabling relapses in one year,and with 1 or more Gadolinium enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared to aprevious recent MRI. Dosage: Adults: Treatment should be initiated and supervised by a physician experienced in multiplesclerosis. One 0.5 mg capsule to be taken orally once daily. Patients can switch directly from beta-interferon or glatiramer acetateto Gilenya provided there are no signs of relevant treatment-related abnormalities, e.g. neutropenia. Use with caution in patientsaged 65 years and over. Safety and efficacy of Gilenya in children up to 18 years has not been established. No dose adjustmentsrequired in patients with mild to severe renal impairment or mild to moderate hepatic impairment. Exercise caution in patientswith mild to moderate hepatic impairment. Do not use in patients with severe hepatic impairment (Child-Pugh class C). Use withcaution in patients with diabetes mellitus due to an increased risk of macular oedema. Contraindications: Knownimmunodeficiency syndrome, patients with increased risk for opportunistic infections, including immunocompromised patients(including those currently receiving immunosuppressive therapies or those immunocompromised by prior therapies), severeactive infections, active chronic infections (hepatitis, tuberculosis), known active malignancies, except for patients withcutaneous basal cell carcinoma, severe liver impairment (Child-Pugh class C), hypersensitivity to the active substance or to anyof the excipients. Warnings/Precautions: Bradyarrhythmia: Initiation of treatment results in a transient decrease in heartrate which may be associated with atrioventricular conduction delays. Observe all patients for 6 hours for bradycardia. In theevent of bradyarrhythmia-related symptoms, initiate appropriate clinical management and observe until symptoms resolve.The same precautions apply if Gilenya is discontinued for more than 2 weeks. Gilenya has not been studied in patients withsitting heart rate

www.gilenya.co.ukA new perspective in MSbilirubin and alkaline phosphatase (ALP) measurement. Stop Gilenya treatment with repeated confirmation of livertransaminases above 5 times the ULN and only re-commence once liver transaminase values have normalised. Patientswith symptoms of hepatic dysfunction should have liver enzymes checked and discontinue Gilenya if significant liverinjury is confirmed. Resume Gilenya only if another cause of liver injury is determined and if the benefits of therapyoutweigh the risks. Exercise caution with Gilenya use in patients with a history of significant liver disease. Serologicaltesting: Peripheral blood lymphocyte counts cannot be utilised to evaluate the lymphocyte subset status of a patienttreated with Gilenya. Laboratory tests involving the use of circulating mononuclear cells require larger blood volumesdue to reduction in the number of circulating lymphocytes. Blood pressure effects: Gilenya can cause a mild increase inblood pressure. Monitor blood pressure regularly during Gilenya treatment. Respiratory effects: Use Gilenya with cautionin patients with severe respiratory disease, pulmonary fibrosis and chronic obstructive pulmonary disease due to minorreductions in values for forced expiratory volume (FEV 1) and diffusion capacity for carbon monoxide (DLCO). Priorimmunosuppressant treatment: No washout is necessary when switching patients from interferon or glatiramer acetateto Gilenya assuming any immune effects (e.g. neutropenia) have resolved. Exercise caution when switching patients fromnatalizumab to Gilenya owing to the long half life of natalizumab and concomitant immune effects. Stopping therapy:Gilenya is cleared from the circulation in 6 weeks. Caution is indicated with the use of immunosuppressants soon afterthe discontinuation of Gilenya due to possible additive effects on the immune system. Interactions: Anti-neoplastic,immunosuppressive or immune-modulating therapies should not be co-administered due to the risk of additive immunesystem effects. Exercise caution when switching patients from long-acting therapies with immune effects, e.g.natalizumab or mitoxantrone. No increased rate of infection was seen with concomitant treatment of relapses with ashort course of corticosteroids. Vaccination may be less effective during and for up to 2 months after Gilenya treatment.Avoid use of live attenuated vaccines due to infection risk. Due to additive effects on heart rate, exercise caution wheninitiating Gilenya in patients receiving beta blockers, or class Ia and III antiarrhythmics, calcium channel blockers likeverapamil or diltiazem, digoxin, anticholinesteratic agents or pilocarpine. Caution is indicated with substances that mayinhibit CYP3A4. Co-administration of fingolimod with ketoconazole increases fingolimod exposure. No interaction has beenobserved with oral contraceptives when co-administered with fingolimod. Fertility, pregnancy and lactation: There is potentialfor serious risk to the fetus with Gilenya. A negative pregnancy test is required before initiation of Gilenya. Female patients mustuse effective contraception during treatment with Gilenya and for 2 months after discontinuation. Discontinue Gilenya if apatient becomes pregnant. Fingolimod is excreted into breast milk. Women receiving Gilenya should not breast feed. Fingolimodis not associated with a risk of reduced fertility. Undesirable effects: Very common (1/10); Influenza viral infections, headache,cough, diarrhoea, increased alanine transaminase (ALT), back pain. Common (1/100 to

BOOK REVIEWStPA for StrokeAs a neurology trainee, I was extremelykeen to read this book, because thrombolysisfor the management of strokehas had an immense impact on mytraining years. As a trainee at StGeorge’s Hospital, London, the on callswere quiet when I first started as aresearch registrar in 2002.The change with 24 hour thrombolysisservice in 2007 was huge (webecame resident neurologists on call)and this has become even busier withthe advent of HASUs (Hyper AcuteStroke Units). So did this book explainhow this drug has changed the face ofstroke and hence neurology from apredominantly outpatient non-acuteservice to that of an emergency? Yes!The book takes you on a journey –the first section, “Discovery”, being onthe product itself (tPA – tissue plasminogenactivator) - from discoveryin 1947 to the publication of thepivotal NINDS study in 1995 in theNew England Journal of Medicine, tothe granting of FDA approval and EUapproval in 1996 and 2002 respectively)and the second section onhow it eventually affected practice,“Change, Resistance and Transition”.Throughout the book, cases wereused to highlight the issues andpersonalise the experience. The mostinteresting section of the book for mewas the controversy surrounding theacceptance or otherwise of tPA. Theauthors dissected why tPA was metwith such scepticism in 1996 for sucha prolonged period. They do notmince their words and one of thereasons given was “due to themakeup of the specialty (neurology)and the people in it”. I have alwayswondered why tPA in stroke was nottaken up by A&E (emergency)doctors, unlike its use in the cardiacworld. This book discussed the issuessurrounding this.tPA for Stroke was Eminently readablebut a timeline would have beenhelpful for orientation. The otherpotential weakness for a UK reader isthat it is mainly about the drug’s UShistory. However, its use in Europe isdiscussed, including how the UK isalone in having developed a publichealth strategy (Act F.A.S.T.) toaddress awareness. The chapter “Deerin the Headlights” highlighted thenumber of legal cases regarding, notthe misuse of tPA, but the lack of itsuse. These cases in the US may beconsidered as useful lessons encouragingus to move away from thehistorical pessimism that surroundsstroke management to active andswift consideration for thrombolysis.That chapter concluded that “if aservice cannot meet that standard, itshould arrange for patients to bypasstheir hospital and go directly to othersthat are prepared to treat strokes asthe emergencies they truly are”. Thisis indeed what happens in the UKsince the creation of HASUs in 2010.The aim of the book, according tothe authors, was to raise awareness oftPA and, at the end, one does feelconvinced of its status as a revolutionaryneurological drug. This bookis an interesting read for those of uswho are stroke enthusiasts, and forthose who are not; I recommend itwholeheartedly to both groups! lAuthors: Justin A Zivin,John Galbraith SimmonsPublished by: OxfordUniversity Press (2010)Price: £17.99ISBN: 978-0-19-539392-7Reviewed by:Arani Nitkunan,Department of Neurology,St George’s Hospital,London.Medical NeurobiologyMedical Neurobiology by PeggyMason is a large volume textreviewing the neurosciences andtheir relevance in clinical practice.The book aims to bridge a perceivedvoid between science and clinicalpractice by presenting the neurobiologywithout losing sight of the‘bigger picture’ of a physician’s day-todaywork.The structure of the book is splitinto two halves. A straighforward butcomprehensive first chapter introducesthe components of the nervoussystem and very much achieves itsgoal of encouraging the reader toread on and delve deeper. Thissection includes overviews ofneurons and glia and the embryologicaldevelopment of the nervoussystem before describing the physiologyof neural communication andgross neuroanatomy.The latter half of the book dealsinitially with sensory perception,specifically visual, auditory andsomatosensory perception. Followingthis, motor outputs are explored.These sections are beautifully writtenand explained in a systematic andlogical manner, which is where thisbook really shines when compared toits peers. Particular highlights includethe chapters on visual perceptionand gaze control. The book successfullyexplains the physiology of eachmajor system in the context of therelevant anatomy. The later chaptersare particularly effective if read whilethe preceding basic sciences chaptersare fresh in the mind.Perhaps the greatest strength of thisbook and, incidentally, the mostenjoyable sections to read, are thosewhere the newly acquired knowledgeis applied to scenarios in clinicalpractice. The book is certainly not aclinical text, but it does explain keyanatomical or physiological principlesas clinical ‘gems’ presented inboxes throughout. For example, whydoes hemiballism result from asubthalamic nucleus lesion? Howdoes the consumption of alcoholcause vertigo via its influence on thecupula? What is the relevance of‘chunking’ in patients with ObsessiveCompulsive Disorder? The authorpromises to deliver many ‘ahhh…sothat’s how it works’ moments of clarityto the undergraduate (or inner undergraduate).Considering its target audience,there are no major criticisms of thistext. One area of basic neuroscienceswhich has seen great advances inrecent years, that of neuroimmunology,is not included. However,this may be reasonably consideredbeyond the remit of a text that aims tointroduce normal neurobiology.Speaking as products of a ‘modern’medical curriculum, featuring the‘Problem Based Learning (PBL)’approach, this text would seem tohave great appeal for the medicalundergraduate with an interest inneurology and for junior traineeskeen to review this fascinating field ofmedicine. The method of learning inPBL is to consider all relevant areasfrom anatomy and physiology,through to clinical diagnosis andtreatment within a ‘module’. For cliniciansbrought up on this medicaldiet, Mason’s book represents anexcellent neurology review. For thosewith fond memories of ‘Martini’ or‘Tortoura’ and their usefulness inrapidly getting to grips with a topicduring their early years of medicalschool, this book could be seen as anextension.Highly recommended for the targetreaders, undergraduates and juniortrainees. lAuthor: Peggy MasonPublished by: Oxford UniversityPress (2011)Price: £36.00ISBN: 978-0-19-533997-0Reviewed by:Graham Powell andBenedict Michael,University of Liverpool.18 > ACNR > VOLUME 11 NUMBER 4 > SEPTEMBER/OCTOBER 2011

11-33325Exclusive 20%-offNeurology books for all ACNR ReadersBuilding Brains:An Introduction to Neural DevelopmentISBN: 978-0-470-71229-0Hormones in Neurodegeneration,Neuroprotection, and NeurogenesisISBN: 978-3-527-32627-3The Year in Cognitive Neuroscience 2011ISBN: 978-1-573-31834-1From DNA to Social CognitionISBN: 978-0-470-54396-2European Handbook of NeurologicalManagement (2 Volumes Available)ISBN: 978-1-4051-8533-2 (Volume 1)ISBN: 978-1-4051-8534-9 (Volume 2)Parkinson’s Disease: Non-Motor andNon-Dopaminergic FeaturesISBN: 978-1-4051-9185-2Cerebrovascular Ultrasound in StrokePrevention and Treatment, 2nd EditionISBN: 978-1-4051-9576-8Clinical Electrophysiology:A Handbook for NeurologistsISBN: 978-1-4051-8529-5Simply quote promotion code ACNRat the checkout to get20% off the listed priceExplore our extensive collection of Neuroscience and Neurology books online atwww.wiley.com/go/neuroscience

CLINICAL DILEMMAS IN NEUROPSYCHIATRYSeries EditorAlan CarsonSeries editor Alan Carson is a ConsultantNeuropsychiatrist and Part-time Senior Lecturer. Heworks between the Neurorehabiltation units of theAstley Ainslie Hospital and the Department of ClinicalNeurosciences at the Western General Hospital inEdinburgh. He has a widespread interests in neuropsychiatryincluding brain injury, HIV and stroke. He has longstandingresearch and teaching collaboration with JonStone on functional symptoms in neurology.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 eighth in a series of articles in ACNRexploring clinical dilemmas in neuropsychiatry. In thisseries of articles we have asked neurologists and psychiatristsworking at the interface of those two specialties towrite short pieces in response to everyday case-based clinical dilemmas.We have asked the authors to use evidence but were also interested intheir own personal views on topics. We would welcome feedback onthese articles, particularly from readers with an alternative viewpoint.Are People with Subjective but no ObjectiveMemory Complaints at Increased Risk of Dementia?CaseAlex J Mitchellis consultant in liaisonpsychiatry at LeicestershirePartnership Trust and honorarysenior lecturer in psychooncologyat the University ofLeicester. In 2004 he authored“Neuropsychiatry & BehaviouralNeurology Explained” and in2009 was co-editor of“Screening for Depression: AnEvidence based Approach.” Hisresearch interests include thescientific approach to clinicaldiagnosis and improving qualityof mental health care. Hemaintains the websitewww.psycho-oncology.infoCorrespondence to:Alex J Mitchell,Consultant in LiaisonPsychiatry,Leicestershire Partnership Trustand Honorary Senior Lecturer,University of Leicester, UK.Tel: 0116 2463470Fax: 0116 2951951A 55-year-old teacher who lives alone seeks help for memory complaints. She reports forgetting the names ofstudents and losing items around the house but has minimal evidence of functional impairment, no difficultydriving and no history of mental or physical illness. She has a history of hypertension but is otherwise well. Shehas previously been tested on the MMSE which revealed a score of 29/30. Testing on the CAMCOG and ACEsuggest she is on the 90th percentile for her age with no appreciable objective cognitive decline. She is worriedabout the risk of future dementia.Should this patient be concerned about the riskof dementia? For younger people with minimalrisk factors is the MMSE sufficient as ascreening test? At this stage are further investigationsindicated and in the absence of a formal diagnosiscan anything be done to help?Subjective memory complaints (SMCs) are everydaymemory and related cognitive concerns expressed bypeople who may or may not have deficits on objectivetesting. SMC are of course common in people with mildcognitive impairment (MCI) and dementia anddepending of how they are defined may occur in up to50% of the healthy elderly population although afterexclusion of depression a rate of around 20-30% is moretypical. 1,2 The rate of complaints in those under 55 yearsis very poorly studied but Commissaris and colleagues(1998) found that 39% of people with a mean age of33.9 answered positively to the question “Do youconsider yourself forgetful?”, 3 suggesting perceiveddeficits are probably more common than thought.One important issue when trying to elicit SMC isthat awareness of deficits generally decreases asseverity of cognitive impairment increases (particularlyin the most severe stages). Moreover many peoplewho suspect cognitive problems may be reticentabout disclosing them and in many cases are reluctantto undergo formal testing. For this reason informantreport is strongly recommended where available, andis independently predictive of diagnosis and decline. 4Although definitions of SMC have not been operationalisednumerous several self-report questionnaireshave been developed and can be used simply in clinicalpractice. Examples of validated tools are theEveryday Memory Questionnaire – Revised (EMQ-R)and the Short Memory Questionnaire (SMQ). It is nowrecognised that the presence of SMC is associated withdistress and reduced quality of life. 5 Causes of SMCwithout objective complaints are diverse but conceptuallyit may be helpful to try and separate those withno evidence of cognitive impairment from those withsubclinical cognitive change and those with mildcognitive impairment. A simple classification basedon these three domains is illustrated (Figure 1 above).Indeed psychological factors such as depressioninfluence expression of memory complaints.Therefore perceived forgetfulness is not always asinister irreversible finding and even when examinedcross-sectionally most purely subjective memorycomplaints do not interfere with daily function. 6 8Practically anyone with memory complaints shouldalso be asked about symptoms of depression, andideally screened with a severity questionnaire such asthe Patient Health Questionnaire (PHQ9).The prognostic significance of SMC is important butuntil recently poorly studied. A review identified onlyseven studies published up to 2000 that considereddementia longitudinally and of these five studiesfound an association between baseline SMC anddementia after two years or more. 9 However these20 > ACNR > VOLUME 11 NUMBER 4 > SEPTEMBER/OCTOBER 2011

THE ASSOCIATION OF BRITISH NEUROLOGISTSHeather Angus-Leppan MSc (Ep),MD, FRACP, FRCPwas born in South Africa,trained in Australia and wona Scholarship as VisitingAustralasian Registrar to theRadcliffe Infirmary, Oxford,in 1993. She is ConsultantNeurologist, HonorarySenior Lecturer and EpilepsyLead at the Barnet and RoyalFree Hospitals, London, UK.She is the HonorarySecretary of the Associationof British Neurologists, pastHonorary Secretary of theNeurosciences Section ofthe Royal Society ofMedicine and Chair of theMap of Medicine EpilepsyGroup, UK.Correspondence to:Heather Angus-Leppan,Honorary AssistantSecretary, ABN.Heather.Angus-Leppan@bcf.nhs.ukAcknowledgement:Drs David Bateman,Steve Pollock and theworking party laboured hardon the joint report; withDr Patrick Cadigan andothers at the RCP, withAlastair Compston andCharles Warlow at the ABN.Martin Rossor,Charles Warlow andGeraint Fuller contributedvaluably to the ABNsubmission on directaccess MRI.Avoiding VOMITs andImproving CareBritish neurology is under pressure to meet newdemands in our outpatient and inpatient work.The two are closely linked and the Association ofBritish Neurologists (ABN) is working hard to influencechanges in both areas.Outpatient neurology, open access MRI andreal efficiencyCancer targets have infiltrated all areas of medicine,including neurology. In particular, headache is seen as apotential area of change. The potential ‘solution’ ofdirect access MRI scanning for GPs for all newheadache patients (trialled locally in some areasalready) won’t solve any problems, will create new onesand at the end of it all, won’t get rid of the patient’sheadache. Instead of more scans, the ABN suggestsincreasing partnership with primary care, working toincrease awareness and utilisation of current headachemanagement guidelines such as BASH (The BritishAssociation for the Study of Headache), Map ofMedicine, and other locally produced guidelines.Eliminating cancer as the underlying cause is only avery small part of neurological practice, and canusually be done clinically in the case of headache.Headache makes up a huge chunk of neurology referrals,and, as an isolated symptom, is almost never theconsequence of a brain tumour. With the large numberof patients with migraine and other headaches, manyscans would be requested if direct access was implemented.Given the limited number of MRI scannersavailable, this will compromise the availability of scansin patients for whom the scan will have a greater rolein diagnosis and management.Given that migraine occurs in 5% to 10% of the population(at least), and may resist treatment for over amonth and sometimes much longer, it would be unnecessaryand costly to arrange MRI brain scans oneveryone with chronic migraine. Patients with chronicmigraine rarely require an MRI scan. Furthermore, a scandoes not cure their headache, and up to 6% will have anincidental or false positive finding such as a smallaneurysm. This creates unnecessary and enormousanxiety, as well as potentially leading to more investigationswith added costs and occasional risks, and even tosurgery with very serious risks. This figure does notinclude the findings of VOMITs, UBOs, and withincreasing age, white matter hyperintensities andmicrobleeds. Incidental findings generate a huge needfor specialist referrals to settle anxiety, and explain findings.Indiscriminate MRI scanning would be enormouslyexpensive over and above the cost of the scan itself.Access to scanning is not the most important issuefor patients with headache, and will not solve theirpain. Education and empowerment of GPs to treatmigraine earlier and more could have a significantimpact on improving their care.Making a difference at the coal-faceA joint report from the ABN and Royal College ofPhysicians (RCP) “Local adult neurology services forthe next decade” has just been launched and is availableon the RCP website. It is staggering that the UK isone of the few places in the world where neurologistsare not acutely involved in neurological emergencies.They are common, making up 10% of emergencymedical admissions (and many more with stroke).Services for patients admitted to hospital with an acuteneurological illness are particularly concerningbecause they are rarely provided by neurologists, incontrast to those for stroke and other acute medicalspecialties, which may result in patients not receivingthe best possible care available. Neurology remains ashortage specialty, with appointments mainly to theregional neurosciences centres and an inequality ofmore than three to one in numbers of neurologists indifferent parts of the UK.Neurology services in the UK are organised aroundlarge regional neurosciences centres with anemphasis on research and academic excellence.These are crucial and should not be threatened, or wewill lose the heart of what is needed to maintain excellence.They have produced world class research andnew treatments for patients. But district generalhospital services remain under-resourced because of alack of local neurologists, in contrast to the USA andEurope with more neurologists per head of the population(1:40,000 versus 1:125,000). The lack of localneurologists in the DGH has resulted in poor localservices exacerbated by an increase in outpatientdemand driven by waiting time targets, inadequateresources and sometimes poorly structured servicesnetworked across health providers.Long-term care of neurology patients also requirebig improvements. Patients need a range of neurologyservices at different stages of their illness - acute admission,outpatient care and long-term care. However,these are currently badly integrated, leaving manypatients unable to access the right specialist at theright time and often far from home. They include sucha variety of conditions that more than one model isneeded for good care. For the patient, and their families,they need to be able to move between services,without fights or delays in provisions.To solve these problems, the report recommendsbetter integrated primary, secondary and tertiaryresources to achieve a neurology network that is easilyaccessible, provides local care where appropriate and,as needed, at the regional neurosciences centre. Thereport proposes changes to cover acute neurologyservices, outpatient care, care for patients with longtermneurological conditions, the relationshipbetween local services and the regional centres,commissioning, workforce planning and training.What can we do?We don’t want the new report to grow dusty on theshelf. It is clear that both large and small scale changesare needed to improve acute and long-term care ofneurology patients.Improvements have been, and can be, made at locallevel and we really would like to hear about more ofthese, as models of good care.The neurological charities support our calls forimprovements in services for patients, both acutely andin the long term, and it is clear that central changes areneeded. It is also clear that some of the changes willrequire more money. The resources required for directaccess MRI would be much better spent on implementationof the RCP-ABN report, and we are making thiscrucial point to the Department of Health. l22 > ACNR > VOLUME 11 NUMBER 4 > SEPTEMBER/OCTOBER 2011

MOTOR CONTROL SERIESThe Premotor Cortexand Mirror NeuronsIn 1991, Nature rejected the first report on mirror neurons for its 'lack of general interest'. Undeterred,the research team managed to publish a report the following year, and mirror neurons have been in thenews ever since. Indeed, claims that mirror neurons underpin such functions as language acquisition,theory of mind and empathy have been made. Here, Fogassi (one of the authors of the original report)and Rodà present an account of mirror neurons and motor control.Martyn Bracewell, Series editorLeonardo Fogassiis full professor of Physiology atthe Department of Psychology ofthe University of Parma. He has afirst degree (cum laude) in Biologyand a PhD in Neuroscience. Hismain research interests concernthe neural cortical mechanisms ofsensorimotor transformation andthe cognitive properties of themotor system in monkeys andhumans, with particular focus onthe mirror neuron system.Francesca RodàPsychologist, PhD in Neuroscience,is a post-doc at The Department ofNeuroscience, Section of HumanPhysiology, of the University ofParma. Her research interestsinclude investigations of monkeymirror neurons and their role inaction and intention understandingand of the neural bases of communication/languageevolution.Several neurophysiological studies in monkeysdemonstrated that neurons of the agranularfrontal cortex code goal-related motor acts,such as reaching an object, grasping it, etc., ratherthan simple movements. In particular, single neuronsof ventral premotor area F5 (Figure 1) code themotor goal at an abstract level, discharging when amonkey grasps an object independent of whetherthis act is performed with the hand, the mouth oreven with a tool. 1 This “internal motor knowledge” isthen exploited, through reciprocal anatomicalconnections between parietal and premotor cortex,by the incoming sensory information, constituting asystem matching the sensory input onto specificmotor representations. This system enables individualsto attribute a “motor meaning” to the sensoryinput. One of the best examples of this matchingprocess is provided by mirror neurons.Mirror neurons in the monkeyMirror neurons, originally described in monkey areaF5, are visuomotor neurons discharging both when amonkey performs a hand or mouth goal-directedmotor act (e.g. grasping, biting, or manipulating anobject) and when it observes the same or a similaract performed by another individual (Figure 2). Asub-class of mirror neurons respond not only duringexecution and observation of a motor act, but alsoto the sound of noisy motor acts such as peanutbreaking. 1 Although mirror neurons are generallynot influenced by many details of the observedmotor acts, recently it has been demonstrated that aconsistent number of them can be modulated bythe visual perspective (egocentric or third personview) from which a motor act is observed 2 or by thedistance at which the observed act is performed. 3Thus these neurons, beyond encoding the goal ofthe observed motor acts, can also contribute torecognize some details of it, probably through feedbackconnections between ventral premotor cortexand posterior, high order visual areas.The idea that mirror neurons have a crucial role inthe understanding of motor acts has been supportedby further neurophysiological investigations. In one ofthese 4 it has been demonstrated that mirror neuronsdischarge also when the hand-target interaction ishidden behind a screen, thus showing that the motorrepresentation of the observed motor act is retrievedeven in absence of its full visual description.The presence of mirror neurons has been demonstratedalso in the inferior parietal cortex, in a cytoarchitectonicarea (PFG) strictly linked with the F5“mirror” sector. Thus, these two areas, together withSTS (containing visual neurons responding to theCorrespondence to:Leonardo Fogassi,Dipartimento di Neuroscienze,Università di Parma,via Volturno 39, 43125 - Parma, Italy.Tel: +39 521 903847Fax: +39 521 903900Email: leonardo.fogassi@unipr.itFigure 1: Lateral View of the monkey brain showing the parcellation of the agranular frontal and posterior parietal cortices. Motorareas are indicated with the letter F followed by a number. The areas forming the posterior parietal cortex are indicated with theletter P, followed by another letter, except the most posterior part of the inferior parietal cortex (Opt). Abbreviations: AI, inferiorarcuate sulcus; AS, superior arcuate sulcus; C, central sulcus; IP, intraparietal sulcus; L, lateral fissure;P, principal sulcus; STS, superior temporal sulcus.ACNR > VOLUME 11 NUMBER 4 > SEPTEMBER/OCTOBER 2011 > 23

MOTOR CONTROL SERIESIntention understandingA series of experiments in monkeys investigatedF5 and PFG neuronal activity whilemonkeys executed or observed differentactions (eating or placing) containing thesame motor act (grasping) 7,8 The resultsshowed that a high percentage of both purelymotor and mirror neurons in both areasdischarged differentially during both executionand observation of the grasping act,depending on the final goal of the action inwhich the act was embedded. Thus, the modulationof grasping neurons reflects the actiongoal, that is the motor intention of the agent.Furthermore, when monkeys had to performmore complex actions the activity of graspingneurons was modulated since its early phases,suggesting that this activity could depend froma neural mechanism, probably located in theprefrontal cortex, that allows one to selectactions on the basis of the context.A mechanism similar to that described inmonkeys might play a role in understandingothers’ intentions also in humans. An fMRIstudy by Iacoboni and coworkers 9 showed thatwhen the context in which a motor act wasobserved suggested to observing subjects theintention underlying it, there was a differentialactivation of the right IFG compared withcontrol conditions in which only the contextor only the motor act were shown.Altogether, monkey and human studies indicatethat the parieto-frontal mirror networksubserves the automatic understanding ofmotor intentions underlying the actions ofothers, through a process of retrieval of actionrepresentations. It is possible, however, that incases in which the interpretation of others’behavior requires reasoning, beyond the ‘mirror’network other cortical areas, considered to bepart of a ‘mentalistic network, 10 are involved.Figure 2: Example of two mirror neurons responding during observation and execution of hand motor acts. A. Top. Illustrationof the experimental condition. Left. The monkey observes the experimenter grasping a piece of food. Right. The monkey graspsa piece of food. Bottom. Neuronal discharge recorded in six trials for each condition. The arrows indicate the experimenter’s(left) and the monkey’s (right) onset of grasping. B. Top Illustration of the experimental condition. The monkey observes aspecific goal-directed motor act (digging out of an object- left) compared to a mimicking of the same motor act (right)without the target. Bottom. Rasters (10 trials) and histograms illustrating the mirror neuron discharge in the two conditions.Note that the discharge is much stronger during observation of the goal-directed act. Abscissae: time. Bin width: 20 msec.Ordinates: Number of spikes/bin. Modified from (3).observation of biological motion, 3 constitute thefunctional circuit involved in transforming thevisual description of a motor act in its motorrepresentation (see Figure 1).The mirror system in humansSeveral electrophysiological andneuroimaging studies demonstrated the presenceof a mirror system also in humans. 3 TMSstimulation of the motor cortex of subjectsobserving a grasping motor act elicits aspecific enhancement of motor evoked potentials(MEPs) of the same muscles used toexecute the same observed motor act. PET andfMRI studies demonstrated that observation ofmotor acts activate three main areas, likelyhomologous of the monkey areas activated inthe same task, namely STS, supramarginal gyrusand the posterior sector of the inferior frontalgyrus (IFG), plus the anterior intraparietal area(AIP) and, in some cases, the superior parietallobule. 1,3 Interestingly, observation of goalrelatedmotor acts performed with differenteffectors (i.e. mouth, hand and leg) determinesa somatotopic activation, with some degree ofoverlap, of frontal and parietal cortices, 1 indicatingthat observation of a motor actperformed with a specific effector activates thecorresponding motor representation.More recent studies demonstrated that inhumans, like in monkeys, the mirror systemcan be activated during observation of motoracts performed with a non-biological effector,such as different types of tools and/or a robotarm. 5,6 However, by comparing human andmonkey brain activation during tool actionobservation Peeters and coworkers 6 showedthat only in humans is there is an extra area ofthe supramarginal gyrus exclusively activatedby tool observation.Plasticity of the mirror systemThe presence of mirror neurons responding alsoto tool actions 11 strongly suggests a plasticity ofthe mirror system. Examples of this plasticityhave been reported also in humans. For instance,Cross et al 12 demonstrated that the ventralpremotor (PMv) and inferior parietal (IPL)activity of expert dancers can be modulatedduring the observation of new complex wholebodydance sequences only if they arerehearsed.In an fMRI study, Gazzola and coworkers 13found that the observation of hand motor actsin aplasic subjects (born without arms orhands), produced an activation of the mirrorsystem that, in the frontal cortex, included themouth and foot representations. This suggestsa recruitment of cortical representationsinvolved in the execution of motor acts thatachieve similar goals using different effectors.In another fMRI study, Ricciardi andcoworkers 14 showed that in congenitally blindpatients listening to the sound of actions therewas an activation of the mirror system, as inthe normally sighted controls observing andlistening to the same actions.The reorganisation of the motor representa-24 > ACNR > VOLUME 11 NUMBER 4 > SEPTEMBER/OCTOBER 2011

MOTOR CONTROL SERIEStions shown by these studies prompts the possibilityto exploit this plasticity for rehabilitativepurposes. For instance, Ertelt and coworkers 15employed a three weeks action observationtherapy on stroke patients with mild paretichand. A group of them, who had to observe andreproduce motor acts of increasing complexity,showed a motor improvement (evaluated withfunctional scales), when compared to thecontrol group observing videos showing nonmotor-related material, and then performing thesame motor acts as the first group. Moreover, anfMRI study on the investigated patients showedthat during execution of an object manipulationtask, the first group, after the therapy, presented agreater activation of areas belonging to themirror network than the second group.In agreement with these findings, a recentpilot study based on Virtual RealityNeurorehabilitation 16 proved that acute strokepatients had particular benefits, as compared tocontrol patients, on recovery of proximal movementsand on the ability to perform functionaldaily life activities after adding, to a standardrehabilitation, exercises (Rehabilitation GamingSystem) requiring the execution and observation(through virtual reality) of motor acts such ashitting, grasping or placing a spherical object.ConclusionsThe discovery of the mirror system prompted itsinvestigation in many social cognitive functionsin healthy and pathological subjects. Oneexample is represented by the autistic spectrumdisorder, characterised by a deficit in intersubjectiverelations, in which a decrease in thefunction of the mirror circuit has beenproposed. Interestingly, EMG and behaviouralstudies showed that autistic children lack thetypical fluidity that characterise the organizationof intentional actions and they are not ableto understand intentions when they can relyonly on pragmatic information. 1 lREFERENCES1. Rizzolatti G, Fogassi L & Gallese V. The Mirror Neuron System: A Motor-Based Mechanismfor Action and Intention Understanding. In: The Cognitive Neuroscience IV, ed. M.Gazzaniga M. 2009; 625-640. Cambridge U.S.A: The MIT Press.2. Caggiano V, Fogassi L, Rizzolatti G, Pomper JK, Thier P, Giese MA & Casile View-basedencoding of actions in mirror neurons of area f5 in macaque premotor cortex. Curr Biol.2011;21:144-8.3. Fogassi L, Ferrari PF. Mirror systems. WIREs Cogn Sci 2011;2:22–38 DOI: 10.1002/wcs.89.4. Umiltà MA, Kohler E, Gallese V, Fogassi L, Fadiga L, Keysers C, Rizzolatti G. I know whatyou are doing: a neurophysiological study. Neuron. 2001;31(1):155-65.5. Gazzola V., Rizzolatti G., Wicker B. & Keysers C. The anthropomorphic brain: the mirrorneuron system responds to human and robotic actions. Neuroimage 2007;35:1674-84.6. Peeters R, Simone L, Nelissen K, Fabbri-Destro M, Vanduffel W, Rizzolatti G & Orban GA.The representation of tool use in humans and monkeys: common and unique human features.J. Neurosci. 2009;29:11523-39.7. Fogassi L, Ferrari PF, Gesierich B, Rozzi S, Chersi F, Rizzolatti G. Parietal Lobe: from ActionOrganization to Intention Understanding. Science 2005;308(5722):662-7.8. Bonini L, Rozzi S, Ugolotti Serventi F, Simone L, Ferrari PF & Fogassi L. Ventral premotorand inferior parietal cortices make distinct contribution to action organization and intentionunderstanding. Cerebr. Cort. 2010;20:1372-85.9. Iacoboni M, Molnar-Szakacs I, Gallese V, Buccino G, Mazziotta JC, Rizzolatti G. Graspingthe intentions of others with one’s own mirror neuron system. PLoS Biol. 2005;3(3):e79.10. Brass M, Schmitt RM, Spengler S & Gergely G. Investigating action understanding: inferentialprocesses versus action simulation. Curr. Biol. 2007;17: 2117-21.11. Rochat MJ Caruana F, Jezzini A, Escola L, Intskirveli I, Grammont F, Gallese V, Rizzolatti G& Umiltà MA. Responses of mirror neurons in area F5 to hand and tool grasping observation.Exp. Brain Res. 2010;204:605–16.12. Cross ES, de Hamilton AF, Grafton ST. Building a motor simulation de novo: observation ofdance by dancers. Neuroimage 2006;31(3):1257-67.13. Gazzola V, van der Worp H, Mulder T, Wicker B, Rizzolatti G, Keysers, C. Aplasics bornwithout hands mirror the goal of hand actions with their feet. Curr Biol.2007;17(14):1235-40.14. Ricciardi E, Bonino D, Sani L, Vecchi T, Guazzelli M, Haxby JV, Fadiga L, Pietrini P. Do wereally need vision? How blind people “see” the actions of others. J Neurosci.2009;29(31):9719-24.15. Ertelt D, Small S, Solodkin A, Dettmers C, McNamara A, Binkofski F, Buccino G. Actionobservation has a positive impact on rehabilitation of motor deficits after stroke. Neuroimage2007;36 Suppl 2:T164-73.16. Da Silva Cameirão M, Bermúdez i Badia S, Duarte E, Verschure PFMJ. Virtual reality basedrehabilitation speeds up functional recovery of the upper extremities after stroke: a randomizedcontrolled pilot study in the acute phase of stroke using the Rehabilitation Game System.Restorative Neurology and Neuroscience 2011; Epub ahead of print.ACNR > VOLUME 11 NUMBER 4 > SEPTEMBER/OCTOBER 2011 > 25

REHABILITATION ARTICLEEffectiveness of NeurobehaviouralRehabilitation for Young Peopleand Adults with Traumatic BrainInjury and Challenging BehaviourProfessor NickAldermanis Consultant ClinicalNeuropsychologist, SpecialtyLead and Associate Director atthe National Brain Injury Centre,St Andrew's Healthcare,Northampton. He specialises inneurobehavioural rehabilitation,and the assessment and managementof the dysexecutivesyndrome in people withacquired brain injury. He is VisitingProfessor at the universities ofGlamorgan, the West of Englandand Newman University College,Birmingham, and Visiting SeniorLecturer at the Institute ofPsychiatry, King's College London.Correspondence to:Prof N Alderman,Consultant ClinicalNeuropsychologist,National Brain Injury Centre,St Andrew’s Healthcare,Billing Road,Northampton,NN1 5DG, UK.Tel: +44 (0)1604 616381Email: nalderman@standrew.co.ukTraumatic brain injury (TBI) can happen toanyone at any time. Very young children, youngmen and older people are particularly at risk.TBI is often caused by road traffic accidents, falls,violence and sport. It has been described as the‘silent epidemic’: a conservative estimate is 295new cases per 100,000 in the UK which equates toapproximately 180,000 people each yearpresenting with head injury at hospital. Improvedmedical services mean more people survive butthe long term effects can be devastating. Theseinclude a wide range of physical, cognitive, sensory,functional and emotional impairments, disabilitiesand handicaps which can be long-term. Despitehigh prevalence and the proven effectiveness ofneurorehabilitation, brain injury has been regardedas a ‘Cinderella’ condition for many years withtreatment and care provided to survivors beingpatchy, under-resourced and of variable quality.Neurobehavioural disability and outcomeNeurobehavioural disability (NBD) and socialhandicap arising from this has a major impact onlong-term outcome. NBD comprises a complex,subtle, pervasive constellation of cognitive-behaviouralchanges that typify post-acute TBI. Thisundermines social independence and is associatedwith poor prognosis. Emotional difficultiesand challenging behaviour are characteristic ofNBD. Relatives frequently describe their familymember as having undergone a personalitychange. In some cases, aggression and sexuallyinappropriate behaviour are evident. Stress andburden on family members are immense. It hasbeen estimated that one new TBI case per 300,000people each year in the UK has severe, persistentbehaviour problems that exclude them from mainstreamservices. 1 As a consequence, at least 200people per year gravitate to care homes, prison andmental health units that are unable to meet theircomplex needs.Neurobehavioural rehabilitationThe National Brain Injury Centre (NBIC) was theUK’s first provider to offer rehabilitation to peoplewith TBI and other types of acquired brain injurywho also presented with challenging behaviour. Partof St Andrew’s Healthcare, the UK's largest not-forprofitmental health care charity, NBIC admitted itsfirst six patients in January 1979. Thirty years later, theservice has grown to over 100 beds with separatecare pathways for young people, men and women,units that cater for those with very challengingbehaviour, and others that offer slow-stream, longstayrehabilitation, both within a hospital setting andthe community. Patients are typically referredbecause they present with challenging behaviour ofsuch severity to preclude them from mainstreamneurorehabilitation services, and often from thecommunities in which they live.The treatment model is psychosocial and NBICwas the first service to evolve what is now termed‘neurobehavioural rehabilitation’. 2 This approachacknowledges that challenging behaviour is primarilya product of physical damage to the brain, butrecognises this is further shaped by the environment.This can help sustain challenging behaviour,which can be unwittingly maintained by thosepeople charged with the care of a person with abrain injury. This clinical population is not popularwith rehabilitation professionals because of theirirritating, threatening, and embarrassing behaviour,as well as their general lack of motivation. 3Consequently, patients with brain injuries may beavoided by staff and carers, and become sociallyisolated. Unfortunately, while challenging behaviourmay be primarily attributable to damagedneural systems, it can be reinforced by environmentsin which there are limited opportunities forappropriate social behaviour. Under conditions inwhich people are habitually ignored for longperiods, it is possible their only social contact iswhen staff intervene when managing challengingbehaviour. This can inadvertently reinforce andmaintain it.Whilst the environment can unwittingly maintainNBD and social handicap, it can also bemanipulated to benefit rehabilitation.Neurobehavioural rehabilitation services attemptto reduce NBD and social handicap by creating anenvironment in which people are re-taught skillsthey have lost through brain injury, which are thenencouraged and reinforced in the context ofeveryday behaviour. Treatment interventions workprimarily to reverse contingencies that previouslymaintained challenging behaviour, first byrequiring staff to interact with patients who maypreviously have been ignored, and second, byensuring social reinforcement is directed at desirable,rather than challenging behaviour. 4 In thisway, interventions based on operant learningtheory create enriched environments that changethe behaviour of people working with challengingbrain-injured patients and encourage developmentof a positive social climate that promotes therapeuticrelationships. Provision of these interventionswithin a highly structured environmentencourages new learning, skill acquisition, andpromotion of independence, giving patients morechoice, control, and freedom as they progress.26 > ACNR > VOLUME 11 NUMBER 4 > SEPTEMBER/OCTOBER 2011

REHABILITATION ARTICLEThe multidisciplinary teamIn addition to challenging behaviour, patientsadmitted to neurobehavioural services invariablyhave a range of complex needs that arepotentially amenable to rehabilitation. For thisreason, a wide range of clinical specialists isdrawn together to form a multidisciplinaryteam who work with the patients includingneurology, neuropsychiatry, neuropsychology,nursing, occupational therapy, physiotherapy,speech and language therapy, education anddietetics. Following a period of assessment,individual programmes are implementedwhose goals are to reduce challenging behaviourto enable patients to benefit from the clinicalspecialties they had been unable toaccess previously. All members of the multidisciplinaryteams implement theseprogrammes: role blurring and effectivecommunication ensure they are delivered allthe time, not just in formal therapy sessions.Evidence baseBecause neurobehavioural rehabilitation wascompletely new, a great deal of researchregarding its effectiveness has been undertaken.In NBIC a diverse research programmethat underpins clinical effectiveness and seeksto find new, innovative ways of helping patientshas been a characteristic of the service since itopened, much of which is conducted in partnershipwith universities and other academiccentres of excellence. In 1985 the first studythat examined outcomes achieved by theinitial 24 service users to pass though the NBICprogramme was published. 5 Results demonstratedthat more than two thirds of this verychallenging group had benefited, and a fifthcontinued to make further gains afterdischarge.A very recent review paper has beenpublished which confirms the evidence baseand efficacy of the different types of interventionsused in neurobehavioural services tohelp patients manage challenging behaviour. 6Other studies have demonstrated functionaland fiscal benefits of neurobehavioural rehabilitation,including savings to be made inproviding care in the medium-to-long term. 7 9Assessing individual outcome: SASNOSA range of bespoke behaviour rating scalesand other outcome measures conceptualisedfor use with people with ABI havebeen designed by clinicians within NBIC.Most recently, a four year project carried outin collaboration with Swansea Universityhas resulted in publication of the ‘StAndrew’s-Swansea NeurobehaviouralOutcomes Scale. 10 (SASNOS). This newmeasure fills a gap in the market byproviding a global measure of symptoms ofNBD and social handicap that has known,robust psychometric properties. Patients arerated by clinical teams on 49 items whichmeasure five major domains of NBD, each ofwhich has 2-3 sub-domains. Standardisedscores are computed so domains can becompared. Initial ratings can be used as aFigure 1: Change in SASNOS ratings in response to participation in neurobehavioural rehabilitation.baseline to track progress in rehabilitation.They can also be compared with those ofneurologically healthy people to help clinicianswith setting goals.Figure 1 illustrates how SASNOS was used toreflect an individual patient’s (KJ) response toneurobehavioural rehabilitation. The standardisedscore plot of symptoms of NBD observedand rated by members of the clinical teamduring the first two weeks of admissionsuggested that social handicap was underpinnedby difficulties in interpersonal relationships,cognitive function and sexual inhibitionand aggression. This plot assisted clinicians todetermine KJ’s strengths-weaknesses profile,determine the priority of his rehabilitationgoals, and design neurobehavioural rehabilitationinterventions. A second set of ratingsmade at discharge show the substantialimprovement in these target areas, with symptomsfor most sub-domains being rated atlevels comparable with the neurologicallyhealthy population.ConclusionFinally, it has been independently acknowledgedin the literature that it is a mistake tobelieve that people with acquired brain injuryand challenging behaviour can be effectivelymanaged in non-specialist services. 1 Opinionand evidence indicates that admission tospecialised neurobehavioural rehabilitationunits is required in such cases, and in additionto the clinical benefits this provides the mostcost-effective solution. Use of appropriateoutcome measures will help determine individualresponse to rehabilitation, and assistcommissioners to benchmark services againstone another. SASNOS is free to download anduse from the St Andrew’s Healthcare website atwww.stah.org/services/brain-injury/sasnos.aspx.REFERENCES1. McMillan T, Oddy M. Service provision for socialdisability and handicap after acquired brain injury. In RLl Wood, T McMillan (Eds), Neurobehavioural Disabilityand Social Handicap Following Traumatic Brain Injury.Hove, Psychology Press; 2001.2. Wood, RL. Brain injury rehabilitation: A neurobehaviouralapproach. London: Croom Helm; 1987.3. Miller E, Cruzat A. A note on the effects of irrelevantinformation on task performance after mild and severehead injury. British Journal of Social and ClinicalPsychology 1981;20:69–70.4. Alderman N. Contemporary approaches to the managementof irritability and aggression following traumaticbrain injury. Neuropsychological Rehabilitation2003;13:211–40.5. Eames P, Wood RL. Rehabilitation after severe braininjury: a follow-up study of a behaviour modificationapproach. Journal of Neurology, Neurosurgery, andPsychiatry 1985;48:613–19.6. Wood RL, Alderman N. Applications of operant learningtheory to the management of challenging behaviour aftertraumatic brain injury. Journal of Head TraumaRehabilitation 2011;26:202-11.7. Eames P, Cotterill G, Kneale TA, Storrar AL, Yeomans P.Outcome of intensive rehabilitation after severe braininjury: a follow-up study. Brain Injury 1996;10:631–50.8. Wood RL, McCrea JD, Wood LM, Merriman RN. Clinicaland cost effectiveness of post-acute neurobehaviouralrehabilitation. Brain Injury 1999;13:69–88.9. Worthington AD, Matthews S, Melia Y, Oddy M. Costbenefitsassociated with social outcome from neurobehaviouralrehabilitation. Brain Injury 2006;20:947–57.10. Alderman N, Wood RL, Williams C. The development ofthe St Andrew’s-Swansea Neurobehavioural OutcomeScale: validity and reliability of a new measure ofneurobehavioural disability and social handicap. BrainInjury 2011;25:83-100.ACNR > VOLUME 11 NUMBER 4 > SEPTEMBER/OCTOBER 2011 > 27

LEADING NORWEGIAN NEUROSCIENCE DISCOVERIESLars Jacob Stovner, MDis since 1994 professor of Neurologyand at present head of the departmentof Neuroscience at theNorwegian University of Science andTechnology in Trondheim. He is alsoconsultant at Trondheim UniversityHospital, leader of the NorwegianNational Headache Centre, anddirector of the international charitableorganization Lifting TheBurden:The Global Campaign AgainstHeadache, which has a official relationswith the World HealthOrganisation. He has published about200 papers and book chapters,mostly on headache.Knut Hagen, MDis, since 2007, Professor of Neurologyat the Norwegian University ofScience and Technology. He is also aConsultant Neurologist at theDepartment of Neurology, and aresearch member of the NorwegianNational Headache Centre. His mainfield of interest is headache epidemiology,but he has also conducted clinicaltrials.The RelationshipBetween BP and Pain:The Nord-Trøndelag Health SurveyChronic pain conditions, includingheadache, constitute large public healthproblems in most societies, but relativelylittle is known about their origins. During the lastthree decades, scientific evidence has accumulatedabout a relationship between pain andblood pressure (BP), showing that increased BP isrelated to lower pain sensitivity (so-called hypertension-associatedhypalgesia). Most of thisevidence stems from experimental studies onanimals, in which the effect of BP manipulationson pain behaviour has been investigated, but thereare also studies on humans where pain sensitivityhas been related to BP levels.HUNT studiesRelatively little has been known about the relevanceof this phenomenon for the most prevalentpain conditions, but in the Nord-Trøndelag HealthSurvey (the Norwegian acronym is HUNT), wherethe whole population above 20 years of age in theNord-Trøndelag county in Middle Norway wasinvited to participate (approximately 92,000), ithas been possible to study the relation betweenBP and pain on a population level. Three HUNTsurveys have been performed till now, in 1984-86,1995-97, and 2006-08 (HUNT 1, 2 and 3), and thetwo last surveys in particular included a widerange of health-related questions, in addition tomeasurements (BP, weight, height and others) andblood and urine samples. In the last two surveys,there was also a study among adolescents (HUNTYouth), covering the age group 13-19 years. Theanalysis of HUNT 3, when the data were releasedin 2009, has recently begun, whereas the HUNT 2data have been thoroughly analysed.Headache and BPOne of our early publications from the HUNT 2was performed to test (or rather to disprove) thecommonly held notion that headache was relatedto increased BP. In this paper, we looked prospectivelyat BP in HUNT 1 as a risk factor for developingheadache 11 years later (HUNT 2). 1 InHUNT 1, there was no data on headache, but morethan 59,000 respondents had answered questionsabout painkillers, and we assumed that 41,000subjects never using such medication had a negligibleamount of headache. Of the 41,000, almost23,000 participated in HUNT 2 eleven years later.As expected, there was no positive associationbetween BP and prevalence of headache. Thiswas, however, not very surprising, since there hadalready been a consensus agreement expressedby the diagnostic classification of the InternationalHeadache Society that moderate to mild hypertensiondid not induce headache. 2It was surprising, however, that the prevalenceof headache in general was 30% lower in thegroup with systolic BP> 150 mmHg compared tothose with BP ≤140. Similar, but less clear findingswere made in the cross-sectional analysis whereErling Tronvik, MD,is Neurology Consultant at theDepartment of Neurology at theUniversity Hospital, and a part-timepost doc at the Department ofNeuroscience at the NorwegianUniversity of Science and Technologyin Trondheim. He has conducted clinical,genetical and physiologicalstudies in the headache researchfield.Correspondence to:Lars Jacob Stovner,Norwegian National HeadacheCentre, Trondheim UniversityHospital, N-7006 Trondheim, Norway.Tel: +47 72 57 50 70Fax: +47 72 57 56 57Email: lars.stovner@ntnu.noFigure: One-year prevalence of chronic musculoskeletal pain related to systolic BP level among 66140 men and women(From the HUNT study, 9 published with permission from Blackwell Publishing Ltd).28 > ACNR > VOLUME 11 NUMBER 4 > SEPTEMBER/OCTOBER 2011

LEADING NORWEGIAN NEUROSCIENCE DISCOVERIESTable: Chronic musculoskeletal pain reported in HUNT 2 specified at different locations related to high BP in HUNT-1 andHUNT 2*. (Reproduced with permission from the Archives of Internal Medicine 6)HUNT-1HUNT-2Location of musculoskeletal symptoms SBP ≥ 160 mm Hg DBP ≥ 100 mm Hg SBP ≥ 160 mm Hg DBP ≥ 100 mm HgOR# (95% CI) OR# (95% CI) OR# (95% CI) OR# (95% CI)Neck (n=9,010) 0.7 (0.6-0.7) 0.7 (0.6-0.8) 0.7 (0.6-0.7) 0.7 (0.7-0.8)Shoulder (n=10,139) 0.6 (0.6-0.7) 0.7 (0.6-0.8) 0.7 (0.7-0.8) 0.7 (0.7-0.8)Elbows (n=4,284) 0.6 (0.5-0.6) 0.6 (0.5-0.7) 0.6 (0.5-0.7) 0.7 (0.6-0.8)Wrist/hands (n=6,357) 0.6 (0.6-0.7) 0.6 (0.5-0.7) 0.6 (0.6-0.7) 0.7 (0.6-0.8)Chest/abdomen (n=2,477) 0.5 (0.5-0.6) 0.6 (0.5-0.7) 0.6 (0.5-0.7) 0.6 (0.5-0.8)Upper back (n=4,365) 0.5 (0.5-0.6) 0.6 (0.5-0.7) 0.6 (0.5-0.6) 0.6 (0.6-0.7)Low back (n=8,182) 0.6 (0.6-0.7) 0.6 (0.5-0.7) 0.6 (0.6-0.7) 0.6 (0.6-0.7)Hip (n=7,257) 0.6 (0.6-0.7) 0.7 (0.6-0.8) 0.7 (0.6-0.7) 0.7 (0.6-0.7)Knees (n=7,263) 0.7 (0.6-0.7) 0.8 (0.7-0.9) 0.7 (0.6-0.8) 0.7 (0.6-0.8)Ankles/feet (n=5,932) 0.7 (0.6-0.7) 0.8 (0.7-0.9) 0.6 (0.6-0.7) 0.7 (0.6-0.8)§ High BP defined as Systolic BP ( SBP) ≥ 160 mm Hg and diastolic BP (DBP) ≥ 100 mm Hg.# Odds ratio (OR) with 95% CI. The reference group (OR=1.0) are individuals with normal BP (SBP < 140 mm Hg, and DBP < 90 mm Hg, respectively). Adjusted for age, gender,education, and use of antihypertensive drug therapy.data on both headache and BP came from theHUNT 2 study. A later, more thorough analysisof the HUNT data confirmed these results. 3The most clear cut relation was found for thevariable pulse pressure (ie the differencebetween systolic and diastolic pressure)showing that a large pulse pressure wasrelated to a low prevalence of headache. Thiswas true for both sexes, for both migraine andnon-migraineous headache, and in both theprospective and the cross-sectional analyses.It could not be due to some effect of BPmedication since the pain-BP-relationshipwas most marked for those not using antihypertensivesin all the analyses.A similar inverse association betweenheadache and BP on a population level hasalso been demonstrated by other groups, inBrazil, France and Iceland (for references, see3). We have also recently confirmed the findingsin another HUNT 2 cohort among adolescents(HUNT Youth), 4 although this cohortwas smaller ( VOLUME 11 NUMBER 4 > SEPTEMBER/OCTOBER 2011 > 29

LEADING NORWEGIAN NEUROSCIENCE DISCOVERIEShealthy middle-aged subjects is associated with reducedbaroreflex sensitivity, which has been shown to correlatewith reduced sensitivity to pain. This accords with a casecontrolstudy by our group, demonstrating increased baroreceptorsenisitivity among female migraineurs, 12 but anotherstudy has shown decreased baroreflex sensitivity inmigraine. 13Undoubtedly, chronic pain conditions in different bodyparts may also have “local” causes in various peripheraltissues (muscles, joints, intestines, vessels, meninges etc), andthe relative contribution of nociceptive impulses from theperiphery and of centrally determined sensitivity to painmay vary. However, according to the HUNT studies, the effectof hypertension-associated hypalgesia on pain in the populationis large, the difference between groups with high andlow BP being from 20 to 60% in our analyses, both forheadache and cMSCs.ConclusionThe HUNT studies have, with epidemiological methods,convincingly shown that the mechanisms involved in hypertension-associatedhypalgesia are operative in the commonpain conditions in the population. These mechanisms arenot of minor importance but can explain a substantial partof the variation in pain between individuals. We are eager toexplore these mechanisms further in the HUNT 3 study,where we have even better prospective data, high qualitybrain MRI images of a sample of the population, and possibilityto do genetical analyses. More knowledge about theprecise mechanisms mediating the relation between BP andpain conditions could lead to better prevention and treatmentof these prevalent, costly and disabling disorders. lACKNOWLEDGEMENTWe are grateful to Blackwell publishing Ltd for the permission to reproduce the Figure, and fromthe Archives of Internal Medicine for permission to reproduce the Table.REFERENCES1. Hagen K, Stovner LJ, Vatten L, Holmen J, Zwart JA, Bovim G. Blood pressure and risk ofheadache:a prospective study of 22 685 adults in Norway. J Neurol Neurosurg Psychiatry2002;72:463-6.2. Classification and diagnostic criteria for headache disorders, cranial neuralgia and facial pain.Cephalalgia 1988;8:1-96.3. Tronvik E, Stovner LJ, Hagen K, Holmen J, Zwart JA. High pulse pressure protects againstheadache:prospective and cross-sectional data (HUNT study). Neurology 2008;70:1329-36.4. Tronvik E, Zwart JA, Hagen K, Dyb G, Holmen TL, Stovner LJ. Association between blood pressuremeasures and recurrent headache in adolescents:cross-sectional data from the HUNT-Youthstudy. J Headache Pain 2011.5. Hagen K, Einarsen C, Zwart JA, Svebak S, Bovim G. The co-occurrence of headache and musculoskeletalsymptoms amongst 51 050 adults in Norway. Eur J Neurol 2002;9:527-33.6. Hagen K, Zwart JA, Holmen J, Svebak S, Bovim G, Stovner LJ. Does hypertension protect againstchronic musculoskeletal complaints? The Nord-Trondelag Health Study. Archives of internalmedicine 2005;165:916-22.7. Pickering TG. Effects of stress and behavioral interventions in hypertension. Pain and blood pressure.J Clin Hypertens (Greenwich) 2003;5:359-61.8. Ghione S. Hypertension-associated hypalgesia. Evidence in experimental animals and humans,pathophysiological mechanisms, and potential clinical consequences. Hypertension1996;28:494-504.9. Stovner LJ, Hagen K, Burstein R. Migraine and Other Pain Disorders. In:Schoenen J, Dodick D,Sandor P, editors. Comorbidity in Migraine: Blackwell Publishing Ltd;2011:81-95.10. Campbell TS, Ditto B, Seguin JR, Sinray S, Tremblay. RE Adolescent pain sensitivity is associatedwith cardiac autonomic function and blood pressure over 8 years. Hypertension2003;41:1228-33.11. Bruehl S, Burns JW, McCubbin JA. Altered cardiovascular/pain regulatory relationships inchronic pain. International journal of behavioral medicine 1998;5:63-75.12. Nilsen KB, Tronvik E, Sand T, Gravdahl GB, Stovner LJ. Increased baroreflex sensitivity and heartrate variability in migraine patients. Acta neurologica Scandinavica 2009.13. Sanya EO, Brown CM, von Wilmowsky C, Neundorfer B, Hilz MJ. Impairment of parasympatheticbaroreflex responses in migraine patients. Acta neurologica Scandinavica 2005;111:102-7.Nicolet EDX not available for sale in the U.S. at this timeOur complete line of neurodiagnostic needles and electrodes provides quality,optimal sharpness and greater patient comfort. Visit our website today to requesta supplies catalog and get more information on the new Nicolet EDX.Nicolet TECA®carefusion.com30 > ACNR > VOLUME 11 NUMBER 4 > SEPTEMBER/OCTOBER 2011

CONFERENCE REPORTSPREVIEW: WCN 2011 – Neurologists from all over theworld to meet in magical MarrakeshWith the theme “With Africa, forAfrica”, the XXth World Congressof Neurology (WCN) 2011 willprovide neurologists from Africa and aroundthe globe with a unique opportunity to shareknowledge at the world’s largest neurologyevent. The congress will take place on 12-17November 2011 in Marrakesh, Morocco.WCN’s scientific programme featuresworld-class speakers and a diverse array ofneurological topics as well as severalteaching courses, with the ultimate aim offinding real solutions to improve the longtermoutcomes for patients with neurologicaldisorders.In addition to the scientific programme,WCN 2011 will feature the dynamicTournament of the Minds competition andlively social events. Participants will alsohave the opportunity to take part in tours ofbeautiful Marrakesh and its surroundings.“Come to Marrakesh, a cultural, artisticand gastronomical capital,” writes Dr.Vladimir Hachinski, President of the WorldFederation of Neurology, in his invitation tocolleagues.“The speakers at the XXth WCN have beenselected not only for their expertise, butbecause they can convey the advances intheir area to neurologists specialising in theirfield. The Congress provides wonderfulupdates in all major areas of neurology andmany opportunities for interaction.”Scientific ProgrammeThe scientific programme will feature animpressive line-up of international experts.The bulk of the programme will be made upof main topic sessions, each with a numberof lectures under a common theme. Many ofthe sessions and lectures will focus on thecongress theme, “With Africa, for Africa,” andwill highlight the achievements of Africanneurologists and the challenges they face.These include “History of Neuroscience inthe Maghreb” on Monday, November 14, and“Neurological Care Policy in Africa” onWednesday, November 16.Daily plenary sessions will include thefollowing topics: The Mirror Neurons and theCognitive Brain (Giacomo Rizzolatti, Italy);The Future of DBS in Neurology andPsychiatry (Alim L Benabid, France);Challenges in Adopting InternationalGuidelines Into National Stroke Programmes(Lu Chuanzhenn,China); Neuroaesthetics:Artistic Creativity and the Brain (Sémir Zeki,UK); and Vertigo and Balance (David Zee,USA). Also included under the plenarysessions are the Named Orations: Melvin DYahr Lecture (presented by Anthony Lang,Marrakesh by Evening, Djemaa el-Fna Square.Canada); the Eddie and Piloo BharuchaLecture (Elly Katabira, Uganda); SorianoLecture (Christian Elger, Germany); and theFulton Symposium Soriano Lecture(Hidehiro Mizusawa, Japan).Teaching CoursesTeaching courses are another highlight ofthe rich scientific programme. The courseswill run throughout each day of the congressin parallel to the rich and varied scientificprogramme. Participation in a course willtranslate into separate CME credits, in additionto the CME credits given for participationin regular congress sessions.The course content will include a range ofclinical and more general topics. The clinicalsubject matter will include epilepsy, stroke,infection, sleep, pain, child neurology, movementdisorders, and dementia, among others.These sessions will feature practical demonstrations,using equipment specific to thecondition or disease under discussion, aswell as live demonstrations on patients. Butthere will also be sessions that addressbroader issues, such as a session on advocacyby the American Academy ofNeurology, neurological education, and howto write a scientific paper. Teaching courseswill also focus on challenges facing neurologistsin low-income countries, such as onetitled, Dementia in the Developing World.The World Stroke Organization will presenta free session titled ABC Cardinal Principlesof Stroke Management, and other freecourses will deal with examining a comatosepatient; tremors; diplopia; and myopathy. TheInternational Working Group of YoungNeurologists and Trainees will host a workshopfor young neurologists.The choice of subject matter reflects theemergence of new therapies and diagnostictechnology, such as Botox, deep-brain stimulation,EEG video, interventional radiology,and neuroimaging, as well as the morerefined distinctions between the subspecialties,such as sports medicine, brain injury,neurorehabilitation, and neurocritical care.The congress secretariat will publish a fullsyllabus for each course ahead of thecongress starting date.Tournament of the MindsIn addition to enjoying a high-quality scientificprogramme and a magical host city,participants will be able to exercise theirbrains in the Tournament of the Minds.The Tournament of the Minds is a uniqueopportunity to interact with colleagues, testintellectual tenacity, and demonstratenational pride, all while competing incountry teams. As such, the aim of theTournament of the Minds is to provide anexperience that is both educational andentertaining for participants. This is thefourth time the tournament has been organisedby the World Federation of Neurology ata World Neurology Congress.WFN member societies are invited toenter a team of four Neurologists in theTournament. Teams will compete with eachother in a knockout competition, to answerquestions on a range of Neurological topicsbased on clinical cases from around theworld; the questions will focus on visualmaterial, videos and stills, with a minimum oftext. Tournament judges will award thewinning team an attractive prize.To participate, please contact the presidentof the relevant local Member Society who isresponsible for coordinating national teams.For more details about WCN 2011,please visit the congress website:www.wcn-neurology.com.ACNR > VOLUME 11 NUMBER 4 > SEPTEMBER/OCTOBER 2011 > 31

RAatE 2011Monday 28th NovemberUniversity of Warwick Conference Centre, CoventryDelegate RegistrationRAatE 2011 is the only UK conference focused on the latest innovations anddevelopments in Assistive Technology. This conference will be of interest toeveryone who uses, works with, develops or conducts research on AssistiveTechnologies (AT).This year's event is run in association with the Health Design & TechnologyInstitute at Coventry University. The HDTI seeks to develop new products andnew systems of care provision for the assisted living sector.The conference program has, over the past years, regularly included newtechnological developments, service innovations, results of formal researchprojects, service based research and development and a wide range of otherstimulating topics.Known as a friendly and productive conference, RAatE offers you a chance tomeet and share knowledge and experience with other people working in AT.RAatE 2011 is delighted to announce this year's keynote speaker as Dr. RogerSmith, Fellow of RESNA and Professor of Occupational Science and Technologyat the College of Health Sciences and the University of Wisconsin, Milwaukee.Dr Smith has published and presented in the area of disability access, assistivetechnology and functional performance measurement and has also secured over$8m of funding for research and projects relating to disability and rehabilitation.Paper presentations at RAatE 2011 will include:• Case studies of innovative AT in practice• Developments & challenges in wheelchair services• Emerging technologies & recent advances in AT• New service demands: Commissioning of re-ablement & AT services• Services – Aspects of service deliveryTo book your place at RAatE 2011 register online at www.raate.org.uk.Cost is £150.Neurology and PsychiatrySpRs Teaching Weekend9 to 11 December 2011, St Anne’s College – OxfordTopics to include: Neurological and psychiatric history takingand examination • Investigations (MRI, EEG)• Psychological presentations of neurological disorder• ‘neurological’ presentations of psychological disorders and thebiological basis of psychiatric symptoms.Course Fee: £250 (Includes two nights’ bed & breakfast, lunches,morning and afternoon coffee/tea and Friday night dinner).BNPA 25thAnnual General Meeting9/10 February 2012Venue: The Institute of Child Health, Guilford St, LondonTopics to include: Huntington’s Disease • Tropical Neuropsychiatry• Conversion Disorder in the developing world • NeuropsychiatryResearch Update • Networks and Rhythms in Health and Disease• What the eye does not see – psychology of magicFor outline programme and registration form visit:www.bnpa.org.ukFor details of exhibition/sponsorship opportunities,contact: Jackie Ashmenall onPhone/Fax: 020 8878 0573/Phone: 0560 1141307Email: admin@bnpa.org.uk or jashmenall@yahoo.comEUROPEAN CHARCOTFOUNDATIONUNIVERSITY CLASSES VIIIEUROPEAN CHARCOTFOUNDATIONSYMPOSIUMFocused on Symptomatic TreatmentsAn Educational Programme onMultiple SclerosisNovember 30, 2011, Marbella, SpainFaculty:M.P. Amato, G. Comi, G. Edan, O. Fernandez, C. Fowler, J. Haas,R. Hupperts, L. Kappos, J. Palace, K. Selmaj, P. Soelberg Soerensen.Call for European Charcot Foundation young investigatorstravel grantsThe European Charcot Foundation is pleased to announce thatthey will provide an unrestricted educational grant to sponsor alimited number of young investigators with a travel grant of€1500,- to attend the University Classes in Multiple Sclerosis VIII.Young investigators are invited to apply before October 15, 2011.Conditions for applications are available on our website.Towards Personalized Treatment inMultiple SclerosisDecember 1, 2 and 3, 2011, Marbella, Spain17th European CharcotFoundation LectureProf. X. Montalban‘Towards Treatment of Persons with Multiple Sclerosis:on detour and access’Sessions on:• Rationale for personalized treatment in face of diseasecomplexity• Tools for prognosis• Treatment heterogeneity, targets and risks• Treatment in practice• Partnership• Personalized treatment, partnership and disease complexityFor detailed information and registration visit our website www.charcot-ms.eu32 > ACNR > VOLUME 11 NUMBER 4 > SEPTEMBER/OCTOBER 2011

CONFERENCE REPORTSBasal Ganglia at the Base of the CN TowerConference details: 5-9 June 2011; Movement Disorders Conference, Toronto, Canada. Reviewed by: Dr Tom Foltynie, Consultant Neurologist, Queen Square, London.So what’s new in Movement Disorders? Ofcourse there’s a growing trend to keepnew unpublished data to yourself thesedays, lest your rivals and competitors getwind of your latest breakthrough, but despitethis, MDS 15 in Toronto had plenty of novelty.PD Mechanisms and PathogenesisYou come all the way to Canada and yet itturns out that one of the star talks of theweek hails from Sheffield, UK. I’d not heardPeter Redgrave speak before, but he gave adelightful talk as part of an Obeso/ Brown/Redgrave basal ganglia trio. He explained theevolutionary existence of the basal gangliawell ahead of the development of the cortexand the fact that it has a clear role in actionselection in response to diverse environmentalstimuli. He elaborated that we shouldthink of our behaviour as either “goaldirected “ or “habitual”, with distinct anatomicalcircuits from cortex to basal ganglia. Heproposed that Parkinson’s disease (PD)patients are trapped in the goal directedbehaviour circuit, and have lost the habitualpathways responsible for automatic walking,postural reflexes and sequential motorprogrammes. There must also be distortion atthe point of convergence between thesecircuits, explaining why even voluntarymovements become slower and moreeffortful.We have long known about interrelatedpathways of proteasomal dysfunction andmitochondrial dysfunction in the neurodegenerativeprocess. It seems that mitochondrialdysfunction and removal (mitophagy)and ongoing replenishment through biogenesisis repeatedly being identified as criticalin PD pathogenesis. Serge Przedborksi gave auseful review of the last 20 years progresssince MPTP toxicity was first identified, allthe way to the recent identification of PGC1αand PARIS (parkin interacting substrate) allwith respect to the mitochondrial pathways.To add further detail, David Park reviewed hiswork on Calpain, cdk-5 and prx-2 that relateoxidative stress mediated by mitochondrialdysfunction with subsequent cell death,while Valina Dawson reviewed some of herunpublished cell biology that has beenrecently discovered, relating oxidative stressas a cause for mitochondrial dysfunctionand subsequent nuclear DNA damage. A keypart of this pathway is PARP-1, and PARP-1inhibitors that cross the blood brain barrierhave been identified and shown to beprotective in vitro and in animal models ofPD. The field has also been greatly advancedby the work of Heidi Macbride who showedreal time fission/fusion and budding of mitochondria,and their dynamic movementthrough the cytosol and into and out of theCN Tower, Toronto, Cananda.Tom Foltynie.nucleus. A novel PD gene VPS35 appears toplay a role in the process of mitochondrialbudding.... watch out for this.The take home message seems to be thatPD pathogenesis undoubtedly involvesproteotoxicity, mitochondrial dysfunctionand neuroinflammation, all interacting withmultiple points for potential therapeuticintervention.TherapeuticsCarl Clarke presented the evidenceregarding treatments for advanced PD.Despite its widespread use, we have littleactual “Evidence” to justify the use ofApomorphine, evidence from only smallnumbers of patients for Duodopa but datafrom trials involving large numbers ofpatients undergoing Deep Brain Stimulation(DBS). While experienced clinicians haveplenty of their own anecdotal experience tounderwrite the use of all three of theseagents in appropriate patients, will thisevidential thin-ice jeopardise our ability tooffer these treatments in these harsheconomic times? Dr Clarke predicted thatcost effectiveness data that is soon to emergefrom the PD surg trial may further jeopardisethe availability of these treatments foradvanced PD patients – I for one, really dohope not.Dr Clarke also discussed the plausibility ofa randomised trial comparing the efficacy ofthese three expensive treatments, andpointed out that this is highly unlikely giventhe need for companies to protect theircommercial interests, and the impossibilityof effective treatment blinding. Even iffinanced, such a trial would prove difficultgiven that different patients and cliniciansalready have well established prejudices/preferences regarding these disparate treatments.In my own opinion, I have no doubtthat one size does not fit all in advanced PDand an attempt to define choice one, twoand three that suits all comers is far toosimplistic. Long term improvements in functionand quality of life can be highly variablein response to these treatments dependingon patient phenotype such as age / severityof motor symptoms / motor phenotype /extent of cognitive impairment / other nonmotor symptoms.To complicate the PD therapeutic horizonfurther, there is no shortage of new andevolving treatments for PD. Olivier Rascolgave a whirlwind tour through these, bothdopamine and non-dopaminergic, oral andinhaled (Apomorphine) as well as thesurgical (particularly the gene therapyapproaches). There is growing interest in theuse of the cholinesterase inhibitors ormethylphenidate as treatments for doparefractory falls in PD, and preliminary dataneeds to be confirmed or refuted in futuretrials.I was keen to hear whether there havebeen further developments in DBS andindeed there were a whole bunch of postersdemonstrating the long term benefits of Sub-Thalamic nucleus (STN) DBS in PD, and highlightingits use in Chorea-acanthocytosis,Tourette syndrome and many forms ofdystonia. Jerry Vitek reminded us of thepossible under-investigated merits of GlobusPallidus externa (GPe) DBS, and Paul Krackreviewed the non-motor issues surroundingthe use of DBS. The most innovative talkcame from Peter Tass who described a novelway of applying different frequency DBS toadjacent populations of cells to de-synchronisetheir activity and lead to prolongednormalisation of firing patterns, thus makinga huge saving on electrical energy requiredACNR > VOLUME 11 NUMBER 4 > SEPTEMBER/OCTOBER 2011 > 33

CONFERENCE REPORTSand thus battery life. Perhaps DBS mightbecome cheaper after all.... For me thoughthe biggest audience cheer of the weekcame from the dry humour and razorcritique of DBS publications relating to thePedunculopontine nucleus by my colleagueMarwan Hariz. He reminded us thatpublishing was not the be-all and end–all ofscience; we should also take time to read,criticise and reflect on new discoveries bothas clinicians and most importantly as peerreviewers.VO GamesTony Lang and Kapil Sethi, prior toperforming their ritual humiliation of theexpert panel, explained that the officialOlympic committee have opposed the use ofthe term “Video Olympics” at the MDS, lest itleads to confusion between the realOlympics and our Annual MDS meeting. Aneedless fear given that cases were all muchmore straightforward this year, with a clearlearning point from each one -1. Methylmalonic aciduria causing chorea(with the clue being the accompanyingprogressive renal failure).2. Presenilin mutation causing an autosomaldominant dementia, but also withataxia, parkinsonism and extensorplantar responses.3. MELAS in a monk with unusual(possibly myoclonic) orofacial movements,accompanied by diabetes andgait freezing4. (For the audience alone) – A young girlvoluntarily and repetitively shaking herhead – to provoke photosensitiveseizures.5. Alpha mannosidosis causing a progressivemyoclonic ataxia with mental retardationand hearing loss – the clue beingthe accompanying bony deformities.6. SCA-2 manifesting as an ataxia withoculomotor apraxia.7. DRPLA with a fairly typical presentationbut unusual Iron deposition in the cerebellumseen using gradient echo MRIpossiblyrelated to a previous subduralhaemorrhage.8. Marchiafava Bignami causing acuteparkinsonism with characteristic callosalatrophy and white matter change.9. Kufs disease presenting as autosomalrecessive young onset PD and aneuroleptic malignant (type) syndromefollowing L-dopa administration - diagnosedon axillary skin biopsy - why didthey think to do this?10. Focal seizures in Wilson’s disease - notall new problems in Wilson’s are relatedto drug side effects & copper leaching.11. Alexander’s disease presenting withataxia, and a palatal tremor (oncesought), showing the typical “tadpole”sign on MRI.12. Sepiapterin reductase deficiencypresenting with Dopa responsivedystonia (as you’d expect), but with thelesson that serotonergic dysfunctionalso needs treatment.13. An ataxia telangiectasia–like disorder in 2 patients that lookedpretty similar to myoclonus dystonia,and doesn’t always feature telangiectasia.14. Molybdenum cofactor deficiency – tobe added to the short list of causes oflens dislocation, but causing massiveswelling and signal change through thebasal ganglia with abulia and acomplex movement disorder. I didn’t getthis one...To summarise, it seems clear that multiplemechanisms of variable relevance in variablepathways are involved in PD pathogenesis.It’s not surprising we see a clinicallyheterogeneous disease. And we must retainour clinical skills – in our sub-specialty wehave a huge number of treatable conditionsthat require accurate diagnoses. See you inDublin next June. lMS –Emerging concepts for 2012Join our breakfast newsupdate at the...Association of British Neurologists Annual Meeting,The Sage Gateshead, Newcastle Upon Tyne07.30 - 08.30 hours Thursday 6th October 2011 Managing mobility in MSDr Omar Malik, Imperial College Healthcare NHS Trust Therapeutic expectations in 2012Professor Gavin Giovannoni, Barts and the London NHS TrustDate of preparation: August 2011. Code No: BI-PAN-0182.This session is sponsored by Biogen Idec Ltd34 > ACNR > VOLUME 11 NUMBER 4 > SEPTEMBER/OCTOBER 2011

CONFERENCE REPORTSModels in Parkinson’s Research:Are we addressing the right questions?Conference details: 18 May 2011; London, UK. Reviewed by: Dr Rosemary Fricker, Senior Lecturer, Keele University, UK.The Seventh Research Conference of theUK Special Parkinson’s Research InterestGroup (SPRING) brought togetherleading scientists and clinicians from acrossthe globe to debate the value of currentmodels of Parkinson’s disease (PD). The aimof this one day meeting was to discuss theusefulness of current PD models in broadeningour understanding of the diseaseprocess, and as a tool to test future therapies.The first session set the scene by identifyingthe key features of PD that need to bereproduced in models. Jose Obeso (NavarraMedical School, Spain) and Tamas Revesz(UCL, London) described the complexity ofneurodegeneration in PD, which affectsmany neuron subtypes and not solely thenigrostriatal dopamine neurons, causing along phase of preclinical pathology, andevolving not only the cardinal motor symptomsbut also cognitive impairments anddementia seen in PD. In addition, neuronalpathology appears as Lewy neurites inneuronal processes as well as Lewy bodieswithin cells, suggesting that problems withneurotransmission may be a key componentof the disease process. There was somedisagreement as to whether PD pathology issynchronised and multisystemic, or if itspreads in a caudo-rostral fashion from oneregion to another (the Braak hypothesis).However, both speakers concluded that anideal animal model should incorporate: agedependentand focal loss of dopamineneurons with associated motor dysfunction,Lewy body and Lewy neurite pathology, andprogressive neurodegeneration that representsthe non-motor components of thedisease.The second session focussed more specificallyon rodent models of PD. TimGreenamyre (Pittsburgh University, USA) gavean eloquent overview of the rotenone modeldeveloped in his laboratory, highlighting thestrengths of this toxin-induced neuron degeneration.Rotenone targets complex 1 in themitochondria, inhibiting mitochondrial respirationand thus energy metabolism.Greenamyre’s group have observed iron depositionin the substantia nigra pars compacta(SNc) following rotenone administration,suggesting that iron may contribute to thepathology of the disease.Peter Magill (Oxford University) reportedwork to elucidate the nature of neuronalfiring patterns in the basal ganglia circuitry,and how these are affected in PD to cause anincrease in bradykinesia and rigidity. Injecting6-hydroxydopamine into the basal ganglia(the 6-OHDA rat model) causes large changesRosemary Fricker is a Senior Lecturer at Keele UniversityMedical School. Her current research is focussed onidentifying novel proteins that influence the differentiationof stem cells to dopamine neurons, for the treatment ofParkinson's disease.in the β oscillation firing patterns of basalganglia neurons, with increased synchrony ofpairs of neurons, particularly within theGlobus Pallidus (GP). A single GP neuron caninnervate neurons in the GP, entopeduncularnucleus, subthalamic nucleus and substantianigra pars reticulata. Thus, death of SNcdopaminergic neurons may cause wholenetworks of neurons to undergo changes inrhythm, oscillation and synchrony and, byfiring at the wrong time or in the wrong placewithin the basal ganglia, cause many of thesymptoms of PD.Dysfunction of the proteasome in clearingunwanted proteins from neurons is a candidatepathway that may be involved in thedevelopment of idiopathic PD. Dr LynnBedford (Parkinson’s UK Senior Fellow,Nottingham University) presented her work todevelop a genetic mouse model, by conditionaldeletion of the 26S proteasome in tyrosinehydroxylase positive neurons. Mice withthis deletion show progressive neurodegenerationand the formation of Lewy-like inclusionscontaining α-synuclein, ubiquitinatedproteins and mitochondria. However, whenthese mice were crossed with α-synuclein nullmice, lack of α-synuclein had no effect onLewy body formation, suggesting that it maynot be a key player in the process.The third session of the conferencefocussed on modelling PD in other animalsand human cellular systems. Tilo Kunath(Parkinson’s UK Senior Fellow, EdinburghUniversity) presented research to generateinduced pluripotent stem cell lines (iPSCs)from a patient with familial PD caused by triplicationof the SNCA gene encoding α-synuclein.These iPSCs were differentiated intomidbrain dopamine neurons and were shownto express double the levels of α-synucleinwhen compared to neurons derived fromiPSCs generated from an unaffected familymember.Animals such as zebra fish, Caenorhabditiselegans and Drosophila have been used tomodel neurodegenerative disease and offeradvantages such as short life cycles, relativelystraightforward gene manipulation, simplicityor easier visualisation of neuronal circuitry,and the potential to screen large numbers ofanimals for pathology or potential therapies.Oliver Bandmann (Sheffield University)described techniques by his group for transientknock down of the PD-related genes DJ-1, parkin and PINK1 by injecting antisenseoligonucleotides into zebrafish embryos atthe single cell stage. This morpholino strategycan generate stable lines that display keyfeatures of PD such as mitochondrial dysfunctionand loss of dopaminergic neurons.Anton Gartner (Dundee University)presented research to generate PD models inC.elegans via α-synuclein gene mutation orusing the 6-OHDA toxin to induce neurodegeneration.Using the 6-OHDA model toscreen for neuroprotective genes, they havefound that the membrane protein tetraspanin-17 may have a neuroprotective role fordopamine neurons depending on its specificexpression level. Alex Whitworth (SheffieldUniversity), presented data on Drosophilamodels of PD derived by mutating the genes:PINK1 and Rhomboid-7. Their researchsuggests that aberrant fusion of mitochondriastops their degradation and this may play arole in neuronal death in PD.The conference ended with an opendiscussion between the audience and apanel of experts: Paul Bolam, Oxford; KieranBreen, Parkinson’s UK; Jose Obeso, Navarra;Richard Wade-Martins, Oxford; and RosemaryFricker, Keele. Many issues were raisedincluding: is PD a syndrome rather than asingle disease, and should we therefore bedeveloping more complex models, or indeedusing humans as models? Which modelsmight be most useful for the pharmaceuticalindustry, enabling better therapeutics to bedeveloped for early PD? One of the problemsdiscussed was the lack of biomarkers formodels, particularly for in vivo imaging ofrodents and primates to assess neuron degenerationand repair. The final conclusion? Weshould continue with both current and newavenues of research, as all models are goodbut none are yet sufficient. lACNR > VOLUME 11 NUMBER 4 > SEPTEMBER/OCTOBER 2011 > 35

SPONSORED FEATUREThis editorial is sponsored by Biogen Idec UK LtdEvolving Strategies for the Management of Patients with MSBiogen Idec Nurse Academy 2011Friday 1st & Saturday 2nd July, Wokingham and Friday 8th & Saturday 9th July, ManchesterThe Biogen Idec Nurse Academy returnedthis year promising to deliver a diverseand challenging programme on a rangeof topics spanning the MS field. MS nursesfrom around the United Kingdom gathered inManchester and Wokingham to hear leadingclinicians discuss new data, emerging productsand evolving opinion on the managementof MS. Some key excerpts from themeeting are presented below.Research has suggested that 40–60% ofpatients with MS will develop cognitive impairment.Whilst this may be graded as mild in 80%patients, even mild cognitive impairment canhave a significant impact on the patient andtheir family and friends. It can be extremelyfrightening, with some patients worrying theyare going insane. Dr Anita Rose, ConsultantNeuropsychologist at Titleworth Neuro,provided a useful insight into dealing withcognition problems in patients with MS in herpresentation ‘Am I Mad, Crazy, Stupid or Nuts?’.Cognitive problems can not only cause relationshipissues and impact on employmentbut, in the later stages, can raise concernsaround safety, independence and the ability toself care. As a symptom, cognition is oftenignored, possibly due to the stigma associatedwith this type of problem and possibly becauseit may not be apparent on initial assessment –it frequently remains a ‘hidden’ symptom.Whilst assessment of cognitive impairment atthe point of diagnosis does not routinely occurin patients in the UK – many HCPs believe itshould be advocated. Dr Rose pointed out thatMS nurses can get involved in this and highlightedthat the Montreal Cognitive Assessment(http://www.mocatest.org/) is a useful testwhich is free, easily accessible and is easy tocomplete with patients. There are a number ofhelpful interventions which can be discussedwith the patient depending on their symptoms.For example, if a patient mentions that they aresuffering with attention problems when tryingto complete a task like doing the shopping,advise them to go to the supermarket at a timewhen it is less busy so that distractions such asnoise and crowds of people will be reduced.“Intervention can have apositive impact on quality oflife, mood, employment andrelationships”Dr Anita Rose1Avonex (interferon beta-1a) Prescribing Information may be found to the right.Figure 1: The negative cycle of thought, emotion andbehaviour (adapted from Kingdon & Turkington, 2005).Also encourage them to remove distractionsthey face when at home, for example by turningoff the television or radio. If a patient is havingtrouble with their memory, encourage them tomodify their environment by using signposts andlabels around the house or encourage the use ofmemory aids such as post-it notes or diaries.Activities including brain training programmescan also help with keeping the brain active andsome research shows this can have a positiveeffect on cognition. In addition to advising interventionsfor cognitive problems, it is also importantto assess for confounding factors such asdepression and stress. It is thought that there is a50% lifetime risk of suffering from depression if aperson has MS. This can have a dramatic impacton cognition and can usually be remedied.Alongside pharmacological treatmentsthere is also a wealth of non-pharmacologicaloptions which offer the potential to helppatients with MS. Peter Phiri, a BABCP accreditedCognitive Behavioural Therapist inSouthampton, discussed one such option –cognitive behavioural therapy (CBT).CBT can help patients with MS to managepain and fatigue, reduce the emotional impact(such as low mood or high stress levels) andreduce depression and anxiety.It can also improve treatment adherenceand help the patient to develop alternativeways of coping with functional problems. Aspeople at the forefront of MS care, there are anumber of advantages for MS nurses usingCBT with their patients:• they have already fostered excellent relationshipswith them• they are credible and dependable• they are trained in interviewing skills• they are aware of other treatments thepatient may be receiving• they often have 1:1 sessions with theirpatients.CBT is based on formulating the patients’ problemsusing a cognitive model. It requires asound therapeutic alliance and structure andinvolves the participation of both the therapistand patient. The therapy is goal orientated andproblem focused with the initial target beingthe ‘here and now’. The aim of CBT is to teachthe patient skills they can use when identifying,evaluating and responding to theircognitive biases, beliefs and assumptions.Figure 1 shows how negative thoughts,emotions and behaviours can becomecyclical.CBT change methods which can be usedwith patients include developing a pleasurepredictingsheet, on which the patient writesdown the activities they plan to do and howmuch pleasure they estimate they will experience.Once the activity is completed the patientwrites down how much pleasure they actuallyexperienced and they can then compare thetwo ratings and consider the reasons they aredifferent/the same. Other change methodsmight involve use of a thought diary on whichthe patient can record the situation, their moodand the intensity of the mood. The therapist willhelp the patient develop a balanced alternativeview taking in to account the evidence both forand against that particular thought. The patientthen rates how much they actually believe thealternative balanced thought on a scale of 0(i.e. they don’t believe it) to 100 (i.e. they totallybelieve it). This is followed by the patient reratingtheir mood. This form of cognitive restructuringallows for a shift in mood, reducing theintensity of distress. The therapist and thepatient collaboratively develop a behaviouralexperiment to test out alternative thought. Onceproblems have been defined and clarifiedachievable goals can be set and solutionsimplemented.Also at the Nurse Academy, Biogen Idecintroduced the Avonex PEN 1 (interferon beta-1a). The PEN addresses some of the issues thatpatients face when considering injectabletherapy for the treatment of their MS. Whilsttreatment frequency may be the initial“CBT is a talking therapy thatasserts connection between theway we think (cognitions),feel (emotions), and behave(behaviours) and our physicalbodily sensations.” Peter Phiri36 > ACNR > VOLUME 11 NUMBER 4 > SEPTEMBER/OCTOBER 2011

SPONSORED FEATURE“CBT aims to break cycles of negativethoughts by working with the patientand empowering them to makeinformed decisions.” Peter Phiriconcern, needle size can also act as a deterrent to somepatients, with larger needles perceived to be more difficultto administer and more painful. Ease of injection is aprimary concern. Self injection may give patients greaterindependence and empower them to feel more in controlof their disease and should be facilitated where possible.In MS, autoinjectors may help to simplify the injectionprocess and reduce injection-related anxiety. There wasdiscussion and a demonstration of the new Avonex PENwhich may provide such benefits to patients alreadyusing Avonex. The Avonex PEN uses a smaller needle thanthe Avonex pre-filled syringe and is designed to simplifythe injection process, reduce injection anxiety andimprove patient independence.Caroline D’Arcy, an independent MS Specialist Nurse,who previously worked in the NHS, presented data on theannual audit of the natalizumab 2 service at Charing CrossHospital. The audit was designed to help patients, medicaland nursing staff and funders understand the effects ofnatalizumab and to provide a platform for any recommendationsor suggestions about the service to bediscussed and highlighted. Data on natalizumab and thenatalizumab infusion service were collected, analysedand presented at a patient study day. The study day whichhad taken place in March last year, found 98% of attendeesfound the day valuable and 92% saying that theywould come again. This year’s audit found that natalizumabtreatment is being started earlier than previously,is being used within the guidelines specified by NICE, andis being used in patients who are relapsing frequently. Interms of the natalizumab service itself, 98% of patientssaid they had seen the MS nurse and 98% found it valuable.Whilst 86% of patients had seen their neurologist,56% of patients would like to see their neurologist moreoften. Since the audit in 2010, access to neurologists hasincreased and the infusion room has been changed to anew, more spacious area which patients prefer. In terms ofclinical outcomes, the observations from this audit wereconsistent with those from previous clinical studies ofnatalizumab. Treatment with natalizumab was shown toreduce relapse rate over two years, lead to stability ofprogression of disability and reduce magnetic resonanceimaging (MRI) activity. With 189 patients being treatedwith natalizumab, Charing Cross Hospital is the largestinfusion centre of its kind in the UK. Annual audits willenable the natalizumab service to continue to improveand serve patients to maximum potential.The Nurse Academy was a successful and engagingmeeting which provided useful insight into a number ofkey areas of MS care. The meeting provided the attendeeswith the opportunity for lively and active debate withtheir peers as well as the opportunity to discuss currentissues with leading clinicians.The views expressed by the speakers are not necessarily thoseof Biogen Idec UK Ltd.Job code: BI-PAN-0180Date of preparation: July 20112Tysabri (natalizumab) Prescribing Information may be found to the right.Prescribing information: AVONEX ® (interferon beta-1a)Please refer to the Summary of Product Characteristics for further information.Indication: For the treatment of patients with relapsing multiple sclerosis or patients who have experienceda single demyelinating event with an active inflammatory process who are determined to beat high risk of developing clinically definite multiple sclerosis. Dosage and Administration: 30 µginjected IM once a week. Contraindications: Initiation of treatment in pregnancy. Patients with ahistory of hypersensitivity to any of the constituents. Patients with severe depression and/or suicidalideation. Warnings & Precautions: Use with caution in patients with previous or current depressivedisorders - depression and suicidal ideation are known to occur in increased frequency in the multiplesclerosis population in association with interferon use. Administer with caution to patients with ahistory of seizures, or receiving treatment with anti-epileptics, particularly if their epilepsy is notadequately controlled with anti-epileptics. Used with caution and monitor closely in patients withcardiac disease, severe renal or hepatic failure or severe myelosuppression. Routine periodic bloodchemistry and haematology tests are recommended during treatment. Development of neutralizingantibodies to AVONEX may decrease efficacy. Pregnancy & lactation: Initiation of treatment iscontraindicated during pregnancy. Women of child bearing potential should take appropriate contraceptivemeasures. If the patient becomes pregnant or plans to become pregnant, or breast feedingwhile taking AVONEX, discontinuation of therapy should be considered. Drug interactions: No formalinteraction studies have been conducted with AVONEX in humans. Corticosteroids or ACTH can begiven during relapses. Caution should be exercised in combining AVONEX with products with anarrow therapeutic index and dependent on cytochrome P450 for clearance. Side Effects: The mostcommonly reported symptoms are of the flu-like symptoms: myalgia, fever, chills, asthenia, headacheand nausea. Other common events include: decreased lymphocyte, white blood cell, and neutrophilcounts; decreased haematocrit and increased blood potassium and blood urea nitrogen. Nervoussystem disorders: muscle spasticity, hypoesthesia. Respiratory, thoracic and mediastinal disorders:rhinorrhoea. Gastrointestinal disorders: vomiting, diarrhoea, nausea. Skin and subcutaneous tissuedisorders: rash, increased sweating, contusion. Musculoskeletal and connective tissue disorders:muscle cramp, neck pain, myalgia, arthralgia, pain in extremity, back pain, muscle stiffness, musculoskeletalstiffness. Metabolism and nutrition disorders: anorexia. Vascular disorders: flushing.General disorders and administration site conditions: flu-like symptoms, pyrexia, chills, sweating,injections site pain, injection site erythema, injection site bruising, asthenia, pain, fatigue, malaise,night sweats. Psychiatric disorders: depression, insomnia. Legal Classification: POM. Pack Size andUK NHS Price: Box containing four injections £654, box containing twelve injections £1962.Reimbursed through High Tech Scheme in Ireland. Package Quantities: AVONEX 30 microgramspowder and solvent for solution for injection: 1 box containing four trays. Each tray contains a 3 mlglass vial with BIO-SET device containing a 30µg dose of interferon beta-1a per vial, a 1 ml pre-filledglass syringe of solvent and one needle. AVONEX 30 micrograms/0.5 ml solution for injection: 1 boxcontaining four or twelve trays. Each tray contains a 1 ml pre-filled syringe made of glass containing0.5 ml of solution (30µg dose of interferon beta-1a) and one needle. AVONEX 30 micrograms/0.5mlsolution for injection, in pre-filled pen: 1 box containing 4 cartons. Each carton contains a single-useAVONEX PEN with one injection needle and a pen cover. Product Licence Numbers:EU/1/97/033/002-005. Product Licence Holder: Biogen Idec Ltd., Innovation House, 70 Norden Road,Maidenhead, Berkshire SL6 4AY, United Kingdom. Date of last revision of Prescribing Information:June 2011.Adverse events should be reported. Reporting forms and information can be found atwww.yellowcard.gov.uk or www.imb.ie. Adverse events should also be reported toBiogen Idec on 0800 008 7401 (UK) or 1800 812 719 (Ireland).Prescribing information: TYSABRI ® (natalizumab)Please refer to the Summary of Product Characteristics for full prescribing information.Indications: Single disease modifying therapy in highly active relapsing remitting multiple sclerosis forthe following patient groups: Patients with highly active relapsing remitting multiple sclerosis orpatients with high disease activity despite treatment with interferon-beta. Dosage and administration:TYSABRI therapy is to be initiated and continuously supervised by specialised physicians experiencedin the diagnosis and treatment of neurological conditions; centres should have resources forthe management of hypersensitivity reactions and timely access to MRI. TYSABRI 300mg is administeredby IV infusion once every 4 weeks. Infuse the diluted solution over approximately 1 hour at2ml/min. Observe patients during infusion and for 1 hour afterwards for signs and symptoms of hypersensitivityreactions. Contraindications: Hypersensitivity to natalizumab or to any of the excipients;progressive multifocal leukoencephalopathy (PML); patients with increased risk of opportunistic infections,including immunocompromised patients (including those currently receiving immunosuppressivetherapies or those immunocompromised by prior therapies, e.g. mitoxantrone or cyclophosphamide);combination with interferon-beta or glatiramer acetate; known active malignancies; childrenand adolescents under 18 years. TYSABRI is not recommended for use in patients aged over 65years. Warnings and precautions: PML; use of TYSABRI has been associated with increased risk ofPML. The risk increases with treatment duration, especially beyond 2 years; if the patient hasreceived prior immunosuppressant treatment and/or if the patient is anti-JCV antibody positive. Forrisk stratification prior or during TYSABRI treatment, anti-JCV antibody testing may provide supportiveinformation. Before initiation of treatment with TYSABRI, a recent (usually within 3 months) MRI shouldbe available and should be repeated yearly. Patients must be monitored at regular intervalsthroughout. If PML is suspected, further dosing must be suspended until PML has been excluded. Ifthe symptoms are suggestive of PML, or if any doubt exists, further evaluation, including MRI(compared with pre-treatment MRI) and repeat neurological assessments should be considered.Once PML has been excluded, dosing of TYSABRI may resume. If patients develop PML, the dosingof TYSABRI must be permanently discontinued. Educational guidance; all physicians who intend toprescribe TYSABRI must ensure they are familiar with the Physician Information and ManagementGuidelines. Physicians must discuss the benefits and risks of TYSABRI therapy with the patient,provide them with a Patient Alert Card and re-inform at 2 years. Patients and their caregiver should beinstructed that if they develop any new or worsening symptoms they should inform their physician thatthey are being treated with TYSABRI. Physicians should counsel patients on the importance of uninterrupteddosing, particularly in the early months of treatment. Hypersensitivity; hypersensitivity reactionshave been associated with TYSABRI, including serious systemic reactions. These reactionsusually occur during the infusion or up to 1 hour after completion of infusion. If a hypersensitivity reactionoccurs, TYSABRI must be permanently discontinued. Immunogenicity; in the case of diseaseexacerbations or infusion related events the presence of antibodies should be evaluated. Treatmentshould be discontinued if persistent antibodies develop. Hepatic events; Serious cases of liver injuryhave been reported. Patients should be monitored for liver impairment. TYSABRI should be discontinuedif serious liver injury occurs. Stopping therapy; if therapy is discontinued the physician needsto be aware that TYSABRI has pharmacodynamic effects for up to 12 weeks. Pregnancy and lactation:If patients become pregnant while taking TYSABRI, discontinuation of TYSABRI should beconsidered. Patients receiving TYSABRI should not breastfeed their infants. Undesirable effects: Themost commonly reported symptoms are: Infections and infestations; urinary tract infection,Nasopharyngitis. Immune system disorders; urticarial. Nervous system disorders; headache, dizziness.Gastrointestinal disorders; vomiting, nausea. Musculoskeletal and connective tissue disorders;arthralgia. General disorders and administration site conditions; rigors, pyrexia, fatigue. Other events:infusion reactions, hypersensitivity reactions, immunogenicity, PML, other opportunistic infections andserious liver injury. Legal classification: POM. Pack size: 1 vial/pack. Price: £1130/vial. Package quantities:300mg/15ml. Marketing Authorisation Number: EU/1/06/346/001. Marketing AuthorisationHolder: Elan Pharma International Ltd., Monksland, Athlone, County Westmeath, Ireland. Date of lastrevision of prescribing information: June 2011.Adverse events should be reported. Reporting forms and information can be found atwww.yellowcard.gov.uk. Adverse events should also be reported to Biogen Idecon 0800 008 7401ACNR > VOLUME 11 NUMBER 4 > SEPTEMBER/OCTOBER 2011 > 37

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 A N N U A L C O N F E R E N C EABN AnnualConferenceFor this year's ABN conference we have sole use of the Sage Gateshead,a stunning building overlookingthe River Tyne.We start on the Tuesday afternoon October 4th with the Medical Students Roadshow andABNT session and finish on the Friday afternoon October 7th with a joint session with the British Societyof Neuroradiology. We have received a record number of abstracts and will be able to offer two or threeparallel platform sessions which will alternate with the teaching/science update sessions and main lectures.This year’s ABN medallist is David Neary and the Gordon Holmes lecturer Professor Eva Feldman fromMichigan who will talk on stem cell therapy. The Gala Dinner will be at the Discovery Museum.All in all anexciting programme at a great venue and I look forward to welcoming delegates to the 2011 conference.Martin Rossor,President, ABN.Martin Rossor,President,ABN.Biba StantonBiba Stanton is a neurology SpR inLondon and Chair of theAssociation of BritishNeurologists Trainees' Committee.The meeting will start on the afternoon of Tuesday4th October with sessions for medical studentsand SpRs.The Roadshow for Medical Students andFoundation Year Doctors aims to inform andinspire those considering a career in neurology.Our first Roadshow in Bournemouth last year wasa great success (despite being timed just beforefinals) and we hope that this year’s will be evenbigger and better. The programme includes talkson careers in neurology and neurophysiology aswell as updates on the latest advances in neurologicaltreatments and an interactive panel discussion.Ourfirst dedicated SpR session,sponsored byMerck Serono, aims to complement the mainmeeting with teaching specifically for trainees.Sessions will include oratory and presentationskills, a cognitive examination masterclass andinteractive case-based teaching. The President’squiz will provide a challenge for both theSpRs andthe speakers to make sure they perform as well asthe students! Both sessions will be followed by thisyear's research forum, with talks on grant-writingand academic careers and an opportunity toexplore research opportunities informally duringthe drinks reception.Next year’s annual ABN meeting will be inthe Brighton Centre 28-31 May 2012. Theplenary lectures will be given by neuroophthalmologistJohn Leigh, andpsychiatrist Iain McGilchrist. The medallistlecture will be delivered by Mark Wiles.There will be teaching sessions on HIV,head injury, epilepsy, and neurologicalantibodies, with a neuroscience updatewhich includes talks from Michel Goederton neurodegeneration and proteinopathies,Martin Schwab on regeneration of thenervous system, and Dimitri Kullmann onchannelopathies. There will also be aneuro-ophthalmology “meet the experts”case discussion session, a movementdisorder video olympics, and a UniversityChallenge, as well as the usual casepresentation competition and CPC.There is also a joint meeting with theAmerican Neurological Association inBoston on 5-11 October 2012.Biba Stanton,Chair,ABNT Committee.38 > ACNR > VOLUME 11 NUMBER 4 > SEPTEMBER/OCTOBER 2011

Tuesday 4 October 2011Neurology Road-Show for Medical Students & Foundation Year Doctors[Newcastle Edinburgh Manchester Liverpool]Chairs: Ian Ormerod & Martin RossorA 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 A N N U A L C O N F E R E N C E P RO G R A M M ESpecialist Registrar SessionSponsored by Merck SeronoChairs: Ralph Gregory & Colin Mumford1300 Trainees ForumBiba Stanton / ABNT Committee1330 Welcome & Ralph Gregory, ABN Honorary Assistant Secretary1400 Welcome & IntroductionIan Ormerod & Martin Rossor1410 What do Neurologists do?Geraint Fuller, ABN President Elect1430 Training to be a NeurologistBiba Stanton, Chair ABNT1450 Ralph Gregory, ABN Honorary Assistant SecretaryNeurophysiology for Neurology SpRsRoger Whittaker, Institute of Neuroscience, NewcastleCognitive Examination MasterclassMartin Rossor, ABN PresidentTea Break1500 Cases from the District General HospitalGeraint Fuller, ABN President Elect1510 New Treatments for Multiple SclerosisColin Mumford, Western General Hospital, Edinburgh1520 Cases from the District General HospitalGeraint Fuller, ABN President Elect1530 What do Neurophysiologists do?Roger Whittaker, Institute of Neuroscience, Newcastle1550 Panel DiscussionBiba Stanton, Martin Rossor, Roger Whittaker & Geraint FullerOratory & Presentation SkillsColin Mumford & Ed Fathers1610 Quiz with PrizeMartin Rossor, ABN President1640 Research Forum IntroductionCareer Paths in Academic Neurology [Rustam Al-Shahi Salman, Western General Hospital, Edinburgh]How to get a Grant [Wellcome Trust, tbc]1700-1800 Drinks Reception & Research Forum PostersCorrect at the time of going to press. For the most up to date programme,please see the ABN website at www.abn.org.uk/Meeting.aspx?type=1Wednesday 5 October 20110730 Special Interest Group: Neuro-Ophthalmology0900 Welcome & Opening AddressMartin Rossor & Lord Walton of DetchantTEACHING/SCIENCE DGH NeurologyChair: Graham LennoxDominic Heaney: Obstetric complications - A Neurologists Perspective Transient Loss of Consciousness - A Cardiologist's PerspectiveJulia Newton: Managing Syncope & Falls- A Geriatricians Perspective1100 Coffee & Exhibition1130 Platforms Platforms History of NeurologyChair: Andrew LeesMichael Swash : Jackson and theNeurological Tradition at the LondonGordon Plant: Hughlings Jackson atMoorfields and the National HospitalJohn Pearce: Neurology1230 Lunch & ExhibitionSponsored Satellite Symposium: Biogen Idec1300 Debate 1: Welcome Chair Dr Eli Silber - King College NHS Foundation Trust, London Dr Mike Boggild, Walton Centre for Neurology and Neurosurgery vs. TBCDebate 2: Dr Chris Clough Kings College NHS Foundation Trust, London vs. Dr Heather Angus-Leppan Royal Free and Barnet Hospitals1400 Presidential AddressProfessor Martin Rossor, ABN President 2011-20131445TEACHING/SCIENCENeuropsychiatryKlaas Enno Stephan: Computational neuroimaging for inference on mechanisms of brain diseaseAnthony David: Insight and awareness in neurology and psychiatryEd Bullmore: Networks and Psychopathology1615 Tea & Exhibition1645 DebateThis house believes that the ABN should be a college of clinical neuroscienceGraham Venables v Gareth Llewelyn1800Welcome receptionSage Gateshead2000 ABNT trainee dinner: Rasa(ticket must be prebooked in advance)ACNR > VOLUME 11 NUMBER 4 > SEPTEMBER/OCTOBER 2011 > 39

ASSOCIATION OF BRITISH NEUROLOGIST ANNUAL CONFERENCE PROGRAMMEThursday 6 October 20110730 Sponsored Breakfast Session: Biogen Idec - MS Emerging concepts for 2012Topic 1: Managing Mobility in MSMobility impairment is a significant issue for people with MS. In this session we will examine its impact on people with MS, evaluate clinicalassessments of mobility and the latest ways of managing mobility problems for people with MSTopic 2: Therapeutic expectations in 2012In recent years the expectations of disease modifying therapy in MS have changed significantly. This session will look at what people with MSshould expect from their therapy in terms of slowing, halting and even reversing disability progression0830 TEACHING/SCIENCEScientific frontiersJohn Hardy: What has genetics done for usHartmut Wekerle: Innate immunity and neurological diseaseAndrew Jackson: Neural prosthetics: Advances at the brain-machine interface1000 Coffee & Exhibition1030 Platforms Platforms Gareth Llewellyn, David Bateman & StephenPollockLocal Adult Neurology Services for the NextDecade1200 Lunch & Exhibition1200 Sponsored Satellite Symposium: Teva Pharmaceuticals - The symposium will be exploring all the options of treating /identifying first signs of wearing off in the elderly Parkinson disease patients. What are the signs of wearing off in PD patients Current management of wearing off in PD patients Challenges of wearing off in PD patients How is it managed? Alternative approaches1215 Training & Education Committee Meeting [closed]1330 Poster session1430 Medallist LectureDavid NearyThe Neurology of Dementia1530 Tea & Exhibition1600 Platform Platform1715 Musical Performance by SpinndriftSpinndrift met in 2006 when four of the members all started the Folk and Traditional Music Degree in Newcastle. They went from playing in each other's livingrooms, having tea and biscuits to gradually playing at bigger and bigger events. In fact, they liked each other's music and company so much that they moved intogether two years later. In 2008 and 2009 they were finalists in the New Roots competition, and in the summers of 08 and 09 played at various festivals such asSidmouth, Towersey, Warwick, Dartmoor and Bideford. After surviving their first few tours together they managed to raise the money to make their first Album:'Far distant', which was released at the end of 2010. They recorded the album as they were graduating from their degree program, where they all excelled,achieving excellent marks and giving fantastic end-of-year performances. In 2011 Spinndrift became a partnership, and have been working on all aspects of theirbusiness and music.1830 for 2000 Gala Dinner: Discovery Museum (lounge suit)Friday 7 October 20110730 Breakfast Session: NMO Interest Group Meeting [open meeting, but numbers restricted]0830 Platforms Case Presentation Competition0945 Coffee & Exhibition1015 17 th Gordon Holmes Lecturer: Eva Feldman, Michigan, USAStem Cell Therapy: The New Frontier of Medicine[Supported by the Guarantors of Brain]1100 TEACHING/SCIENCEUpdate on Muscle DiseaseKate Bushby: Filling in the Gaps Precise diagnosis for inherited muscle diseasesHanns Lochmuller: The diagnosis and treatment of protein aggregation myopathiesGlenn Walter , University of Florida,Gainesville, USA : Imaging muscle disease1230 Lunch & Exhibition1400 Clinico Pathological ConferencePatrick Chinnery & Dip MitraDiscussant: Kevin Talbot1430 Joint Session with the British Society of Neuroradiology: Controversies in Neuroradiology"Should we screen for familial aneurysms?"Andrew Clifton (For) Rustam Al-Shahi (Against)"Should GP direct access brain CT scanning be provided?" John Straiton (For) Richard Davenport (Against)"CT or MRI for acute stroke?" Peter Sandercock (CT) Robin Sellar ( MRI)1600 Close of meeting40 > ACNR > VOLUME 11 NUMBER 4 > SEPTEMBER/OCTOBER 2011

CONFERENCE REPORTS2nd Oxford Neurology CourseConference details: 29 June - 1 July 2011; Oxford, UK. Reviewed by: Alastair Webb, MRC Clinical Fellow / Neurology Trainee, Oxford.An eclectic group of over 50 neurologistsfrom first-year trainee toconsultant gathered in the beautifulsurroundings of St. Anne’s College for thesecond Oxford Neurology Course, an excellentvenue with superb hospitality for thoseall-important lunch and coffee breaks. Theprogram was unusually well-balancedbetween practical neurology and academicinsight delivered by local and visiting worldleadingneurologists.The course kicked off with a welcomefrom Christopher Kennard, Head ofNeurosciences, before Michael Sharpe fromEdinburgh gave us a tour through MedicallyUnexplained Symptoms, from theory to practice.He showed that these are not ‘heart-sick’patients lacking intellectual challenge ortherapeutic potential but are a criticallyimportant patient group with massivemorbidity, occupying more than 40% of ourclinics, a demand upon services farexceeding that of more ‘organic’ conditions.In addition, he demonstrated a simpleapproach with the potential for significanttherapeutic benefits. The psychologicaltheme continued with Simon Wessely givinga fascinating discourse on the psychologicaleffects of war, focussing in particular on theearliest known footage of the effects onmental health, with a film of shell-shockvictims from the First World War.The afternoon concentrated on the diagnosisand classification of headachesyndromes by Jes Olesen, Chairman of theInternational Headache ClassificationCommittee. From classical migraine tohypnic headache, he demonstrated how thenuances of the new classification aid diagnosisand practical management, as well asdiscussing less common current treatmentoptions and those yet to come. ManjitMatharu from Queen’s Square then showedhow SUNCT and SUNA fit into the spectrumfrom trigeminal autonomic cephalalgias totrigeminal neuralgia, with extensive elaborationof how current research helps to informthe classification and management of thesediseases. After a brief history of Medicine atOxford and its role in the development ofour specialty by Alastair Buchan (Head ofMedical Sciences, Oxford University), day 1closed with Charles Warlow delivering avigorous exhortation on how neurology hasfailed to resist pressures to limit medicaltraining and increase over-specialisation andhow our reticence to take on acuteneurology and stroke harms our specialty,balanced by a positive view on the intrinsicwonder of neurology itself.Day 2 started with a superb description ofmyotonic dystrophy 1 and 2 and theirThree days of neurological updates were followed by awalking tour through the historic city centre to visit someof the sights showing the contribution of Oxford scholarsto medicine through the centuries.management, laced with practical tips basedon David Hilton-Jones’ copious experiencein Oxford. The peripheral theme thencontinued with a run-through of peripheralneurophysiology by King’s College’s KerryMills, covering how clinical presentationshould be matched with appropriate testsand their results. The flavour of the day wasmore academic after the next caffeinatedhiatus. George Ebers from Oxford gave afascinating, personal account of his seminalresearch into the epigenetic basis of multiplesclerosis, demonstrating how clinical insightplus genetic epidemiology of astonishingscope and imagination was brought into thelab, resulting in novel understanding withmassive potential therapeutic benefit. Themorning closed with Christopher Conlon,Reader in Infectious Diseases at Oxford,giving a national and global perspective onthe neurological importance of tuberculosis,with practical tips such as the use of the T-spot test.After another excellent lunch, the firstsession of the afternoon was anything butsoporific: Paul Reading from Middlesboroughexplained clearly the physiological basis ofsleep and how it is disturbed in neurologicaldiseases such as narcolepsy-cataplexy, andZenobia Zaiwalla from Oxford spoke on thedifferentiation of parasomnias from normalsleep behaviours and nocturnal epilepsy,both enlivened by videotelemetry footage.Following another caffeine-based wake-upcall, the course proceeded with threeunusual cases from Oxford Grand Rounds,ranging from coeliac encephalopathy andsneeze-induced stroke to semanticdementia, with willing victims expected toprovide wisdom and insight. The educationalpart of the day finished with David Spencefrom Ontario delivering his view on cuttingedgeaspects of secondary stroke prevention,from new antiplatelet agents to patentforamen ovale, before Colin Blakemore,Professor of Neuroscience at Oxford, finishedthe course with his perspective on the challengesfacing neuroscience research, particularlyour inappropriately small share of adeclining funding pot due to limited politicalclout and the fragmented state of our thirdsectororganisations. We then happily retiredto Wadham College for bubbly in theCloisters and a sumptuous meal in theirancient, traditional hall.The final morning began with a lightheartedview of the relationship betweenneurology and neurosurgery over the pastthirty years, and how it really should function,by Richard Kerr, Neurosurgeon inOxford and a lead investigator on the ISATtrial. Keith Muir from Glasgow followed withan excellent lecture on hemicraniectomyfor malignant MCA infarction, from earlyresearch into clinical trials and how thesestudies inform practical decision-making.The final session focussed on brainstemreflexes with a tremendously practical talkon the assessment and management ofdizzy patients by Adolfo Bronstein, Neurootologistat Queen’s Square, followed byChristopher Kennard giving a detailed physiologicaldescription of the control ofextraocular movements and how thesemechanisms fail, resulting in a plethora ofclinical manifestations. The course finishedwith another delicious lunch, and theoption of a walking tour in the sunshinearound the ‘dreaming spires,’ illustrating thecontribution of Oxford’s more notable sonsto medicine, putting everything learnt intohistorical context.Overall, the course offered a rarely-found,well-balanced programme of clinical practiceand academic insight and demonstratedhow the latter informs the former. However,there were still plentiful practical neurologicaltips to satisfy any neurologist, whether agreen trainee or an experienced consultantseeking a refresher or further developmentof their skills. As an added bonus, all of thistook place in the stunning setting of Oxfordin summer, heightening the atmosphere ofthe course through its historical location andfabulous hospitality. lACNR > VOLUME 11 NUMBER 4 > SEPTEMBER/OCTOBER 2011 > 41

EVENTS DIARYTo list your event in this diary, email brief details to Anna Phelps at anna@acnr.co.uk by 6th October, 20112011September15th Congress of the European Federation ofNeurological Societies10–13 September, 2011; Budapest, HungaryE. headoffice@efns.orgwww.efns.org/efns2011World Congress on Huntington Disease11-14 September, 2011; Melbourne, Australiawww.worldcongress-hd2011.org/17th Congress of the European Section of theInternational Society on Toxinology11-15 September, 2011; Valencia, SpainT. 0034 96 197 4670E. catedrasg@cac.eswww.fundacioncac.es/catedrasg10th European Meeting on Glial Cells in Healthand Disease13-17 September, 2011; Prague, Czech Republicwww.europeglia2011prague.cz/14th WFNS Interim Meeting14-17 September, 2011; Pernambuco, Brazilwww.wfns.orgAANEM Annual Scientific Meetings14-17 September, 2011; San Francisco,California, USAT. + (507) 288-0100F. + (507) 288-1225E. aanem@aanem.orgVenice Summer School on AphasiaRehabilitation14-17 September, 2011; Lido of Venice, ItalyE: viviana.zanin@ospedalesancamillo.netCarmarthen Cardiac Update Course15th September, 2011; Carmarthen, Waleswww.stars.org.uk/news-events/events-healthcare%20professionals)17th Joint Annual Meeting of theGerman-Austrianswiss Society Against Epilepsy15–17 September, 2011;Prien/Chiemsee, Germanywww.epilepsiezentrumerlangen.deUnderstanding Brain Injury16 September, 2011; Cambridge, UKT. 01353 652173E. Rachel.everett@ozc.nhs.ukUnderstanding and Dealing with BehaviourProblems following Brain Injury16–17 September, 2011; London, UKT. 01276 472 369E. enquiries@braintreetraining.co.ukwww.braintreetraining.co.ukCzech Conference on multidisciplinary care forpatients with spinal atrophy16-18 September, 2011; České Budějovice,Czech RepublicT. 0191 241 8605www.treat-nmd.eu/events/240/Duchenne Family Support Group AnnualConference17 September, 2011; Stratford-upon-Avon, UKT. 0191 241 8605www.treat-nmd.eu/events/256/International conference on Muscle Wasting18-23 September, 2011, Ascona, SwitzerlandE. musclewasting2011@demariaevent.chMuscle Study Group Annual Meeting19-22 September, 2011; New York, USAT. 585-275-1274E. donna_ladonna@urmc.rochester.eduJoint MS Trust and Kent ACPIN MS Study Day20 September, 2011; Maidstone, UKT. 0800 032 3839E: education@mstrust.org.ukwww.mstrust.org.uk/studydaysDementia21 September, 2011; London, UKT. 020 7647 3577www.rcn.org.uk/eventsNeurological Upper Limb for OT's21 September, 2011; Derby, UKT. 01332 254679E. ncore@derbyhospitals.nhs.ukPain in Europe VII21-24 September, 2011; Hamburg, GermanyE. myatsiv@kenes.com17th Congress of Child Neurologists ofMediterranean21–24 September, 2011; Piran, SloveniaE. milivoj.velickovic@mf.uni-lj.siwww.cnm2011.eu/child-neurologists-ofmediterranean/35th Annual Meeting of European Society ofNeuroradiology22-25 September, 2011; Antwerp, BelgiumT. +39 06 330531E. esnr2011@aimgroup.euwww.esnr2011.orgSinapsa Neuroscience Conference, 1122-25 September, 2011; Ljubljana, SloveniaT. + 386 1 241 7133E. alenka.kregar@cd-cc.siwww.sinapsa.org/snc11The three Rs of innate immume recognition:Toll like receptors (TLRs), RIG-like receptors(RLRs) and Nod-like receptors (NLRs)23 September, 2011; Brighton, UKE. enquiries@euroscicon.comwww.regonline.co.uk/workihc201013th ILAE Specialist Registrar Teaching Weekendin Epilepsy23-25 September, 2011; Oxford, UKwww.genesisadoration.com/epilepsy.html136th Annual American NeurologicalAssociation Meeting25-28 September, 2011; San Diego, USAT. 952 545 6284www.aneuroa.org11th International Conference on CognitiveNeuroscience25-29 September, 2011; Palma, Mallorca, SpainT. +34 971 172750www.icon11mallorca.org/Assessment of a client with Perceptual andCognitive Dysfunction26-27 September, 2011; Derby, UKT. 01332 254679E. ncore@derbyhospitals.nhs.ukwww.ncore.org.ukNMD – chip steering committee meeting27-28 September, 2011; London, UKT. 0191 241 8605www.treat-nmd.eu/events/200/Co-Morbidities of Epilepsy27-30 September, 2011; Ontario, CanadaE. mpoulter@robarts.caExploring Gait29 September, 2011; Derby, UKT: 01332 254679E: ncore@derbyhospitals.nhs.ukwww.ncore.org.ukGene-environment interplay: shaping behaviourand CNS dysfunction29th September, 2011; Liverpool, UKT. 01223 766450www.bna.org.uk/events/Cognition Disorders in MS30 September – 1 October, 2011; Florence, ItalyT. +39 06 420 413W: www.seronosymposia.org/en/Neurology/Symposia/cognitiondisordersms/page.htmlOctoberMuscular Dystrophy Campaign ScottishConference1 October, 2011; Glasgow, ScotlandT. 020 7803 4804E. 2011conference@muscular-dystrophy.orgCongress of Neurological Surgeons AnnualMeeting1-6 October, 2011; Washington D C, USA.Congress of Neurological SurgeonsT. +847 240 2500F. +847 240 0804E. info@1CNS.orgwww.neurosurgeon.orgSTARS Patients Day2 October, 2011; Birmingham, UKwww.stars.org.uk/news-events/patient-eventsHRC 20112-5 October, 2011; Birmingham, UKT. 01789 451822www.heartrhythmcongress.com8th UK SMA Researchers’ Conference3-4 October, 2011; Oxford, UKE. kevin.talbot@clneuro.ox.ac.ukImproving the use of electromyography inpaediatrics3-5 October, 2011; London, UKT. 0191 241 8605www.treat-nmd.eu/events/285/Cognitive Behavioural Therapy Intermediatelevel workshop4 October, 2011; Derby, UKT. 01332 254679E. ncore@derbyhospitals.nhs.ukwww.ncore.org.ukABN Annual Meeting5-7 October, 2011; Newcastle, UKT. 020 7405 4060www.theabn.orgOne day workshop: jitter analysis in children6 October, 2011, London, UKT. 0191 241 8605www.treat-nmd.eu/events/284/21st Alzheimer Europe Conference6-8 October, 2011; Warsaw, PolandT. +352-29 79 70E. info@alzheimer-europe.orgwww.alzheimer-europe.org/EN/Conferences/Warsaw-201114th European Congress of Neurosurgery (EANS)9-14 October, 2011; Rome, ItalyT. +41 22 908 0488 ext: 531www.kenes.com13th Congress of the European Federation ofAutonomic Societies (EFAS)12-15 October, 2011; Bern, SwitzerlandE. mail@imk.chwww.imk.ch/efas20115th World Congress on Controversies inNeurology: Life Course Related Conditions(CONy) - Asia Pacific13-16 October, 2011; Bejing, ChinaT. +972-3-5666166www.comtecmed.com/cony/2011/Default.aspxFatigue/Managing Sleep14 October, 2011; Cambridge, UKT. 01353 652173E. Rachel.everett@ozc.nhs.ukNeurology Update Meeting 201114 October, 2011; Galway, IrelandT. +353 (0)61 622652E. info@iicn.ieMDC National Conference15 October, 2011; Nottingham, UKT. 020 7803 4804E. 2011conference@muscular-dystrophy.orgNinth WMS Satellite Teaching Course17-18 October, 2011; Algarve, PortugalT. 351 214048772E. wms2011@parceiro-base.ptWMS Congress 201118-22 October, 2011; Algarve, PortugalT. 351 214048772E. wms2011@parceiro-base.ptECTRIMS 2011: 27th Congress of the EuropeanCommittee for Treatment and Research in MS19–22 October, 2011; Amsterdam,The Netherlands(with ACTRIMS & LACTRIMS)E. secretariat@ectrims.euENRC 1st European Neuro-rehabilitationCongress20-22 October, 2011; Merano, ItalyT. +43-512-575600E. enrc2011@come-innsbruck.atwww.enrc2011.eu7th International Congress on VascularDementia20-23 October, 2011; Riga, LatviaT. + 41 22 908 0488E. vascular@kenes.comwww.kenes.com/VascularHow to do Cognitive Rehabilitation Therapy22 October, 2011; London, UKT. 01276 472 369E. enquiries@braintreetraining.co.ukwww.braintreetraining.co.ukNovemberStroke services: Controversies in managementand service delivery3 November, 2011; London, UKT. 020 7290 3940www.rsm.ac.uk/academ/cnc02.phpAction Duchenne 9th Annual InternationalConference4-5 November, 2011; London, UKT. 020 8556 9955www.treat-nmd.eu/events/289/TREAT-NMD curator and oversightcommittee meeting11-12 November, 2011; Geneva, SwitzerlandT. 0191 241 8605E. info@treat-nmd.eu187th ENMC workshop on Dystroglycan andDystroglycanopathies11-13 November, 2011; Naarden, NetherlandsT. 0191 241 8605E. info@treat-nmd.eu7th Essential Neuro MRI Course12 November, 2011: Liverpool, UKT. 07799 723 925essentialneuromri@hotmail.co.ukNeuroscience 201112-16th November; 2011, Washington, DC, USAT. (202) 962-4000www.sfn.org/AM201120th World Congress of Neurology12–18 November, 2011; Marrakesh, MoroccoT. +41 22 908 0488E. wcn@kenes.comwww.wcn-neurology.orgMS Trust Annual Conference 201113th-15th November, 2011; Kenilworth UKT. 0800 032 3839E. conference@mstrust.org.ukwww.mstrust.org.uk/conferenceNeurology Symposium16 November, 2011; RCP Edinburgh, ScotlandE. c.gray@rcpe.ac.ukhttp://events.rcpe.ac.uk/events/142/neurologySNO 201117-20 November, 2011; California, USAT. (281) 554 6589F. (713) 583 1345E. Linda@soc-neuro-onc.orgwww.soc-neuro-onc.org/index.cfm42 > ACNR > VOLUME 11 NUMBER 4 > SEPTEMBER/OCTOBER 2011

EVENTS DIARYThe West of England Seminars in AdvancedNeurology (WESAN)24-25 November, 2011; Exeter, UKE. cgardnerthorpe@doctors.org.ukMood Assessment and Compassionate Mind25 November, 2011; Cambridge, UKT. 01353 652173E. Rachel.everett@ozc.nhs.ukBIO-NMD steering committee Meeting28-30 November, 2011, Ferrara, ItalyT. 0191 241 8605E. info@treat-nmd.eu6th UK Stroke Forum Conference29 November-1 December, 2011;Glasgow, ScotlandT. 0845 521 2505E. sally.atkinson@stroke.org.ukwww.ukstrokeforum.orgInternational Myotonic DystrophyConsortium IDMC-830 November – 3 December, 2011;Florida, USAT. (352) 294-0846E. cgentilman@dce.ufl.eduUniversity Classes in Multiple Sclerosis VIII,focused on Symptomatic Treatments30 November, 2011; Marbella, SpainE. m.friedrichs@charcot-ms.euwww.charcot-ms.euDecemberCARE-NMD midterm meeting1-2 December, 2011; Czech RepublicT. +49 761 27043440E. info@care-nmd.euInternational Symposium on Learning,Memory and Cognitive Function1-3 December, 2011; Valencia, SpainT. 0034 96 197 4670E. catedrasg@cac.eswww.fundacioncac.es/catedrasgTowards Personalized Treatment in MultipleSclerosis1-3 December, 2011; Marbella, SpainE. m.friedrichs@charcot-ms.euwww.charcot-ms.eu.Understanding Brain Injury2 December, 2011; Cambridge, UKT. 01353 652173E. Rachel.everett@ozc.nhs.ukAdvanced Cognitive Rehabilitation Workshop(Attention & Information Processing)2–3 December, 2011; London, UKT. 01276 472 369E. enquiries@braintreetraining.co.ukwww.braintreetraining.co.ukXIX WFN World Congress on Parkinson'sDisease and other Movement Disorders11-14 December, 2011; Shanghai, ChinaT. + 41 22 908 0488E. parkinson2011@kenes.comwww.kenes.com/parkinson2012JanuaryCognitive Rehabilitation Workshop13–14 January, 2012; London, UKT. 01276 472 369E. enquiries@braintreetraining.co.ukwww.braintreetraining.co.ukHow to do Cognitive Rehabilitation Therapy28 January, 2012; London, UKT. 01276 472 369E. enquiries@braintreetraining.co.ukwww.braintreetraining.co.ukMarch1st International Conference on Heart andBrain - ICHB 20121-3 March, 2012; Paris, FranceE. heart-brain@kenes.comInsight Workshop2–3 March, 2012; London, UKT. 01276 472 369E. enquiries@braintreetraining.co.ukwww.braintreetraining.co.ukXIII Pan American Congress of Neurology4-8 March, 2012; La Paz, BoliviaT. +56-2-946 2633www2.kenes.com/pcn2012/pages/home.aspxThe 6th World Congress on Controversies inNeurology (CONy)8-11 March, 2012; Vienna, AustriaT. 972-3-566-6166noam@comtecmed.comwww.comtecmed.com/Cell culture technology: recent advances,future prospects9 March, 2012; Welwyn Garden City, UKE. enquiries@euroscicon.comwww.regonline.co.uk/workihc201010th Austrian Society of Neurology (ÖGN)Annual Congress14-17 March, 2012; Graz, AustriaT. +43 1 512 80 91-19E. weinhart@oegn.atwww.oegn.at/kongress20129th World Congress on Brain Injury21-25 March, 2012; Edinburgh, Scotland, UKT. 01512 80 9119E. mjroberts@internationalbrain.orgwww.internationalbrain.org9th International Brain Injury AssociationWorld Congress22-25 March, 2012; Edinburgh, ScotlandT. + 703 960 0027www.internationalbrain.orgInternational Congress on Neurology andEpidemiology22-25 March, 2012; Seville, SpainT. +33 4 78 176 176www.neuro-conference.com/2012/2nd International Congress on Epilepsy, Brainand Mind28-31 March, 2012; Prague, Czech Republicwww.epilepsy-brain-mind2012.euAprilASNR 201221-26 April, 2012; New York, USAT. (630) 574 0020www.asnr.org/May8th International Congress On MentalDysfunction & Other Non-Motor Features InParkinson’s Disease and Related Disorders3-6 May, 2012; Berlin, GermanyT. + 41 22 9080488 ext. 524E. Dnuriel@kenes.comwww.kenes.com+47th World Congress for NeuroRehabilitation16-19 May, 2012; Melbourne, AustraliaT. +612 9954 4400W: www.dcconferences.com.au/wcnr2012Join the debate...CURRENT CONTROVERSIES IN MULTIPLE SCLEROSISA debate at the Association of British Neurologists Annual Meeting,The Sage Gateshead, Newcastle Upon Tyne13.00 - 14.00 hours Wednesday 5th October 2011Chaired by Dr Eli Silber, Kings College Hospital, London “We place too much emphasis on the risks oftreatment rather than the risks of MS”Dr Mike Boggild, The Walton Centre, Liverpool vsDr Nikos Evangelou, Queen's Medical Centre, Nottingham “NHS reform provides an opportunity to improveservices for people with neurological conditions”Dr Chris Clough, Kings College Hospital, London vsDr Heather Angus-Leppan, Royal Free and BarnetHospitals, LondonASSOCIATION OF BRITISH NEUROLOGISTSThe debate is sponsored by Biogen Idec LtdDate of preparation: August 2011Code No: BI-PAN-0181a.ACNR > VOLUME 11 NUMBER 4 > SEPTEMBER/OCTOBER 2011 > 43

JOURNAL REVIEWSA bit more about the devils you knowMuch awaited and longer in coming than even the most precious babyare these results from a pan-European register of epilepsy in pregnancy,with a smattering of cases from America (1%), South East Asia (3%) andsomewhat more from the Western Pacific (10%). Even after many exclusions,there were still a massive 4540 monotherapy pregnancies whichcould be analysed: 1402 on carbamazepine; 1280 on lamotrigine, 1010on valproic acid and 217 on phenobarbital. The cases were definedaccording to treatment at the time of conception on an “intention totreat” basis and subsequent drug changes during the pregnancy werenot considered. Seizure freedom rates during pregnancy were similarfor all the drugs at about 70%. The headline figures of this study are thatthe risk of major malformation from carbamazepine at doses less than400mg per day was 3%, with doses of 400-1000mg per day, it was 5% andabove 1000mg per day it was 9%. For lamotrigine doses less than 300mgper day malformation rate was 2% and over 300mg per day it was 4%. Forvalproic acid doses less than 700mg per day, the rate was 6%, 700-1500mgper day it was 10% and over 1500mg per day (n=99) 24%. Phenobarbitalin doses less than 150mg per day was associated with a risk of 5% butwith a risk of 14% in higher doses. The commonest malformations werecardiac but hypospadias was also common and neural tube defectswith valproic acid and carbamazepine especially. Although of thecommonly used drugs, valproic acid clearly carried the highest risk, inhigh doses, it is noteworthy that in doses less than 700mg, the risks werecomparable (overlapping confidence intervals) to more than 300mg oflamotrigine per day or 400-1000mg of carbamazepine. Although far fromideal, it lends some reassurance to those of us who find ourselves in thesituation where it is the only drug that seems to control a woman’sepilepsy. It also gives us more information on which to base our choicesin treating these women. It will be interesting to see how new drugs (thedevils we don’t know) compare, as the number of monotherapy pregnancieswith them increases. Already, there are starting to be moderatenumbers with levetiracetam and promising but inconclusive results.– Dr Mark Manford, Consultant Neurologist, Addenbrooke’s Hospitaland Bedford Hospitals NHS Trust.Tornson T, et al. Dose-dependent risk of malformations withantiepileptic drugs: an analysis of data from the EURAP epilepsy andpregnancy register.LANCET NEUROLOGY 2011;10:609-17.Glucocerebrosidase administrationcorrects memory deficits in a mousemodel of Gaucher’s/Parkinson’s diseaseThe link between Gaucher’s disease/mutant glucocerebrosidase(GBA1) and Parkinson’s disease (PD) is now well established. This papershows that GBA1 mutant mice display progressive synucleinopathy(previously known), increased glucosylsphingosine (GlcSph) (its neurotoxicityhaving been previously demonstrated in vitro) although notglucosylceramide (GlcCer), and cognitive deficits likely via both gainandloss- of function (using a variety of mutant, knock-in and knock-outmice), which can be reversed by exogenous intra-hippocampal administrationof GCA. Gba1D409V/ D409V mice exhibit alpha-synuclein andubiquitin aggregates in hippocampal neurites (and to a lesser extent thecortex and cerebellum; no mention was made of the basal ganglia),from six months of age (but not at two months), increasing at 12 months.Beclin was reduced, suggesting that initiation of autophagy may beimpaired (another potential story in the pathophysiology of PD). Incontrast to humans and some other mouse models, Gba1D409V/ D409Vmice exhibited no markers of inflammation or cell death. Perhaps the25% residual GCA activity may be enough to cause cellular toxicity andcognitive deficits without inflammation and cell death. It is possible thatthis model represents an ‘early stage’ of PD and thus may negate thetheory that inflammation initiates the disease cascade.Mutant mice displayed deficits in tests of hippocampal function,although the earliest mice were tested was four months. It would havebeen interesting to test two-month-old mice (that have increasedGlcSph but not synucleinopathy). Having said that, Gba1D409V/+ micedid not display memory deficits (at six months), suggesting that it isindeed GlcSph accumulation rather than synucleinopathy thatproduces the memory deficits – this clearly has interesting implicationsfor the pathophysiology of PD. It may also have been useful to performmotor tests on these mice.The authors suggested that both loss- and gain-of function of GCAcause pathology. Mice carrying one normal Gba1 allele (Gba+/- andGba1D409V/+) did not accumulate GlcSph but Gba1D409V/+ mice hadsynucleinopathy (at 50% of Gba1D409V/ D409V mice). Thus, one mutantallele causes synucleinopathy (not present in mice lacking one allele),implying a toxic gain of function. That the deficits can be largely rescuedby administration of normal GCA implies an additional loss of function(and knock-outs accumulate GlcCer and GlcSph and die aged 14 days).Human GCA1 (carried by a viral vector) was administered directlyinto the hippocampus of mutant mice at two months of age. At fourmonths of age, the memory deficits were reversed, and synuclein, ubiquitinand GlcSph were significantly reduced in those mice. The effect ofadministering GCA to older mice (once synucleinopathy is established)would also have been of interest.This study then takes the field forward in suggesting that GCA causesdisease by both a gain and loss of function; that GlySph accumulation cancause hippocampal deficits; and that these effects can be substantiallyameliorated using direct exogenous administration of GCA. It thereforehas implications for the pathophysiology of not only Gaucher’s related PDbut also idiopathic PD, and raises intriguing therapeutic possibilities.– Dr Wendy Phillips, Consultant Neurologist, Addenbrooke’s Hospitaland Princess Alexandra Hospital, Harlow.Sardi SP, et al. CNS expression of glucocerebrosidase corrects α-synucleinpathology and memory in a mouse model of Gaucher-related synucleinopathy.Proceedings of the National Academy of Sciences 2011.On-line 5 July 2011.Expression by skippingTwenty-five years have passed since the identification of the genemutated in Duchenne Muscular Dystrophy. The X-linked gene, DMD, wasfound to encode a large cytosolic protein named dystrophin, which waslater shown to link the underlying cytoskeleton in muscle to thesarcolemma by binding to actin via its N-terminus and to β-dystroglycanvia its C-terminus. Spanning 2.4 megabases, DMD is the largest knowngene in the human genome and contains 79 exons encoding a proteinof molecular weight 427 kDa. Duchenne Muscular Dystrophy is associatedwith deletions, duplications and point mutations in the DMD gene,many resulting in loss of protein expression. Since the identification ofDMD, a host of suggested therapeutic strategies have been promised topatients and their families but most developments have been disappointing.However, the recent publication by Cirak et al. has the potentialto revolutionise not only the field of Muscular Dystrophy, but alsoother diseases whose underlying molecular defect is genetic.Cirak et al.’s work is based on previous knowledge that the milderform of muscular dystrophy, Becker Muscular Dystrophy, is also associatedwith mutations in DMD. However, unlike Duchenne MuscularDystrophy, DMD mutations associated with Becker Muscular Dystrophydo not disrupt the open reading frame and therefore lead to truncatedbut partially-functional dystrophin protein. Therefore, if it were possibleto ‘skip’ across a deleted area of the gene during transcription ofmessenger RNA and maintain an open reading frame, then a functional,albeit smaller version of dystrophin will be expressed. Indeed, this techniquehas become reality over the past decade in vitro, known as exonskipping, and has been applied with some success in animal models ofthe disease and also when administered locally to specific muscles.In an exciting development, Cirak et al. now report in The Lancet thatsystemic intravenous administration of the splice-switching phosphorodiamidatemorpholino oligomer (PMO), AVI-4658, results in increasedexpression of dystrophin in biopsied muscles. Moreover, the newlyexpressed dystrophin appears functionally active by also increasing theexpression of α-sarcoglycan and neuronal nitric oxide synthase (nNOS)at the sarcolemma. Nineteen boys in total were included in this open44 > ACNR > VOLUME 11 NUMBER 4 > SEPTEMBER/OCTOBER 2011

JOURNAL REVIEWSlabelled dose-escalation study with seven patients responding to treatment,all receiving the higher dose of AVI-4658. Importantly, no seriousdrug-related adverse events were reported and no evidence of animmune-response to the drug or to the newly expressed dystrophinprotein was seen.Despite these promising results, a few questions remain. The expressionlevel of dystrophin in responders was variable between patients and it isunclear how this can be explained. Furthermore, the restoration ofdystrophin expression was variable within the muscle itself suggestingthat complex factors may be relevant with respect to uptake and functionof the drug within individual muscle fibres. One must also remember thatthe selection criteria for this study included a genetically-confirmed diagnosisof Duchenne Muscular Dystrophy with an out-of-frame deletion inDMD eligible for correction by skipping exon 51 and therefore AVI-4658will not be applicable to all patients. Most importantly, the current studydid not set out to determine the clinical effectiveness of this drug inpreventing muscle degeneration or reversing the currently inevitabledisabilities that we see as the boys grow older. It is likely that AVI-4658would need to be taken lifelong and therefore many questions can onlybe answered by a study lasting significantly longer than 12 weeks.However, on the basis of Cirak et al.’s work, a clinical trial is now urgentlyneeded to determine the effectiveness of AVI-4658 in the clinical setting.With the long history of false hopes for patients and families livingwith Duchenne Muscular Dystrophy since the beginning of the geneticage, the time may have finally come when real advances made inmanipulating gene expression in vitro can at last be applied to offerhope not only to patients harbouring mutations in DMD, but also topatients with other genetic diseases amenable to exon skipping.– Dr Rhys Roberts, Honorary Consultant in Neurology, Addenbrooke’sHospital, Cambridge.Cirak, S et al. Exon skipping and dystrophin restoration in patients withDuchenne muscular dystrophy after systemic phosphorodiamidatemorpholino oligomer treatment: an open-label, phase 2, dose-escalationstudy. (2011) LANCET. DOI:10.1016/S0140-6736(11)60756-3.What’s in a name?Acronyms are only really effective in communicating informationwhen they become an accepted part of common medical terminology.Who decides when and how this happens? Clearly there is a memeticspread of widely used terms. This process is far from flawless – “FSH”may mean something very different to a gynaecologist (follicle-stimulatinghormone) and a neurologist (facioscapulohumeral musculardystrophy). The process is more opaque when naming well defined butunlabelled clinical entities. The eponymous route has fallen fromfavour, somewhat, and it may be more helpful to try to name thingsaccording to what they actually are. Although this may seem to be intuitivelysimpler and less confusing, consider the emotional baggage andmeaning of “chronic fatigue syndrome” compared with “myalgicencephalomyelitis”.A small number of patients who have sustained a severe brain injury(from a range of different causes) are seen to develop a stereotyped setof autonomic changes with tachycardia, pyrexia, muscle rigidity andsweating. The treatment is really symptomatic and supportive, but it isimportant to recognise this constellation of features as secondary tobrain injury rather than representative of ongoing untreated infectionor another pathological entity. This review paper looks at attempts toclassify and demarcate these features over the years into a clinicallydiscrete syndrome. Of course, an important part of this process isattributing a specific name and hence identity. The current favourite is“paroxysmal sympathetic hyperactivity” (PSH) although in theirattempts to characterise and label this, previous authors have gone for“dysautonomia”, “central autonomic dysfunction”, “paroxysmal autonomicinstability with dystonia”, “autonomic storming” and “dysautonomiccrisis”. There are nine different sets of criteria that have beenused to describe the salient features. Although they share manycommon parameters (tachycardia, pyrexia), the duration, time of onsetand aetiology are different for each set. The authors clearly demonstratehow the criteria employed by different groups have evolved overtime, with the majority evolving from two separate studies. What isconcerning in trying to use this literature in a broader sense is the factthat only a third of published papers attempted to use any criteriaabove and beyond a simple description of the condition.The lack of unified and universally agreed criteria potentiallyhamper attempts at research into the causes and management of PSH.A consensus on clinical features and nomenclature would allow agreater recognition and awareness of the condition, particularly in nonspecialistsettings.– Dr Lloyd Bradley, Consultant in Rehabilitation Medicine, WesternSussex Hospitals.Perkes IE, Menon DK, Nott MT, Baguley IJ. Paroxysmal sympathetichyperactivity after acquired brain injury: A review of diagnostic criteria.BRAIN INJURY 2011;25(10):925–32.An SMA motor neuron: I will survive!Despite being associated with the commonest genetic cause of death inyoung children, we know very little about the physiological function ofthe ubiquitously expressed protein, survival of motor neuron (SMN).SMN is found in large multi-protein complexes within cells both withinthe nucleus (in the form of ‘gems’) and in the cytoplasm. What rolesSMN plays at these sites remains unclear. However, we know that mutationsin SMN that lead to reduced expression of the SMN protein,resulting in cellular levels of VOLUME 11 NUMBER 4 > SEPTEMBER/OCTOBER 2011 > 45

JOURNAL REVIEWSPredicting Parkinson’s disease dementiausing EEG microstructureThere is an urgent need for reliable biomarkers capable of predictingParkinson’s disease (PD) complications, particularly dementia. Whilstmost attention is given to genetics, brain imaging and biological fluidmarkers (mainly in CSF), Klassen et al from the Mayo Clinic set out todetermine whether quantitative EEG could fulfil this role.They longitudinally studied 106 PD patients (mean age = 76 years)following a baseline resting EEG. They excluded those taking anticonvulsantsand benzodiazepines. By collecting 100 seconds of EEG datawhen the patient was in a state of “relaxed wakefulness” (sat in recliningchair with eyes shut) and transforming this into its component waveforms,they calculated the global EEG bandpower for each of the fourfrequency bands (δ = 1.5-3.9 Hz, θ = 4-7.9 Hz, α = 8-12.9 Hz, β = 13-30 Hz).They also calculated the background rhythm frequency (BRF) whichwas defined as the dominant waveform present in the posterior electrodes.The mean follow-up duration was 3.3 years (range 0.31 - 8.8years), during which time patients underwent annual neuropsychologicaltesting to detect emerging PD dementia. Clinicians were blinded tothe baseline EEG.Using a Kaplan Meier curve, the incidence of dementia within 5 yearsof baseline EEG for the entire sample was 34%. Patients with mild cognitiveimpairment (MCI) at baseline had a hazard ratio (HR) of 4.3compared to those who did not. Surprisingly, age or PD duration at baselinedid not significantly alter dementia risk.After dichotomising at the median, patients with ‘low’ BRF (less thancut-off of 8.5 Hz) had a significantly greater dementia risk (HR 13)compared to those with ‘high’ BRF. This translates into a dementia incidencewithin 5 years of EEG of 66% compared to 8.1%. Those with ‘high’θ bandpower had a smaller but still significant increased incidence ofPD dementia (HR 3.0) compared to those with ‘low’ θ bandpower. Otherbandpowers did not significantly alter dementia risk. The BRF hazardwas not reduced in the multivariate modelling by more than 15% byeither PD-MCI or any of the other neuropsychological tests. The authorsbelieve that this supports the argument that BRF truly predicts dementiarisk rather than simply acting as a surrogate marker of current cognitivedeficits. θ bandpower, on the other hand, was confounded by both PDduration and MMSE.The authors hypothesise that structural pathology in PD may interferewith the normal background alpha rhythm generated by subcorticaland corticocortical circuits, thereby resulting in a downward spectralshift (i.e. slowing) of the BRF frequency. However, they acknowledge thatfurther work is needed to understand the neural substrates of cognitivedeterioration in PD.The findings are interesting but do they help our PD patients? In theshorter term, it and other biomarkers may allow enrichment of neuroprotectivedrug trials with cognitively ‘at-risk’ patients. The usefulness ofquantitative EEG in detecting cognitive decline and predicting futurerisk on an individual basis still needs to be proven in larger studies withlonger follow-up, and the need for specialist training and equipmentshould be borne in mind. Nonetheless, the concept of using EEGmicrostructure to predict disease progression is an exciting one.– Dr David P Breen, Clinical Research Fellow in Neurology, CambridgeCentre for Brain Repair.Klassen BT, et al. Quantitative EEG as a predictor biomarker forParkinson’s disease dementia. NEUROLOGY 2011;77:118-24.Graft and blockDiaphragmatic paralysis is a major complication of high cervical cordinjury. Unfortunately, many patients sustaining such injuries requirelong-term mechanical ventilation with its myriad of associated complicationsand obvious negative impact on quality of life. A bleak outlook,most would agree. Alilain et al, however, writing in Nature, provide hopefor those left in this desperate state. Using rats receiving C2 hemisectionas their model of injury, the authors describe their experiments thateventually lead to apparent recovery of diaphragmatic innervation onthe lesioned side.It is known that the extracellular space within the mature spinal cordcontains chondroitin sulphate proteoglycans (CSPGs), creating a potentinhibitory environment for neuronal regeneration. Moreover, it is knownthat this inhibitory extracellular matrix is upregulated at sites of injury.Firstly, Alilain et al. show that enzymatic breakdown of this inhibitoryextracellular matrix at the level of the phrenic nerve nuclei leads toincreased number of serotonergic neurons, known to be involved inrespiratory plasticity. Although functional recovery was disappointing,the authors then investigated the effects of implanting autologous nervegrafts in addition to enzymatic treatment, hypothesising that theSchwann cells contained in the grafted nerve would provide the necessaryfactors and support to guide lesioned axons to the denervatedphrenic nerve nuclei ipsilateral and caudal to the C2 hemisection.Remarkably, by 12 weeks, the hemisectioned rats receiving both enzymaticbreakdown of CSPGs and peripheral nerve grafts showedrecovery of ipsilateral diaphragmatic function, often surpassing measuresof activity compared to the contralateral side and the diaphragmsof uninjured animals. Importantly, the authors show that recovery isdependent on the implanted nerve graft as transection leads tocomplete loss of ipsilateral diaphragmatic activity.Time will tell whether these findings can be translated in order tohelp patients who have sustained high cervical cord injuries.Furthermore, Alilain et al.’s work points again to the remarkable potentialability of the nervous system to regenerate, given the appropriateenvironment, and gives hope that such approaches may be applied to awide range of neurological injuries in the context of neurorehabilitationin years to come.– Dr Rhys Roberts, Honorary Consultant in Neurology, Addenbrooke’sHospital, Cambridge.Alilain WJ, Horn KP, Hu H, Dick TE and Silver J. Functional regenerationof respiratory pathways after spinal cord injury.NATURE 2011;475:196-200.Ambu ® Inoject NeedlesThe main points Used for relaxation of muscles that are spasmodic inthe face, particularly around the eyes, head and neck. Help bring relief to sufferers of cerebral palsy andother genetic nerve diseases that cannot be relaxedby manipulation, including laryngeal spasms.The rangeProducts with pre-attached lead wiresSix colour coded sizes from 25mm length0.30mm calibre to 75mm length0.55mm calibreTel: 01480 498 403Fax: 01480 498 405email: uksales@ambu.comWeb: www.ambu.co.uk46 > ACNR > VOLUME 11 NUMBER 4 > SEPTEMBER/OCTOBER 2011

NEWS REVIEWPediatric Neurology – A Color HandbookThis new book is written byspecialist authors whorecognise the needs ofnonspecialists and trainees.Recognising patterns ofdisease can be the first stepto successful management ofthe child with a neurologicalproblem; this is emphasisedby the authors throughoutthe book. Their concise,precise account reflects theremarkable recent advancesin paediatric neurology andrelated disciplines, whilestressing the fundamentals ofclinical examination andhistory taking in reaching anaccurate diagnosis. The bookbegins with a detailed discussion of neurologicalexamination techniques and the basic formulationof differential diagnoses and management, usingneuroradiology, electrophysiology, cerebrospinalfluids, genetic and metabolic testing. The secondsection of the book follows a problem-basedIncrease in sales of Ambu’s Inoject needleAmbu are a Danish headquartered company with animpressive portfolio of products. One product that is nowmaking its way into many hospital departments and has seena recent increase in demand is the Inoject needle used forEMG procedures. When asked why use of this needle seemedto be more frequent Chris Smith, UK sales manager for therange, replied “ The Inoject needle provides superiorperformance with reduced friction for ease of skinpenetration and a high quality signal for consistent reliableresults, helping in the accurate use of Botulinum for manyconditions. Inoject needles are currently being used for therelaxation of muscles that are spasmodic in the face,particularly around the eyes, head and neck. The needles alsohelp bring relief to sufferers of cerebral palsy and othergenetic nerve diseases, as well as general nerve spasms thatcannot be relaxed by manipulation, including laryngealspasms. These high quality products are available in a fullrange of sizes and I believe this is reflected in their popularity.”For more information Email. skg@ambu.comapproach, just as diseasespresent in the real world. Itemploys practical, symptomandsign-based strategies forvirtually all conditionsencountered by thepractitioner. The final sectionon neurological emergenciesrecognises that suchconditions present first tosomeone other than apaediatric neurologist.Authors: James F Bale,Joshua L Bonkowsky, FrancisM Filloux, Gary L Hedlund,Denise M Nielsen, Universityof Utah School of Medicine,Salt Lake City, Utah, USA, PaulD Larsen, University ofNebraska College of Medicine, USA.ISBN 9781840761344.For more informationEmail. matt@mansonpublishing.comMerck Serono submitsapplication forextension ofindication for Rebif®in EuropeMerck Serono, a division of Merck KGaA,Darmstadt, Germany has submitted an applicationto the European Medicines Agency (EMA) to extendthe indication of Rebif®, its leading treatment formultiple sclerosis (MS). The requested labelextension is for the use of Rebif® in patients whohave experienced a single demyelinating event, anearly sign of the disease, and who are at high risk ofconverting to MS.“Our application to extend the indication ofRebif® is based on the REFLEX study, which focusedon patients with early signs of multiple sclerosis,”said Dr. Bernhard Kirschbaum, Executive VicePresident for Global Research and Development atMerck Serono. “We remain strongly committed toaddressing the medical needs of patients withmultiple sclerosis at the various stages of thisdevastating disease.”Merck Serono’s submission of a type II variationto extend the indication of Rebif® is supported byresults of the REFLEX study, which were presentedat the American Academy of Neurology (AAN) inApril 2011. The REFLEX study was designed toevaluate the effect of two different doses of Rebif– the currently approved 44mcg three times a weekand 44mcg once a week – versus placebo, on the“Time to conversion to McDonald MS (2005)” inpatients with a first clinical demyelinating event andhaving magnetic resonance imaging (MRI) brainscans consistent with early signs of MS. The studymet its primary endpoint for both doses bydemonstrating that Rebif® significantly delayedconversion to McDonald MS (2005) in thosepatients.The REFLEX study was conducted with thehuman serum albumin (HSA) – free formulation ofRebif®, which is now available in all European Unioncountries, Australia, Canada and Switzerland, as wellas a number of countries in Asia, Latin America,Africa and the Middle East. The HSA-freeformulation of Rebif® is currently not available inthe United States.Tremendous achievement of climbers with MS or PDIn July, 7 men and women withMultiple Sclerosis (MS) and 4 withParkinson’s disease (PD), along withnine climbing companions, reachedthe highest peak in Africa. This is thefirst time that a group of people withboth of these neurodegenerativediseases have united to reach asummit this high. The climb clearlydemonstrated that neurodegenerativediseases do not represent the end of‘normal’ life. Mount Kilimanjaro in Tanzania stands at 19,340 feet, not onlymaking it the highest peak in Africa, but also the highest free-standingmountain in the world.“This ‘Kilimanjaro Leap of Faith Adventure’ was meant to challenge thebody, expand the mind and foster courage in dealing with the diagnosis of aneurodegenerative disease. There have been some really tough parts of thetrek, especially altitude sickness, for which there is nothing you can do.Imagine that on top of our neurodegenerative diseases. But, we’ve made itand that’s a credit to all of us whobelieve that we can go beyond thelimitations of our disease and stillachieve incredible results, bothphysically and mentally,” said triporganiser Lori Schneider, founder ofEmpowerment Through Adventure.“Most of the group dedicatedthemselves to training to preparethemselves for this challenge. A keyattribute of the group is theiroutstandingly positive outlook, regardless of the hurdles they face, and theirunwavering commitment to supporting one another throughout the trip”.Communication activities for the Kilimanjaro Leap of Faith Adventure2011 are kindly supported by Sanofi.For further information on Empowerment Through Adventuresee www.EmpowermentThroughAdventure.comACNR > VOLUME 11 NUMBER 4 > SEPTEMBER/OCTOBER 2011 > 47

Confidence to takeaction everydayCOPAXONE® (glatiramer acetate)PRE-FILLED SYRINGE PRESCRIBING INFORMATIONPresentation – Glatiramer acetate 20mg solution forinjection in 1ml Pre-filled Syringe. Indication – Treatment ofpatients who have experienced a well-defined first clinicalepisode and are determined to be at high risk of developingclinically definite multiple sclerosis (MS). Reductionof frequency of relapses in relapsing-remitting MS inambulatory patients. In clinical trials this was characterisedby at least two attacks of neurological dysfunction overthe preceding two-year period. Dosage and administration– 20mg of glatiramer acetate (one pre-filled syringe)administered sub-cutaneously once daily. Children (12 - 18years) No specific studies. Limited published data suggestthe safety profile of 20mg administered sub-cutaneouslyonce 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.Please refer to the SPC for a full list of adverse effects.Overdose – Monitor, treat symptomatically. PharmaceuticalPrecautions – Store Copaxone in refrigerator (2ºC to 8ºC).If the pre-filled syringes cannot be stored in a refrigerator,they can be stored at room temperature (15ºC to 25ºC)once for up to one month. Do not freeze. Legal Category– POM. Package Quantity and Basic NHS Cost – 28 prefilledsyringes of Copaxone: £513.95. Product LicenceNumber – 10921/0023.Further Information – Further medical informationavailable on request from Teva Pharmaceuticals Limited,The Gate House, Gatehouse Way, Aylesbury, Bucks, HP198DB. Date of Preparation – 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: February 2011(glatiramer acetate)C0111/673aStanding up to RRMS everyday