Paul Reading Maurice Curtis, Andrew Naylor, Richard Faull ... - ACNR

EditorialPaul Reading in the first in his twopart series on the NeurologicalSleep Clinic takes us through hisown views on how best to treat patientswho have excessive daytime sleepinessand hypersomnolence. This account,whilst being a very personal one, neverthelesscontains a very helpful frameworkin which to investigate and seepatients who complain of this disorder.Stem cells continue to be a majorarea of research interest in neuroscienceand in their review article MauriceCurtis, Andrew Naylor and RichardFaull discuss the adult neural precursorstem cell. They discuss the evidence forthe existence of two populations ofsuch cells in the adult mammalianbrain and how they respond to diseaseand might be manipulated in the futureto promote repair. A stimulating articleby one of the foremost groups workingon this system in human neurodegenerativedisorders.Dysautonomia reflects a disorder of paroxysmal changes in autonomicnervous system activity which may have its origins in a disconnectionsyndrome targeting the midbrain in a subgroup of patients with severeacquired brain injury. This condition is often not recognised and IainPerkes and Ian Baguely seek to educate us on this disorder and how it canbe treated with a concluding plea for bigger, more multi centre studiesinto this condition.Emma Matthews and Mike Hanna in our ‘Neurogenetics’ series editedby Tom Warner, provide an up to date account of novel therapies for musculardystrophies. In particular they discuss therapies designed to workon exon skipping, read through of premature stop codons by small moleculesthat suppress these, transfection of truncated dystrophic minigenes using viral vectors and the blocking of myostatin. This excellentreview highlights once more how the better identification of genetic causesof disease can lead to the development of novel disease specific therapiesfor patients.Peter Whitfield in our Neurosurgery article in this issue discusses theNICE guidelines on head injury. The guidance is summarized in a seriesof tables which is an extremely helpful distillation, and to date what isproposed seems not as contentious as other similar guidelines, as AndrewLarner and Mark Doran discuss in their piece for ‘Controversies inNeurology’. In this they discuss in detail whether the NICE/SCIE dementiaguidelines are as useful as they would initially appear; in particularthey question the wisdom in allowing neurological input to be peripheralrather than more central to the future development and managementof patients with dementia. This is an interesting, thought-provoking articlewhich again raises questions about the process by which one can bestarrive at guidelines for widespread clinical practice.The Neuropathology article is a clear informative account of thepathology of intracerebral haemorrhage byArundhati Chakrabarty and AdityaShivane. In this article, the authors highlighttwo important new concepts thathave emerged on the pathophysiology ofthis condition, namely, that many haemorrhagescontinue to grow and expand overseveral hours after the onset of symptoms,and secondly that most of the brain injuryand swelling occurs after intracerebralhaemorrhage as a result of inflammationcaused by thrombin and other end productsof coagulation. However, even knowingthis has not yet altered the poor prognosisassociated with this condition.Whilst MS is common in the UnitedKingdom, it is much less so in more tropicalcountries such as India, although LekhaPandit argues that this might not truly bethe case in her illuminating account of MSand related disorders in India. The contrastin the management of MS in the UK andIndia is brought into sharp focus but withit comes the real belief and excitement thatthings are about to change for the better and that Dr Pandit is one ofthose leading this.We also have a summary of a roundtable discussion on the cognitiveconsequences of MS which covers the extent of the problem and how itcan be better assessed and integrated into normal patient care is discussed.In our Neurophysiology series, Antonio Valentín and Gonzalo Alarcóndiscuss the technique of single pulse electrical stimulation (SPES) to showthat delayed responses to cortical stimuli are predictive and thus helpidentify epileptigenic areas of cortex. They present their data from 125patients and discuss why the technique may be an important additionalinvestigation in the pre surgical assessment of patients with refractoryepilepsy.Roald Dahl has made two significant contributions to neurologyaccording to the short article by Andrew Larner in this issue of ACNR.Firstly, he helped in the construction of a valve for hydrocephalus, andsecondly, developed a method for improving language recovery in aphasicpatients.Finally, we are sad to have to announce the loss of another great Britishneurologist, with the passing of Professor PK Thomas, who died on the25th January this year.We have our usual book, journal and conference reviews as well as ourfirst column from the ABNT. On our website more can be found, includingall the previous issues of ACNR a well as case reports. We hope thatyou continue to enjoy our journal and do let us know if we can improveon it.Roger Barker, Co-Editor,Email: roger@acnr.co.ukACNR is published by Whitehouse Publishing, 1 The Lynch, Mere, Wiltshire, BA12 6DQ.Publisher: Rachael Hansford • Email: rachael@acnr.co.ukAdvertising. Patricia McDonnell • Email. sales@acnr.co.uk • Tel/Fax. +44 (0)288 289 7023Editorial. Anna Phelps • Email. anna@phelps1972.freeserve.co.ukDesign & Production Email. design.dept@sky.comPrinted by. Warners Midlands PLC, Tel. +44 (0)1778 391000ACNRISSN 1473-9348 Volume 8 Issue 1 March/April 2008www.acnr.co.ukAdvances in Clinical Neuroscience & RehabilitationCopyright: All rights reserved; no part of this publication may be reproduced, stored in a retrieval system or transmitted in any form orby any means, electronic, mechanical, photocopying, recording or otherwise without either the prior written permission of the publisheror a license permitting restricted photocopying issued in the UK by the Copyright Licensing Authority.Disclaimer: The publisher, the authors and editors accept no responsibility for loss incurred by any person acting or refraining fromaction as a result of material in or omitted from this magazine. Any new methods and techniques described involving drug usageshould be followed only in conjunction with drug manufacturers' own published literature.This is an independent publication - none of those contributing are in any way supported or remunerated by any of the companiesadvertising in it, unless otherwise clearly stated. Comments expressed in editorial are those of the author(s) and are not necessarilyendorsed by the editor, editorial board or publisher. The editor's decision is final and no correspondence will be entered into.Paul ReadingThe Neurological Sleep Clinic – Part 1 – The Sleepy PatientMaurice Curtis, Andrew Naylor, Richard FaullManipulation of Neural Stem Cells as a Rehabilitative TherapyEmma Matthews, Mike HannaPossible New Treatments in Muscular DystrophyConference News • Journal Reviews • Book Reviews • Diary of EventsNational Brain Science WritingPrize 2008www.youramazingbrain.org4 I ACNR • VOLUME 8 NUMBER 1 • MARCH/APRIL 2008

I’m going to win.®One AED,many livesDestination FreedomABBREVIATED PRESCRIBING INFORMATION(Please consult the Summary of Product Characteristics (SPC) before prescribing.)KEPPRA® film-coated tablets 250 mg, 500 mg, 750 mg, 1000 mgKEPPRA® 100 mg/ml oral solutionKEPPRA® 100 mg/ml concentrate for solution for infusionActive Ingredient: Tablets: levetiracetam 250, 500, 750 and 1,000 mg. Oral Solution: levetiracetam 100 mgper ml. Infusion: levetiracetam 100 mg per ml. Uses: Monotherapy for partial onset seizures with or withoutsecondary generalisation in patients from 16 years of age with newly diagnosed epilepsy. Adjunctive therapyfor partial onset seizures with or without secondary generalisation in adults and children from 4 years of age,for myoclonic seizures in adults and adolescents from 12 years of age with Juvenile Myoclonic Epilepsy andfor primary generalised tonic-clonic seizures in adults and adolescents from 12 years of age with IdiopathicGeneralised Epilepsy. Infusion: an alternative for patients when oral administration is temporarily not feasible.Dosage and Administration: Oral solution should be diluted prior to use. Infusion: Keppra concentrate mustbe diluted in at least 100 ml of a compatible diluent and administered intravenously as a 15 minute infusion.Monotherapy (adults and adolescents from 16 years): Recommended starting dose of 250 mg twice daily whichshould be increased to an initial therapeutic dose of 500 mg twice daily after two weeks. The dose can befurther increased by 250 mg twice daily every two weeks depending upon the clinical response. The maximumdose is 1500 mg twice daily. Adjunctive therapy: Adults and adolescents older than 12 years or weighing 50kg or more: 500 mg twice daily can be increased up to 1,500 mg twice daily. Dose changes can be made in500 mg twice daily increases or decreases every two to four weeks. Elderly: Adjustment of the dose isrecommended in patients with compromised renal function. Children aged 4 to 11 years and adolescents (12to 17 years) of less than 50 kg: 10 mg/kg twice daily, increased up to 30 mg/kg twice daily. Do not exceedincreases or decreases of 10 mg/kg twice daily every two weeks. The lowest effective dose should be used.(For full dosage recommendations see SPC.) Patients with renal impairment: Adjust dose according tocreatinine clearance as advised in SPC. Patients with hepatic impairment: No dose adjustment with mild tomoderate hepatic impairment. With severe hepatic impairment (creatinine clearance

Review ArticleThe Neurological Sleep Clinic – Part 1The Sleepy PatientTraditionally, at least in the UK, sleep disorders havereceived a low profile in neurology training programmessuch that only a handful of practisingneurologists have an active interest in sleep medicine. As aconsequence, most sleep centres are run exclusively by respiratoryphysicians who understandably focus, to varyingdegrees, on sleep-related breathing disorders. However,perhaps due to the astonishing developments in the neurobiologyof primary sleep disorders, their inherent interest,together with an increasing recognition that abnormalsleep contributes to numerous common neurologicalconditions such as migraine and epilepsy, the situation isslowly changing. I have held a weekly ‘Sleep Clinic’ forseven years in the North-East of England and propose tosummarise my personal approach to the assessment ofsleep-related symptoms from a neurological perspective.It is often wrongly assumed that most patients withabnormal sleep require elaborate and expensive investigationsin a “sleep laboratory”. In fact, the reverse is true: ifthe diagnosis is totally unclear despite an accurate history,it is relatively rare for overnight investigations to illuminatethe situation. I am particularly fond of an adage froma respected, now retired, doyen of sleep medicine,Professor David Parkes, namely: “A good sleep centre hasfar more need of a psychiatrist than an EEG machine”.In this, the first of a two part article, the assessment ofsleepy patients will be discussed.Excessive daytime sleepinessIt is only fairly recently that the symptom of excessivesleepiness has been taken seriously by medical practitionersrather than being seen as a moral failing or sin. In aneurological sleep clinic, it is probably the commonestproblem that prompts referral, usually with the implicitunderlying question: “Is it narcolepsy?” Narcolepsy isalmost certainly massively underdiagnosed, especially ifthe quoted prevalence rate of 0.05% is accepted. This ispartly because there is clearly a spectrum of disease severity.This should not be too surprising given the underlyingspecific neurochemical deficiency in typical cases. In particular,most narcoleptics lose around 40,000 hypothalamicneurons containing the neuropeptide, hypocretin (ororexin) in adolescence, presumably by an autoimmuneprocess. Although yet to be confirmed, it is entirely possiblethat a partial deficiency produces less severe or atypicalforms of the syndrome that may be more difficult torecognise.A detailed sleep-wake history, together with a numberof directed questions, will usually allow a confident clinicaldiagnosis. It is important to recognise that the key elementof narcolepsy is an inability to maintain stable statesof wakefulness (or sleep) for more than a few hours. Inother words, it reflects ‘state instability’ with most of thesymptoms reflecting an intrusion of sleep elements intowakefulness. For example, visual hallucinations and cataplexyare due to dream imagery and REM sleep paralysis,respectively, occurring when the subject is still awake.Cataplexy is an extremely specific symptom very rarelyseen outside of narcolepsy. It is present to varying degreesin over 60% of narcoleptics, in whom it usually occurs duringemotional situations. Laughter in the relaxed presenceof friends or family is the commonest trigger, althoughsome report that anticipation of a positive emotion provesto be the most effective precipitant. For example, some narcolepticshave partial attacks in which they cannot reach thepunchline of jokes without becoming tongue-tied orfrankly dysarthric. Full blown cataplectic episodes usuallystart with irregular jerking of the face or head with eye closurebut retained awareness. There is subsequent descendingparalysis such that the subject slumps to the floor as theknees give way. Because attacks evolve over two or threeseconds and narcoleptics usually recognise situations inwhich they are vulnerable, injury is rare. Similarly, episodesare not generally seen in dangerous or life-threatening situations,presumably because other arousal systems intercede.A variety of emotions can act as triggers including(pleasant) surprise, frustration and anger. However, oneshould be careful not to over-interpret mild symptoms ofknee buckling in extreme laughter or, indeed, anger as thisprobably reflects a normal reaction.The nature of the excessive daytime sleepiness in narcolepsyis usually characteristic. It is described as ‘irresistible’and invariably worse if the subject is unoccupiedor bored. Short naps are generally restorative and maycontain dreams or hallucinatory experiences. Most narcolepticswill admit to having dropped off in unusual situations.A recent extreme example that comes to mindwas a young car mechanic who fell asleep whilst bent overthe open bonnet of a car with the engine running!Vivid or unusual dreams at night due to REM sleepfragmentation and other nocturnal phenomena are alsovery common. Many narcoleptics report that they cancontrol their dreams to some extent. Indeed, some developunusual notions that they have paranormal powersand can predict the future. Distinguishing dreams fromreality can also be difficult and may produce embarrassingsituations. Other nocturnal symptoms such as sleep paralysisare not particularly discriminative symptoms.However, if sleep paralysis occurs as the subject is fallingasleep, rather than at the point of waking, narcolepsyshould be considered. In keeping with the notion of “stateinstability”, many narcoleptics wake frequently throughthe night for no apparent reason and may even have difficultydropping back to sleep. The full gamut of parasomniasis also relatively common in narcolepsy and includesarousal disorders, sleep talking and dream enactment.It seems likely that there are subtle metabolic abnormalitiesin narcolepsy and it is always worth asking aboutappetite control and the possibility of an eating disorder.Many subjects report cravings for sweet foods in particularwhich can produce bingeing, especially at night.Narcoleptics tend to be overweight, it seems at least partlyas a consequence of altered appetite control.Finally, from the history, it is worthwhile exploring theconcept of ‘automatic’ behaviours. Most narcoleptics complainthat they are ‘switched off’ for most of the day,unable to focus, concentrate or take in information effectively.As a result of this, brief so-called ‘micro-sleeps’ arecommon such that subjects perform complex tasks includingwriting without full awareness or control. Placingobjects in bizarre places or simply losing items around thehouse are particularly common examples of this.Because narcolepsy can be disabling and is generally lifelong,some authorities suggest that confirmatory tests aremandatory before treatment is started. This is debatable,especially if appropriate resources are scarce, althoughinvestigation is often appropriate in cases where the historyis not classical and particularly if cataplexy is absent.The recently published criteria for diagnosing narcolepsyseem clear-cut in that a positive diagnosis is achieved whenCSF levels of hypocretin are less than 110pg/ml or if thesubject falls asleep in under eight minutes, on average, in aDr Paul Reading, MA, FRCP, PhD,is a consultant neurologist based atthe James Cook UniversityHospital, Middlesbrough. He hastrained in Cambridge, Edinburghand Newcastle. Over the last sevenyears he has developed an academicand clinical interest in sleep medicineand been secretary of theBritish Sleep Society for four years.Narcolepsy and the sleep disordersassociated with neurodegenerativedisease are particular areas ofinterest.Correspondence to:Dr Paul Reading,Department of Neurology,The James Cook UniversityHospital,Middlesbrough, TS4 3BW, UK.Email. Paul.Reading@stees.nhs.ukKey references for further readingAmerican Academy of SleepMedicine. The InternationalClassification of Sleep Disorders,2nd Edition. AASM. Rochester2005.Dauvilliers Y, Arnulf I, Mignot E.Narcolepsy with cataplexy. Lancet2007;369:499-511.Silber MH, Krahn LE,Morgenthaler TI. Sleep Medicinein Clinical Practice. London :Taylor and Francis, 2004.6 I ACNR • VOLUME 8 NUMBER 1 • MARCH/APRIL 2008

Review ArticleFigure 1: Algorithm for assessing subjects with excessive sleepiness. Oximetry can usually be performed in the home setting.PSG – polysomnography; MSLT – multiple sleep latency test; CSF – cerebrospinal fluid; HCT – hypocretin (also called orexin).multiple sleep latency test (MSLT) and achievesREM sleep in at least two of the nap opportunities.Unfortunately, at a practical level, thesetests are not always very helpful in cases wherethere is clinical doubt from the history. Forexample, hypocretin CSF levels may be preservedin mild or atypical cases and, in any case,reliable assays are offered by very few centres.Determining hypocretin levels can be useful,however, if results from a MSLT are surprisingor if there are problems with interpretation. It isalso useful in diagnosing childhood narcolepsy.The MSLT is a notoriously fragile investigationand prone to producing false negativeresults. This is probably because most centresperforming the test do not have particularexpertise or, indeed, interest in sleep investigationsand rarely have strict protocols. Severalstudies have demonstrated the widely varyingresults that can be obtained from a MSLT,depending purely on the advice given to thesubject or the nature of their activities betweennap opportunities. From a diagnostic perspective,I believe a convincing history should holdsway over a ‘negative’ MSLT.Given that a very high proportion of narcolepticshave a DQ1B*0602 histocompatibilityhaplotype, many clinicians believe that HLAtesting has an important role in diagnosing narcolepsy.I think this is very rarely the case as Ihave seen numerous cases of DQ1B*0602-positivesleepy people who are not narcoleptic and asmaller number of ‘negative’ patients with definitenarcolepsy who have turned out to behypocretin deficient. Despite its relative ease, itis simply not a specific or sensitive enough testto be of general use.Other causes of excessive sleepinessA brief algorithm is provided for assessingsomnolent patients (Figure 1). Most sleepexperts will claim that an identifiable cause willbe found for the majority of sleepy subjects,even if it turns out that they are simply ‘overdoingit’. Certainly amongst respiratory physicians,the Epworth score is used as a screen todifferentiate sleepiness from chronic fatigue, forexample, and scores over 10 are usually deemedworthy of further assessment. In my opinion,the most useful discriminatory stem questionfrom the Epworth scale is the one that asksabout typical levels of sleepiness if a subject is apassenger in a car for an hour or more. In mostpopulations, the commonest cause of significantdaytime somnolence is obstructive sleepapnoea which effectively produces symptomsby severely disrupting overnight sleep. In thetypical clinical setting with a good history froma bed partner or family member, the diagnosisFigure 2: A T2 weighted axial image (top) revealing anarachnoid cyst in the region of the third ventricle in a 45year-old male patient presenting with excessive sleepiness,headaches and likely cataplexy. Sagittal views (bottom)demonstrate likely compression of the hypothalamus whichmay well account for his apparent secondary narcolepsy.is generally straightforward and, as such,patients rarely present to neurologists.However, if the subject is not particularly overweightor if there is no corroborative history, itcan easily be missed. Furthermore, it can occuras co-morbidity in patients with other diagnoses,including narcolepsy. If a patient admitsto long but unrefreshing sleep and wakes with adry mouth, feeling ‘hungover’, it is almostalways appropriate to arrange at least overnightoximetry to explore the possibility of significantnocturnal hypopnoea or apnoea.If narcolepsy is being considered but the historyis not clear cut and cataplexy is absent, forexample, the somewhat enigmatic diagnosis ofidiopathic hypersomnia often needs to be considered.Typical cases are fairly rare compared tonarcolepsy and are characterised by long butunrefreshing overnight sleep that appears ostensiblynormal even when monitored in a laboratorysetting. The main complaint is usually anextreme difficulty getting up in the morning anda subsequent propensity to long daytime naps.There are no symptoms suggestive of abnormalREM sleep mechanisms in contrast to narcolepsy.Diagnostic criteria require a sleep latency ofless than eight minutes. Controversially, idiopathichypersomnolence is now recognised asoccurring with and without long overnightsleep. A number of commentators suggest thatthe latter category might, instead, reflect a formof monosymptomatic narcolepsy.Most other causes of daytime somnolence canbe attributed to poor quality overnight sleep. Ofthese, perhaps the most important treatable diagnosisis restless legs syndrome (RLS) and associatedperiodic limb movement disorder. RLS is aclinical diagnosis and, relatively unusually, both acause of insomnia and daytime somnolence. Ifsymptoms are severe, a therapeutic trial of a drugbefore bed is usually warranted, if only for a shortperiod. Occasionally, in the absence of RLS andeven if a bed partner is not aware of excessivemovement, overnight tests pick up significantperiodic leg movements or jerks that can beshown to partially arouse the sleeping subject.Given a number of potentially effective treatmentoptions, this is a relatively rare situation in whichovernight polysomnography can be extremelyhelpful, albeit often in retrospect.A number of neurological patients will complainof troublesome somnolence and, assumingthat breathing-related disorders have beenexcluded, it is debatable whether thoroughinvestigation will aid management. Examplesinclude patients with parkinsonism, myotonicdystrophy and multiple sclerosis. In many suchpatients, the ultimate cause of their somnolenceis likely to be multi-factorial and an empiricalapproach, perhaps using wake-promotingagents, is probably justified if symptoms aretroublesome. Occasionally, there will bepatients with no underlying diagnoses or cluesas to the cause of their somnolence. In these, arelatively low threshold for brain imaging isrecommended as the author has occasionallypicked up otherwise asymptomatic pathologiessuch as arrested hydrocephalus, arachnoid cystsin the region of the third ventricle (see Figure2), and various hypothalamic lesions as likelysubstrates for the sleepiness.ACNR • VOLUME 8 NUMBER 1 • MARCH/APRIL 2008 I 7

Review Articledopamine signalling through the D2 receptorson proliferative cells. 8 However, whether thelack of proliferation contributes to the symptomologyof Parkinson’s disease is dubious due tothe long distance from the substantia nigra tothe SVZ. Stem cells are equally affected inAlzheimer’s disease (AD) where the accumulationof toxic amyloid beta (Aβ) reduces thenumber of dividing cells; in addition, Aβ promotessynaptic dysfunction and death ofmature neurons in AD. 9 Increased Aβ productionand depressed synaptic transmission inhippocampal slices 10 suggest that Aβ could participatein a negative feedback loop involved insynaptic modulation, since newly formed hippocampalneurons are sensitive to the intensityof synaptic transmission. The reports on stemcells in AD are conflicting, but in severe ADthere is a reduction in stem cell production 11,12For more detailed review see Curtis et al. 13Stem cells in an enriched environmentStem cells in the brain can be altered by exposingan individual to a range of enhanced externalstimuli, such as social and physical / behaviouralsituations, hence, environmental enrichment.In this context, the key components of anenriched environment are in the novelty andcomplexity that these type of environmentsoffer. These concepts have now moved forwardtowards a new and major focus; the enrichmentof the environment in order to alter the characteristicsof stem cells in the neurogenic niches.Environmental manipulations of the laboratoryanimal’s habitat, using toys, ladders, tunnels,platforms and running wheels, significantlyincreases animal social interactions, improveslearning and memory and promotes stem cellfunction in the SVZ and hippocampus. 14Furthermore, enrichment experiences lead tosubstantial neuron remodelling, with increaseddendritic branching, synaptic plasticity(including long-term potentiation) andincreased numbers of dendritic spines in corticaland hippocampal regions.In enriched animals, stem cells are stimulateddifferentially in the discrete neurogenic compartmentsof the normal and damaged brain.Under normal conditions in the SVZ, no effectis generally seen on cell proliferation or neurogenicoutcome after enrichment. However,environmental enrichment really comes to thefore after damage to the brain, with increasedproliferation and neurogenesis seen after experimentalstroke 15 and in the enhancing effect thatenrichment has on SVZ stem cell integrationafter stem cell transplantation in experimentalstroke. 16 Enriched environments may also play alarge role in behavioural alterations in AD. Inthe hippocampus, enrichment increases proliferationand neurogenesis, 17 increases neurotrophins,such as nerve growth factor (NGF)and brain derived neurotrophic factor(BDNF), 18 mediates effects on angiogenesis andlevels of vascular endothelial growth factor(VEGF), 19 and plays a significant role in regulatingand boosting cognition and improving spatialmemory.Stem cells respond to physical exerciseOne of the major components of the enrichedbehavioural model for enhanced brain plasticityis the lab animal’s free access to a runningwheel. Physical exercise strongly and robustlyinduces hippocampal stem cell proliferationand neurogenesis. 14 The effects of exerciseinducedproliferation and neurogenesis is highlydependent on the neurotrophins BDNF andNGF, and the growth factors, insulin-likegrowth factor I (IGF-I) and levels of VEGF.Exercise also increases dendritic complexityand spine density in the hippocampus, increasesangiogenesis and, importantly, significantlyimproves and enhances cognitive function andspatial memory. However, during periods ofstress, increased levels of glucocorticoids significantlydecrease hippocampal neurogenesis.The level of progenitor proliferation in runninganimals is decreased with excessive amounts ofrunning activity. Together with increased levelsof glucocorticoids, hippocampal proliferationlevels are highly dependent on the distance runand subsequent negative activation of thehypothalamic pituitary adrenal (HPA)-axis. 20Given these findings, the magnitude of physicalexercise should be carefully considered in devisingenriched environment regimes.However, challenges to the brain are wellmet by the stimulatory actions of exercise andmay significantly involve changes in proliferationand neurogenesis. There is overwhelmingevidence that regular exercise improves cognitivefunction in aged mice and elderlyhumans. 21 In respect to AD, increased physicalactivity (walking, swimming and cycling)reduces the risk of cognitive decline. However,current preclinical models of AD suggest agreater effect on improved memory, increasedneurogenesis and growth factor levels in animalsexposed to the enriched environmentcompared to physical exercise. The enrichedenvironment still demands greater physicalactivity and movement compared to more conventionallyhoused animals and this type ofphysically-linked behaviour may still play astrong role in enhancing brain functionthrough stem cells.ConclusionThe adult brain stem cell niches maintain theability to respond to some neurodegenerativedisorders throughout life. The SVZ and SGZalso have the ability to respond to external environmentalchanges that improve the plasticityof the adult brain. Whilst the virtues of lifelongregular physical exercise and enriching experienceson the prevention of various diseases andillnesses cannot be reiterated enough, adoptingpractices of healthy lifestyle with the rightamount of physical activity and social interactionmay prove to be vital for the appropriaterehabilitation of patients with neurological diseases.This focus will improve not only themotor but also the equally important sensoryand social needs of the affected individuals.References1. Luskin MB, Boone MS. Rate and pattern of migration of lineally-related olfactory bulbinterneurons generated postnatally in the subventricular zone of the rat. Chemical Senses.1994;19:695-714.2. Curtis MA, Penney EB, Pearson AG, van Roon-Mom WMC, Butterworth NJ, DragunowM, Connor B, Faull RLM. Increased cell proliferation and neurogenesis in the adult humanhuntington's disease brain. Proceedings of the National Academy of Sciences of the USA.2003;100:9023-7.3. Quinones-Hinojosa A, Sanai N, Soriano-Navarro M, Gonzalez-Perez O, Mirzadeh Z, Gil-Perotin S, Romero-Rodriguez R, Berger MS, Garcia-Verdugo JM, Alvarez-Buylla A.Cellular composition and cytoarchitecture of the adult human subventricular zone: A nicheof neural stem cells. J Comparative Neurology. 2006;494:415-34.4. Hansel DE, Eipper BA, Ronnett GV. Neuropeptide y functions as a neuroproliferative factor.Nature. 2001;410:940-4.5. van Praag H, Schinder AF, Christie BR, Toni N, Palmer TD, Gage FH. Functional neurogenesisin the adult hippocampus. Nature. 2002;415:1030-4.6. Tattersfield AS, Croon RJ, Liu YW, Kells A, Faull RLM, Connor B. Neurogenesis in thestriatum of the quinolinic acid lesion model of huntington’s disease. Neuroscience.2004;127:319-32.7. Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O. Neuronal replacement from endogenousprecursors in the adult brain after stroke. Nature Medicine. 2002;8:963-70.8. Höglinger GU, Rizk P, Muriel MP, Duyckaerts C, Oertel WH, Caille I, Hirsch EC.Dopamine depletion impairs precursor cell proliferation in parkinson disease. NatureNeuroscience. 2004;7:726-35.9. Mattson MP. Apoptosis in neurodegenerative disorders. Nat Rev Mol Cell Biol. 2000;1:120-9.10. Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D, Iwatsubo T, Sisodia S, MalinowR. App processing and synaptic function. Neuron. 2003;37:925-37.11. Boekhoorn K, Joels M, Lucassen PJ. Increased proliferation reflects glial and vascular-associatedchanges, but not neurogenesis in the presenile alzheimer hippocampus. Neurobiologyof Disease. 2006;24:1-14.12. Jin K, Galvan V, Xie L, Mao XO, Gorostiza OF, Bredesen DE, Greenberg DA. Enhancedneurogenesis in alzheimer's disease transgenic (pdgf-appsw,ind) mice. Proceeding of theNational Academy of Sciences of the USA. 2004;101:13363-7.13. Curtis MA, Faull RLM, Eriksson PS. The effect of neurodegenerative diseases on the subventricularzone. Nature Reviews Neuroscience. 2007;8:712-23.14. van Praag H, Christie BR, Sejnowski TJ, Gage FH. Running enhances neurogenesis, learning,and long-term potentiation in mice. Proceeding of the National Academy of Sciencesof the U S A. 1999;96:13427-31.15. Komitova M, Mattsson B, Johansson BB, Eriksson PS. Enriched environment increasesneural stem/progenitor cell proliferation and neurogenesis in the subventricular zone ofstroke-lesioned adult rats. Stroke. 2005;36:1278-82.16. Hicks AU, Hewlett K, Windle V, Chernenko G, Ploughman M, Jolkkonen J, Weiss S,Corbett D. Enriched environment enhances transplanted subventricular zone stem cellmigration and functional recovery after stroke. Neuroscience. 2007;146:31-40.17. Kempermann G, Kuhn HG, Gage FH. More hippocampal neurons in adult mice living inan enriched environment. Nature. 1997;386:493-5.18. Pham TM, Ickes B, Albeck D, Soderstrom S, Granholm AC, Mohammed AH. Changes inbrain nerve growth factor levels and nerve growth factor receptors in rats exposed to environmentalenrichment for one year. Neuroscience. 1999;94:279-86.19. Cao L, Jiao X, Zuzga DS, Liu Y, Fong DM, Young D, During MJ. Vegf links hippocampalactivity with neurogenesis, learning and memory. Nature Genetics. 2004;36:827-35.20. Naylor AS, Persson AI, Eriksson PS, Jonsdottir IH, Thorlin T. Extended voluntary runninginhibits exercise-induced adult hippocampal progenitor proliferation in the spontaneouslyhypertensive rat. J Neurophysiology. 2005;93:2406-14.21. Colcombe S, Kramer AF. Fitness effects on the cognitive function of older adults: A metaanalyticstudy. Psychol Sci. 2003;14:125-30.ACNR • VOLUME 8 NUMBER 1 • MARCH/APRIL 2008 I 9

Rehabilitation ArticleCurrent Understanding of Dysautonomia AfterSevere Acquired Brain InjuryDysautonomia is one of a number of names used todescribe a clinical syndrome affecting a subgroupof survivors of acquired brain injury (ABI). 1 Thesyndrome consists of paroxysmal elevations of autonomicnervous system (ANS) parameters, for example, heartrates (HR) up to 190 beats per minute, respiratory rates(RR) of 60 breaths per minute, temperatures to 42°C,arterial blood pressures (BP) of 170/120mmHg andsweating. These signs are accompanied by assorted formsof muscle overactivity such as decerebrate or decorticateposturing, dystonias, rigidity and spasticity.Traumatic brain injury (TBI) is the most commonlyreported causative condition, with an estimated incidenceof 8-15% in moderate and severe TBI admitted to an intensivecare unit (ICU). 2 There is no incidence data on otheraetiologies, although anecdotally dysautonomia appears tobe much rarer. Acute neurological events that have beenreported to precipitate dysautonomia include: spontaneoussubarachnoid or intracerebral haemorrhages, pressurefrom tumours, intra-aqueductal abscess, hydrocephalusand cerebral hypoxia in the absence of other trauma. 3In a prospective cohort study, 2 dysautonomic subjectshad a significantly worse outcome, a greater period ofhospitalisation and higher estimated costs compared tonon-dysautonomic survivors of TBI. However, dysautonomicand non-dysautonomic patients were found tohave a comparable degree of improvement with rehabilitation,albeit dysautonomic patients start at a lower pointand take longer to improve. 1There is considerable disparity between the estimatedincidence of dysautonomia in prospective research andthe quantity of scientific literature. There are a number ofplausible explanations for this discrepancy. The mostapparent difficulty is the proliferative and synonymousnature of the nomenclature, with at least 10 differentnames being used for the same condition. These includeparoxysmal sympathetic storms, autonomic dysfunctionsyndrome, acute midbrain syndrome, hypothalamic-midbraindysregulation syndrome, fever of central origin,hyperpyrexia associated with muscle contraction, dysautonomia,sympathetic or autonomic storming and paroxysmalautonomic instability with dystonia. 3Another explanation for the discrepancy is that dysautonomiais currently a diagnosis of exclusion and relies ona high index of suspicion. Firstly, some degree of autonomicarousal is a common feature during the early postacuterecovery from ABI and there is no clear thresholdwhere this activity should become classified as dysautonomia.Furthermore, dysautonomia shares a high degree ofoverlap with the presentation of common complicationssuch as opioid withdrawal, epileptic seizures, and sepsis,as well as rarer conditions such as neuroleptic malignantsyndrome, malignant hyperthermia and others. 3Natural history / clinical featuresAnalysis of the hospital course of post TBI dysautonomiasuggests that the syndrome follows a common three phasepattern. The first phase runs from admission to ICU tothe cessation of paralysis and/or sedation. There is little todifferentiate the dysautonomic and non-dysautonomicpatients in terms of physiological variables during thisstage. 1The second phase commences with the cessation of regularsedation. The dysautonomic patient will usually haveconsistently raised HR and temperature, and increasingregional muscle tone. Paroxysms of posturing and ANSoveractivity are superimposed on these elevated baselinelevels. In the early parts of this second phase, episodes arefrequent, prolonged and intense. Some episodes will beprovoked by identifiable stimuli (for example, pain, endotrachealsuctioning, passive movements such as turning,bathing and muscle stretching, constipation, a kinked urinarycatheter, emotional stimuli, as well as environmentalstimuli such as loud noises), 3 but others show no overtcause. The pattern of posturing is most often asymmetricaland may not fit into classical decorticate or decerebratepostures. 4 With increasing time post injury, the paroxysmsdecrease in duration, frequency and magnitude; restingBP, RR, HR and temperature return to normal. The patternof posturing may change, revealing an underlyingtetraplegia or other focal neurological deficit. Sweatingpatterns often alter, from whole body to upper trunk,head and neck, before ceasing entirely. 5 In the majority ofpatients, background muscle tone increases with variableflexor, extensor or mixed dystonias in the limbs, neck,trunk and facial muscles. The end of phase two is markedby the cessation of regular dysautonomic paroxysms.Extinguishment of episodes usually coincides withimproving neurological status, although most are left withsome degree of dystonia and spasticity. 1 The high degreeof physical disability can prevent voluntary muscle activity,limiting the accuracy of cognitive assessment.The final phase commences with the termination ofregular paroxysms, though by this stage, dysautonomiapatients with severe dystonia will have major deformitiesof joints and markedly reduced range of movement. 1Although ANS variables are within normal limits, noxiousstimuli may still provoke an episode for at least 14 monthspost injury. 6 Patients who develop a mechanism for communicationoften report persistent abnormal painfulresponses to normally non-noxious stimuli.ManagementPharmacological management is difficult and there is limiteddata available to guide decision-making. In the ICUsetting, widespread use of paralysis/sedation has beenshown to delay the onset of clinical features. 1 Anecdotally,the best available evidence for treatment efficacy includesbromocriptine, gabapentin and intrathecal baclofen(ITB). 7,8 Intravenous morphine and midazolam are effectivebut have problematic sedative effects. Drugs withsympathetic activity (particularly clonidine, propanololand labetolol) are also commonly used; however there aresuggestions that these drugs treat the symptoms ratherthan the underlying disease process. Equally, there is noevidence that anticonvulsants other than gabapentin areeffective in this condition. The potential to trigger paroxysmsvia noxious stimuli has led one author to suggestpre-treatment in this context. 9The rehabilitation management of dysautonomia centreson the usual approach of minimising unnecessarydisability and complications while maximising the potentialfor the individual to regain a maximal quality of life.In the rehabilitation setting, this includes adequate fluids,nutrition, and spasticity management including splinting,serial casting and pressure area management. Given thecombination of spasticity and nociception, ITB is increasinglybeing used earlier in the management.Clinical significanceThere are a variety of reasons to believe that dysautonomiawarrants active management. A lack of early recognitionIain E Perkes is enrolled in B Medand B Med Sci at the University ofNewcastle, Australia. He is alsoemployed as a Research Assistantby the Division of Anaesthesia,Cambridge University. His previousposts include Research Officerat: the NSW Centre for HealthResearch in Criminal Justice, theNational Centre in HIV SocialResearch at the University of NewSouth Wales, and the School ofPublic Health, University ofSydney. His primary researchinterest is traumatic brain injury.Ian J Baguley is a Senior StaffSpecialist and Research TeamLeader of Westmead Hospital’sBrain Injury RehabilitationService and a Clinical SeniorLecturer in the Department ofRehabilitation Medicine at theUniversity of Sydney. Dr Baguleyregularly reviews for professionaljournals and research fundingbodies and has authored manypublications in various fields ofRehabilitation Medicine. His principalresearch interests includetraumatic brain injury and spasticityrehabilitation.Correspondence to:Dr Ian J Baguley,Brain Injury RehabilitationService,Westmead Hospital,Westmead, NSW 2145, Australia.Tel. (612) 9845 7941Fax. (612) 9635 8892Email. ianb@biru.wsahs.nsw.gov.au10 I ACNR • VOLUME 8 NUMBER 1 • MARCH/APRIL 2008

Rehabilitation Articleand management contributes to increasedmorbidity. In particular, core temperaturesabove 38-39°C produce neuronal death in animalbrain injury models. 10,11 While transienttemperatures at these levels occur in 68% ofpeople following severe TBI, 11 dysautonomicsubjects mean daily maximum temperaturescan remain above this level for more than twoweeks. 1 The increased metabolic consumptionof posturing patients 12 and prolonged irregularitiesof gastrointestinal tract function 13 producea highly catabolic state causing an estimated25% decrease in body weight. 1 The subsequentmalnourishment places the individualat risk of developing critical illness neuropathy.Spastic tetraparesis in patients at rest anddystonic posturing during paroxysms are typical;and combined with weight loss, these leadto increased risk of pain, pressure areas andcontractures. Dysautonomic episodes makesplinting an extremely difficult prospect, withpotential complications such as pressure areasand ruptured tendons. Lack of voluntarymovement and the potential for ‘locked-in’syndromes to occur 1,14 can result in undermanagedpain or a misdiagnosis of persistentvegetative state.PathophysiologyWhile the earliest theories proposed an epileptogenicaetiology, 15 multiple attempts to eitheridentify or treat epilepsy in dysautonomicpatients have produced negative results. 3 Thereis greater evidence for supporting a disconnectionpathogenesis. The limited autopsy andpathophysiological data has recently beenreviewed, suggesting that the critical region ofinterest in dysautonomia is the mesencephalon.3 Conventional disconnection theoriessuggest that excitatory centre/s located inthe upper brainstem and diencephalon driveparoxysms. A more recent disconnection theory,the Excitatory:Inhibitory Ratio (EIR)Model, 16 suggests the causative brainstem/diencephaliccentres are inhibitory innature, with damage releasing excitatory spinalcord processes.Evidence from literature on dysautonomiaand other conditions suggests that disconnectionsyndromes can result from structuraland/or functional disconnection. Accordingly,functional disconnection may ensue fromtransient exacerbations of structural change(such as raised ICP) or neurotransmitterabnormalities.ConclusionThe clinical research clearly shows that dysautonomiaplaces a considerable burden on bothpatient and health care services and that thereis potential for reducing this burden throughtimely recognition and intervention. However,the field is hampered by under-recognition,misdiagnosis, a poor understanding of pathophysiologyand anecdotal management protocols.Recent advances suggest that new physiologicalinvestigatory techniques will allow thedevelopment of evidence based treatment paradigmsfor the first time. It is hoped that moreeffective treatment protocols will, in turn,result in improved outcomes and decreasedoverall costs. It is recommended that multicentreresearch be utilised and targetedtowards modifying outcomes for patients withthis condition.References1. Baguley IJ, et al. Dysautonomia after traumatic braininjury: a forgotten syndrome? Journal of Neurology,Neurosurgery & Psychiatry 1999;67(1):39-43.2. Baguley IJ, et al. The incidence of dysautonomia and itsrelationship with autonomic arousal following traumaticbrain injury. Brain Inj 2007;21(11):1175-81.3. Baguley IJ, et al. A Critical Review of the Pathophysiologyof Dysautonomia Following Traumatic Brain Injury.Neurocrit Care 2007.4. Bricolo A, et al. Decerebrate rigidity in acute head injury.Journal of Neurosurgery 1977;47:680-98.5. Bullard DE. Diencephalic Seizures: Responsiveness toBromocriptine and Morphine. Ann.Neurol1987;21(6):609-11.6. Baguley IJ, et al. Dysautonomia and Heart RateVariability Following Severe Traumatic Brain Injury.Brain Injury 2006;20(4):437-44.7. Baguley IJ, et al. Pharmacological management ofDysautonomia following traumatic brain injury. BrainInjury 2004;18(5):409-17.8. Baguley IJ, et al. Gabapentin in the management ofdysautonomia following severe traumatic brain injury: acase series. Journal of Neurology, Neurosurgery &Psychiatry 2007;78(5):539-41.9. Lemke DM. Sympathetic Storming After SevereTraumatic Brain Injury. Critical Care Nurse2007;27(1):30.10. Minamisawa H, Smith ML, Siesjo BK. The effect of mildhyperthermia and hypothermia on brain damage following5, 10, and 15 minutes of forebrain ischemia. AnnNeurol 1990;28(1):26-33.11. Albrecht RF, Wass CT, Lanier WL. Occurrence of potentiallydetrimental temperature alterations in hospitalizedpatients at risk for brain injury. Mayo Clinic Proceedings1998;73(7):629-35.12. Clifton GL, Robertson CS, Choi SC. Assessments ofnutritional requirements of head-injured patients. Journalof Neurosurgery 1986;64:895-901.13. Ott L, et al. Altered gastric emptying in the head-injuredpatient: relationship to feeding intolerance. J Neurosurg1991;74(5):738-42.14. Scott JS, et al. Autonomic dysfunction associated withlocked-in syndrome in a child. American Journal ofPhysical Medicine & Rehabilitation 1997;76(3):200-3.15. Penfield W. Diencephalic autonomic epilepsy. ArchNeurol Psychiatry 1929;22:358-74.16. Baguley IJ. The excitatory:inhibitory ratio model (EIRmodel): An integrative explanation of acute autonomicoveractivity syndromes. Med Hypotheses 2007.ACNR • VOLUME 8 NUMBER 1 • MARCH/APRIL 2008 I 11

PRIMARY CARENEUROLOGY- A Practical ApproachWed 30th April 2008, CardiffOne of the highlights of this year's programme is theinclusion of a debate on "Should placebo be used as an activetreatment for neurological conditions?" which will involve oneof the most highly respected and world renownedexperts on complementary medicine, Professor Edzard Ernst,who will be speaking against the use of placebo. Professor Ernstqualified as a physician in Germany in 1978 where he alsocompleted his MD and PhD theses. He has receivedtraining in acupuncture, autogenic training, herbalism,massage therapy and spinal manipulation. He was Professor inPhysical Medicine and Rehabilitation (PMR) at HannoverMedical School and Head of the PMR Department at theUniversity of Vienna. In 1993 he established the first Chair ofComplementary Medicine in the UK, at the University of Exeter.Talking in favour of placebo is the dynamic Dr Stephen Allen,who has been a pain consultant in Reading for 25 years. DrAllen has grown his pain clinic in Reading from a very small'one-man band' into what is now a large unit embracing amulti-disciplinary approach to Pain Management, havingsignificant input from both physiotherapy and psychology. Weare in for a fascinating debate!This year's programe will deal with a number of practical issuesincluding:• Straightening out Dizziness - a general practice approach• Dementia and Minimal Cognitive Impairment - Making anaccurate assessment• Commissioning Neurological Services• Managing Anxiety and Depression in People withLongterm Neurological Conditions• Yellow Flags and Non-Pharmacological Approaches toManagement of Chronic Non Malignant Pain• Management of Facial Pain - learning the essentials• Recognition and management of an MS Relapse• Movement disorders - deciphering the organic from thenon-organic.For full programme details go towww.p-cns.org.ukwhere this year you will also be able to save 10% on theearly bird registration fee by booking online. If you have anyproblems accessing the website then please emailinfo@p-cns.org.ukPRESCRIBING INFORMATION – UK AND ROIREBIF® 8.8 MICROGRAMS AND 22 MICROGRAMS SOLUTION FOR INJECTIONREBIF® 22 MICROGRAMS SOLUTION FOR INJECTIONREBIF® 44 MICROGRAMS SOLUTION FOR INJECTIONInterferon beta-1aPresentation Rebif 8.8 and 22: Pre-filled glass syringe containing 8.8 µg or 22 µg of Interferonbeta-1a in respectively 0.2 or 0.5 ml. Rebif 22 or 44: Pre-filled glass syringe containing 22 µg or44 µg Interferon beta-1a in 0.5ml. Indication Treatment of relapsing multiple sclerosis. Efficacyhas not been demonstrated in patients with secondary progressive multiple sclerosis withoutongoing relapse activity. Dosage and administration Initiate under supervision of a physicianexperienced in the treatment of multiple sclerosis. Administer by subcutaneous injection.Recommended dose: Weeks 1 and 2: 8.8 µg three times per week (TIW); weeks 3 and 4: 22 µgTIW; week 5 onwards: 44 µg TIW (22 µg TIW if patients cannot tolerate higher dose). Limitedpublished data suggest that the safety profile in adolescents aged 12-16 years receiving Rebif 22TIW is similar to that in adults. Do not use in patients under 12 years of age. Prior to injection andfor 24 h afterwards, an antipyretic analgesic is advised to decrease flu-like symptoms. Evaluatepatients at least every second year of the treatment period. Contraindications History ofhypersensitivity to natural or recombinant interferon beta, or to any of the excipients; treatmentinitiation in pregnancy; current severe depression and/or suicidal ideation. Precautions Informpatients of most common adverse reactions. Use with caution in patients with previous or currentdepressive disorders and those with antecedents of suicidal ideation. Advise patients to reportimmediately any symptoms of depression and/or suicidal ideation. Closely monitor patientsexhibiting depression and treat appropriately. Consider cessation of therapy. Administer withcaution in patients with a history of seizures and those receiving anti-epileptics, particularly ifepilepsy is not adequately controlled. Closely monitor patients with cardiac disease for worseningof their condition during initiation of therapy. Patients should use an aseptic injection techniqueand rotate injection sites to minimise risk of injection site necrosis. If breaks in skin occur, patientsshould consult their doctor before continuing injections. If multiple lesions occur, discontinueRebif until healed. Use with caution in patients with history of significant liver disease, active liverdisease, alcohol abuse or increased serum ALT. Monitor serum ALT prior to the start of therapy,at months 1, 3 and 6 and periodically thereafter. Stop treatment if icterus or symptoms of liverdysfunction appear. Treatment has potential to cause severe liver injury including acute hepaticfailure. Full haematological monitoring is recommended at months 1, 3 and 6 and periodicallythereafter. All monitoring should be more frequent when initiating Rebif 44. New or worseningthyroid abnormalities may occur. Thyroid function testing is recommended at baseline and ifabnormal every 6 – 12 months. Use with caution in, and closely monitor patients with, severerenal and hepatic failure or severe myelosuppression. Serum neutralising antibodies may developand are associated with reduced efficacy. If a patient responds poorly and has neutralisingantibodies, reassess treatment. Use with caution in patients receiving medicines with a narrowtherapeutic index cleared by cytochrome P450. Women of childbearing potential should use effectivecontraception. Limited data suggest a possible increased risk of spontaneous abortion. Duringlactation, either discontinue Rebif or nursing. If overdose occurs, hospitalise patient and givesupportive treatment. Side effects In the case of severe or persistent undesirable effects, considertemporarily lowering or interrupting dose. Very common: flu-like symptoms, injection siteinflammation/reaction, headache, asymptomatic transaminase increase, neutropenia, lymphopenia,leucopenia, thrombocytopenia, anaemia. Common: injection site pain, myalgia, arthralgia, fatigue,rigors, fever, pruritus, rash, erythematous/maculo-papular rash, diarrhoea, vomiting, nausea,depression, insomnia. Serious side effects include: injection site necrosis, hepatitis with or withouticterus, severe liver injury, anaphylactic reactions, angioedema, erythema multiforme, erythemamultiforme-like skin reactions, seizures, thromboembolic events, suicide attempt. Consult theSummary of Product Characteristics for more information relating to side effects.Legal category POMPriceRebif 8.8 and 22: 6 (0.2 ml) + 6 (0.5 ml) syringes - £586.19Rebif 22: 12 syringes (0.5 ml) - £650.13Rebif 44: 12 syringes (0.5 ml) - £863.28For prices in Ireland, consult distributors Allphar Services Ltd.Marketing Authorisation Holder and Numbers:Serono Europe Ltd, 56 Marsh Wall, London, E14 9TP; EU/1/98/063/007; 003 & 006For further information contact:UK: Merck Serono, Bedfont Cross, Stanwell Road, Feltham, Middlesex, TW14 8NX.Tel: 020 8818 7373.Republic of Ireland: Merck Serono, 3013 Lake Drive, Citywest Business Campus, Dublin 24.Tel: 01 4661910Date of Preparation: September 2007Adverse events should be reported to Merck Serono - see contactdetails within PI. Information about adverse event reporting in the UKcan be found at www.yellowcard.gov.uk.Date of preparation: October 2007REB07-014612 I ACNR • VOLUME 8 NUMBER 1 • MARCH/APRIL 2008

Rebif ® New FormulationBalancing Performance & SafetyPrescribing information is available on the adjacent pageDate of preparation: October 2007REB07-0146A balanced choice in MS

Neurophysiology ArticleSingle Pulse Electrical Stimulation in Presurgical Assessment ofEpilepsy: A New Diagnostic ToolEpilepsy is a major source of disability amongst allage groups. Although most epilepsies are well controlledon antiepileptic drugs, around 20% ofpatients fail to gain medical control, and are potentialcandidates for surgery. However, despite recent technicaladvances, the overall success rate of surgery for epilepsyremains at about 75%.At the department of Clinical Neurophysiology atKing’s College Hospital, we have developed single pulseelectrical stimulation (SPES) as a method to identifyepileptogenic cortex in the human brain. Corticalresponses to SPES (1msec duration pulses, 4-8mA, 0.1-0.2Hz) were studied in 125 consecutive patients evaluatedwith intracranial electrodes as candidates for resectivesurgery for the treatment of their epilepsy.Two main groups of cortical responses were generatedby SPES: 1) early responses (ER), starting immediatelyafter the stimulus and considered as responses of normalcortex to stimulation; and 2) late responses (LR), corticalresponses seen in some areas after the initial ER. Two differenttypes of LR were seen: a) delayed responses (DR):responses resembling spikes or sharp waves occurringbetween 100 milliseconds and 1 second after stimulation;and b) repetitive responses (RR): two or more consecutivesharp-and-slow-wave complexes, each resembling the initialearly response. DR were seen when stimulating temporaland extratemporal structures and RR when stimulatingfrontal structures. Late responses to SPES are related toareas where spontaneous seizure onset occurs. They canidentify epileptogenic cortex and predict surgical outcome,especially when a frontal or temporal focus is suspected.Single-pulse electrical stimulation (SPES) could be animportant additional investigation during presurgicalassessment and can be particularly useful in patients whohave widespread or multiple epileptogenic areas, normalneuroimaging, or few seizures during telemetry.Table 1: Cross tabulation between type of late response and seizure onset.IntroductionEpilepsy is one of the most common neurological disorders,with a prevalence of 4-10/1000 and an incidence of50-70/100,000 per year. 1,2 About 20% of patients withepilepsy are not satisfactorily controlled by medical treatmentand are potential candidates for surgery.In focal epilepsies, there is a localised area of abnormalnervous tissue from which seizures originate (epileptogeniccortex). A successful outcome of resective epilepsysurgery depends on accurate identification of the epileptogeniccortex which is structurally and functionallyabnormal. Recent developments in medical imagingprovide powerful means to localise structural lesions.Identification of functional abnormalities still requireselectroencephalographic (EEG) recordings of seizureonset. Despite technical advances in surgical proceduresand presurgical assessment over recent decades, theoverall success rate of resective surgery of epilepsyremains at about 75% even in the best centres. 3 The reasonsfor a 25% failure rate are unclear, but might berelated to difficulties in identifying the area from whichthe seizures originate. Its location is inferred from clinical,imaging and electrophysiological findings.Sometimes seizure recordings with intracranial electrodesare necessary to identify epileptogenic cortex. Asthe number of intracranial electrodes implanted is necessarilylimited and seizures can rapidly propagatebetween regions, intracranial recordings can sometimesbe misleading in seizures arising from areas where noelectrodes were implanted.Since epilepsy is due to an imbalance between excitationand inhibition, an alternative is to map corticalexcitability in order to identify hyperexcitable areas thatcould be epileptogenic. This can in principle be achievedby recording EEG responses to electrical stimulation inpatients with intracranial recordings. Electrical stimulationwith trains of pulses at 50-60Hz is routinely used insome centres to map cortical function and after-dischargethreshold, and to elicit habitual seizures. However,it is difficult to study cortical excitability with such stimulationparameters because they are likely to producemassive and widespread cortical activation. In theDepartments of Clinical Neurophysiology andNeurosurgery at King’s College Hospital, we have developeda method to identify hyperexcitable cortex throughthe study of EEG responses to single pulse electrical stimulation(SPES). 4-6 In the present article we review theIctal Onset Zone typeDR/RR typeFocal Regional Diffuse Bilateral Indep. No sz TotalFocal DR 18 7 0 3 2 30Regional DR 6 33* 1 0 0 40Bilateral DR 4 4** 0 7 3*** 18Only RR 0 5 0 0 0 5No DR/RR 3 18 7 2 2 32Total 31 67 8 12 7 125Patients showing focal and regional ictal onset zones were considered as having regional ictal onset zone. Patients showing focal andregional DR were considered as having regional DR. The ictal onset zone was defined as the region where the initial ictal changes wereseen in intracranial recordings.* Two patients also had repetitive responses (RR).** One patient also had repetitive responses (RR).*** One patient had delayed and repetitive responses when stimulating both medial frontal regions.DR=Delayed Responses; Bilateral DR=independent DR seen on both hemispheres; RR=Repetitive Responses; Indep=independent;sz=seizures.Antonio Valentin, MD, PhD, is aClinical Lecturer in the Departmentof Clinical Neuroscience of theInstitute of Psychiatry at King’sCollege London and HonoraryClinical Fellow at the Departmentof Clinical Neurophysiology atKing’s College Hospital. Hisresearch interests are the developmentof new diagnosis and treatmenttechniques for Epilepsy andMovement Disorders. He qualifiedfrom the University Complutense(Madrid, Spain).Gonzalo Alarcón, MD, PhD, isSenior Lecturer in the Departmentof Clinical Neuroscience of theInstitute of Psychiatry andHonorary Consultant in ClinicalNeurophysiology at King’s CollegeHospital. His research interests arepresurgical assessment of epilepsyand the mechanisms involved inthe generation of human epilepticseizures. He qualified from theUniversity Complutense (Madrid,Spain).Correspondance to:Dr Antonio Valentin, MD, PhD,Department of Neuroscience,Institute of Psychiatry,King’s College London,London SE5 8AF, UK.Tel. +44 20 7848 5161Fax. +44 20 7346 3725Email. antonio.valentin@iop.kcl.ac.ukThe corresponding author hashad full access to all the data inthe study and has had finalresponsibility for the decision tosubmit the paper.14 I ACNR • VOLUME 8 NUMBER 1 • MARCH/APRIL 2008

Neurophysiology Articleresults of SPES from 125 consecutive patientsevaluated with intracranial recordingsbetween 1999 and 2006.Experimental protocolSPES was performed between adjacent electrodeswith a constant-current neurostimulator(Medelec ST10 Sensor, OxfordInstruments) using monophasic single pulsesof 1ms duration and current intensity rangingbetween 4mA and 8mA (4mA was mostoften used). A single pulse was deliveredevery 5-10s and EEG responses to each pulsewere recorded by the electrodes not used forstimulation. At least ten pulses were appliedto each intracranial electrode. In eachpatient, all available electrodes located ingrey matter were used to stimulate.SPES responsesTwo main groups of cortical responses weregenerated by SPES:1) Early responses (ER): Responses resemblingsingle sharp-and-slow waves followingthe stimulus artefact, sometimes associatedwith a low amplitude sharp wavewith a fixed latency. ER can be consideredas responses of normal cortex to stimulation(Figure 1).2) Late responses (LR): cortical responsesseen in some areas after the initial ER.Two different types of LR were seen:2.a) Delayed responses (DR): responsesresembling spikes or sharp waves occurringbetween 100 milliseconds and onesecond after stimulation (Figure 1). DRwere not always seen after every identicalstimulus and their latency is alwaysvariable after each stimulus. DR wereseen when stimulating temporal andextratemporal structures.2.b) Repetitive responses (RR): two or moreconsecutive sharp-and-slow-wave complexes,each resembling the initial earlyresponse (Figure 2). RR were mainly seenwhen stimulating frontal structures.Among the 125 patients, 93 had shown lateresponses to SPES, 84 had exclusively DR,five had exclusively RR, and four patients hadboth DR and RR (Table 1).Relation between late responses toSPES and seizure onsetApart from early responses, DR were themost commonly observed responses to SPES.The relation between the topography of DRand ictal onset zone can be seen in Table 2.The ictal onset zone was defined as the regionwhere the initial ictal changes were seen inintracranial recordings. Ictal onset zone wasclassified as focal (involving less than threecontiguous electrodes), regional (involvingthree or more contiguous electrodes on onehemisphere), diffuse (involving most electrodesbilaterally), or bilateral independent(different focal seizures starting on differenthemispheres). Among the 83 patients withDR and seizures during telemetry, 70 showedDR exclusively within the ictal onset zone(Figure 3), 10 showed DR within and outsidethe ictal onset zone, and only three showedFigure 1: Early and Delayed responses to SPESA: Frontal radiograph showing implanted subdural subtemporal strips in a patient with left temporal lobe epilepsy. All thecontacts of the subdural strips are highlighted. B: Intracranial recordings of early and delayed responses to SPES. Delayedresponses were seen at electrode 1 of left subtemporal strip (LsT1, marked as green) when stimulating through electrodes 5and 6 of same strip (LsT5 and LsT6, marked as red). Early responses were mainly seen at electrodes 3, 4, 7, and 8 of samestrip. Electrode 1 was the most distal electrode to the insertion burr hole and closest to mesial temporal structures.Recording displayed in common reference to Pz.Arrow=electrical stimulation; RsT=right subtemporal strip; LsT=left subtemporal strip; ER=early response; DR=delayedresponse.Figure 2: Repetitive responses to SPESA: Frontal radiograph showing implanted intracerebral (depth) electrode bundles. B: Intracranial recordings of early andrepetitive responses to SPES. Repetitive responses were evident when stimulating through electrodes 1 and 2 of the leftposterior frontal electrode bundle (LpF1 and LpF2, marked as red). Electrode 1 was the most distal electrode to the insertionburr hole and closest to medial frontal structures. Recording displayed in common reference to Pz.Arrow=electrical stimulation; RapF=right anterior polar frontal; RmF=right mid frontal; LmF=left mid frontal; LpF=leftposterior frontal; LaF=left anterior frontal; Lorb=left orbitofrontal; Lpcing=left posterior cingulate; Lacing=left anteriorcingulate; ER=early response; DR=delayed response.DR exclusively outside the ictal onset zone.Moreover, the vast majority of patients (27/30)without DR did not have a focal onset, probablyimplying that the electrodes were not incontact with the area of origin for the seizures(Table 1). Therefore, DR appear to be associatedwith the ictal onset zone and can be consideredas a reliable marker of epileptogenicity.In a further study of 30 patients with frontalintracranial electrodes, RR and/or frontal DRwere seen exclusively in patients with frontalseizure onset. 5 The best match between seizureACNR • VOLUME 8 NUMBER 1 • MARCH/APRIL 2008 I 15

Neurophysiology ArticleFigure 3: Relation between the distribution and topography of late responses to SPES and seizure onset in a patient with bitemporal subdural strips.A: Intracranial recordings of early and delayed responses to SPES. Delayed responses were seen at contact 2 of left subtemporal strip (LT2) when stimulating through electrodes 3 and4 of same strip (LT3 and LT4) B: Subdural recording of a focal seizure onset. Note the fast activity building up at electrodes 1 and 2 of the left subtemporal strip (LT1 and 2). Electrode1 was the most distal electrode to the insertion burr hole and closest to mesial temporal structures Recording displayed in common reference to Pz.Arrow=electrical stimulation; RT=right subtemporal strip; LT=left subtemporal strip.onset and responses to SPES was seen in theareas where DR were recorded and thosewhich, when stimulated, gave rise to RR(abnormal SPES areas).Neuropathology and prediction ofoutcome:We have studied 40 consecutive patients operatedon at King’s College Hospital who had previousSPES, and have more than 12 months offollow-up. 6 A strong relationship betweenfavourable post-surgical seizure control andremoval of the abnormal SPES areas was found.Whereas around 96% of patients who had completeremoval of abnormal SPES areas enjoyeda favourable outcome, only 71% of patientswhere these areas were partially removed had afavourable outcome. The three patients whereabnormal SPES areas were not removed hadpoor outcomes (Table 3). More specifically, asimilar relation has been observed after frontallobe resections. 5 An important finding was theconsistent presence of structural abnormalitiesdemonstrated by neuropathology in theremoved abnormal SPES areas despite normalneuroimaging. 6 This means that delayed andrepetitive responses arose from structurally andfunctionally abnormal regions.SPES in childrenIn a study performed in King’s CollegeHospital and in Great Ormond Street Hospitalfor Sick Children (London UK), the utility ofSPES in the paediatric population has beenevaluated in 35 children. We identified corticalresponses to SPES that were similar or identicalto those reported in adults. 7 These results areespecially important because in children withfocal epilepsy there is a compromise betweensafety and early surgical intervention. SPESTable 2: Comparison between the topographies of DR and ictal onset zones in the 83 patients withDR and seizures during telemetry.DRIctal onset zone topographytopography Focal Regional Bilateral Indep. Diffuse Totalin out in out in outFocal 17 1 7 0 3* 0 0 28Regional 6 0 31** 2 0 0 1 40Bilateral 4*** 0 4*** 0 7 0 0 15Total 27 1 41 2 10 0 1 83Patients showing focal and regional ictal onset zones were considered as having regional ictal onset zone.Patients showing focal and regional DR were considered as having regional DRin=DR inside the ictal onset zone; out=DR seen outside ictal onset zone and not within the ictal onset zone;indep=independent* All three patients had unilateral focal DR and bilateral seizures.** Two patients had DR inside and outside the ictal onset zone*** All patients had DR inside and outside the ictal onset zonecould reduce the duration of intracranial monitoringby optimising electrode placement andby providing reliable information during theinterictal period, avoiding long waiting timefor multiple seizures to occur.Early responses and brain connectivitySince early responses appear to be normalresponses to SPES, they can be used to assessconnectivity between different corticalregions. 8-10 We have studied connectionsbetween temporal and frontal cortices in 51patients. 10 Our findings suggest that connectionsbetween temporal and ipsilateral frontalregions were relatively uncommon (seen in upto 25% of hemispheres) whereas connectionsbetween frontal and ipsilateral temporal corticeswere more common, particularly fromorbital to ipsilateral medial temporal regions(40%). Contralateral bi-temporal connectionswere rare (

mother: 365 days a yearms patient: 15 minutes every FridayAvonex is the only DMT to show signifi cantbenefi cial effects on cognitive dysfunction 1Treatment with Avonex leads to a reductionin disability over the long term 2Avonex is the only once-weekly treatment for MSEffi cacy that fi ts livesPrescribing information is available overleaf

Neurophysiology ArticlePrescribing information: AVONEX ®Presentations: Lyophilised powder for injection for IM administration containinga 30µg dose (6 million IU) of Interferon beta-1a per vial. Solution for injection ina pre-fi lled syringe of 0.5ml for IM administration containing 30µg dose (6 millionIU) of Interferon beta-1a. Indications: For the treatment of ambulatory patientswith relapsing multiple sclerosis characterised by at least 2 recurrent attacks ofneurologic dysfunction (relapses) over the preceding 3-year period without evidenceof continuous progression between relapses. AVONEX ® slows the progression ofdisability and decreases the frequency of relapses. AVONEX ® is also indicated forthe treatment of patients who have experienced a single demyelinating event withan active infl ammatory process if it is severe enough to warrant treatment withintravenous corticosteroids, if alternative diagnoses have been excluded, and if theyare determined to be at high risk of developing clinically defi nite multiple sclerosis(see SPC for further information). Treatment should be discontinued in patients whodevelop chronic progressive multiple sclerosis. Dosage and Administration: Therecommended dosage of AVONEX ® in the treatment of relapsing MS is 30µg injectedIM once a week. AVONEX ® lyophilised powder presentation should be reconstitutedwith the solvent supplied. Treatment should be initiated under supervision of aphysician experienced in the treatment of the disease. An antipyretic analgesic isadvised to decrease the fl u-like symptoms associated with AVONEX ® administration.AVONEX ® should not be used in children. Contraindications: Initiation of treatmentin pregnancy. Patients with a history of hypersensitivity to natural or recombinantinterferon beta or any of the excipients. Patients with current severe depressiondisorders and/or suicidal ideation. Precautions: CNS: AVONEX ® should be used withcaution in patients with previous or current depressive disorders, in particular to thosewith antecedents of suicidal ideation. Depression and suicidal ideation are known tooccur in increased frequency in the multiple sclerosis population in association withinterferon use. Patients treated with AVONEX ® should be advised to immediately reportany symptoms of depression and/or suicidal ideation to their prescribing physician.AVONEX ® should be administered with caution to patients with a history of seizures,to those receiving treatment with anti-epileptics, particularly if their epilepsy is notadequately controlled with anti-epileptics. Pregnancy and lactation: Initiation oftreatment is contraindicated during pregnancy. Women of child bearing potentialshould take appropriate contraceptive measures. If the patient becomes pregnant orplans to become pregnant while taking Avonex, discontinuation of therapy should beconsidered. General: AVONEX ® should be used with caution in patients with cardiacdisease, severe renal or hepatic failure or severe myelosuppression, and these patientsshould be closely monitored. Routine periodic blood chemistry and haematologytests are recommended during treatment with AVONEX ® . Laboratory abnormalitiesmay also occur which do not usually require treatment. Drug interactions: No formalinteraction studies have been conducted with AVONEX ® in humans. Clinical studiesindicate that corticosteroids or ACTH can be given during relapses. Caution should beexercised in combining AVONEX ® with medicinal products with a narrow therapeuticindex and dependent on hepatic cytochrome P450 for clearance. Side Effects: Themost commonly reported symptoms are of the fl u-like syndrome: muscle ache, fever,chills, asthenia, headache and nausea. Other less common events include: Bodyas a whole: Anorexia, hypersensitivity reactions, weight loss, weight gain, severeallergic reactions (anaphylactic reactions or anaphylactic shock), syncope. Skin andappendages: Alopecia, angioneurotic oedema, injection site reaction including pain,pruritus, rash, urticaria. Digestive system: Diarrhoea, hepatitis, liver function testabnormalities, vomiting. Cardiovascular system: Chest pain, palpitations, tachycardia,and vasodilatation and rarely arrhythmia, cardiomyopathy, congestive heart failure.Haematological system: Thrombocytopenia and rare cases of pancytopenia.Reproductive system: Metrorrhagia and/or menorrhagia. Nervous system: Anxiety,dizziness, insomnia, paraesthesia, seizures, depression, suicide (see Precautions).Transient neurological symptoms that mimic MS exacerbations may occur followinginjections. Musculoskeletal system: Arthralgia, pain, transient hypertonia and/or severe muscular weakness. Respiratory system: Dyspnoea. Autoimmunedisorders, central nervous system disorders and laboratory abnormalities havebeen reported with interferons. Rare cases of arthritis, hypo- and hyperthyroidism,lupus erythematosus syndrome, confusion, emotional lability, psychosis, migraineand very rare cases of autoimmune hepatitis have been reported with AVONEX ® . Forfurther information regarding adverse events please refer to the Summary of ProductCharacteristics. Preclinical Safety: Fertility and developmental studies with a relatedform of Interferon beta-1a in Rhesus monkeys show anovulatory and abortifacienteffects at high doses. No teratogenic effects or effects on foetal development wereobserved. Legal Classifi cation: POM. Pack Size and UK NHS Price: Box containingfour injections £654. Reimbursed through High Tech Scheme in Ireland. PackageQuantities: Lyophilised Powder: 1 box containing four trays. Each tray contains a3ml glass vial with BIO-SET device containing a 30µg dose of Interferon beta-1a pervial, a 1ml pre-fi lled glass syringe of solvent and one needle. Pre-fi lled Syringe: 1box containing four trays. Each tray contains a 1ml pre-fi lled syringe made of glasscontaining 0.5ml of solution (30µg dose of Interferon beta-1a) and one needle.Product Licence Numbers: EU/1/97/033/002-003. Product Licence Holder: BiogenIdec Ltd., 5 Roxborough Way, Foundation Park, Maidenhead, Berkshire SL6 3UD,United Kingdom. Date of last revision of Prescribing Information: September 2006.Please refer to the Summary of Product Characteristics for further information.For UK only:Information about adverse event reporting can be found at www.yellowcard.gov.uk.Adverse events should also be reported to Biogen Idec Ltd., on 08000 286639.References:1. Halper J et al. J Neurosci Nurs 2003; 35: 70-81.2. Rudick RA et al. Poster presented at ECTRIMS. October 2007; Prague.Date of preparation: January 2008AVOO-PAN-22918Table 3: Relation between seizure outcome and removal of abnormalSPES areas.Favourable Poor TotalOutcome (I-II) Outcome (III-IV)Completely removed (CR) 21 1 22Partially removed (PR) 5 2 7Not removed (NR) 0 3 3No late responsesobserved (NL) 5* 3 8Total 31 9 40*4 patients showed continuous interictal spikes (cis) suggestive of corticaldysplasia at the areas of seizure onset, which made assessment of thepresence of delayed responses at these regions impossible (probably falsenegatives of SPES).those of spontaneous epileptiform discharges. Thirdly, at present SPEScan only be carried out in patients assessed with intracranial electrodes,and shares with such recordings their limitations with regard to spatialsampling. The combined use of transcranial magnetic stimulation(TMS) and simultaneous EEG could help to study cortical excitability infocal epilepsy. 11ConclusionSingle pulse electrical stimulation is a safe and reliable technique for identifyingepileptogenic cortex, as evidenced by the close relationship betweenthe topography of abnormal responses and location of electrographicseizure onset, surgical outcome, and pathological abnormalities. Our findingssuggest that surgery should remove abnormal SPES areas. This is ofparamount clinical relevance since SPES appears to provide additional evidenceof epileptogenicity during the interictal period, and it appears to bea good predictor of pathology and surgical outcome.At the very least, SPES provides additional evidence that can be used toreduce the need to capture seizures, allowing invasive EEG telemetry tobe performed for shorter periods. It may in some instances even replaceictal recording as a method of locating the epileptogenic zone, allowingintraoperative identification of epileptogenic cortex immediately beforeresection. Furthermore, the technique may also prove of value duringelectrode implantation to determine whether the sites chosen are likely tolie within the epileptogenic zone.References1. Hauser WA, Annegers JF, Kurland LT. Incidence of epilepsy and unprovoked seizures inRochester, Minnesota: 1935-1984. Epilepsia 1993;34(3):453-68.2. Brodie MJ, Shorvon SD, Canger R, Halasz P, Johannessen S, Thompson P et al. Commissionon European Affairs: appropriate standards of epilepsy care across Europe. ILEA. Epilepsia1997;38(11):1245-50.3. Alarcón G, Valentín A, Watt C, et al. Is it worth pursuing surgery for epilepsy in patientswith normal neuroimaging? J Neurol Neurosurg Psychiatry 2006 Apr;77(4):474-80.4. Valentín A, Anderson M, Alarcón G, et al. Responses to single pulse electrical stimulationidentify epileptogenesis in the human brain in vivo. Brain 2002;125(Pt 8):1709-18.5. Valentín A, Alarcón G, Garcia-Seoane JJ, et al. Single-pulse electrical stimulation identifiesepileptogenic frontal cortex in the human brain. Neurology 2005;65(3):426-35.6. Valentín A, Alarcón G, Honavar M, et al. Single pulse electrical stimulation for identificationof structural abnormalities and prediction of seizure outcome after epilepsy surgery: a prospectivestudy. Lancet Neurol 2005;4(11):718-26.7. Flanagan D, Valentín A, Alarcón G, Boyd SG. Single pulse electrical stimulation of the cortexduring prolonged subdural EEG monitoring in children. Abstract for presentation at 21stAnnual Scientific Meeting of the Epilepsy Society of Australia 2006.8. Wilson CL, Isokawa M, Babb TL, Crandall PH. Functional connections in the human temporallobe. I. Analysis of limbic system pathways using neuronal responses evoked by electricalstimulation. Exp Brain Res 1990;82:279-92.9. Wilson CL, Isokawa M, Babb TL, Crandall PH, Levesque MF, Engel J, Jr. Functional connectionsin the human temporal lobe. II. Evidence for a loss of functional linkage between contralaterallimbic structures. Exp Brain Res 1991;85:174-87.10. Lacruz ME, García Seoane JJ, Valentín A, Selway R, Alarcón G. Frontal and temporal functionalconnections of the living human brain. Eur J Neurosci. 2007 Sep;26(5):1357-70.11. Valentín A, Arunachalam R, Mesquita-Rodrigues A, et al. Late EEG responses triggered bytranscranial magnetic stimulation (TMS) in the evaluation of focal epilepsy. Epilepsia. 2007Nov 19 [Epub ahead of print].18 I ACNR • VOLUME 8 NUMBER 1 • MARCH/APRIL 2008

Neuropathology ArticleTable 2: Pathological evolution of ICH (Reproduced with kind permission from Nicoll JAR et al. Parenchymal brain haemorrhage. In-Pathology &Genetics-Cerebrovascular Diseases. 2005 ISN, Basel, Switzerland, pp 294-300)Time Macroscopic MicroscopicSecondsRupture of blood vessel wallSeconds to minutes Haematoma formation (bright red acute haemorrhage) Extravasation of bloodMinutes to hours Space-occupying effect. Distortion and compression of surrounding tissue, Lysis of erythrocytes(may include: raised intracranial pressure, internal herniations, brain stem compression)Several hours Development of peri-haematoma oedema and ischaemia. Increasing space-occupying effect. Oedema, ischaemia, polymorph infiltrate.2-3 days to weeks Brown coloration of haematoma Haemosiderin formation. Phagocytosis by macrophages.Astrocyte hypertrophy and new blood vessel formationat the haematoma margin.Weeks to months Friable brown clot Organisation of the haematoma with phagocytosis ofblood and necrotic tissue by macrophages.Months to years Cavity containing dark blood-stained fluid Continued resorption of blood clotMonths to years Cavity containing clear fluid resembling CSF with brown haemosiderin-stained cavity wall Cavity lined by hyperplastic and hypertrophic glial cells;residual macrophages and haemosiderinand amphetamines; and those due to therapeuticmanipulations including anticoagulation,fibrinolytic therapy and carotid endarterectomy.Heavy alcohol consumption predisposes to ICHby inducing hypertension (particularly acutelyafter a binge), by its inhibiting effects on plateletfunction or by causing liver dysfunction.Cocaine and amphetamines are sympathomimeticagents known to have effects on pulseand blood pressure. Cocaine also induces a cerebralvasculitis, which may be partly responsiblefor ICH associated with its use. Most patientswith drug-related ICH have an associated vascularlesion such as an aneurysm or an arteriovenousmalformation. 4,7Figure 1: Cerebral amyloid angiopathy. Coronal slice showing a large superficial haemorrhage in the right frontal lobe withextension into the subarachnoid space and ventricle (A). Same case as in (A) showing also a large hematoma in the right occipitallobe (B). Photomicrograph showing thickened hyalinized blood vessels in the leptomeninges (C) and in the brain parenchyma(D) (H&E x200). Immunohistochemistry for beta-amyloid showing strong positivity in the blood vessel walls (E) (x200).Cerebral amyloid angiopathy (CAA)CAA results from the deposition of the insolubleamyloid-beta (Aβ) peptides (derived fromamyloid precursor protein/APP) in the walls ofleptomeningeal and cortical arteries, arteriolesand capillaries (Figure 1). Replacement ofsmooth muscle cells in the artery walls by Aβincreases exponentially with age, making theartery less compliant. CAA-associated haemorrhagein some cases may be related to an interactionwith other risk factors, notably hypertension.Haemorrhages are superficial, lobarand quite commonly breach the cortical surfaceresulting in secondary subarachnoid haemorrhage;they can also be multiple or recurrent.Specific vasculopathic complications occurmore commonly with CAA-associated haemorrhagethan in CAA without haemorrhage. Suchcomplications include concentric splitting ofthe vessel wall (‘double barrel’ appearance), fibrinoidnecrosis, microaneurysms, stenoticlumina, microhaemorrhages and corticalinfarction. 9,10GeneticsMost genetic studies have focussed on theapolipoprotein E alleles ε4 and ε2 that are associatedwith predisposition to ICH, particularlywith CAA and lobar haemorrhages. McCarronand colleagues 9 found that patients with ICHwho carried the apolipoprotein E ε4 allele had agreater hospital mortality rate than non-carriers(40% Vs 25%). The apolipoprotein E ε4allele is also associated with poor outcome aftertraumatic brain injury, but there is no suchassociation for ischaemic stroke. Polymorphismsin various other genes such as methylenetetrahydrofolatereductase, angiotensinconvertingenzyme, and alpha1-antichymotrypsinhave been found to be associatedwith ICH in other fairly small studies. 2Iatrogenic forms of ICHThe iatrogenic forms of ICH can be broadlydivided into two groups: those due to selfadministrationof substances with toxic effectswhich include mainly alcohol, drugs like cocaineConclusionsThe prognosis for patients suffering from ICHis still poor. Size and location of the haemorrhage,together with age and presence of hypertension,represent the main prognostic indicators.6 The role of oedema, ischaemia, masseffect, direct cellular toxicity, inflammation,and apoptosis are being evaluated in variousexperimental studies of ICH. 5 The future maysee the translation of this basic informationinto clinical trials and also lead to the developmentof highly effective treatments.References1. Mayer SA, Rincon F. Treatment of intracerebral haemorrhage.Lancet Neurol 2005;4:662-72.2. Xi G, Keep RF, Hoff JT. Mechanisms of brain injury afterintracerebral haemorrhage. Lancet Neurol 2006;5:53-63.3. Qureshi AI, Tuhrim S, Broderick JP, Batjer HH, HondoH, Hanley DF. Spontaneous intracerebral hemorrhage. NEngl J Med 2001;344(19):1450-60.4. MacKenzie JM. Intracerebral haemorrhage. J Clin Pathol1996;49:360-4.5. Fewel ME, Thompson BG, Hoff JT. Spontaneous intracerebralhemorrhage: a review. Neurosurg Focus2003;15:1-16.6. Sacco S, Marini C, Carolei A. Medical treatment ofintracerebral hemorrhage. Neurol Sci 2004;24:S6-9.7. Kase CS, Caplan LR. Intracerebral hemorrhage. Boston:Butterworth-Heinemann, 1994.8. Skidmore CT, Andrefsky J. Spontaneous intracerebralhemorrhage: epidemiology, pathophysiology, and medicalmanagement. Neurosurg Clin N Am 2002;13:281-8.9. McCarron MO, Cohen NR, Nicoll JAR. Parenchymalbrain hemorrhage. In-Pathology & Genetics-Cerebrovascular Diseases. 2005 ISN, Basel, Switzerland,pp 294-300.10. Sutherland GR, Auer RN. Primary intracerebral hemorrhage.J Clin Neurosci 2006;13:511-17.ACNR • VOLUME 8 NUMBER 1 • MARCH/APRIL 2008 I 21

Neurology and LiteratureTales of the Unexpected: Roald Dahl’s NeurologicalContributionsRoald Dahl (1916-1990) is best known as an authorof children’s books, although his oeuvre also extendsto other works, including screenplays, ghost talesand novels. It may therefore seem surprising at first sightthat he might have made any contributions to neurology.However, in the second volume of his autobiography, Goingsolo (1986), he declares “All my life I have taken an intenseand inquisitive interest in every form of medicine”, perhapsin part because of the head injury he suffered as a pilot inWorld War 2. Recovering in Alexandria, he was blind forsome time, and reports “Both my senses of smell and ofhearing had become very acute since my blindness, and Ihad developed an instinctive habit of translating soundsand scents into a coloured mental picture”. 1 This accountsuggests the phenomenon of hyperpilaphesie, but not oftrue (“strong”) synaesthesia.Dahl’s book George’s marvellous medicine (1981) containsthe epigraph (in the hardbackedition, but not in subsequent paperbackeditions) “This book is for doctorseverywhere”. This bold statementis not further elaborated upon, but certainlythe book may be read as a salutarylesson about the grave consequencesof unregulated experimentationin clinical pharmacology. Theauthor advises readers not to try therecipes reported in the book.It has been suggested elsewhere (reference2, case 3) that in his first volumeof autobiography, Boy: tales of childhood(1984), Dahl portrays a schoolmaster,“Captain Hardcastle”, who mayhave suffered from Tourette syndromesince he seems to manifest both vocal and motor tics. Thisteacher was almost certainly the inspiration for “CaptainLancaster”, also a teacher, who appears in the book Dannythe champion of the world (1975): “I could hear him snortingand snuffling through his nose like a dog outside arabbit hole.” In the film version, Captain Lancaster (asportrayed by Ronald Pickup) has a larger role than in thebook but neither snorting nor snuffling are in evidence.Why Dahl should have recalled this particular teacher isnot certain, but of possible note is the fact that Dahl himselfhad some characteristics which might be suggestive ofthe obsessive-compulsive spectrum, for example whenwriting in his famous shed he had to have a particulartype of paper (yellow American Legal), and both a particularbrand and a specific number (6) of pencils. 3These descriptions may hardly be termed “contributions”,but two personal tragedies certainly did lead todevelopments of clinical import. Whilst living in NewYork in 1960, Dahl’s son Theo, aged 3-4 months, wasinvolved in a road traffic accident which caused somebrain damage and secondary hydrocephalus, the latterrequiring shunting. Problems with blocked shuntsoccurred. The family returned to England and Theo cameunder the care of Kenneth Till, a neurosurgeon at GreatOrmond Street Hospital (1956-80). Prompted by Dahl,and in collaboration with Stanley Wade, an hydraulicengineer, a new type of shunt valve was designed.Reported in the Lancet by Kenneth Till, under the rubricof “New Inventions”, the special characteristics werereported to be “low resistance, ease of sterilisation, noreflux, robust construction, and negligible risk of blockage”.The author acknowledged that the valve was“designed by Mr Stanley C.Wade … with the assistance ofMr Roald Dahl and myself”. 4 The Wade-Dahl-Till (orWDT) valve became widely used.Kenneth Till subsequently wrote a preface for a newedition of Valerie Eaton Griffith’s book entitled A strokein the family, a manual of home therapy (www.strokescheme.ie/articles/reviews/family.htm), wherein liesanother Dahl connection. In 1965, Dahl’s first wife, theAmerican actress Patricia Neal, suffered a stroke due to aruptured intracranial aneurysm, one of the consequencesof which was marked aphasia, a potential career-endingmisfortune for an actress (her illness and recovery arerecorded in a book by Barry Farrell 5 ). Dahl appealed toValerie Eaton Griffith, who lived in the same village, forhelp. With Dahl, she devised a rota of volunteer carers toengage the patient in conversation and hence to stimulatelanguage recovery. This approach, different from formalspeech therapy, was documented inGriffith’s book (initially published in1970, with an introduction by RoaldDahl 6 ). It earned the approbation, as“treatment of a surreptitious character”,of no less a neurological figurethan Macdonald Critchley, 7 and stillhas advocates today. 8 It has been suggestedthat Patricia Neal’s aphasia mayhave influenced Dahl’s creativeprocesses, for example in the neologismsof The BFG (1982). 9The Roald Dahl Foundation(www.roalddahlfoundation.org) continuesto provide charitable grants forneurological conditions affectingyoung people including epilepsy;acquired brain injury due to benign brain tumour,encephalitis, head injury, hydrocephalus, meningitis, andstroke; and neurodegenerative conditions causing progressiveintellectual or neurological deterioration.AcknowledgementsThanks to Elizabeth Larner for drawing my attention to theWade-Dahl-Till valve.References1. Dahl R. Going solo. London: Puffin 2001:106,107.2. Larner AJ. Three historical accounts of Gilles de la Tourette syndrome.ACNR 2003;3(5):26-7.3. Donkin A. Dead famous: Roald Dahl and his chocolate factory.London: Scholastic, 2002:167-8.4. Till K. A valve for the treatment of hydrocephalus. Lancet 1964;1:202.5. Farrell B. Pat and Roald. New York: Random House, 1969.6. Griffith VE. A stroke in the family. A manual of home therapy.New York: Delacourte Press, 1970.7. Critchley M. The chronic aphasiac, a sociological problem. In: Thedivine banquet of the brain and other essays. New York: Raven Press,1979:83-7 [esp. 86-7].8. Hale S. The man who lost his language. A case of aphasia(Revised edition). London: Jessica Kingsley, 2007:50,57.9. Op. cit. ref. 3:156-7.Dr Andrew Larner is the editor ofour Book Review Section. He is aConsultant Neurologist at theWalton Centre for Neurology andNeurosurgery in Liverpool, with aparticular interest in dementia andcognitive disorders. He is also anHonorary Apothecaries' Lecturerin the History of Medicine at theUniversity of Liverpool.Correspondence to:Dr Andrew Larner,Walton Centre for Neurologyand Neurosurgery,Lower Lane,Fazakerley, Liverpool,L9 7LJ, UK.E. a.larner@thewaltoncentre.nhs.uk22 I ACNR • VOLUME 8 NUMBER 1 • MARCH/APRIL 2008

A positive difference inthe early stagesof idiopathic Parkinson’s diseaseRight from the startAzilect® 1mg tablets Prescribing information (Please refer to the Summary of Product Characteristics (SmPC)before prescribing) Presentation: Tablets containing 1mg rasagiline (as the mesilate). Indication: Treatment ofidiopathic Parkinson’s disease as monotherapy or as adjunct to levodopa in patients with end of dosefluctuations. Dosage and administration: Oral, 1mg once daily taken with or without food. Elderly: No changein dosage required. Children and adolescents (1%: headache,flu syndrome, malaise, neck pain, dyspepsia, arthralgia, depression, conjunctivitis, allergic reaction, fever, anginapectoris, anorexia, leucopenia, arthritis, vertigo, rhinitis, contact dermatitis, vesiculobullous rash, skin carcinoma,hallucinations, urinary urgency. 1%:abdominal pain, accidental injury, postural hypotension, constipation, vomiting, weight loss, dyskinesia, neck pain,anorexia, dry mouth, arthralgia, tenosynovitis, dystonia, abnormal dreams, ataxia, rash, hallucinations.

Neurogenetics ArticleRecent Advances in Genetic Muscle Disease –Possible New Treatments in Muscular DystrophyMuscular dystrophies are amongst the mostimportant genetic muscle diseases and patientsfrequently come under the care of a neurologist.Younger onset muscular dystrophies often result in significantdisability and cardiorespiratory complications maybe fatal. In the last few years there have been significantadvances in the area of gene discovery in muscular dystrophyand this has aided diagnosis. Recent research is nowmoving from gene discovery to molecular therapy andhere we have focussed on new gene intervention treatmentsand new treatments to promote muscle regeneration.Important phase I/II trials in these areas are either inprogress or starting.DiagnosisFor many neuromuscular diseases diagnosis is based on acombination of clinical features and careful evaluation,including EMG, muscle biopsy and, increasingly, genetesting. Standard light microscopy of a biopsy for diagnosisin muscular dystrophy is now inadequate and carefulimmunohistochemical evaluation using a range of specificantibodies is mandatory to advance to a precise geneticdiagnosis - especially in the limb girdle muscular dystrophies.The discovery of causative genes in this group ofmuscular disorders has led to more accurate diagnosis,clinical management and genetic counselling 1 (Tables 1and 2). The recognition of important phenotype-genotyperelationships allows selection of patients at risk ofcardiorespiratory complications, facilitating early interventionwhich prolongs life. An accurate genetic diagnosiscan enable prenatal diagnosis in carefully selected cases.New treatment trials in muscular dystrophy- Gene therapy and satellite cell stimulationRecently two new treatment approaches for muscular dystrophyhave reached the stage of phase I/II clinical trials.The first group are new gene therapy approaches inDuchenne muscular dystrophy and the second is themodulating of muscle myostatin levels.Several gene therapy approaches have been developedin Duchenne muscular dystrophy (DMD); these includeexon skipping, transfection of truncated dystrophin minigenesusing viral vectors and “read through” of prematurestop codons by small molecules that suppress stopcodons. Recognition of myostatin as an inhibitor of musclegrowth has led to the development of myostatin antibodiesthat knock down myostatin production in muscle.There is much interest in the potential of myostatin suppressionas a treatment in a range of genetic muscle diseasesincluding muscular dystrophy.Duchenne muscular dystrophyDuchenne muscular dystrophy (DMD) is the commonestmuscular dystrophy, affecting 1 in 3 500 live male births. 2It is an X-linked recessive disorder due to mutations in thedystrophin gene that encode the subsarcolemmal proteindystrophin leading to a lack of dystrophin expression inskeletal and cardiac muscle. It is a progressive musclewasting disease and death usually occurs in the thirddecade from respiratory or cardiac muscle involvement.Animal models which also lack dystrophin expression dueto premature stop codons in the dystrophin gene havebeen used extensively to research this disease. The mdxmouse, although having an almost total lack of dystrophin,has a milder phenotype than that seen inhumans, with an almost normal life span. 3 Thus somecaution has to be used when considering how results oftrials in mice may relate to human disease. For this reasonthe mdx dog is often used in treatment trials as its phenotypeis much closer to that seen in boys, with a reducedlifespan resulting from cardiac or respiratory involvement.Furthermore, the muscle mass of the dog is morecomparable to that of a child with DMD. 3Exon skippingMutations of the dystrophin gene in DMD often disruptthe reading frame, resulting in no production of the keymembrane structural protein dystrophin. In contrastmutations in the dystrophin gene found in the milderBecker Muscular Dystrophy (BMD) typically do not disruptthe reading frame and there is some production of asemi-functional dystrophin protein, hence the milderphenotype. 4 The recognition that a significantly truncateddystrophin gene could still produce a functional proteinled to the concept of skipping mutated exons in DMD asa therapeutic strategy. In the last few years morpholinoanti-sense oligonucleotides have been developed in DMDto do just this with resultant restoration of the readingframe and increased production of dystrophin.Intramuscular delivery of such oligonucleotides in experimentswith the mdx mouse model of DMD confirmed atransient local production of the dystrophin protein withno significant immune response. 5 More recently, systemicdelivery to the mdx mouse has produced dystrophinexpression in all skeletal muscles with functional improvement,although expression was not uniformly seen. 6 ToEmma Matthews is a research fellowat the MRC Centre forNeuromuscular Disease, Instituteof Neurology, UCL and NationalHospital for Neurology andNeurosurgery Queen Square,London. Her main research interestsare in the skeletal musclechannelopathies.Prof Mike Hanna is a consultantneurologist at the MRC Centre forNeuromuscular Disease, Instituteof Neurology, UCL and NationalHospital for Neurology andNeurosurgery Queen Square,London. He is also ClinicalDirector of the National Hospitalfor Neurology and Neurosurgery.Correspondence to:E Matthews, MRCP,M G Hanna, MD, FRCP,MRC Centre for NeuromuscularDisease,Institute of Neurology,UCL,Queen Square, London, UK.Email. ematthew@ion.ucl.ac.ukTable 1: The Dominantly Inherited Limb Girdle Muscular DystrophiesLGMD Chromosome Gene Protein Additional Clinical Features1A 5q22-q34 Myotilin Myotilin DysarthriaCardiomyopathy1B 1q11-q21 Laminin A/C* Laminin A/C Cardiomyopathy1C 3p25 Caveolin-3 Caveolin-3 Calf HypertrophyRippling muscle disease1D 6q23 Unknown Unknown Cardiac arrhythmias and cardiomyopathy1E 7q Unknown Unknown DysphagiaNo associated systemic features* Mutations in the Laminin A/C gene are also known to cause Emery-Dreifuss Muscular Dystrophy Type 2, Familial PartialLipodystrophy and peripheral neuropathy.24 I ACNR • VOLUME 8 NUMBER 1 • MARCH/APRIL 2008

Neurogenetics ArticleTable 2: The Recessively Inherited Limb Girdle Muscular DystrophiesLGMD Chromosome Gene Protein Additional Clinical Features2A 15q15.1-q21.1 Calpain-3 Calpain-3 Distribution of weakness cf. FSHD (scapular,pelvis,trunk). Contractures can occur.Cardiac involvement rare.2B 2p13 Dysferlin* Dysferlin Gastrocnemius wasting. Cardiac involvement rare.2C 13q12 γ-sarcoglycan γ-sarcoglycan Phenotype can be similar to Duchenne Muscular Dystrophy. Respiratory Involvement.Cardiac involvement. Neurosensory hearing loss. Death can occur in 2nd decade.2D 17q12-q21.3 α-sarcoglycan α-sarcoglycan Earlier onset more aggressive than later onset. Cardiomyopathy.2E 4q12 β-sarcoglycan β-sarcoglycan Can be severe phenotype. Can be wheelchair bound in teens. Calf hypertrophy.Cardiomyopathy.2F 5q33-34 δ-sarcoglycan δ-sarcoglycan Can be severe phenotype. Calf hypertrophy. Can be wheelchair bound in teens.Death can occur in 2nd decade. Cardiomyopathy.2G 17q11-12 Telethonin (Titin Cap) Telethonin Foot drop. Cardiac involvement.2H 9q31-q34.1 TRIM-32 TRIM 32 Variable but generally mild phenotype. Facial weakness.2I 19q13.3 FKRP gene FKRP Respiratory failure. Cardiomyopathy. Calf hypertrophy.2J 2q31 Titin Titin Anterior tibial wasting. No cardiomyopathy reported.2K 9q34.1 POMT-1 POMT-1 Childhood onset. Contractures. Severe mental handicap.2L 9q31 Fukutin Fukutin Infantile onset. Respiratory and cardiac involvement can occur.2M 11p13 Unknown Unknown Exercise induced myalgia.2N 19q13 POMT-2 POMT-2 Variable phenotype. Learning difficulties can occur.*Dysferlin gene mutations are also known to cause Miyoshi Distal Myopathy.Research is moving from gene discovery to molecular therapydate none of the experiments with anti-senseoligonucleotides have altered dystrophinexpression in the heart. The advantages of thisapproach are that, in animal models, they haveproven to be beneficial without any significantadverse effects or unwanted immune response.The limitations are that the beneficial effectsseem to be limited to skeletal muscle and do notinclude the heart. Due to their transient naturerepeated doses are required and the long-termeffects of this are not known. The oligonucleotidesrequired to achieve skipping have to bespecifically synthesised and tailored to the exactdeletion in the dystrophin gene in each patient.This underlines the need to have detailed databases of carefully genotyped patients as anessential requirement for such translationalresearch efforts. Clinical trials employing intramuscularinjections of anti-sense oligonucleotidesin boys with DMD are now underwayin the UK and Europe. 7Viral vectorsAnother approach to restore some functioningdystrophin to the muscle fibre membrane hasbeen to use viral vectors to deliver ‘mini’ or‘micro’ dystrophin genes. Several viral vectorshave been tried but currently adeno-associatedviruses are the vectors of choice because of theirlow pathogenicity in humans and their abilityto cross the vascular endothelium and enterskeletal muscle when injected intravenously. 8Intravenous administration in the mdx mouseof an rAAV6 – microdystrophin produced uniformdistribution of dystrophin not only inskeletal muscles but also in the heart withoutprovoking an immune response. An improvementin skeletal muscle function and prolongedlife expectancy was also observed. 9 Extension ofexperiments to canine models however provokeda profound T-cell mediated immunologicalresponse to the AAV capsid proteins followingIM injection of AAV-mediated transgeneswith inhibition of long-term transgene expression.10,11 A recent study has indicated that transientimmunosuppression may limit the reactionand prevent disruption of transgeneexpression. This was achieved in canines butrequired an aggressive immunosuppressantregime of anti-thymocyte globulin,cyclosporine and mycophenolate. 12The advantages of the viral vector approachare that uniform expression of dystrophin canbe achieved in all skeletal muscles and in thecardiac muscle. There is also prolonged transgeneexpression, although the exact duration isunclear; it is not considered to be infinite. Themajor disadvantage is the possibility of a similarimmunogenic response that is observed incanines being found in humans. Anotherpotential limitation to clinical use is the currentlarge number of viral particles required toproduce a single effective human dose. 13Clinical trials are currently underway in Franceand the USA in limb girdle muscular dystrophy(LGMD) 2C and DMD using viral vectors fortransgene delivery . 14Read through of stop codonsA third approach in the treatment of DMD hasbeen to consider read through of prematurestop codons which could potentially benefit the10-15% of BMD cases with stop codon mutations.Aminoglycosides are known to achievethis by preventing nonsense mediated mRNAdecay leading to increased protein production,but their use is limited by their oto- andnephrotoxicity. This observation however led tothe development of PTC124, a new drug thatselectively promotes read through of prematurestop codons without affecting normal non-prematurestop codons. 15 Trials in the mdx mouseconfirmed increased dystrophin production inall skeletal muscles tested and the heart withaccompanying improvement in muscle functionand lack of adverse events. Clinical trialsare now underway.MyostatinIn 1997 a new member of the transforminggrowthfactor β family of growth and differentiationfactors was discovered. Initially labelledas growth/differentiation factor-8 (GDF-8),studies in mice demonstrated a specific effecton skeletal muscle, with null animals exhibitinga uniform dramatic increase in skeletal musclemass. This negative inhibitor of skeletal musclegrowth therefore became known as myostatin. 16It was predicted that blocking myostatin couldbe used to increase muscle mass in musclewasting diseases. Animal studies tested this byweekly intraperitoneal injections of myostatinantibodies in the mdx mouse for three months.Treated mice displayed a significant increase inskeletal muscle mass and strength, with reduc-ACNR • VOLUME 8 NUMBER 1 • MARCH/APRIL 2008 I 25

MOVING YOUR PATIENTSA STEP CLOSER TO FREEDOMFROM MS DISEASE ACTIVITYUntil now, MS therapies have only beenmoderately effective, reducing the annualisedrate of relapse by about one third.* 1,2Available on the NHS for patients with HighlyActive RRMS, TYSABRI ® offers a proven:81% reduction in annualised relapse ratevs placebo over 2 years (p < 0.001)** 3,464% reduction in the risk of disabilityprogression, sustained for 24 weeks,as assessed over 2 years (p = 0.008)** 3,4* There have been no head to headprospective studies to compareTYSABRI and other MS therapies** Patients with ≥ 2 relapses inprevious year and ≥ 1 Gd+ lesionat baselineReferences:1. Galetta SL, et al. Arch Intern Med2002; 162: 2161–2169.2. Polman CH, et al. NEJM 2006;354(9): 899–910.3. TYSABRI SmPC, Biogen Idec Ltd.4. TY00-032, Data on file.Biogen Idec Ltd.Date of preparation:January 2008TY00-PAN-22968Prescribing information: TYSABRI ® (natalizumab)Presentations: 300 mg concentrate for solution for infusion. Colourless, clear toslightly opalescent solution. Each ml of concentrate contains 20 mg of natalizumab.When diluted, the solution for infusion contains approximately 2.6 mg/ml of natalizumab.Indications: Single disease modifying therapy in highly active relapsing remitting multiplesclerosis for the following patient groups: patients with rapidly evolving severe relapsingremitting multiple sclerosis or patients with high disease activity despite treatment with abeta-interferon. Dosage and Administration: The recommended dosage is 300 mgadministered by intravenous infusion once every 4 weeks. The diluted solution is to beinfused intravenously over 1 hour at a rate of approximately 2 ml/minute and patients areto be observed during infusion and for 1 hour after the completion of the infusion for signsand symptoms of hypersensitivity reactions. TYSABRI ® therapy is to be initiated andsupervised by specialised physicians experienced in the diagnosis and treatment ofneurological conditions, in centres with resources for management of hypersensitivityreactions and timely access to MRI. Continued therapy must be carefully reconsideredin patients who show no evidence of therapeutic benefit beyond 6 months.Patients treated with TYSABRI ® must be given the Patient Alert Card.Contraindications: Hypersensitivity to natalizumab or to any of theexcipients, progressive multifocal leukoencephalopathy (PML);patients with increased risk of opportunistic infections,including immunocompromised patients (including thosecurrently receiving immunosuppressive therapies or thoseimmunocompromised by prior therapies, e.g. mitoxantroneor cyclophosphamide); combination with beta-interferonsor glatiramer acetate; known active malignancies;children and adolescents. TYSABRI ® is notrecommended for use in patients aged over 65 years.Special Warnings and Precautions; CNS: Use of TYSABRI ® hasbeen associated with increased risk of progressive multifocalleukoencephalopathy (PML). Before initiation of treatment withTYSABRI ® , an MRI image of the patients should be available3 months within starting treatment. Patients must be monitoredat regular intervals for any new or worsening neurologicalsymptoms or signs suggestive of PML. If new neurologicalsymptoms occur, further dosing should be suspended until PMLhas been excluded. If the symptoms are suggestive of PML, orif any doubt exists, further evaluation, including MRI scan(compared with pre-treatment MRI) and repeat neurologicalassessments should be considered. Once PML has been excluded, dosing of TYSABRI ® mayresume. If patients develop PML, the dosing of TYSABRI ® must be permanently discontinued.Other Opportunistic Infections: Other opportunistic infections have been reported with use ofTYSABRI ® . If an opportunistic infection is suspected, dosing with TYSABRI ® is to besuspended until such infection can be excluded through further evaluation. Hypersensitivity:Hypersensitivity reactions have been associated with TYSABRI ® , including serious systemicreactions. These reactions usually occur during the infusion or up to 1 hour after completionof infusion. If a hypersensitivity reaction occurs TYSABRI ® must be permanently discontinued.Immunogenicity: In the case of disease exacerbations or infusion related events the presenceof antibodies should be evaluated. Treatment should be discontinued if persistent antibodiesdevelop. Stopping Therapy: If therapy is discontinued be aware that TYSABRI ® haspharmacodynamic effects for up to 12 weeks. Pregnancy and lactation; If patients becomepregnant while taking TYSABRI ® , discontinuation of TYSABRI ® should be considered. Patientsreceiving TYSABRI ® should not breastfeed their infant. General: Physicians must discuss thebenefits and risks of TYSABRI ® therapy with the patient and provide them with a Patient AlertCard. Patients should be instructed that if they develop any infection they should inform theirphysician that they are being treated with TYSABRI ® . Drug interaction: Combination withbeta-interferons or glatiramer acetate is contraindicated. The safety and efficacy of TYSABRI ®in combination with other immunosuppressive and antineoplastics therapies have not beenfully established. Concurrent use of these agents with TYSABRI ® may increase the risk ofinfections including opportunistic infections. No formal interaction studies have beenconducted with TYSABRI ® in humans. Undesirable Effects: The most commonly reportedsymptoms are: Infections and infestations: Urinary tract infection, nasopharyngitis. Immunesystem disorders; urticaria. Nervous system disorders; headache, dizziness. Gastrointestinaldisorders; vomiting, nausea. Musculoskeletal and connective tissue disorder; arthralgia.General disorders and administration site conditions; rigors, pyrexia, fatigue. Other lesscommon events include: hypersensitivity reactions, infusion reactions, PML, otheropportunistic infections, immunogenicity. For further information regarding adverse eventsplease refer to the Summary of Product Characteristics. Legal Classification: POM. Packsize: 1 vial/pack. NHS Price: UK; £1130/vial. Ireland; €1636.85/vial. PackageQuantities: 300 mg/15 ml. Product Licence Number; EU/1/06/346/001. ProductLicence Holder: Elan Pharma International Ltd., Monksland, Athlone, County Westmeath,Ireland. Date of last revision of Prescribing Information: August 2006. Please refer tothe Summary of Product Characteristics for further information.For the UK only: Information about adverse event reporting canbe found at www.yellowcard.gov.uk. Adverse events should bereported to Biogen Idec Ltd., on 08000 286639

Association of British Neurologists TraineesABNT - Message from the ChairWelcome to the first column from the ABNT – anew communicative venture in collaborationwith the ACNR.What is the ABNT?The Association of British Neurologists Trainees (ABNT)is the trainees group of the Association of BritishNeurologists (ABN), and is open to all associate membersof the ABN who are neurology trainees. We work using asystem of regional representatives (elected locally), whoact as the first point of contact for matters relating to neurologytraining in the UK. Policy is devised using a committee,at present with eight positions. Individuals areelected to the committee by ABNT members for a periodof two years, and represent trainees interests on all thecommittees of the ABN, as well as within the BMA andRoyal College of Physicians.What’s happening at the moment?Modernising Medical Careers (MMC)We can’t avoid MMC I’m afraid – this continues to be anenormous problem for neurology trainees nationally.With an average competition ratio of 3:1 for ST3 jobs inthe UK, higher in neurology, and run-through traininghonoured from 2007 in Scotland (and for some of thejobs in England), it’s never seemed more difficult to breakinto higher specialist training.Extensive lobbying (partly by us but mainly from theABN President, and Geraint Rees on behalf of the BMA)has resulted in the allocation of around 15 extra ST3 positionsin England, which are to be reserved for open competition,along with 2/3 of the posts available via vacatedSpR numbers. We know from data that we’ve collectedthat this roughly corresponds to the number of researchfellows seeking re-entry to training, so this year might bea very good year to apply for specialty training. However,with another 25-30 research fellows projected to ‘mature’in 2009/10, and a need to identify consultant vacancies forall the extra training positions created, it’s up to all of usto keep the pressure on for the future.Tooke InquiryThe final report of the Tooke Inquiry was publishedrecently, and although it is broadly supportive of theissues that we think are important, it remains to be seenquite how the Department of Health implements it.Decoupling has been confirmed at ST2/ST3, in linewith the views of many of the medical specialties, and theneed to identify transferable competences has been reinforced,important in specialties like ours that attracttrainees from a wide range of backgrounds.The threat of the sub-consultant grade seems to havebeen downplayed in this final version (compared withprevious drafts), but this remains a threat to the provisionof neurology care in the UK.The commission of a new body for postgraduate medicaleducation (NHS Medical Education England) mayseem like an extra layer of bureaucracy, but this is a modelthat has worked well in Scotland for some years, and mayalso help to safeguard study leave budgets, under threatand essential to our training. Additionally, for specialtiesthat have strong national structures and a common voice(such as ours), it should provide a single portal of entryfor negotiation and accountability.Exit ExamThe Training and Education Committee (TEC) of theABN has prepared a summative assessment in Neurology,similar to the pilot run in 2006, and is proposed to becompulsory for CCT for ST trainees. It was planned thatthe first sitting of this exam would be open in May 2008,although recent last-minute concerns of some of the specialistsocieties allied with the RCP (of which the ABN isone) may delay implementation.Contact Us!We are here to represent you, but can only do thateffectively if we know what you think, or if youthink we’re doing the right things. We can be contactedvia the ABN Office (see correspondenceaddress), or via your regional representative(http://theabn.org/members/ABNT.php). As wellas regular email updates of important and breakinginformation, we post information of theABNT forum (http://www.theabn.org/forum/,accessed via the ABN website). Make sure theABN office has your up to date email address sothat we can contact you.Andrew Kelso is Secretary andActing Chair of the ABNT. He is anSpR in Neurology in Edinburgh,with a special interest in epilepsy.He is also a member of the BMAJunior Doctors Conference AgendaCommittee, Junior DoctorsCommittee and Scottish JuniorDoctors Committee.Correspondence to:Association of BritishNeurologists,Ormond House,27 Boswell Street,London, WC1N 3JZ, UK.Tel. +44 (0)20 7405 4060Web. www.theabn.orgEmail. info@theabn.orgBrainVision UK Ltd wasestablished in 2004. We are adistribution company dedicated tothe provision of technical andsoftware solutions to universitiesand hospitals in the UK andIreland. We represent specialistmanufacturers from around theworld to offer novel and uniqueproduct lines forNeurophysiological andpsychophysiological research andclinical applications.The home in the UKand Ireland forBrainAmp MR SeriesMedoc StimulatorsSupplies and consumablesFor more informationplease contact:-Brain Vision (UK) LtdSuite 4, Zeal House8 Deer Park Rd.London SW19 3GY020 8543 0022www.brainvision.co.uk28 I ACNR • VOLUME 8 NUMBER 1 • MARCH/APRIL 2008

Today, unnecessary seizures restrict 69,000 lives 1The chance to control seizures, not livesABBREVIATED PRESCRIBING INFORMATIONZonegran® (zonisamide)Please refer to the SmPC before prescribing.Presentation: Hard capsules containing 25 mg, 50 mg or 100 mgzonisamide. Indication: Adjunctive therapy in the treatment of adultpatients with partial seizures, with or without secondary generalisation.Dose and administration: Adult: Zonegran must be added to existingtherapy. Initial daily dose is 50 mg in two divided doses. After one week,increase to 100 mg daily and then at one weekly intervals, in 100 mgincrement. Consider two weekly intervals in renal or hepatic impairmentand patients not receiving CYP3A4-inducing agents. Zonegran can beadministered once or twice daily after the titration phase. Withdrawgradually. Elderly and patients with renal or hepatic impairment:Caution (see SmPC). Not recommended in severe hepatic impairment.Children and adolescents under 18 years: Not recommended.Contra-Indications: Hypersensitivity to zonisamide, sulphonamideor any excipient. Pregnancy: Zonegran must not be used duringpregnancy unless benefit justifies the risk, in the opinion of thephysician. Specialist advice should be given to women who are likelyto become pregnant in order to consider the optimal treatment duringpregnancy. Women of childbearing potential must use contraceptionduring treatment and for one month after discontinuation. Lactation:Zonisamide is excreted into breast milk. A decision must be made toeither discontinue Zonegran or stop breast-feeding. Breast-feedingshould not be resumed until one month after stopping Zonegran.Warnings and Precautions: Serious rashes occur in associationwith Zonegran therapy, including cases of Stevens Johnson syndrome.Zonegran contains a sulphonamide group. Serious immune basedadverse reactions are associated with the sulphonamide group, e.g. rash,allergic reaction, major haematological disturbances including aplasticanaemia. Closely supervise and consider discontinuation in patientswith unexplained rash. Cases of agranulocytosis, thrombocytopenia,leukopenia, aplastic anaemia, pancytopenia and leucocytosis havebeen reported. Kidney stones have occurred. Use with caution inpatients with risk factors for nephrolithiasis, including prior stoneformation, a family history of nephrolithiasis and hypercalcuria. Usewith caution in patients treated with carbonic anhydrase inhibitors,e.g. topiramate. Decreased sweating, elevated body temperature andheat stroke have been reported. Patients should maintain hydrationand avoid excessive temperatures. Monitor pancreatic lipase andamylase levels and consider discontinuation in patients with signs andsymptoms of pancreatitis. In cases of severe muscle pain/weakness withor without fever, assess markers of muscle damage, e.g. serum creatinephosphokinase and aldolase levels, and consider discontinuation.Zonegran 100 mg hard capsules contain E110, which may cause allergicreactions. Caution in patients less than 40 kg. In patients with weight lossconsider dietary supplement, increased food intake or discontinuation.Drug Interactions: No clinically relevant pharmacokinetic effectson carbamazepine, lamotrigine, phenytoin, sodium valproate, oralcontraceptives (ethinylestradiol or norethisterone). Insufficient datawith carbonic anhydrase inhibitors, e.g. topiramate. Zonegran wasnot affected by lamotrigine or CYP3A4 inhibitors. Caution with drugsinducing urolithiasis, CYP3A4, N-acetyltransferase, glucuronic acid,or drugs which are P-gp substrates. Side effects: The most commonadverse reactions in controlled adjunctive therapy studies weresomnolence, dizziness and anorexia. Adverse reactions associatedwith Zonegran in clinical studies and post marketing surveillance: Verycommon effects (>1/10): anorexia, agitation, irritability, confusionalstate, depression, ataxia, dizziness, memory impairment, somnolence,diplopia. Common effects (>1/100, 1/1000,

Neurology in IndiaMultiple Sclerosis and Related Demyelinating Disorders in IndiaDemyelinating disorders of the central nervous systemhave assumed significance in recent years inIndia, coinciding with the availability of magneticresonance imaging facilities (MRI) in teaching and privatehospitals in the metropolitan cities of India. Neurologistsare in agreement that they see more cases of multiple sclerosis(MS) recently than they did a decade ago. However itis not yet certain whether this is apparent, as a consequenceof better diagnostic facilities and greater awarenessamong specialists, or real. On the other hand postinfectious demyelinating disorders or acute disseminatedencephalomyelitis (ADEM) are likely to be more commonin view of prevailing conditions.The study of demyelinating disorders of the nervoussystem in India has been limited by many factors.Neurologists in the past have been significantly influencedby Kurtzke’s 1 epidemiological studies which clearlyshowed India among other tropical countries to havea low prevalence for MS. The diagnosis of MS in Indiahas relied heavily on clinical criteria. Lack of facilitiesand or financial constraints have prevented the use ofradiological and other paraclinical tests on a wide scalein diagnosis. Evaluation of optic neuritis in a tropicalsetting is beset with problems. Toxic, nutritional andinfectious causes of optic neuritis are under-diagnosed.Most patients presenting with acute visual loss are evaluatedby ophthalmologists and evaluation of the centralnervous system by imaging and lumbar puncture areseldom considered. Record keeping and long term followup of patients have seen serious limitations in allbut the teaching hospitals and continue to hinder datacollection and analysis of diseases in India, includingdemyelinating disorders. One of the direct fall outs forthis problem is that there are no longitudinal studies onclinically isolated syndromes (CIS) suggestive ofdemyelination in India.In this article a brief overview of demyelinating disordersseen in India is discussed, particularly the prevalenceof MS, the contentious issues of opticospinal MSand neuromyelitis optica, and the available data onimmunogentics of MS. There are many mimics for CNSdemyelinating disorders in a tropical set up which arealso highlighted.Multiple SclerosisThere are no large scale epidemiological studies fromIndia on the incidence and prevalence of Multiple sclerosis.Based on hospital statistics a prevalence of approximately1.33/100,000 was reported by Singhal et al 2 in themid eighties from the west coast of India. An indication tosuggest that more cases are being diagnosed in recenttimes comes from data published from the northwest ofIndia. 3,4 The incidence of hospitalised MS patients seen ata premier teaching hospital, nearly doubled within a spanof 15 years. In the Parsi population of India, Wadia 5observed a prevalence of 26/100,000. Parsis are a closelyknit community which migrated to and settled predominantlyin the west coast of India, between the 7th and 8thcentury and more recently in the 19th century, from thePars province of Iran. Recently a high prevalence of MSwas detected in Isfahan, a province that adjoins Pars inIran, supporting the notion of genetic susceptibility inthis community. 6Is MS seen in India different from that in the west?Results of some of the recent Indian studies 7,8 done in theMRI era have found relatively few differences from thewest, lending support to the theory that the differencesbetween MS in the West and Indian population are moreapparent than real. However what cannot be ignored isthe report of high frequency of optic and spinal cordinvolvement in several Indian studies. 9 In a recentprospective and longitudinal study of CNS demyelinatingdisorders which included 51 patients, Pandit et al 10 found47% of their MS cases to have clinical attacks confined tothe optic nerve and spinal cord. The MRI of brain andspinal cord was indistinguishable from conventional MSin all. A larger prospective study with careful documentationof clinical events supported by MRI imaging of brainand spinal cord is important to settle the issue of opticospinalphenotype of MS and its prominence in IndianMS. The results of one such study, which will be completedby 2010, are awaited. Immunogenetics of MS in Indiahave not been studied in detail. Class II HLA associationstudies were done for the first time recently in 23 MSpatients of non Parsi origin in whom the commonlyreported association was with DRB1*1501 (50%) similarto western studies. 11Neuromyelitis opticaIn earlier studies neuromyelitis optica was diagnosed asa monophasic illness with involvement of both opticnerve and spinal cord and an interval not exceeding amonth between involvement of both sites. 9,12 Most studieshave collectively shown an incidence of 20% or fewercases of neuromyelitis optica defined by these criteria. Apaper by Jain et al 13 has been widely quoted in westernliterature as evidence for high prevalence of NMO inIndia. A careful review of their data of 354 cases of MScollected from nine centres reveal that 33 cases (10.1%)were neuromyelitis optica, defined according to theabove mentioned criteria. Prospective studies 10 using thenewer diagnostic criteria of Wingerchuck have shown anincidence of 9.5% of NMO. Recurrent myelitis, which isprobably a variant of NMO has been reported from theIndia. 14 Whilst it is probable that NMO is seen morecommonly than in western countries, it is certainly notseen in the magnitude reported from other Asian countries,especially Japan.1a 1b 1c 1dDr Lekha Pandit, MD, DM Neurologyis the Professor and head ofdepartment of Neurology at KSHegde Medical Academy,Mangalore, Karnataka, in southIndia. Her areas of interest includeMultiple Sclerosis and post infectiousdemyelinating disorders ofthe nervous system. Currently sheis funded by the government ofIndia for longitudinal and observationalstudies, epidemiology andimmunogenetics of demyelinatingdisorders seen in India.Correspondence to:Dr Lekha Pandit,Professor of Neurology,KS Hegde Medical Academy,Deralakatte,Mangalore - 575018Tel. 91 824 2204471 - Ext 2216Fax. 91 824 2203747Email. panditmng@gmail.comDifferential diagnosis ofwhite matter diseases inthe tropicsFrom left – Figure 1a: A case ofbiopsy proven ADEM, MRI brainwith contrast showing incompletering enhancing lesion with masseffect.Figure 1b: A case ofNeuromyelitis optica, with MRIspine showing longitudinallyextensive transverse myelitis.Figure 1c: An asymmetric whitematter lesion on brain MRI of anHIV positive patient withprogressive multifocalleucoencephalopathy.Figure 1d: A case of Japanese Bencephalitis with bilateralthalamic lesions.30 I ACNR • VOLUME 8 NUMBER 1 • MARCH/APRIL 2008

Neurology in IndiaAcute disseminated encephalomyelitis (ADEM)ADEM is a commonly made diagnosis in tropical countries like Indiawhere infections abound and vaccinations, especially anti-rabies vaccination(Semple’s vaccine) are still freely in use. ADEM as an entityhas no definite diagnostic criteria and has a heterogeneous clinicalpresentation. Most importantly it is a diagnosis of exclusion.Infections, especially HIV, neurosyphilis, Arboviral encephalitides,especially Japanese B encephalitis, which target the basal ganglia andthalamus, tuberculosis of the CNS presenting as isolated parenchymalwhite matter disease, neurosyphilis and cystic infective brain lesionssuch as neurocysticercosis can mimic ADEM. Osmotic demyelinatingsyndrome, especially of the extrapontine type, vitamin B12 deficiencyand occasionally mitochondrial disorders which flare up in the backgroundof systemic infections can cause diagnostic confusion.ConclusionOne of the priorities for specialists working in demyelinating disordersin India is to collect data using uniform criteria, especially whendefining conditions such as opticospinal MS and neuromyelitis optica.Clinical descriptions have to be correlated with MRI data of boththe cord and brain. This is particularly important in the context ofchoosing the appropriate disease modifying agents and while recruitingpatients for clinical trials for drugs with potentially disease modifyingeffect. While it is true that only a fraction of diagnosed patientsin India are able to afford beta interferon or glatiramir acetate, alternatetherapies such as mitoxantrone 15 are being tried with varyingdegree of short term success. The MS society has 4000 registeredpatients and it is estimated that there are approximately 40,000 morein the community. Epidemiological studies are urgently warranted toestablish the burden of disease in the country. In India, issues regardinghealth insurance for MS patients (which is not currently available),subsidies for disease modifying agents, disease awareness andrehabilitation of affected patients are concerns which have to beaddressed jointly by health professionals, MS societies, the pharmaceuticalindustry and governmental agencies. The Multiple SclerosisSociety of India, having over ten branches in Indian cities, is veryactive in arranging social and financial help for the patients and actsas an effective interface between the doctors and the patients.References1. Kurtzke JF. Epidemiology of multiple sclerosis. In: Koetssier JC, edtor. Handbook ofclinical neurology. Vol.3 Demyelinating diseases. Amsterdam: Elsevier Science1985;259-87.2. Singhal BS. Multiple Sclerosis-Indian experience. Ann Acad med Singapore1985;14:32-6.3. Chopra JS, Radhakrishnan K, Sawhney BB et al. Multiple sclerosis in North-westIndia. Acta Neurol Scand 1980;62:312-21.4. Syal P, Prabhakar S, Thussu A, Sehgal S, Khandelwal N. Clinical profile of multiplesclerosis in north-west India. Neurol India 1999;47:12-7.5. Wadia N, Bhatia K. Multiple sclerosis is prevalent in the Zorastrians (Parsis) of India.Annals of Neurol 1990;28:177-9.6. Etemadifar M, Janghorbani M, Shaygannejad V, Ashtari F. Prevalence of MultipleSclerosis in Isfahan, Iran. Neuroepidemiol 2006;27:39-44.7. Bansil S, Singhal BS, Ahuja GK et al. Comparison between multiple sclerosis in Indiaand the United States: A case control study. Neurology 1996;46:385-7.8. Bhatia M, Behari M, Ahuja GK. Multiple sclerosis in India: AIIMS experience. J AssocPhysicians India 1996;44:765-7.9. Singhal BS, Wadia NH. Profile of multiple sclerosis in the Bombay region - on the basisof critical clinical appraisal.J Neurol Sci 1975;26:259-70.10. Pandit L, Shetty R, Bhat IG, Misri Z, Hegde S. Spectrum of Multiple Sclerosis andrelated demyelinating disorders in India in the background of revised diagnostic criteria.Ann Ind Acad Neurol 2007;10:(S2)44-5.11. Kankonkar S, Jeyanti G, Singhal BS, Shankarkumar U. Evidence for novel DRB1*15allele association among clinically definite multiple sclerosis patients from Mumbai,India. Hum Immunol 2003;64:478-82.12. Pandit L, Subramanya R and Rao SN. Multiple sclerosis in coastal Karnataka. NeurolIndia 1993;41:143-6.13. Jain S, Maheshwari MC. Multiple Sclerosis: Indian Experience in the last thirty years.Neuroepidemiol 1985;4:96-107.14. Pandit L, Rao SN. Recurrent Myelitis. J Neurol Neurosurg Psychiatry 1996;60:336- 8.15. Mehndiratta MM, Phul P, Garg S. Mitoxantrone a disease modifying agent in multiplesclerosis. GB Pant experience. Ann Ind Acad Neurol 2007;10:(S2)53.FULLINSTITUTE OF NEUROLOGYin association with theNational Hospital for Neurologyand Neurosurgery,Queen Square, London WC1Short Courses12th-23rd May 2008Sleep(12 May)Neuro-ophthalmology(13 May)Movement Disorders(14 May)*Statistical Parametric Mapping (15, 16& 17 May)Neurosurgery(19 May)Neuroanatomy of the Basal Forebrain (20 May)Dementia(21 May)Stroke(22 May)Neuro-oncology(23 May)* another SPM course will run in October 2008Course fee £175 per day(£125 for 5 or more days;£150 per day for clinical trainees;£125 per day student rate).£600 for the three-day SPM course.(to include morning and afternoon refreshments,but not lunch)For further details please contact:The Education UnitInstitute of NeurologyNational Hospital for Neurology and NeurosurgeryQueen Square, London WC1N 3BGTel: 020 7692 2346 Fax: 020 7692 2345Email: J.Reynolds@ion.ucl.ac.ukwww.ion.ucl.ac.ukThe Institute of Neurology promotes teachingand research of the highest quality inneurology and the neurosciencesACNR • VOLUME 8 NUMBER 1 • MARCH/APRIL 2008 I 31

Neurosurgery ArticleThe National Institute of Clinical Excellence Head InjuryGuidelines: A Summary to Assist ImplementationThe National Institute for Clinical Excellence guidelinesaim to improve the quality of healthcare. Theyprovide evidence based recommendations for thetreatment and care of patients with specific disorders. Theguidelines can be used to develop standards of care andprovide a useful tool for auditing clinical practice. In2003, NICE first published guidelines for the managementof head injured patients (Clinical Guideline 4). 1 InSeptember, 2007, an extensive update including amendmentsto existing advice and new recommendations waspublished (CG 56). 2 The guidelines and the update werecompiled by a large panel of interested parties after anexhaustive review of the available literature. This paperaims to summarise the features of head injury care as recommendedby the guidelines.The objective of care for head injured patients is toensure timely recognition and treatment of significantinjuries in an appropriate healthcare setting. The NICEguidelines have led to a shift in management from an“admit and observe” strategy to a “diagnose and decide”approach. The guidelines provide advice on pre-hospitalmanagement, assessment in the emergency department,investigation for brain and cervical spine injuries (seeBox 1 – CT head imaging in adultsCT Head Imaging in adultsImmediate CT (within 1 hour of request):GCS 30 minAge >65 years if any amnesia or loss of consciousnesssince the injuryDangerous mechanism if any amnesia or loss ofconsciousness since the injury (e.g. pedestrian orcyclist hit by motor vehicle; ejected vehicleoccupant; fall >1m or 5 stairs)Box 2 – CT head scanning in childrenCT Head in Children (under 16):Age 5 minSeizure (with no history of epilepsy)Suspicion of open or depressed #Tense fontanelleSigns of basal skull #Focal neurological deficitBoxes 1, 2 and 3), recommendations for referral andtransfer to a neurosurgical unit (see Box 4) and guidelinesregarding the admission, care and discharge of braininjured patients (see Box 5).The key features of the guidelines include the following:• Head injured patients should be transported to a facilitywith the resources to resuscitate, investigate andprovide initial management of multiple injuries. Theinitial assessment and management should follow theprinciples of the Advance Trauma Life Support system.For patients with a GCS 3-8 the paramedic crewshould make a stand-by call to ensure that appropriatepersonnel are available to treat the patient at thereceiving hospital.Box 3Cervical Spine ClearanceIf undertaking urgent head CT the cervical spineshould also be scannedIn patients who are alert it is safe to fully examinethe neck if:• Simple rear end collision• Patient has been ambulant at any time since injuryand there is no midline tenderness• Patient can sit comfortably in emergencydepartment• Patient presents with delayed onset of neck painRequests for cervical spine radiographs in adultsand childrenFor adults and children age 10-16 years use AP,lateral and odontoid peg viewsFor children age 1m or 5 stairs; axial load; highspeed RTA; ejection from vehicle; rollover;bicycle collision; recreational vehicle)• Cervical spine status required e.g. pre-surgeryCT Cervical Spine requests in adults and children 10years or olderCT Cervical Spine should be requested if:• GCS

Neurosurgery Article• The spine should be immobilised for allpatients with GCS < 15, any history of neckpain or tenderness, any extremity paraesthesia,any focal neurological deficit or any othersuspicion of a cervical spine injury.Immobilisation should remain in place untila full assessment has been conducted (Box 3).• Immediate clinical assessment should beconducted in the Emergency Departmentfor all patients with a GCS 4 hours• Deterioration in GCS after admission• Progressive focal neurological signs• Seizure without full recovery• CSF leak• Definite or suspected penetrating injuryThe South West Neurosurgery Centrerecommends that all patients not obeyingcommands after resuscitation and imagingare discussed with on-call neurosurgical SpR.Transfer of Patients to the NeuroscienceUnit• All patients with GCS 13 kPa and PaCO2 4.5-5.0 kPareported improvements in outcome can beachieved across the board.5. Robust clinical decision tools need to bedeveloped to help predict those patientswith mild injury who are likely to developlong term sequelae.ConclusionIn summary, the NICE Head Injury Guidelinesprovide the many clinicians involved in the careof brain-injured patients with a sound foundationupon which to build patient care. The challengefor neurosurgeons is to improve the efficacyof management for patients with intracranialmass lesions and to conduct further work toestablish the best pathway of care for patientswith diffuse brain injury. Neurosurgeons are wellplaced to aid national guideline implementation.References1. CG4. Head injury: triage, assessment, investigation andearly management of head injury in infants, children andadults. http://www.nice.org.uk/nicemedia/pdf/headinjury_full_version_completed.pdf2. CG56. Head injury: triage, assessment, investigation andearly management of head injury in infants, children andadults. http://www.nice.org.uk/nicemedia/pdf/CG56NICEGuideline.pdf3. ERNIE Head injury. http://www.nice.org.uk/usingguidance/evaluationandreviewofniceimplementationevidenceernie/searchernie/resultsummary.jsp?o=109184. Sultan HY, Boyle A, Pereira M, Antoun N, Maimaris C.Application of the Canadian CT head rules in managingminor head injuries in a UK emergency department:implications for the implementation of the NICE guidelines.Emerg Med J 2004;21:420-5.Box 5 – Criteria for admission, observation,medical review and dischargeAdmission Criteria• New, significant abnormalities onimaging• GCS

Controversies in NeurologyNICE/SCIE Dementia Guidance:Time to ReconsiderIn November 2006, the National Institute for Healthand Clinical Excellence and the Social Care Institutefor Excellence (NICE/SCIE) jointly published guidanceon the identification, treatment, and care of peoplewith dementia. 1 This document has been somewhat overshadowedby the concurrently issued recommendationsof NICE regarding the use of cholinesterase inhibitors(ChEIs) and memantine for the treatment of Alzheimer’sdisease (AD). 2,3 However, as NICE/SCIE guidance isimplemented by commissioning bodies, its implicationsare being brought into sharper focus since, though titled‘guidance’, adherence is required rather than optional, andwill be used as a marker of a Trust’s ‘performance’.The system of NICE guidance in various domains ofmedical practice is in general to be welcomed. It is helpfulto have available a systematic approach to diseasesand treatments in order to ensure that practising cliniciansare aware of best practice. However, in a subject ascomplex as medicine, where patients do not always fitneatly into simply defined problems, guidelines may, likeall other medical interventions, have unintended adverseeffects as well as possible benefits. Often what is offeredas guidance becomes de facto a prescription of rigidlydefinedlimitations against which Trusts are judged.In the specific case of dementia, the aspiration toeffect a seamless transition between the medical/diagnosticand social/pastoral aspects of patientcare, to bridge the health care/social care divide, sooften previously a stumbling block, is one that allinvolved clinicians – old age psychiatrists, geriatricians,neurologists – will share; likewise patients, families, carersand patient organisations. However, the care pathwayis not so linear as the NICE/SCIE guidance seems toenvisage, such that the required service restructuringruns the risk of disadvantaging patients who fall outsidethe ‘typical’. In particular, the proposal that there be ‘asingle point of referral’ for all suspected cases of dementia,to wit generic ‘memory assessment services’ whichmay be provided by a ‘memory assessment clinic or bycommunity mental health teams’ (p10), requires carefulexamination.Dementia is not a unitary, homogeneous conditionbut a syndrome with many different causes. Althoughneurodegenerative disorders in which cognitive impairmentand dementia are the predominant features, theso-called primary dementias, account for the majorityof cases, in particular AD, many other neurological andmedical conditions may present with cognitive complaintsand/or cognitive decline, including cerebrovasculardisease, Parkinson’s disease and parkinsonian syndromes,multiple sclerosis, epilepsy syndromes, motorneurone disease, Huntington’s disease, prion diseases,HIV, certain autoimmune, endocrinological and inflammatoryconditions, and structural lesions such astumours, subdural haematoma and hydrocephalus, theso-called secondary dementias. 4,5 Hence, treatment ofdementia syndromes extends well beyond simply ChEIs,and the inputs required for patients as disparate as, say,an 80-year-old with AD and a 40-year-old with priondisease or HIV, are manifestly not the same.In dementia of early onset (arbitrarily defined asoccurring before 65 years of age), which recent estimatessuggest accounts for 2.2% of all dementia cases, 6the differential diagnostic possibilities become evenbroader, 4,7 including an increased frequency of genetically-determineddiseases such as familial AD, frontotemporaldementia, Huntington’s disease, andCADASIL. It was previously acknowledged in a jointreport from the Royal College of Psychiatrists and theAlzheimer’s Disease Society that patients with earlyonsetdementia and their families have special requirementsand that specialist resources, under the auspicesof neurologists, psychiatrists, or jointly in multidisciplinaryteams, are required to address them, 8 conclusionswith which NICE/SCIE seem to agree (“specialist multidisciplinaryservices should be developed”, p13).Most ‘memory assessment services’ and ‘communitymental health teams’ are under the auspices of old agepsychiatrists. It is not clear whether these clinicians havethe appropriate training to diagnose and manage neurologicalconditions, some of which are not even acknowledgedas possible causes of dementia in the Diagnosticand Statistical Manual of Mental Disorders (e.g.MND). 9 Furthermore, even so-called primary psychiatricdisorders associated with cognitive decline, such asdepression and schizophrenia, may be referred to neurology-ledcognitive clinics for assessment. A recentstudy showed that not less than 20% of referrals to sucha clinic over a 5-year period were from psychiatrists. 10The diagnosis of dementia often requires specialistinvestigations, including structural (CT, MRI) andfunctional (SPECT, PET) brain imaging, cerebrospinalfluid studies, neurogenetic testing, neurophysiologicalstudies (EMG, EEG) and sometimes tissue biopsy(brain, bone marrow, skin, rectum) as well as detailedneuropsychological assessment. Some of these areacknowledged by NICE/SCIE (p24-26). Incorporationof such biomarkers into diagnostic criteria is now recommendedfor AD. 11 Again it is not clear whether, outsidespecialist centres, a ‘single point of referral’ will beequipped to provide these services.The heterogeneity and complexity of the dementiasyndrome at the clinical, aetiological, therapeutic andprognostic levels 4,7 argues the need for a flexible yetDr Mark Doran is a consultantneurologist with an interest incognitive disorders at the WaltonCentre for Neurology andNeurosurgery in Liverpool. Hereceived neurological training atQueen Square, the Hammersmith,and Cambridge before beingappointed in Liverpool, where hefounded the Cognitive FunctionClinic at the Walton Centre in theearly 1990s.Dr Andrew Larner is the editor ofour Book Review Section. He is aConsultant Neurologist at theWalton Centre for Neurology andNeurosurgery in Liverpool, with aparticular interest in dementia andcognitive disorders. He is also anHonorary Apothecaries' Lecturerin the History of Medicine at theUniversity of Liverpool.Correspondence to:AJ Larner,Cognitive Function Clinic,Walton Centre for Neurology andNeurosurgery,Liverpool, L9 7LJ, UK.Tel. +44 (0)151 529 5727Fax. +44 (0)151 529 8552Email. a.larner@thewaltoncentre.nhs.ukThe problem lies in giving the impression, which maybe acted upon by commissioning bodies, that this is auniversal approach to dementia irrespective of age orother attendant neurological disorder34 I ACNR • VOLUME 8 NUMBER 1 • MARCH/APRIL 2008

Turn to page 16 for the history of the Association of British NeurologistsControversies in Neurologystructured approach to case management.Dementia is neither a neurological nor a psychiatricdisease – neurology and psychiatrybeing cultural artefacts and political constructs– but a brain disease. A “single point ofreferral”, with its connotations of “one size fitsall” – so definitively rejected in the sphere ofeducation policy – will not suffice. An integratedcare pathway which encompasses thevarious clinical disciplines with an interest indementia has been proposed. 12The NICE/SCIE guidance is sensible withregards to the provision of care services forelderly people with dementia of neurodegenerativeand cerebrovascular aetiology. Theproblem lies in giving the impression, whichmay be acted upon by commissioning bodies,that this is a universal approach to dementia(“recommendations that apply to all types ofdementia” p4) irrespective of age or otherattendant neurological disorder.Whatever the original intentions ofNICE/SCIE, the consequence of implementationof their guidance by commissioning bodieswho may know no better is to marginalise,if not abandon altogether, neurological inputinto the diagnosis and management ofdementia syndromes (neurologists are mentionedonly once in the document, in the contextof initiation of pharmacological therapyfor the cognitive symptoms of AD, p30). Webelieve that such a prescription will inevitablylead to a reduction in the quality of serviceprovision for this vulnerable group ofpatients.These oversights are easily understandable– wittingly or otherwise, there was no neurologiston the Guideline Development Group orReview Panel – and easily rectified in futureguidance. In the meantime, we suggest confusionmay be avoided by NICE/SCIE explicitlyre-titling their current guidance as applicableto typical dementias in adults over age 65.This would alert clinicians to the need forcritical evaluation of all individuals withdementia or cognitive decline, irrespective ofage, so that the highest standards of medicalcare provision are available to all.References1. National Institute for Health and ClinicalExcellence/Social Care Institute for Excellence.Dementia: supporting people with dementia and theircarers in health and social care. NICE ClinicalGuidance 42. London: National Institute for Healthand Clinical Excellence, 2006(www.nice.org.uk/cG042).2. National Institute for Health and Clinical Excellence.NICE technology appraisal guidance 111. Donepezil,galantamine, rivastigmine (review) and memantine forthe treatment of Alzheimer’s disease. Includes a reviewof NICE technology appraisal guidance 19. London:National Institute for Health and Clinical Excellence,2006.3. Day M. NICE emphasises social care for people withdementia. BMJ 2006;333:1085.4. Hodges JR (ed.). Early-onset dementia: a multidisciplinaryapproach. Oxford: Oxford University Press, 2001.5. Kurlan R (ed.). Handbook of secondary dementias.New York: Taylor & Francis, 2006.6. Alzheimer’s Society. Dementia UK. A report into theprevalence and cost of dementia prepared by thePersonal Social Services Research Unit (PSSRU) at theLondon School of Economics and the Institute ofPsychiatry at King’s College London, for the Alzheimer’sSociety. London: Alzheimer’s Society, 2007.7. Doran M. Diagnosis of presenile dementia. Br J HospMed 1997;58:105-10.8. Royal College of Psychiatrists/Alzheimer’s Society.Services for younger people with Alzheimer’s disease andother dementias. London: Royal College ofPsychiatrists/Alzheimer’s Society, 2006.9. American Psychiatric Association. Diagnostic and statisticalmanual of mental disorders, 4th edition, textrevison (DSM-IV-TR). Washington: AmericanPsychiatric Association, 2000.10. Larner AJ. Neurologists still have a role in the dementiacare pathway. Clin Med 2007;7:528-9.11. Dubois B, Feldman HH, Jacova C, et al. Research criteriafor the diagnosis of Alzheimer’s disease: revising theNINCDS-ADRDA criteria. Lancet Neurol2007;6:734-46.12. Larner AJ. Integrated care pathways in dementia: achallenge to National Institute for Health and ClinicalExcellence/Social Care Institute for Excellence guidance.J Integrated Care Pathways 2007;11:in press.Read ACNR free on-lineYou can read every issue of ACNR free of chargeby downloading PDFs from our website atwww.acnr.comSimply register by sending an email toRachael@acnr.co.uk, and we will notify youevery two months when new issues areuploaded to the site.Do you have an idea for an article?Are you organising an event,can we help with publicity?Would you like to review a book,perhaps you’re writing one?Please contactPatricia McDonnellACNR(Advances in Clinical Neuroscience & Rehabilitation)T/F. +44 (0)288 289 7023E. Sales@acnr.co.ukwww.acnr.comACNRISSN 1473-9348 Volume 8 Issue 1 March/April 2008www.acnr.co.ukAdvances in Clinical Neuroscience & RehabilitationPaul ReadingThe Neurological Sleep Clinic – Part 1 – The Sleepy PatientMaurice Curtis, Andrew Naylor, Richard FaullManipulation of Neural Stem Cells as a Rehabilitative TherapyEmma Matthews, Mike HannaPossible New Treatments in Muscular DystrophyConference News • Journal Reviews • Book Reviews • Diary of EventsACNRISSN 1473-9348 Volume 7 Issue 5 November/December 2007www.acnr.co.ukAdvances in Clinical Neuroscience & RehabilitationTom Hayton, Julian Furby, Raj KapoorThe Demyelinated AxonAngela Vincent, Christian BienParaneoplastic Neurological DiseasesStephen Casper“Then why not an Association of British Neurologists?”:British Neurologists and the Founding of an Elite Medical SocietyConference News • Journal Reviews • Book Reviews • Diary of EventsACNRISSN 1473-9348 Volume 7 Issue 5 November/December 2008www.acnr.co.ukAdvances in Clinical Neuroscience & RehabilitationJohn SteinDyslexiaPhil CowenTreatment of Major Depression: Beyond Generalised Serotonin PotentiationLouis LemieuxEEG, FMRI and Their Combination in the Study of EpilepsyConference News • Journal Reviews • Book Reviews • Diary of EventsACNRISSN 1473-9348 Volume 7 Issue 4 September/October 2007www.acnr.co.ukAdvances in Clinical Neuroscience & RehabilitationJoseph Anderson, Phil Smith‘Collapse ? Cause’ - Avoiding Misdiagnosis in FallsSimon Baron-CohenAutismChristine Collin, Andrew HanrahanWilson’s Disease - A Rehabilitation PerspectiveConference and Society News • Journal Reviews • Diary of EventsACNR • VOLUME 8 NUMBER 1 • MARCH/APRIL 2008 I 35

Roundtable DiscussionCognitive Function in Multiple Sclerosis –A Roundtable DiscussionIn June 2007, a panel of healthcare professionals with astrong interest in and/or practical experience of cognitiveproblems in people with multiple sclerosis (MS)met to explore the potential for routine screening of cognitivefunction in the clinical management of people withMS. The purpose would be to examine whether changesin cognitive function were significantly affecting a person’slife. This paper provides a summary report of thegroup’s discussion and views on cognitive function andscreening, including the measures being used, theirappropriateness for use in MS clinical services and thepotential for a measure that encourages healthcare professionalsto monitor cognitive function routinely.Cognitive dysfunction affects up to 65% of peoplewith MS. 1 It threatens confidence and self-esteem andcan disrupt employment, social interactions, and dailyroutines. 2,3 Symptoms of cognitive dysfunction, whichcan cause significant upset for patients and families, aresubtle and complex and therefore, can be challenging toidentify. They may produce memory decline whichaffects 40-60% of individuals, 4 reduction in: new learningcapacity, 1 verbal working memory, 5 visual memoryand auditory memory. 6 Other changes include dysexecutivesymptoms, with a reduced ability to engage in testing,7 attention deficits, 8 reduction in processing speed 9and intellectual decline. 10 There was a view during thediscussion that many people with MS are unaware ofthe meaning of cognitive changes and may confusethem with symptoms of mental health problems.Rehabilitation and cognitive declineRehabilitation can be regarded as a problem solving andeducational process aimed at reducing the level of disabilityand increasing the level of independence.However, this is always within the limitations imposedboth by available resources and by the underlying diseaseprocess. 11 It encompasses the ability to learn newTable A: Reasons for cognitive screening• To provide a baseline as a measure of deterioration• To give reassurance• To inform how a multidisciplinary team should work witha patient.• To inform on intervention/medical treatment• Cognitive Rehabilitation- Individual- Groups- Carer Support/education• Research• Highlighting to commissioners the need for resources andcoherent psychological services to address the variousproblems arising as a result of cognitive impairment.healthcare providersshould offer periodicscreening and/orassessment of cognitivefunctioninformation and adapt to new ways of functioning,which utilises feedback, taking into account cognitiveability. Therefore, cognitive and related impairments arelikely to have an impact on rehabilitation when domainsof cognition such as communication, recall, processingspeed, problems in abstract thinking, coping strategies,mood and relationships are affected.According to a recent observation of one of the groupmembers, approximately 90% of people with MS whowere admitted to a rehabilitation centre agree with thefollowing statements to some degree: ‘I begin to talk andforget what I was going to say’ and ‘I have difficultyfinding words when trying to explain things’. 11 However,when the same patients were asked if they had speechproblems, there was a lack of awareness of such problems,suggesting that cognitive impairment may limitthe strategies which can be adopted to cope with illness,such as problem solving (if working memory isimpaired) and organisation, if there are dysexecutiveproblems. Given that people with MS deteriorate, learningto cope and adjust is an important part of maintaininga person’s quality of life. From the group’s experienceit was felt that people generally cope better if theyfeel they have control over what happens to them and achoice in their lifestyle. 11Mood changes are common in people with MS, withup to 42% reported to suffer significant depression. 12Depression itself can affect short term memory, learningand attention 12 and anxiety may also impair attention14 but the relationship between cognition and moodis complex. One viewpoint at the meeting was that aperson’s lack of expression of distress could be due tocommunication or cognitive problems.The group generally felt that there is a relationbetween fatigue and cognitive problems and that recognisingthese links, treating the fatigue and/or associateddepression, may reduce the impact of cognitive declineon daily life. 15 Developing and using strategies for dealingwith cognitive problems, such as memory impairment,may also help improve general well-being.Cognitive impairment may put a strain on thecarer/patient relationship. For example forgetting,Working PartyJane Bradshaw,Lead Nurse Specialist inNeurology, Norfolk PCT.Nadina Lincoln,Professor of Clinical Psychology,University of Nottingham,Nottingham.Chris Manning,Chief Executive, Primhe, London.Susan Mitchell,GP Lead for NeurologyPro-Active Care Team(NeuroPACT), Surrey.Dawn Reeve,Clinical Neuropsychologist,Chatsworth RehabilitationCentre, NottinghamshireHealthcare NHS Trust, Mansfield.Anita Rose,Clinical Psychologist,Walton Centre of Neurology andNeurosurgery, Liverpool.Jane Ware,MS Specialist Nurse,Wessex Neurological Centre,Southampton General Hospital.Margaret White,Speech and Language Therapist,Clinical Lead for ProgressiveDisorders, ChatsworthRehabilitation Centre,Mansfield Community Hospital.Adam Zeman,Professor of Cognitive andBehavioural Neurology,Peninsula Medical School, Exeter.Publication of this article has been made possible by an unrestricted educational grant from Biogen Idec36 I ACNR • VOLUME 8 NUMBER 1 • MARCH/APRIL 2008

Roundtable Discussionrepeating one-self and confusion can lead tothe need to work with patients and their carerson ways to manage the cognitive problemstogether. Executive problems may also affectbehaviour, leading to difficulties in relationshipswith staff and others.Table B: Neuropsychological Tests included in the MACFIMSTestBenton Judgement of Line Orientation TestControlled Oral Word Association TestCalifornia Verbal Learning Test, Second EditionBrief Visuospatial Memory Test – RevisedPaced Auditory Serial Addition TestSymbol Digit Modalities TestDelis Kaplan Executive Function SystemMonitoring cognitive function inclinical practiceThe experience of practicing ClinicalNeuropsychology within a Neuro-rehabilitationService highlighted several practical reasonswhy assessment of cognitive function isnot routinely performed, including the factthat tests are long and not standardised forpeople with MS, the limited availability ofassessments for people with physical difficulties,including poor vision, communicationproblems and fatigue, and lack of resources.The rationale for cognitive assessment needsto be established and consideration needs tobe given to when, where, why and how tocarry out cognitive assessment as well bywhom. One view was that it is important totake into consideration that screening someonehas the potential to unnecessarily highlighta cognitive problem.It has been recommended that healthcareproviders should offer periodic screeningand/or assessment of cognitive function, 16 asdeficits may not always be reported ornoticed. For example, The NICE guidelinesstate: ‘Any person with MS complaining ofcognitive problems… should be offered a formalcognitive assessment’ and yet it is an areathat is not assessed routinely. 17 Early screeningwould be helpful and it may be useful to askquestions both to elicit information and alsoto give reassurance. Patients are often relievedto be told that cognitive changes they may beexperiencing, are not dementia and that theyare not ‘going mad’.At the meeting, several reasons why screeningfor changes in cognitive function may behelpful were raised (Table A). Although consultationrates have been found to increase ascognitive function worsens, the generally heldview was that once an appropriate care packageis put in place the rate of consultationlessens thereafter. It is feasible that earlyrecognition and intervention in cognitive dysfunctioncan have a positive impact, becauseDomainVisual/Spatial PerceptionGenerative Verbal FluencyAuditory/Verbal Learning and MemoryVisual/Spatial Learning and MemoryProcessing Speed and Working MemoryProcessing Speed and Working MemoryExecutive Functionpeople are likely to be able to stay in work forlonger and maintain relationships for longer.Early recognition of cognitive functiondecline enables early intervention. Oncememory loss becomes too impaired, teachingstrategies to cope become of little use.The most appropriate format for cognitiveassessment remains unclear. Asking specificquestions about problems at work, in daily lifeand hobbies may be beneficial. However, askingglobal questions such as “Are you havingmemory problems?” can be inappropriate asthey may lead to false positives and conflictinginformation. Subtle enquiry with a patientor carer may educate patients and carers,highlight concerns and reduce anxiety.Although the necessity to perform in-depthassessments at the point of diagnosis remainsdebatable, performing in-depth neuropsychologicalassessments soon after a diagnosis ofMS may sometimes be helpful especially whenemployment is threatened, there are difficultieswith independence in the home or educationproblems.Routine screening for cognitivedysfunction in MSTo encourage cognitive screening of peoplediagnosed with MS, the measure should ideallybe brief, sensitive, and specific, with a clear cutoffpoint (i.e. provide a score to indicate thatfurther evaluation is required) and be independentlyvalidated. It should also be able toevaluate specific cognitive domains including;memory, attention, executive abilities andspeed of processing. It should be independentof mood, fatigue and disability. It is clear thatthere is a drive for something brief and whichdoes not necessarily require the involvement ofa neuropsychologist, although it is importantnot to overemphasise the need to save time.Detailed assessment of cognitive functionrequires the appropriate time. It is difficult toknow from the outset which cognitive functionsare impaired and consequently measuresof most cognitive domains should be included.Two main strategies have been used toassess cognitive function in people with MS.These are self-report measures e.g. MSNQ(MS Neuropsychological Questionnaire), 18and short batteries of cognitive tests.Discussion focussed on the MSNQ, whichhad general appeal because it is short and easyto administer. There are only 15 questionsrated on a 5 point scale. It is non-invasive,standardised and validated. 18 However, withthe self report form of the MSNQ, a replicationstudy found the specificity to be only 0.6,with false negatives seen in people with lowmood. 19 The self report version was highlycorrelated with mood and not significantlycorrelated with cognitive tests. 19 The informantMSNQ shows higher sensitivity and speci-Publication of this article has been made possible by an unrestricted educational grant from Biogen IdecACNR • VOLUME 8 NUMBER 1 • MARCH/APRIL 2008 I 37

Roundtable DiscussionIdentification of cognitive deficits in people with MS requiresgreater emphasisficity than the self report version 19 and is significantlycorrelated with cognitive tests andnot with mood. Self report and informantmeasures can lead to conflicting results, buteach provides useful information.Cognitive tests have the advantage of standardisationand are usually independent ofmood. The Addenbrookes CognitiveExamination – Revised (ACE-R), is used inclinical practice to monitor cognitive functionand takes between 10 minutes to half an hour.Although the ACE-R has not been validatedfor use with MS patients it had been used by amember of the group. It is not sensitive tomild cognitive decline. There are timed elementswithin the assessment, which is anadvantage, as slowness is a common problemin MS patients. 13 The ACE-R includes a drawingwhich the group felt may limit the completionof the assessment, although it isunlikely to misclassify patients on the basis ofone item.Undue length is a concern with some cognitivetest batteries, a disadvantage in fatiguedpatients especially. They take from 20 minutes,for example for the MMSE, up to 90minutes for the MACFIMS (MinimumAssessment of Cognitive Function in MS),because they assess a number of differentdomains (Table B). 19 Furthermore, some testsrequire motor skills that limit their applicabilityto severely physically disabled patients.Other drawbacks include poor specificity andsensitivity; and the batteries are not alwaysrelevant to the usual pattern of cognitiveimpairment in people with MS,There have been attempts to compare theeffectiveness of the tests. Aupperle et al 20 foundthat the sensitivity of the NeuropsychologicalScreening Battery for Multiple Sclerosis (NPS-BMS) and the Screening Examination forCognitive Impairment (SEFCI) was greaterthan the Repeatable Battery for theAssessment of Neuropsychological Status(RBANS). The best sensitivity was achievedfrom a combination of the NPSBMS andSymbol Digit Modalities Test (SDMT). Theysuggested that if one test is to be used theSymbol Digit Modalities Test (SDMT) may bethe most sensitive.Conclusion and summaryThe identification of cognitive deficits in peoplewith MS requires greater emphasis.However, to introduce cognitive assessmentinto routine clinical management is challenging.One approach may be to develop a simplemeasure that incorporates questions pertainingto cognitive function while at the sametime going over the main challenges that aperson with MS has to cope with. If at this initialscreen a decline in cognitive function isidentified, then further cognitive screening(e.g the MSNQ) could be implemented. Thedevelopment of a measure would help to raiseawareness of cognitive problems and wouldguide professionals when attempting to determineoverall priorities for the patient, carerand healthcare professionals. It should therefore,be designed to monitor the patient’s,carer’s and healthcare professional’s perspectives.Enabling patients, professionals and carersto contribute equally to the assessment ofcognitive function may help to provide amore balanced perspective. This balancedapproach could encourage a discussion ofareas where the patient and carer would wishto concentrate, but also it could help thehealthcare professionals to identify otherareas of concern. It is therefore vital that anyscreening or assessment should be patient ledand done within the context of a professionalrelationship.References1. Rao SM, Leo GJ, Ellington L, Nauertz T, Bernardin L,Unveragt F. Cognitive dysfunction in multiple sclerosis. I.Frequency, patterns and prediction. Neurology.1991;41:685-91.2. Amato MP, Ponziani G, Pracucci G, Bracco L, SiracusaG, Amaducci L. Cognitive impairment in early-onsetmultiple sclerosis: pattern, predictors, and impact oneveryday life in a 4-year follow-up. Arch Neurol1995;52:168-72.3. Rao SM, Leo GJ, Ellington L, Nauertz T, Bernardin L,Unveragt F. Cognitive dysfunction in multiple sclerosis. II.Impact on employment and social functioning.Neurology. 1991;41:692-6.4. Grafman J, Rao S, Litvan I. Disorder of memory. In RaoSM (ed) Neurobehavioral aspects of multiple sclerosis.Oxford., New York, 1990;pp102-17.5. Rao SM, Grafman J, DiGiulio D et al. Memory dysfunctionin multiple sclerosis: its relation to working memory,semantic encoding and implicit learning.Neuropsychology 1993;7:364-74.6. Brassington, JC, and Marsh, NV. Neuropsychologicalaspects of multiple sclerosis. Neuropsychology Review.1998;8:43-77.7. Rao SM. Neuropsychology of multiple sclerosis: a criticalreview. J Clin Exp Neuropsychol 1986;8:503-42.8. Beatty WW and Monson N. Picture and motor sequencingin multiple sclerosis. J Clin Exp Neuropsychol1994;16:165-72.9. Diamond BJ, DeLuca J, Kim H, Kelley SM. The questionof disproportionate impairments in visual and auditoryinformation processing in multiple sclerosis. J Clin ExpNeuropsychol 1997;19:34-42.10 Ron MA, Callanan MM, Warrington EK. Cognitiveabnormalities in multiple sclerosis: a psychometric andMRI study. Psychol Med. 1991;21(1):59-68.11. White M. Paper in preparation.12. Jefferies K. The neuropsychiatry of multiple sclerosis.Advances in Psychiatric Treatment 2006;12:214-20.13. Winkelmann A, Engel C, Apel A, Zettl UK. CognitiveImpairment in multiple sclerosis. J Neurol2007:254(suppl 2):35-42.14. Maurelli M, Marchioni E, Cerretano R, Bosone D,Bergamaschi R, Citterio A, et al. Neuropsychologicalassessment in MS: clinical neurophysiological and neuroradiologicalrelationships. Acta Neurol Scand1992;86:124-8.15. Parmenter BA, Denney DR, lynch SG. The cognitive performanceof patients with multiple sclerosis during periodsof high and low fatigue. Mult. Scler. 2003;9:111-8.16. Medical Advisory Board of the National MultipleSclerosis Society (NMSS). Assessment and Managementof Cognitive Impairment in Multiple Sclerosis 2006, USNeurological Disease.17. National Institute for Health and Clinical Excellence(NICE). Management of multiple sclerosis in primaryand secondary care. 2003.18 Benedict RHB, Munshauer FE, Linn R, Miller C, FoleyFW, Jacobs LD. Screening for multiple sclerosis cognitiveimpairment using a self-adminstered 15-item questionnaire.Mult Scler. 2003;9:95-101.19. Benedict RHB. Integrating Cognitive Function Screeningand Assessment into Routine Care of Multiple SclerosisPatients. CNS Spectrums. 2005;10(5):384-91.20. Aupperle RL, Beatty WW, Shelton F de NAP andGontkovsky ST. Three screening batteries to detect cognitiveimpairment in multiple sclerosis. Mult Scler.2002;8:382-9.Publication of this article has been made possible by an unrestricted educational grant from Biogen Idec38 I ACNR • VOLUME 8 NUMBER 1 • MARCH/APRIL 2008

Conference ReportRecent Advances in Assistive Technology and Engineering(RAatE) 200726-27 November, 2007; Sheffield, UK.RAatE 2007 is the only UK conference focused on the latestinnovations in assistive technology and is attended bypeople who use, work with, develop and research onassistive technology (AT). RAatE is held annually and attracts aregular but diverse audience, with this year’s audienceapproaching 150 over two days. The ACT Programme, a SouthYorkshire based programme of research and development andknowledge transfer, acted as co-sponsors for 2007, and enableda number of overseas based keynote speakers to be brought tothe conference.The conference started with training courses on various areasof AT delivered by key professionals and organisations. Theseshort courses enabled people to reinforce or extend their skillsin some key areas. Topics covered were Alternative andAugmentative Communication (AAC); Accessing Technology;Paediatric Postural Management; and a workshop on OutcomeMeasures in AT. The keynotes throughout the conference wereall stimulating and delivered by well renowned presenters: DrBranko Cellar from the Laboratory for Health Telematics inNew South Wales, Australia delivered a talk around his foundingwork in Telecare; Dr Jeff Jutai, from the Lawson Health ResearchInstitute in London, Ontario, Canada discussed OutcomeMeasures in Assistive Technology including his PIADS measure;and Adam Walker, assistant director of Triangle, gave a user’sperspective on AT, particularly how persistent one has to be tosecure adequate funding.Paper sessions demonstrated the range and depth of workoccurring within AT – the number of paper submissions havingincreased substantially over previous years and the highquality of papers presented reflected this. Themes for thepapers included:• AAC – an innovative communication aid, project reviewand task analysis were presented;• Outcomes – including different services’ experiences andperspectives of different measures;• Telecare and housing – innovative monitoring technologyin addition to large scale research projects in housingtechnology were addressed;• Trade presentations – the latest innovations fromcompanies in AAC, telecare and powered mobility;• New Research Programmes – updates from two new, large,AT research, development and funding programmes;• Eye Gaze – two case studies of the application of this newtechnology as well as development of a new eye-gaze baseddevice;• Cognitive Support – the research and development ofdifferent systems to support people with various cognitivedifficulties;• Wheelchairs – research innovations in control of manualand powered chairs, navigating and also analysing attendantpropulsion of chairs;• ICT – the impact of new and emerging informationtechnology on people with disabilities, novel AT softwareapplications and modelling;• AT devices – a wide variety of device development,including a novel urine collection device, switch inputmethod and tremor compensation;• Telecare – evaluation of smart home technology andlocation-independent monitoring using GPS.Workshops covered a number of areas and brought about arange of discussion, as did the parallel papers on projects runby the ACT programme. Workshops covered:RAATE is the only UK conferencefocused on the latest innovations inAssistive Technology and is attended bypeople who use, work with, develop andresearch on Assistive Technology (AT)• Speech driven assistive technology – looking at the reason’s that voice isnot heavily used as an access method and feeding into the development ofa new speech controlled product;• Workforce development – examining the workforce requirements fortraining and discussing recent initiatives in this area;• Bringing an AT device to market – the process of designing, developing,manufacturing and testing an AT device and the steps required to bringthis to market were discussed.Of note, too, was the exhibition, which was constantly ‘buzzing’ with activityduring the breaks and had an excellent range of over 20 AT exhibitors. Areascovered within the exhibition included: powered mobility; posture managementsystems; alternative and augmentative communication; voluntary sector;environmental control; eye-gaze; telecare and telehealth.RAatE is organised by IPEM and the RAatE Committee: Donna Cowan(Chailey Heritage Clinical Services), Keren Down (FAST), Paul Dryer (KingsCollege Foundation Trust), Colin Clayton, Sarah Vines (Croydon WheelchairServices), Ruth E Mayagoitia (King’s College London) & Simon Judge (BarnsleyAT Team). Check the RAatE website for details of future conferences.Simon Judge,Senior Clinical Scientist, Barnsley AT Team.ACNR • VOLUME 8 NUMBER 1 • MARCH/APRIL 2008 I 39

Conference ReportRAatE 2007 – Key topic – Eye Gaze© COGAINOne of the most talked about topics atRAatE this year was the use of eye gazefor control of computers or AAC. Thistechnology has been available for sometime in different fields, however technologicaland cost improvements haveraised its profile as a method of control.The COGAIN project - an EU wide ‘networkof excellence’ - and the ACECentre-led user-involvement work packagehas also done much in recent yearsto progress eye gaze within AT.RAatE 2007 featured a paper sessionon eye gaze, in addition to several systemsand suppliers demonstrating systemsin the exhibition and eye gazeforming part of the ACE Centre’s trainingpackage on accessing AT. The paperspresented featured two interesting casestudies of recent use of eye gaze. Thecases presented were both ‘challenging’cases – the Barnsley AssistiveTechnology Team presented the successfuluse of a system with a client who hasonly a single up-down eye movement,they also detailed the system the teamhad developed to enable him to communicateusing this limited eye gazedata. Chailey Heritage Clinical Servicespresented the second case study of achild who used an existing paper basedeye-pointing system but wished toinvestigate options which would allowmore autonomous communication.The rationale behind choice of systemwas discussed and the client’s case history,which eventually ended in rejectionof eye gaze as a method, helped buildthe case history of where eye gaze isappropriate. To complete the session, anovel new eye gaze system was presenteddesigned for environmental control,demonstrating the continuedresearch interest in this area.Eye gaze will undoubtedly continueto make an impact in the AT field overthe next years and RAatE will, nodoubt, have more papers and excitinginnovations in the future on thistheme.Resources:The RAatE website – for details of future conferences andconference proceedings: www.raate.org.ukwww.raate.org.uk/raate-programmewww.raate.org.uk/exhibitionThe ACT Programme: www.actprogramme.org.ukA blog entry about RAatE:http://eduspaces.net/stevelee/weblog/225753.htmlCogain: www.cogain.orgA number of papers from RAatE will feature in the new Journal ofAssistive Technologies: www.pavpub.com/pavpub/journals/JAT/18th International Symposium on ALS/MND1-3 December, 2007; Toronto, Canada.This year’s annual International Symposium on ALS/MND was heldin a cold, overcast Toronto. As ever, the meeting was extremelywell-organised by the Motor Neurone Disease (MND) AssociationUK, in co-operation with the International Alliance of ALS/MNDAssociations. The only hitch was the late arrival of the conference abstractbooklets, which finally pitched up on the last morning of the meeting,having spent several days in scrutiny by Canadian customs. The drearinessof the grey Toronto December weather was more than compensatedfor by the excellent hotel and conference facilities and the liveliness of themeeting. As in previous years the programme was run mainly as parallelsessions, with emphasis on basic research and clinical aspects respectively,catering to the 750 basic scientists, clinical researchers, clinicians andhealth care professionals attending.TDP-43 – Innocent bystander or key in pathogenesis?The meeting opened with a clinical and pathological review by MichaelStrong, (London, Canada) in which he emphasised the heterogeneousclinical disease we term ALS, and the varying biochemical abnormalities.A highlight of his overview was his discussion of the role of TDP-43 in the disease. Intracytoplasmic, ubiquitinated inclusions are apathological hall mark of ALS/MND, and similar ubiquitinated inclusionsare also evident in the clinical disorder of frontotemporal lobardementia. In late 2006 hyperphosphorylated forms of the DNA andRNA binding protein TDP-43 were identified in these inclusions inboth disorders, and several recent papers have since confirmed thesefindings. Interestingly, the inclusions evident in SOD-1 mutation positivecases of familial ALS do not seem to stain with antibodies to TDP-43, suggesting that the inclusions (and possibly the pathogenic mechanisms)in this familial variant differ from those seen in sporadic ALS.Some have suggested that this casts doubt on the validity of the mutantSOD-1 overexpressing mouse model as a useful model for the sporadicdisease. Professor Strong outlined elegant studies in his laboratoryshowing that TDP-43 binds to and stabilises neurofilament light chainmRNA, and forms complexes with both SOD1 and 14-3-3 protein. Healso showed data suggesting that TDP-43 and ubiquitin do not alwaysco-localise in ALS, and suggested that cytoplasmic TDP-43 aggregationmay be the earlier event, with the inclusions subsequently being decoratedby ubiquitin. Merely showing the presence of abnormally hyperphosphorylatedTDP-43 in these inclusions does not of course confirmtheir pathogenicity, and it is anticipated that ongoing studies will shedlight on whether and how this abnormal protein may cause disease.Genetics of ALSThe other plenary presentation at the Opening Session was devoted tothe genetics of ALS. Peter Andersen (Umeo, Sweden) gave an excellent,if very detailed, over-view of SOD-1 mutations in familial ALS. It hasnow been over 15 years since such mutations were first identified andsome 156 different mutations have been detailed. Most of thesemutants are ‘missense, 17 are ‘nonsense’, 8 are ‘silent’, 8 are intronic and2 are thought to affect intronic splice sites. Their identification hasallowed specific molecular diagnosis, earlier clinical diagnosis, someprognostic information (e.g. rapid disease progression associated with40 I ACNR • VOLUME 8 NUMBER 1 • MARCH/APRIL 2008

Conference Reportthe A4V mutation) and the development of the mutant SOD-1 mousemodel, but unfortunately no effective therapies as yet. He presented astudy showing that more individuals with ALS had a family history ofthe disease (23%) when this was carefully inquired about, compared to5% previously recorded in that same population. While this discrepancymay not be so large elsewhere, I think it behoves all of us to ensurethat we take adequate family histories and document when the familyhistory is simply not known, rather than assume it is negative.Highlights of the genetics presentations elsewhere in the meetingincluded discussion of the genome wide association studies (GWAS)performed in the last year. There have been a number of these (fromthe US, Holland and Ireland), all now published, and following theexample of Traynor et al, data is being made publicly available to allowsubsequent meta-analysis. My take on the GWAS in ALS to date is thatno study has as yet had sufficient sample numbers, and further collaborationis required. Extrapolating from the recent GWAS in type II diabetes,Frayling has suggested that ‘hits’ with p values < 5 X 10 -7 tend tobe replicated in different populations, and are probably significant.None of the studies in ALS has yielded association with such certaintyas this, but again, with collaboration and pooling of resources, adequatelypowered studies in ALS should soon be achievable. If howeversusceptibility to the heterogeneous disorder of ALS is due to multiplerare genetic variants, standard genome wide approaches which dependon common alleles conferring susceptibility are unlikely to prove successful.Hypermetabolism in ALSAnother interesting session considered hypermetabolism in ALS. Jean-Philippe Loeffler (Strasbourg, France) reviewed the evidence for ahypermetabolic state in some ALS patients, a state that seems to confersurvival advantage. His group has recently reported that hyperlipidaemiais a typical feature of ALS patients and that an abnormally elevatedLDL/HDL ratio significantly increases survival by more than 12months. A high fat diet early in the disease improves survival in mutantSOD-1 mice, and he presented data to suggest that increased energydemand of itself is sufficient to damage the motor unit. Clinical recommendationswhich might follow on from these observations would bethat high lipids might be protective in ALS, and that patients with ALSshould not be on lipid-lowering agents. A poster by Zinman et al(Toronto) showed data that agrees with this advice. This groupobserved that the rate of decline in ALS-FRS in patients in their clinicwho were taking statins was 1.29 units/month, compared to a declineof 0.77 units/month in patients not on statins. Patients on statins alsoreported greater frequency and severity of muscle cramps. I have certainlyseen patients with ALS who relate onset of their symptoms tostarting a statin, and I think it is prudent to advise patients with ALS toconsider stopping these drugs.Clinical trialsIn this short review it is impossible to do justice to the many othergood sessions at the meeting. In the session on clinical trials, no neweffective agents were reported. The disappointing results of the USminocycline trial were presented (Gordon et al, New York). Analysisshowed a 25% faster deterioration in the decline in ALS-FRS in theminocycline group compared to placebo. This has been interpreted asperhaps being due to an adverse interaction of minocycline with riluzole,and there are additional concerns about an inappropriately highdose of minocycline having been used. Nevertheless, the data at presentare such that we cannot recommend minocycline to patients.I managed to get to some of the session on ‘Evaluating UnprovenTreatments’, in which Leonard Van den Berg (Utrecht) gave an excellentupdate on the use of olfactory ensheathing cell transplants in the disease.He reviewed the two studies by Huang that have been publishedin Chinese journals, one of which reports improvements in the ALS-FRS scores within four weeks in 77% of 327 patients who received suchtransplants. As outlined by Van den Berg, these publications were notpeer-reviewed, the follow-up was too short, the intervention was notplacebo-controlled, and it is not clear that appropriate consent procedureswere followed. He then reported his follow-up of 13 Dutchpatients who had received cell transplants in China. Seven of thesereported a subjective increase in well-being and muscle strength within24 hours of the procedure (possibly due to the steroid therapy givenat the time of transplant), but none of them showed any improvementsat 4 or 12 month post-procedure assessments in Holland. Leonard gavea straightforward plea for clinicians to tell patients of placebo effects,to warn of the high costs of such unproven therapies ($25,000 upwardsfor ensheathing cell transplants), to outline the side-effects if knownand to defend to patients our system of ethical scrutiny of the researchwe do. Yes, ethics applications are cumbersome, but they do afford ourpatients some protection. While not wanting to dash patients’ hopes,we have a duty to tell them when proposed treatments have not beenshown to work.And to next year…The meeting included a video by Steven Hawking inviting delegates toreconvene for the 19th International ALS/MDS Symposium next year.The venue – a sunny Birmingham, UK, the city which hosted the firsttwo of these symposia back in the 1990s with a handful of delegates inattendence. I hope that many UK neuroscientists and clinicians willcome along from 3-5 November, 2008. ALS has not yet been cracked,and attracting more minds to the research and care of this progressivedisease can only be a good thing.Karen E Morrison, Professor of Neurology,University of Birmingham,Honorary Consultant Neurologist,University Hospitals Birmingham NHS Foundation Trust,Co-Director of Birmingham MND Care and Research Centre.ACNR • VOLUME 8 NUMBER 1 • MARCH/APRIL 2008 I 41

Conference ReportThe UK Stroke Forum Conference4-6 December, 2007; Harrogate, UK.The second annual conference of the UK Stroke Forum hosted byThe Stroke Association met at the Harrogate International Centrefor three days in the first week of December – a historic week forUK stroke services that saw the launch of the Department of Health’sNational Stroke Strategy for England.Building on the success of last year’s inaugural conference, this year’sconference welcomed around 1300 delegates from the stroke communityto share best practice and expertise, to network with colleagues, and toenjoy a varied programme which attracted some of the leading experts intheir field sharing their knowledge and updating the conference on thelatest research.In response to delegate feedback, this year’s conference was expandedto include additional educational sessions as part of a training programmeoffering designated sessions forstroke physicians, nurses, and rehabilitationspecialists. On Tuesday 4 December, theBritish Association of Stroke Physiciansorganised training sessions on identifying andtreating the complications of stroke, theNational Stroke Nursing Forum organisedsessions on hyperacute care, continence andmedication management, and a rehabilitationsession covered managing the delivery of therapyand rehabilitation for people who haveimpaired communication and cognition.The auditorium.Later in the day there was a Community Stroke Research and TRACSdrop-in session, and both the British Association of Stroke Physicians andthe National Stroke Nursing Forum held their respective annual generalmeetings.On Wednesday 5 December, the opening plenary session organised byThe Stroke Research Network focussed on ethical issues in stroke care andresearch, including presentations on the ethical justification for resourceallocation to stroke, and a legal perspective on assessing incapacity and itsimplications for stroke research.Parallel sessions on the second day of the conference covered a widerange of topics including neuroradiology, participating in the communityand returning to work after stroke, the future of stroke nursing, andpsychological support. A free papers session updated delegates on the latestdevelopments in various aspects of stroke research, and there was ashowcase of recent rehabilitation trials.The day closed with the Princess Margaret Memorial Lecture, withguest lecturer Professor Willy de Weerdt from the Department ofRehabilitation Sciences, KU Leven, Belgium, presenting a collaborativeevaluation of rehabilitation in stroke across Europe.In the evening, Harrogate’s Majestic Hotel was the venue for the UKStroke Forum Gala Dinner attended by 650 of the delegates.The following day’s opening plenary session focussed on the implementationof a national stroke strategy. The Secretary of State for Health,Alan Johnson, addressed the conference to introduce the National StrokeStrategy for England and to mark its launch. Professor Martin Dennis(Chair of the National Advisory Committee for the Scottish StrokeStrategy) updated the conference on the progress of the Scottish StrokeStrategy, and Professor Mike Harmer (Deputy Chief Medical Officer,Wales) and Dr Carolyn Harper (Deputy Chief Medical Officer, NorthernIreland) also made presentations.Parallel sessions on the final day again covered a wide range of topicsincluding driving and vision, atrial fibrillation and glucose, acute strokemanagement, delivering augmented rehabilitation therapy, and goodpractice in user involvement. There was also a further free papers session.The final plenary session in the afternoon began with a speech by TheDuke of Kent and the presentation of the British Stroke Research Groupprizes, followed by a showcase of research funded by UK Stroke Forumcharities with presentations by Professor Charles Wolfe (King’s CollegeLondon) on the South London Stroke Secondary PreventionProgramme, Jacqui Crosbie (University of Ulster) on virtual reality inthe rehabilitation of the upper limb following stroke, Professor FenellaSecretary of State for Health, Alan Johnson.Kirkham (University College London Instituteof Child Health) on the prevention of morbidityin sickle cell anaemia, Professor PeterLanghorne (Glasgow Royal Infirmary) on thedevelopment of the stroke unit, and Dr WendyBest (University College London) on aphasiatherapy.Certainly, the feeling at this year’s conferencewas that the event had been even bigger and better than last year, bringingtogether even more people from the stroke community and establishingthe UK Stroke Forum Conference as an invaluable and truly multidisciplinaryoccasion. With a lively exhibition hall, ideas fair, and posterdisplays covering acute care, clinical trials, cognitive and emotional issues,good practice in user involvement, hyperacute care, nursing, swallowing,and vision, delegates were offered a varied programme throughout thethree days with the programme highlight being the launch of the NationalStroke Strategy for England.For further information on the 2007 conference, and to downloadspeaker presentations, please visit www.ukstrokeforum.orgMatthew King, The Stroke Association.Specific examples of research presented at the conference include:• A new study has found that that Post Traumatic StressDisorder is the likely cause of psychological problems affectingsome carers of stroke survivors. The study, which focused onstroke survivors with subarachnoid brain haemorrhage, wasconducted by Doctoral Research Student Adam Noble andcolleagues at Durham University (in collaboration withNewcastle General Hospital and James Cook UniversityHospital in Middlesbrough).• A study comparing the benefits of surgery (endarterectomy)to endovascular therapy (angioplasty) to reopen a blockedcarotid artery has found that over a follow up period of eightyears, a recurrent distinct narrowing of the artery (by 70% ormore) was three times more likely after endovascular therapythan surgery. The study was conducted by the Stroke ResearchGroup at the UCL Institute of Neurology in London• A new NHS clinical service which helps stroke patients withdropped foot is being used at the Salisbury NHS FoundationTrust. The conference provided the opportunity for staff fromthe Trust to explain the condition and how this new clinicalservice is proving of benefit to many stroke survivors.42 I ACNR • VOLUME 8 NUMBER 1 • MARCH/APRIL 2008

Conference ReportEncephalitis – the Broader Spectrum: Rare Forms of Encephalitis22 January, 2008; London, UKThe Encephalitis Society started out 15 yearsago as a fairly modest support group, inresponse to the very limited help availablefor people, and their families, who had been affectedby encephalitis. Since then, it has expanded itsactivities very substantially and is the only resourceof its kind in the world, providing evidence-basedinformation, education and support services. TheSociety has also supported and funded a number ofresearch studies and is currently involved in a largescale collaborative study of the outcome ofencephalitis with the University of York. The societyorganises an annual seminar, which this year hadas its topic some of the less familiar varieties ofencephalitis.Professor Tom Solomon from the new LiverpoolBrain Infections Group (www.liv.ac/braininfections)opened the meeting with a presentation onEncephalitis in the Global Village, which highlightedthe threat of emerging viruses. He has worked extensivelyon Japanese encephalitis in Vietnam and,although still a rarity in the UK, this is actually oneof the more important brain infections on a worldwide scale. There areanything from 35,000 to 50,000 cases each year with a 30% mortality and30% of survivors left with significant neurological sequelae.It has a varied neurological profile which, as well as the more familiarfeatures of encephalitis, such as fever, headache, confusion, seizures,raised ICP and coma, may involve acute movement disorders withparkinsonism, orofacial dyskinesias, and choreoathetosis. The Japaneseencephalitis virus can also attack anterior horn cells, leading to presentationwith a polio-like ascending flaccid paralysis. Dengue is another mosquitoborne flavivirus which can cross the blood-brain barrier to producean encephalitic illness in a proportion of infected patients. Humanenterovirus 71 (HEV71) was isolated from the stool of a child withencephalitis in California in 1969. After sporadic cases and small outbreaksof HEV71 infection worldwide in the 1970s and 1980s, there was alarge and severe outbreak in Sarawak in 1997 with 34 deaths in 2628reported cases. Neurological involvement included aseptic meningitis,encephalitis and acute flaccid paralysis. Since then there have been furtheroutbreaks in Southeast Asia and Australia.Although these illnesses have tended to be viewed in this country asexotic rarities, the ease and speed of international travel and the effects ofclimate change are making awareness of them increasingly relevant – apoint illustrated by the appearance of West Nile fever in New York City.Fungal infections of the CNS are mostly familiar to us in the UK assomething seen on a relatively small scale in immunocompromisedpatients. However, as Dr William Hope, Infectious Diseases Physician andSenior Research Fellow, The University of Manchester, emphasised, theyactually represent a major problem from a global perspective.Cryptococcus neoformans is a leading cause of AIDS-related deaths insub-Saharan Africa and aspergillus is a major source of morbidity andmortality in immunocompromised patients, with an associated mortalityof 40-50%. The expenditure on antifungal drugs worldwide is astronomical– billions of dollars – and rising. Dr Hope’s presentation emphasisedthat the key to understanding the pathological process in cerebralaspergillosis is the recognition that Aspergillus is angiotropic andangioinvasive. He also reviewed the under-recognised but quite commoncondition of neonatal haematogenous candida meningoencephalitis, inwhich there is widespread involvement of the CNS with Candida.The second theme of the meeting was the role of the immune systemin the pathogenesis of encephalitis. Oxford has been a leading centre inthe characterisation of voltage gated potassium channel antibody(VGKC) encephalitis and Professor Angela Vincent from the WeatherallInstitute of Molecular Medicine reviewed the work of their group.VGKC antibody-associated limbic encephalitis occurs in both men andwomen. It is an adult-onset condition seen in people from 30 to over 70years of age, with an acute or subacute onset of memory loss, seizures,personality change and occasionally more floridpsychotic features, with high signal in the hippocampion MRI. Associated malignancies areuncommon and immunological treatments withintravenous immunoglobulins and steroids mayproduce significant clinical improvement. Thisantibody-mediated disorder seems to be anexpanding phenotype. VGKC antibodies may belinked predominantly to seizures or atypical psychosisoccurring in isolation, with some indicationthat immunosuppressive treatment may be helpful.A proportion of patients with adult onset temporallobe seizures with hippocampal sclerosis may actuallyhave a history of a previous encephalitic illnesswith evolving MRI changes, raising the possibilitythat untreated limbic encephalitis may be acausative factor in some cases. So what started outas something of a rarity may turn out to have muchbroader implications for epileptology and neuropsychiatry.Dr Ian Hart, Consultant in Neurology andNeuroimmunology from the Walton Centre inLiverpool, developed the theme of autoimmune encephalitides, dealingwith Hashimoto’s encephalitis, Rasmussen’s encephalitis and paraneoplasticencephalitis.He emphasised that these relatively rare conditions should not be forgottenin the differential diagnosis, looking for serum antibodies is usefuland can help make the diagnosis. They need to be thought of soonerrather than later, since immune treatments may be helpful in individualpatients if they can be started early enough, before brain cell deathand permanent disability has developed.The meeting ended with a fascinating presentation from ProfessorGavin Giovannoni from Barts and the London on encephalitis lethargica,which in contemporary neurology is defined as an acute or sub-acuteencephalitis with at least three of the constellation of basal gangliainvolvement, oculogyric crises, ophthalmoplegia, obsessive-compulsivebehaviour, akinetic mutism, central respiratory irregularities and somnolenceor inversion of the sleep-waking cycle. There is evidence of aninflammatory process in the basal ganglia, brainstem and hypothalamus.Encephalitis lethargica may be one of a spectrum of autoimmune CNSdisorders, characterised by anti-basal ganglia antibodies associated withrecent streptocococcal infection.The encouraging message from this seminar is that the future forencephalitis research in the UK looks bright, with the very active involvementof several different research groups of international standing. It isalso encouraging that the Encephalitis Society is able to convene meetingslike this one, to make sure that the practical benefits from this new knowledgewill reach a wide audience as quickly as possible, helping improvethe care of people with encephalitis both in this country and on a moreglobal scale.The Encephalitis Society7b Saville Street, Malton, YO17 7LLwww.encephalitis.infoTel. +44 (0)1653 692 583Email. ava@encephalitis.infoDr Steve White and Ava Easton,Encephalitis Society, UK.Ava Easton is the Society’s Development Manager andDr Steve White is Consultant Neurophysiologist,St Mary’s Hospital, London.ACNR • VOLUME 8 NUMBER 1 • MARCH/APRIL 2008 I 43

Conference ReportPREVIEW European Association for Neuro-Oncology12-14 September, 2008; Bacelona, Spain.The European Association of NeuroOncology (EANO) has been inexistence for 15 years and over that time has grown and developedto include over 600 members from 40 countries. Members includescientists, neurologists, neurosurgeons, medical and radiation oncologists,neuropathologists, neuroradiologists, specialist neuro-oncologynurses, paediatricians and many other groups. Major EANO meetings areheld every two years in Europe and jointly with the American Society forNeuroOncology and the Asian Society of Neuro-Oncology as part of theWorld Federation of Neuro-Oncology. In May 2005, EANO had the pleasureof hosting the Second Meeting of World Federation of Neuro-Oncology, with the participation of more than 1200 delegates from 35different countries. In 2006, EANO held their VII meeting in Vienna,attracting 1,000 participants. In 2008, EANO VIII will be held inBarcelona. EANO is a full member of the Federation of European CancerSocieties (FECS) and has developed a section devoted to the education ofneuro-oncology cancer nursing.The aim of the association is to encourage the multidisciplinaryexchange of knowledge and to implement cooperative studies in the fieldof neuro-oncology, including different experts involved in cancerresearch, treatment and care.A special educational program is planned for young researchers fromCentral and Eastern Europe with the goal of promoting a high standardneuro-oncological qualification and favouring a more intense integrationwith these countries. We have launched a new website to provide bettercommunication between members and to allow a forum for discussionand ideas (www.eano.eu).If you have an interest in neuro-oncology, we would be delighted to seeyou at the next EANO meeting, scheduled in Barcelona on 12th-14thSeptember 2008. The congress will take place in the “Palau de Congressosde Catalunya”, a modern, multipurpose building situated in a smart areaof Barcelona. Barcelona is a modern multicultural city and the mainexponent of the Catalan culture and heritage. The city is known worldwidefor its architecture, cuisine, and most importantly, the way peoplefrom Barcelona enjoy life. We hope you will take at least a glimpse of allthese wonders during the Congress.Registration forms and the programme details are available viathe website. We are looking for active members – please registeras a member via our website (www.eano.eu) or email us atsecretariat@eano.euWe look forward to welcoming you in Barcelona.Es veiem a Barcelona!Nos vemos en Barcelona!PREVIEW 18th Meeting of the European Neurological Society7-11 June, 2008; Nice, France.Neurology: Learning, knowledge, progress and thefutureTeaching programme :• 22 practical workshops• Interactive case presentations• Practical sessions in clinical neurophysiology• 24 Teaching courses covering all important topics inNeurologyThe eighteenth meeting of the European Neurological Society (ENS)will be held at the Nice Acropolis Congress Centre on June 7-11,2008. This year we will celebrate the 20th anniversary of the firstmeeting of the ENS, which was also held in Nice, in June 1988.From the very beginning we have pursued the original goals of oursociety, namely excellence in the teaching and scientific programmes,and support to young scientists. The number of participants of courses,symposia and free communications has dramatically increased sincethe beginning, but the spirit remains the same. The ENS bets on neurologistsin training, with 300 of them invited to attend the meeting.Younger colleagues are especially interested in teaching courses. 37courses will be available, including eight practical hands-on sessionsand four teaching courses jointly organised with colleagues of theAmerican Academy of Neurology. In addition, 22 workshops coveringthe different fields of clinical neurology will take place during themeeting.The Presidential Symposium will be dedicated to current knowledgeand practical management of coma and locked-in syndrome. On thefollowing day a symposium will cover behavioural disorders anddementia with talks on physiopathological bases of behaviour, synucleinopathies(Parkinson’s disease, Lewy body); mild cognitive impairmentand Alzheimer disease; and tauopathies (Fronto-temporal, PSP,etc.). A symposium on autoimmune disorders of the nervous systemwill include talks on latest developments in multiple sclerosis; autoimmunediseases of the neuromuscular junction; pathogenesis and treatmentof the Guillain Barré syndrome and immunopathogenesis ofinflammatory myopathies.On the last day of the meeting there will be a symposium on multiplesclerosis: when to start a treatment, and which treatment with thebest experts in the field from Europe and USA. Finally there will be asymposium on imaging and management of transient ischaemic attack(TIA) confronting the diagnosis and risk assessment for TIA, yield ofbrain and vascular imaging (MRI, ultrasound etc.); feasibility and efficacyof ultra early evaluation and intervention after a TIA, and the conceptof the TIA clinic.In addition to the symposia, the Scientific Programme includes fiveposter sessions and approximately 16 oral sessions of free communications.We will once again have poster walks to display the posters in alively and interesting format. Experts will lead a review of selectedposters promoting discussion with their authors. The selection of scientificpapers is based on the review by three experts in the field. Onaverage 800-900 free scientific papers are selected for presentation atthe meeting. We are looking very much forward to these stimulatingsessions.Prof G Said, ENS Executive Committee.Visit the ENS 2008 website www.ensinfo.com• Continuously updated scientific programme• Online registration as well as hotel & tour registration• Option to compose your personal congress programme• Details about the industrial exhibition and symposiaarranged with the industry• Information about NICEEARLY REGISTRATION DEADLINE: 8th APRIL 200844 I ACNR • VOLUME 8 NUMBER 1 • MARCH/APRIL 2008

ISSN 1473-9348 Volume 8 Issue 1 March/April 2008Academic SymposiaSleep and the hospital doctorDate: Monday 14 April 2008 | Examination of thefactors and research underpinning the sleep requirementsof hospital doctors in the context of shiftworking.Key advances in the treatment ofPost Traumatic Stress DisorderDate: Tuesday 13 May 2008| Evidence based view ofthe treatments currently used for PTSDFrontiers in the degenerative dementias:pathogenesis, diagnosis and therapyDate: Monday 9 June & Tuesday 10 June 2008 | A twoday conference jointly organised by The Royal Societyof Medicine and the New York Academy of MedicineCall Miss Chandni Kohar on 02072902965or book online www.rsm.ac.uk/diaryAnnualScientificMeeting9-11th July 2008Apex City Quay Hotel, DundeeTopics include:• Genetics and its Relevance to Clinical Practice:ION Channel and Chromosomal Disorders;Pharmacogenetics; Complex Inheritance in Epilepsy• ILAE UK Chapter and Epilepsy Research UK Basic Science Session:Submitted Topics• Epilepsy Neurosurgery Network Meeting: Case Discussions• GABA and Epilepsy: From the Receptor to the Clinic:GABA Receptors: A Review; Depolarization and GABA;GABAergic AEDs• Intracranial EEG Monitoring – Different Approaches:Review of EEG Basics; Marseilles Approach; Cleveland Approach• Non-Epileptic Attacks and Dissociative Seizures:Epidemiology; Clinical Observations; Conversational Analysis;Management• Provision of Care:Managed Clinical Networks for Epilepsy; Measurement of Adherence;Joint Decision Making in Epilepsy ManagementRegistration includes the conference dinner at historic Guthrie CastleFor more information please contact Denise Hickman-Rowe, Conference2k Ltd, Capstan House, Western Road, Pevensey Bay, East Sussex BN246HG • Tel: 01323 740612 • denise@conference2k.comFull programme, registration forms, abstract and Gowers’ forms are availablefor download at www.ilae-uk.org.uk and www.conference2k.comWhat can advertising in ACNR’sCourses and Conferencessection do for you?lllllReach a UK audience of 5000 neurologicalspecialists and neuroscientistsHeighten the profile of your event in one of theleading magazines in its fieldPenetrate international markets via our website atwww.acnr.com - 4000 readers each month and theoption to use interactive publicityA variety of opportunities exist - advertisements.loose inserts, press releases, web links etcA design and typesetting service - just email us thedetails and we’ll do the rest.For more information,or to book publicity foryour event, contact:Patricia McDonnell,ACNRT/F 0288 289 7023E. sales@acnr.co.ukDeadline for May/June issue:7 April, 2008.ACNRwww.acnr.co.ukAdvances in Clinical Neuroscience & RehabilitationPaul ReadingThe Neurological Sleep Clinic – Part 1 – The Sleepy PatientMaurice Curtis, Andrew Naylor, Richard FaullManipulation of Neural Stem Cells as a Rehabilitative TherapyEmma Matthews, Mike HannaPossible New Treatments in Muscular DystrophyConference News • Journal Reviews • Book Reviews • Diary of EventsAdvance Programme - www.eano.euContact: Marieke Hodel, Romana KoenigVienna Medical Academy, Alser Strasse 4, 1090 Vienna, AustriaT: +43 1 40513830, F: +43 1 4078274, E: eano2008@medacad.orgACNR • VOLUME 8 NUMBER 1 • MARCH/APRIL 2008 I 45

Events DiaryTo list your event in this diary, email brief details to Rachael Hansford at rachael@acnr.co.uk by 7 April, 20082008March2nd International Conference onHypertension, Lipids, Diabetes and StrokePrevention6-8 March, 2008; Prague, Czech Republicwww.kenes.com/strokeprevention2008Putting Rehabilitation into Practice –Advanced6 March, 2008; Derby, UKE. ncore@derbyhospitals.nhs.ukwww.ncore.org.ukT. 01332 2546793rd Meeting of the UK Parkinson’s Disease NonMotor Group8 March, 2008; London, UKE. yogini.naidu@uhl.nhs.uk, www.pdnmg.comCognitive Rehabilitation Workshop10-11 March, 2008; Auckland, New ZealandE. Janis Henry jan@iphltd.co.nzChild and Adolescent Addiction: risks, consequences,treatments and management10-11 March, 2008; London, UKE. annehaylock@markallengroup.comHead Injury Conference: The Claiming Culture11 March, 2008; Derby, UKE. ncore@derbyhospitals.nhs.ukwww.ncore.org.ukT. 01332 254679Posture and Balance in NeurologicalConditions - Lower Limb Qualified Staff12-13 March, 2008; Derby, UKE. ncore@derbyhospitals.nhs.ukwww.ncore.org.ukT. 01332 254679Birmingham Movement Disorders Course12-14 March, 2008; Birmingham, UKT. 0121 507 4073, E. susan.pope@swbh.nhs.ukCommunity Therapists Network Workshop –Building Your Business Case in CommunityRehabilitation13 March, 2008; Lutterworth, UKwww.communitytherapy.org.ukInternational Neuroimmunology Symposium14 March, 2008; Dublin, IrelandT. +353 1 716 6700, E. mniest@ucd.ie,www.ucd.ie/mniest/Neuroimm_workshop.htmlMental Capacity Act Training17 March, 2008; Derby, UKE. ncore@derbyhospitals.nhs.ukwww.ncore.org.ukT. 01332 254679Cognitive Rehabilitation Workshop17-18 March, 2008; Auckland, New ZealandE. Janis Henry jan@iphltd.co.nz8th Advanced Prosthetic & AmputeeRehabilitation Course17-19 March, 2008; London, UKT. Sandy Weatherhead on 01992 638865Aiming Higher. A one-day conference with aEuropean perspective on the social impact ofchildhood acquired brain injury19 March, 2008; Birmingham, UKE. sharon@cbituk.orgwww.cbituk.orgT. 01869 341075Genomic Disorders17-20 March, 2008; Cambridge, UKhttp://firstcontact.hinxton.wellcome.ac.ukABN Spring Meeting26-28 March, 2008; Dublin, IrelandE. info@theabn.orgComputational Biology26-29 March 2008; Cambridge, UKhttp://firstcontact.hinxton.wellcome.ac.ukThe Science, Culture and Art ofNeurorehabilitation, Tripartite RegionalMeeting of Neurological Rehabilitation27-29 March, 2008, Cebu City, PhilippinesE. NeuroRehab@yahoogroups.comRecognising Post Traumatic Stress28 March, 2008; Derby, UKE. ncore@derbyhospitals.nhs.ukwww.ncore.org.ukT. 01332 254679Motor Neurone Disease Study day28 March, 2008; Derby, UKE. ncore@derbyhospitals.nhs.ukwww.ncore.org.ukT. 01332 254679MS Life29-30 March, 2008; Manchester, UKwww.msconvention.org.ukExplain Pain with Lorimer Moseley30 March, 2008; Worcester, UKE. info@physiouk.co.ukPractical Neurology Study Days31 March – 1 April, 2008, London, UKT. 020 7242 9789,F. 020 7831 0488,E. courses@ich.ucl.ac.ukAprilReport Writing for Doctors and Consultants2 April, 2008; Derby, UKE. ncore@derbyhospitals.nhs.ukwww.ncore.org.ukT. 01332 254679Witness Skills for Doctors and Consultants3 April, 2008; Derby, UKE. ncore@derbyhospitals.nhs.ukwww.ncore.org.ukT. 01332 25467960th Annual Meeting of the American Academyof Neurology5-12 April, 2008; Chicago, USAT. +1 651 6952717,E. memberservice@aan.comThe Psychosocial Burden of Epilepsy:Ameliorating the impact6-8 April, 2008; Oxford, UKE. Isabella@eruk.org.uk,www.epilepsyresearch.org.ukSexuality and Acquired Brain Injury Workshop7 April, 2008; London, UKT/F. 0208 780 4530, E. psimonson@rhn.org.ukThe International Brain Injury Association’s7th World Congress on Brain Injury9-12 April, 2008; Lisbon, PortugalE. mjroberts@aol.com, orT. 001 703 960-6500World Parkinson’s Disease Day conference10 April, 2008; Cairo, EgyptE. lizzie@epda.eu.comThe British Pain Society's 2008 AnnualScientific Meeting15-18 April, 2008; Liverpool, UKwww.britishpainsociety.org/meet_futureasm.htmMobility On The Edge International seminar16-18 April, 2008; Oswestry, UKKaren Edwards,E. karen.edwards@rjah.nhs.ukT. 01691 404531Nicotinic Receptors23-26 April, 2008; Cambridge, UKhttp://firstcontact.hinxton.wellcome.ac.ukBISWG-Brain Injury and Mental Health -National Conference in Cardiff24 April, 2008; Cardiff, UKT/F. 0208 780 4530,E. psimonson@rhn.org.ukPhysiotherapy Research Society ScientificMeeting24 April, 2008; Manchester, UKT. 01332 299017E. pdziunka@yahoo.co.ukW. www.prs-uk.org2nd National Treating Schizophrenia24-25 April, 2008; London, UKE. annehaylock@markallengroup.com3rd Essential Neuro MRI Study Day: Basicapproach to reading MRI of Brain & Spine26 April, 2008; Liverpool, UKE. kath.tyler@thewaltoncentre.nhs.ukT. 0151 529 5416/5552Applied Bioinformatics & Public HealthMicrobiology27- 29 April, 2008; Cambridge, UKhttp://firstcontact.hinxton.wellcome.ac.ukMay13th European Congress of ClinicalNeurophysiology5-8 May, 2008; Istanbul, Turkeywww.eccn2008.org/9th European Congress of Neuropathology8-10 May, 2008; Athens, GreeceE. i.m.huang@amc.uva.nl, T. 30-2-107-257-693,F. 30-2-107-257-5326th Workshop of the International Society forMusculoskeletal and Neuronal Interactions8-11 May, 2008; Cologne, GermanyE. info@mes-berlin.com Mrs Yvonne Beetz,T. 00 49-3-070-078-950F. 49-3-07-007-895-111V Scientific Symposium of Polish Society forNeurological Rehabilitation9-10 May, 2008; Tarnowskie Gory, PolandW. www.repty.plAAC:Basic Principles & Practical Solutions16 May, 2008; London, UKT. 0208 780 4500 x5140E. institute@rhn.org.uk1st Asian Oceania Conference of Physical andRehabilitation Medicine16-19 May, 2008; Nanjing, ChinaDanny YanT. 86 10 62 180 141F. 86 10 62 174 061E. info@aocprm2008.com5th International Symposium onNeuroprotection and Neurorepair:CerebralIschemia and Stroke17-20 May, 2008; Magdeburg, GermanyT. +49(391)67-13088E. georg.reiser@medizin.uni-magdeburg.deW. www.neurorepair-2008.de/BSRM Spring Meeting19-20 May, 2008; Birmingham, UKE. admin@bsrm.co.ukT. 01992 6388653rd National Neuroscience NursingConference: back to basics20 May, 2008; London, UKE. annehaylock@markallengroup.comBISWG Annual General Meeting and StudyDay: ‘Money Matters 2’21 May, 2008; Birmingham, UKT/F. 0208 780 4530E. psimonson@rhn.org.ukPlasticity, Learning, and Development30-31 May, 2008; London, UKE. rosalyn.lawrence@ucl.ac.ukBrain Injury and the Law-Scotland Event30 May, 2008; Dunfermline, UKT. 0131 537 6857E. fenparry@blueyonder.co.uk/mhairi.mckay@lpct.scot.nhs.ukMagstim/ Institute of Cognitive NeuroscienceSecond TMS Summer School30 – 31 May, 2008; London, UKwww.magstim.comT. 01994 240798E. nick.lewis@magstim.comJune2nd Migrating Course on Epilepsy1-8 June, 2008; Trakai, LithuaniaE. Milda Endziniene endziniene@gmail.com orPetra Novotny petra@epilepsy-academy.orgSignalling to Chromatin4-8 June 2008; Cambridge, UKhttp://firstcontact.hinxton.wellcome.ac.uk18th Meeting of the European NeurologicalSociety7-11 June, 2008; Nice, FranceT. +41 61 686 77 11F. +41 61 686 77 88E. info@akm.chW. www.ensinfo.com6th International Society for Stem CellResearch Annual Meeting11-14 June, 2008; Philadelphia, USAE. isscr@isscr.orgGenomics of Malaria Epidemiology15-18 June, 2008; Cambridge, UKhttp://firstcontact.hinxton.wellcome.ac.uk9th Eilat Conference on New AntiepilepticDrugs (EILAT IX)15-19 June, 2008; Sitges, SpainF. +972 3 5175155E. eilatix@targetconf.comW. www.eilat-aeds.comStudy Day on MND17 June, 2008; Birmingham, UKE. pam.aston@mndassociation.orgCognitive Rehabilitation Workshop20-21 June, 2008; London, UKE. enquiries@braintreetraining.co.ukW. www.braintreetraining.co.ukInternational Congress of Parkinson’s Diseaseand Movement Disorders22-26 June, 2008; Chicago, IL, USAT. +1 414 2762145E. info@movementdisorders.org12th Congress of the Movement DisorderSociety22-26 June, 2008; Chicago, USAE. congress@movementdisorders.orgJulyFourth International NeuroacanthocytosisSymposium: Bridging clinical and basic aspects1-2 July, 2008; London/Oxford, UKE. glenn@naadvocacy.orgT. 020 7937 2938SRR Summer Meeting2-3 July, 2008; Preston, UKW. www.srr.org.uk, E. dforshaw@uclan.ac.ukInflammatory Neuropathy Consortium (INC)Meeting of the Peripheral Nerve Society (PNS)4-5 July, 2008; Paris, FranceW. http://pns.ucsd.edu/INC.htmILAE UK Chapter Annual Scientific Meeting9-11 July, 2008; Dundee, UKE. denise@conference2k.comT. 01323 740612, F. 01691 670302W. www.ilae-uk.org.ukTechniques & Applications of MolecularBiology14- 17 July, 2008; Coventry, UKT. 024 7652 3540E. Charlotte.Moonan@warwick.ac.ukParkinson’s Academy/PD Section, BritishGeriatrics Society Specialist RegistrarMasterclass28 July – 1 August, 2008; Truro, CornwallE. Red Publishing Ltd, redoffice@btinternet.comAugustNeuSIG Satellite to the Glasgow 2008 WorldCongress on Pain13-15 August, 2008; London, UKW. www.kenes.com/neuropathic2008/12th World Congress on Pain17-22 August, 2008; Glasgow, UKT. 001 206 547 6409E. iaspdesk@iasp-pain.org12th European Federation of NeurologicalSocieties Congress23-26 August, 2008; Madrid, SpainF. 00 43 1 88 92 581E. headoffice@efns.orgInteractome Networks27-30 August, 2008; Cambridge, UKhttp://firstcontact.hinxton.wellcome.ac.uk2nd Baltic Sea Summer School on Epilepsy31 August-1 September, 2008; DenmarkE. petra@epilepsy-academy.org.SeptemberGenetics of EpilepsySeptember, 2008;ILAE–VIREPA distance learning courseE. office@epilepsy-academy.org,www.epilepsy–academy.org46 I ACNR • VOLUME 8 NUMBER 1 • MARCH/APRIL 2008

Eighteenth Meeting of theEuropean Neurological SocietyJune 7–11, 2008Nice, France20 th Anniversary of the first ENS Meeting in NiceNeurology: Learning, knowledge, progress and the futureKey symposia:Coma and locked-in syndromeBehavioural disorders and dementiaAutoimmune disorders of the nervous systemMultiple sclerosis: when to start a treatment and which treatmentTransient ischemic attacks: diagnosis and managementThe congress programme includes interactive case presentations, 23 teaching courses,workshops organised by the ENS subcommittees and selected scientific sessions in theform of oral sessions, poster sessions (guided poster walks) and satellite symposia.Abstract Submission Deadline: January 31, 2008Early Registration Deadline: April 8, 2008For further information please contact:Administrative Secretariat:18 th ENS 2008, c/o AKM Congress ServiceP.O. Box, CH-4005 Basel / SwitzerlandPhone +41 61 686 77 11 Fax +41 61 686 77 88 E-mail info@akm.chwww.ensinfo.com

Journal ReviewsEDITOR’S CHOICEStem cells become front page news again! Why?One of the most sought after solutions in medicine is the developmentof an ethically neutral, readily available and reliable source ofcells by which repair could be effected by their use, and diseasepathogenesis possibly studied by growing them in the lab. To date,the big problems have either been difficult ethical and theologicalissues associated with pluripotential embryonic stem (ES) cellsderived from blastocysts from IVF programmes or the limitedcapacity to generate sufficient numbers of appropriate cells withother ethically more acceptable cells such as adult stem cells frombone marrow or brain. It is therefore of great interest that twogroups have independently generated embryonic stem like cellswith all their attendant pluripotentiality using reprogrammed skinfibroblasts – papers that have spurred numerous reports in thenewspaper and scientific journals alike. These two papers in Celland Science have both shown that adult human fibroblasts can betransduced with four factors to make pluripotent stem cells.Takahachi et al found that Oct4, Sox2, Klf4 and c-Myc were neededto produce pluripotential ES like cells which show all the characteristicsof true embryonic stem cells in terms of their behaviourin culture, profile of molecular markers using gene arrays andbehaviour in vivo. In contrast Yu et al used Oct4, Sox2, Nanog andLin28 to produce similar results. These are exciting findingsbecause if they can be refined to avoid the need for viral vectors(and especially the risk of tumours with the c-myc transfection),then one truly has the potential to repair damaged systems, includingbrains, in patients using their own cells. In addition, one couldstart to study disease pathogenesis in these individuals using thesevery same cells to model disease. Of course this work is predicatedon the grounds that:1. Cell repair therapies work and that any such human inducedpluripotential stem cells (iPS) are not going to be affected bythe same disease process in the short term whilst also allowing2. The cells to accurately reflect disease states which have widerrelevance to the modelling of disease beyond that of the individualaffected by it.Nevertheless the capacity to generate iPS cells using human fibroblastsis a tour de force although what the moral status of such a cellis in terms of its potentiality for human life is still debatable.Indeed the ethics of embryonic stem cell research will continue tovex many working in the field at the same time as the scientificadvances take us into the realm of therapeutic reality. – RABYu J, Vodyanik MA, Smuga-Otto K et al.Induced pluripotent stem cell lines derived from human somaticcells.SCIENCE2007;318:1917-20.Takahashi K, Tanabe K, Ohnuki M et al.Induction of pluripotent stem cells from adult human fibroblastsby defined factors.CELL2007 131(5):861-72.BRAIN REPAIRThe relationship between injury and repair in the brain is complicated.Take, for example, the bizarre observation that regeneration of retinal ganglioncells following an optic nerve crush injury can be improved by injuringthe lens of the eye. (Who said two wrongs don’t make a right?) Thestandard thinking had been that the lens injury attracted macrophagesinto the eye, which went on to secrete neurotrophic factors, specifically therather grandly-named oncomodulin. In the latest issue of Brain, a teamfrom Ulm, Germany, show otherwise. They injured the optic nerve andlenses of rats and then, five days later, dissected out the retina to study retinalcell behaviour in culture. Their first discovery was that lens injuryupregulated the neurotrophin CNTF in the retina; and, secondly, that thiswas not in macrophages but in retinal astrocytes. They went on to showthat the same CNTF secretion could be induced in uninjured retinas bythe application of lens proteins; in other words, that CNTF release was notjust due to injury or an inflammatory response. This is intriguing: perhapsastrocytes recognise lens proteins through Toll-like receptors, or otherinnate immunity mechanisms? Antibodies to CNTF (but not anti-oncomodulin)blocked the regeneration of retinal ganglion cells induced bylens injury. And, crucially, dibutyryl-cAMP (which raises intraocularcAMP) amplified this regeneration. So, is the implication that everyonewith an optic nerve injury should have a scalpel through their lens?Perhaps not. But there are real implications for treatment: the CNTF-productionfacility of astrocytes could be exploited to promote optic nerverepair by applying non-toxic lens proteins and drugs to boost cAMP. Giventhat this might be the difference between useful sight and not, this is nosmall discovery. – AJCMüller A, Hauk TG, Fischer D.Astrocyte-derived CNTF switches mature RGCs to a regenerative state followinginflammatory stimulation.BRAIN2007 Dec;130(Pt 12):3308-20.NEUROLOGY JOURNALS: Oooops!It is rare to get frank self-criticism in the editorial of a journal. But StephenHauser has gone out of his way to apologise for a press-release from theAnnals of Neurology. This all arose because of a growing feeling that epidemiologicalresearch gets too much, or inappropriate, press attention. SoHauser set up a little internal research to decide how the Annals promotedsuch research. In 2006, 84 of the 280 published manuscripts were epidemiological.Five of the 20 top-cited publications were epidemiological. And, ofthe 7 press releases for 2006, six were epidemiological. So, it does seem theyare giving disproportionate attention to this sort of research. And, when theyreviewed their press release for one of these studies [Scarmeas N et alMediterranean diet and risk for Alzheimer's disease Ann Neurol 2006Jun;59(6):912-21], they felt the journal had to take some of the blame formedia distortions of the investigators’ careful conclusions. Surely, never aproblem for ACNR! – AJCJohnston SC, Hauser SL.Epidemiology in the Annals: part of the problem or the solution?ANNALS OF NEUROLOGY2007;62(4):A8-9.EPILEPSY: Moving from epilepsy treatment topreventionThere are certain lesions which we know have a high risk of being complicatedby epilepsy: major cerebral trauma, parenchymal CNS infection andintracerebral haemorrhage. So far all we can do is to wait and see ifseizures occur and then treat them as best we can. How much better toidentify those patients in whom epileptogenesis is taking place and treatingthem with drugs to abort the process. In this study, rats were given alateral fluid-percussion brain injury, the laboratory rodent equivalent ofassault with a baseball bat. They then had repeated MRI scans from hoursafter injury up to one year. All animals, whether having suffered traumaticbrain injury or not, were exposed for just one hour to the epileptogenicagent pentylenetetrazole (PTZ) at one year after injury, using previouslyrecognised subconvulsant doses and then underwent video-EEG-telemetry.At the end of this process, their brains were examined for mossy fibrereorganisation in the hippocampus, a common marker of epileptogenesis.The injury on its own was not enough to produce epileptic activity in anyof the control animals but subconvulsant doses of PTZ caused electrographicabnormalities in all animals, controls and injured. There was noassociation between MRI evidence of cortical damage and the increasedseizure susceptibility. The latency to onset of spikes was significantlyshorter, and the number of spikes and epileptiform discharges significantlygreater, in animals with traumatic brain injury. MRI showed an early(hours) fall in diffusion tensor signal from the ipsilateral hippocampus ofinjured animals and which then rose progressively compared to controlanimals, peaking at three months. T2 weighted signal in the ipsilateralhippocampus rose compared to controls progressively from about 3months. Injured animals had mossy fibre sprouting into the inner molecularlayer of the hippocampus and this was positively correlated with EEGmeasures of seizure susceptibility. This study identifies changes which maybe markers of evolving seizure susceptibility. The questions to beaddressed include their applicability to humans and whether any treat-48 I ACNR • VOLUME 8 NUMBER 1 • MARCH/APRIL 2008

Journal Reviewsments can influence this development and help to prevent late post-traumaticseizures, rather than simply trying to treat them (regrettably oftenunsuccessfully) after they have started. – MRAMKharatishvilli, Immonen R, Grohn O, Pitkanen A.Quantitative diffusion MRI of hippocampus as a surrogate marker for posttraumaticepileptogenesis.BRAIN2007;130:3155-68.BRAIN INJURY: Trauma, drugs and alcoholBecause of the circumstances in which traumatic brain injuries are sustained,issues around drugs and alcohol often emerge during a patient’srehabilitation. This study looks at drug and alcohol use pre- and post- traumaticbrain injury in an attempt to establish factors associated with heavypost-injury substance abuse. The basic method involved patients recalling(which is surely a problem in the brain-injured population) their pre-morbidlevels of usage, and then re-assessing them at 1 and 2 years post-injury.There are no differences in baseline (pre-morbid) levels of substance usebetween patients and demographically matched controls. Perhaps, not surprisingly,the authors show that young, male, heavy drinkers are most likelyto return to alcohol. Drug and alcohol use tends to diminish at 1 year butrises to levels approaching pre-morbid use at 2 years. What was encouraging,but somewhat understated in the discussion, was that very few peopleactually increased their drug and alcohol consumption following a braininjury. From this the authors conclude that there is a need for more activeintervention to reduce alcohol and drug use following brain injury. While,as a principle, this would seem admirable, it would be interesting to seeresearch demonstrating the effectiveness of such an intervention in thispopulation. It is also, perhaps, worth considering if it is not overly paternalisticto try and modify peoples’ lifetime basic behaviours and attitudes justbecause they happen to have had a brain injury. The social environment is astrong factor in guiding attitudes to recreational substances, generally, andit is interesting that the authors highlight the advice given in the States tocompletely abstain from alcohol permanently following a head injury conflictswith that given in Australia, where patients are advised that a return todrinking after a year has passed is permissible. – LBPonsford J, Whelan-Goodinson R, Bahar-Fuchs A.Alcohol and drug use following traumatic brain injury – a prospectivestudy.BRAIN INJURY2007;21:1385-92.HEADACHE: Migraine and sinusesWWW RECOMMENDEDWe all meet patients who vehemently deny migraine but have regular“sinus” headaches. Sometimes these even get worse perimenstrually, andoften have other migrainous features. So this article is interesting. Itexamined the rate of radiological sinus disease in migraineurs and thosewith “sinus headache”. It is a step in untangling the knot of people withmigraine and sinus changes, a step towards getting them onto the righttreatment. The impetus for the study is that previous work suggests thatmost patients with “sinus headache” fulfil the International HeadacheSociety (IHS) criteria for migraine. This makes it difficult to know what iscausing their symptoms. There are few studies on this question, and onwhether CT scan findings distinguish the groups. Thirty-five patients presentingwith sinus headache were prospectively scanned for sinus disease.Using validated methodology (Lund-Mackay score, [L-M score]), thesescans were assessed for sinus abnormalities. A control group ofmigraineurs had their scans analysed in the same way. Of the sinusheadache group, 74 % had migraine by IHS criteria. There was no differencein CT scan L-M scores between the two groups (2.07 in the migrainegroup and 2.66 in the “sinus” cohort). Five of the migraine group had significantsinus disease radiologically. The authors conclude that the majorityof “sinus headache” patients satisfy IHS criteria for migraine, and aresurprised that many of these have sinus disease radiologically. Because anumber of migraine patients also have sinus disease they suggest we shouldbe looking harder for sinus disease in migraineurs. I would view the situationsomewhat differently. This small but useful study shows that radiologicalfindings don’t correlate well with the clinical diagnosis. There are falsepositives and negatives, and further it’s hard to estimate the level of incidentalsinus disease in the background population. This adds to the needfor caution in interpretation of radiological changes of sinus disease. Thedistinction between migraine and sinus headache is sometimes opaque,and radiological disease is not enough to diagnose causality. As its notalways the cause of the symptoms, we need to remain careful to avoid sendingthe wrong patients down medical and surgical sinus treatment paths,when what they need is good migraine prophylaxis. – HALMehle ME, Kremer PS.Sinus CT findings in “sinus headache” migraineurs.HEADACHE2008;48:67-71.HEADACHE: Migraine incidenceThere is little definitive data on the incidence of migraine in the community.This study quantified incidence and comorbidity in a large cohort using theGeneral Practice Research Database. 51,688 patients with a first time diagnosisof migraine were found, between 1994 and 2001. The migraine incidencerate was 3.69% cases per 1000 person-years and was 2.5 times more commonin women. Compared to age-matched controls, most common chronic diseaseswere slightly more prevalent in migraineurs. Patients using triptanshad higher health care utilization than other migraineurs. Possibly thesepatients were those who developed chronic daily and analgesia overuseheadaches. However, this finding is open to so many interpretations that it ishard to draw any definite conclusions from it. The study provides solid incidencedata on the most common neurological ailment we see. – HALBecker C, Brobert GP, Almqvist PM, Johansson S, Jick SS, Meier CR.Migraine incidence, comorbidity and health resource utilization in the UK.CEPHALGIA2008;28:57-64.EPILEPSY: Does your mother’s epilepsy or educationmatter most?The authors assessed 71 children of mothers with epilepsy (CME), identifiedprospectively from an epilepsy and pregnancy register. The children underwentan Indian adaptation of the Wechsler IQ test and a specially designedlanguage test in the local Malayalam language at around the age of six andwere compared to controls, matched for age and educational status. Theydeveloped a score for AED exposure, comprising tenths of a standard dailydose (each tenth scored ten points) of each drug and this allowed them tohave a measure of total drug load, independent of which drug was beingtaken, as well as looking at different AED and monotherapy versus polytherapy.Their mothers had mild epilepsy compared to a standard neurologyoutpatient cohort, with over half having either no seizures or just one seizureduring their pregnancy.The mean FSIQ of CME was 87.7 compared to 93 (P=0.02) for controls.There was an especially dramatic difference in language function between thetwo groups. In a multiple regression analysis, the strongest predictor of IQwas maternal education, with medication having a weaker association andseizure type or severity no association at all. There was no difference betweenmonotherapy and polytherapy, but numbers were small. For 50 CMEexposed to an AED score 90.If maternal education is the key determinant, the study begs the question ofwhat factors underlie this? Is it their epilepsy, their drugs or other factors?The study does raise the optimistic possibility that poorly educated motherswith epilepsy could be identified and they and their children targeted foreducational support. – MRAMThomas SV, Sukumaran S, Lukose N, Geore A, Sarma P.Intellectual function and language functions in children of mothers withepilepsy.EPILEPSIA2007;48:2234-40.BRAIN INJURY: Calling time on prognosisWWW RECOMMENDEDOne of the most challenging elements to dealing with the families and friendsof those who have suffered severe brain injury is being able to have a sensiblediscussion about the longer term prognosis without either being too vague ortoo definitive (and, inevitably being proved wrong). There are many indicators,in the acute stage, which have varying degrees of usefulness. Glasgowcoma scale on admission, duration of post-traumatic amnesia and initialbrain scan findings can all provide clues as to what the longer term outlookACNR • VOLUME 8 NUMBER 1 • MARCH/APRIL 2008 I 49

Journal Reviewsis likely to be for an individual being admitted to the neuro-intensive careunit. Uncertainty, however, is accepted in this environment. Six months later,in an outpatients’ clinic, the situation has changed, somewhat. “Will he get anybetter?” The authors of this study have used the Glasgow Outcome ScaleExtended (GOSE) to track the outcomes for 214 brain-injured patients admittedto an intensive care unit with a GCS of

Book ReviewsIf you would like to review books for ACNR, please contact Andrew Larner, Book Review Editor, c/o rachael@acnr.comUnderstanding Neurology – A Problem Orientated ApproachIn the veritable forest of publications to bring neurologyto students, and vice versa, another sapling springs forth.Whether it will survive and find a niche time & sales willtell but I doubt it will be the last on the subject. Theauthors have wrestled with an old problem. Clinicallyorientated neurological information is relevant andinteresting, fun to learn, easy to retain, and makes youlook good at the bedside. But it is based on preclinicalneurological information which for some poor souls canbe less fascinating, seldom fun to learn, hard to retain,and producing it could make you look either sad or aswot. This offering of a “problem-orientated approach tothe commonly presenting complaints seen by neurologists”is an admirable effort to get the balance right.Thirteen contributors, a dozen working in Glasgowand one representative from the not-so-soft South(Essex) take us through familiar territory with 11 pageson history taking (of which half concerns cognitive neurology).This is supplemented throughout the book byexcellent subsections on “focused” history taking whichserve to highlight the immense and undiminished diagnosticpotential of this clinical art which, though seeminglyless appealing to those who feel diagnosis can beachieved by just ordering a scan or two, survives (andeven excels through the unlikely persona of Hugh Laurieas Dr Greg House; Channel 5US – don’t miss!). Indeedone doesn’t have to wait long for the first brain scan (fivepages in). Furthermore, the second chapter - neurologicalinvestigation, runs to 35 pages perhaps underpinningsentiments expressed that “the advent, easy availability,and low risk of cross sectional imaging have undoubtedlydiluted clinical skills….the current danger is that ofover –investigation and that clinical skills are reducedsuch that investigations are targeted to the wrong site orincidental imaging findings are mistaken as relevant.”And don’t neurologists, increasingly invited to extinguishthe fireworks ignited by ill-advised colleaguesdoing ill-advised tests (“just to be on the safe side / reassurethe patient” / insert your own pet hate phrase) knowit! Perhaps a section on the pitfalls of investigation,“When scanning is a bad idea”, may come one day. Theradiological images in this book are appropriately illustrativewith a valiant effort to explain how MR actuallyworks, still a mystery to me. Again a “pitfalls” or “incidentaloma”section would, I think, be very informative.I was surprised to read in the spinal cord section of thischapter that the spinal cord ends at L2/L3. I have alwaysthought & taught it to be a space higher, as do laterauthors in this book.The neurophysiology section is informative in a qualitativeif not quantitative way.A few more problem-orientated “peripheral” cases toillustrate the values (& pitfalls) of these tests wouldenable normative data to be included and bring what canappear a rather dry subject to its appropriately vibrantstatus.And so to “The Problems” which constitute ¾ of thebook and this bit I liked a lot.Divided into five subsections with disorders of consciousnessincluding acute confusional states, (withinevitable overlap with), cognition, special senses(vision, dizziness & vertigo, with inevitable overlapwith), a seminal chapter on “motility” (incoordination,weakness, movement disorders), and finally “sensation”(headache, neck pain & back ache, numbness & tingling).Cognition features a lot in this book which is no badthing given the high prevalence, imperfect understandingnot wholly confined to juniors, and undeniably neurologicalnature of dementia. As in all sections the end ofchapter cases help make it relevant and demonstrate howknowing stuff helps. An additional nod to the problemorientatednature of life in the clinic would include a bitmore on helpful clinical pointers that differentiate thoseworried well with “short term memory” problems thatare not dementing, but attend neurology clinics in everincreasing numbers, from those who are.The sections on vision and vestibular disorders areawash with illustrative cases and more digestible andenjoyable for that. A few quibbles if I may: do patientswith paretic eye muscles really tilt their heads “away”from the direction of the paretic muscle to minimizediplopia?; an explanation of why only the first divisionof V is affected in cavernous sinus lesions despite twodiagrams showing that both first & second divisions canbe found there would be informative. These are minor, ifimportant, points.The “dizziness & vertigo” and “motility” sections bothmake the obvious but crucial point that many patientsreferred to neurology with neurological symptoms havediseases outside the nervous system. This cannot beoveremphasised in our era of subspecialisiation. Again afew quibbles detract somewhat from what are in manyways well written sections. Hip flexion appears in the L1,2 myotome and also L4: knee flexion appears as an L5 rootphenomenon and an S1 phenomenon two pages later; andwhilst many would argue the value of the incorrectlynamed “supinator” jerk I’m not sure it is yet timely toexclude it completely from “Reflexes routinely tested,”especially if the finger jerk (admittedly more useful butsurely less widely known at junior level) is included. Alater table of reflexes & roots would seem to concur. Also(sorry to go on but..) a table listing what distinguishesUMN & LMN problems that proceeds - power, tone,reflexes, plantar responses, bulk - would jar with many ofmy more particular colleagues (and to be honest, me too).The well written movement disorder section includedsome functional images which always provide visualrelief if not pleasure. I now know that Froment (assumingit’s the same docteur) has two signs, the other onebeing accentuation of muscle tone with contralaterallimb activity. Done it for years & never knew it had aneponym – ah, the joy of learning!The final two sections on spinal symptoms and numbness& tingling show how just much useful informationcan be crammed into 24 pages – with pictures and tables(one even duplicated in case you missed it five pages previously!)included.Perhaps one should accept that whilst demystifyingneurology remains an urgent necessity amongst trainees,the development, acquisition and retention of such skillscannot exist without a solid grounding of neurologicalknowledge, which informs knowing what questions toask, and why. This book strives with some success toachieve this educational balance. A touch of editorialrigour would go a long way, too.Andrew Larner, WCNN, Liverpool, UK.Authors: John Greene andIan BonePublished by: Manson PublishingISBN: 978-1-84076-061-3Price: £24.95ACNR • VOLUME 8 NUMBER 1 • MARCH/APRIL 2008 I 51

Book ReviewsIf you would like to review books for ACNR, please contact Andrew Larner, Book Review Editor, c/o rachael@acnr.comDizziness – A Practical Approach to Diagnosis and Management“There can be few physicians so dedicated to their art thatthey do not experience a slight decline in spirits on learningthat their patient’s complaint is of giddiness.” BryanMatthews’ famous quote (Practical Neurology, 3rd edition.Oxford: Blackwell, 1975: 76), recently paraphrased inthese pages by John Bowen (ACNR 2007; 7(2): 19), isfamiliar to many neurologists. But what is it that causesthe spirits to sink? The complex neuroanatomy of thevestibular systems? A feeling that ENT surgeons ratherthan neurologists should be dealing with the problem ofdizziness (they often send patients our way, so perhapsfeel the converse)? The concurrence of psychiatric symptomswhich may perhaps “drive” the complaint of chronicdizziness, as in chronic headache?This well-produced volume in the Cambridge ClinicalGuides series is a symptom-oriented text accompanied bya CD-ROM with 45 clips by two well-known neuro-otologistswhose target audience includes any doctor calledupon to assess dizziness, hence primary care physiciansand A&E doctors as well as neurologists and ENT surgeons.They hope to make clinicians more optimisticwhen approaching these problems.Introductory chapters on anatomy, symptoms andexamination are followed by specific symptoms: acutesingle episode vertigo, recurrent vertigo, positional vertigo,chronic dizziness, falls in the elderly, concluding withnotes on vestibular rehabilitation. The importance ofclinical history taking and examination, especially of eyemovements, is emphasized throughout. The fact that“vestibular function tests” generally address only one-fifthof the vestibular system (2) may explain the common scenario(Clin Otolaryngol 2007;36:217-8) of the dizzypatient referred from ENT to neurology to exclude a centralcause because “vestibular function tests are normal”yet whose history and examination suggest a peripheralorigin for symptoms. Migrainous vertigo seems underdiagnosedas a cause of recurrent vertigo and Meniere’soverdiagnosed (30). The intimate connection of vestibularand psychological symptoms (anxiety, panic, depression,somatisation) is addressed (117-24). The conceptsof vertebrobasilar insufficiency (10) and cervical (28,185)or head extension (153-4) vertigo are debunked, and thelack of utility (low specificity) of the hyperventilation testpointed out (123,169). Betahistine does not feature in thelist of “10 common vestibular suppressants and antiemetics”(209-12), despite the frequency with which it is usedin the patients reaching my clinic.This is a pragmatic text, steeped with the authors’ experience.I have few quibbles: it would have been desirablein the index of videoclips (xii-xiii) to cross reference thetext where they are discussed. I foresee circumstances inwhich the recommendation a propos chronic dizziness to“send a few too many patients for neurological consultation”(171) might be misconstrued by an enthusiasticENT SpR or GP trainee with rather significant consequencesfor local neurology outpatient clinics. A 70% hitrate for the aetiology of peripheral neuropathy (181)seems optimistic.Short of having Adolfo Bronstein universally availableto sort out dizzy people, this book is a very acceptableaddition to a neurologist’s armamentarium for dealingwith a common clinical problem.AJ Larner, WCNN, LiverpoolAuthors: Adolfo M Bronstein andThomas LempertPublished by: CambridgeUniversity PressISBN: 0-521-83791-XPrice: £35.00Neurological Disorders in Famous Artists (Part 2)The visual arts seem to predominate in this second volumeof neurological disorders in famous artists fromthe Karger Frontiers of Neurology and Neuroscienceseries. The effects of both neglect and of aphasia onvisual artistic output are examined (Blanke), the formermostly after right hemisphere stroke (Bazner &Hennerici x2), for example in the painter Lovis Corinthand the film-makers Visconti and Fellini (Dieguez et al),the latter after left hemisphere stroke, for example in thepainter Reutersward (Colombo-Thuillard & Assal). Thehigh quality illustrations support the various authors’theses. A possible depiction of sleep paralysis in a paintingby Fussli (Baumann et al) is also presented.There are several chapters of straight pathography:Proust (Bogousslavsky) did not clearly have any neurologicalailment although his asthma was regarded as a“nervous” disease, not least by his medical father, and heconsulted Babinski amongst many others; Heine (Aufder Horst), a victim of syphilis; Baudelaire (Dieguez &Bogousslavsky) developed aphasia with recurrent utterances.Musicians are in a distinct minority: von Bulow(Wohrle & Haas) is best known for being cuckolded byWagner but had additional problems, not least occipitalneuralgia and strokes. The evidence for and againstMozart having had Tourette syndrome is carefullyweighed and found wanting (Kammer).The emergence of artistic behaviour following braininjury (Pollak et al), mostly frontotemporal dementiabut also in selected cases of epilepsy, Parkinson’s disease,and following subarachnoid haemorrhage, is trulyfascinating. The problem of de Kooning’s late work,produced when he was suffering from Alzheimer’s disease,is reported solved (Espinel) through the developmentof no less than an entirely new intellectual discipline,“ArtScience”, requiring specific thinking andobservation methods, all devised (single-handedly) bythe author. Myself a dullard, subscribing to the GordonHolmes approach (“Observe and describe, that’s all”),methinks this author doth protest too much! The placeof synaesthesia in creativity is discussed (Mulvenna): isit a chance concurrence or over-represented in artists?Surprisingly in this context, Kevin Dann’s book, Brightcolors falsely seen: synaesthesia and the search for transcendentalknowledge (New Haven and London: YaleUniversity Press, 1998) is not referenced. The discussionprompts a distinction between “creative cognition”(= having ideas) and creative output (= trying to communicatethem).As with the first volume (reviewed ACNR 2005; 5(5):37) one can enthusiastically recommend this volume.Although not cheap, many neurologists with broaderinterests will be keen to have a copy.AJ Larner, WCNN, Liverpool, UK.Edited by: J Bogousslavsky,MG HennericiPublished by: Karger, 2007ISBN: 978-3-8055-8265-0Price: €88.0052 I ACNR • VOLUME 8 NUMBER 1 • MARCH/APRIL 2008

News ReviewNews Review£140 Million Managed Equipment Service Commences Artis zeego provides imagingexcellence and unrivalledflexibility for interventionalenvironmentsUniversity Hospitals ofLeicester NHS Trust andAsteral have announced a£140 million (at today’sprices), 18.9 year ManagedEquipment Service (MES) contract.This is the largest standalone MES contract in Europeto date.Under the terms of theagreement, Asteral will install,commission, maintain andmanage the latest equipmentacross the Trust’s multiple sitesfor the lifetime of the contract. It will alsoprovide project management, training andrelated support services across each site.Helen Seth, Deputy Director of Operationsat the University Hospitals of Leicester NHSTrust, states, “This is an innovative approachto the procurement, managementand replacement of over 210items of clinical equipment thatwill deliver real benefits to thepatients served across the healthcarecommunity of Leicester,Leicestershire and Rutland usingour hospitals.”Asteral’s MES model delivers afully integrated approach to procurement,management and maintenanceof medical equipment.Asteral is completely independentof the equipment supply companies.In partnership with the Trust it uses itsscientific and medical engineering expertise toensure the optimum combination of equipmentis selected to meet each Hospital’s needs.Further information can be found atwww.asteral.comGreat Ormond Street Hospital opens innovative new MR& CT Imaging CentreUnique MR & Cardiac Angiography suite connected byMyabi table in situ and operational at Great Ormond StreetHospital’s new MR & CT Imaging Centre.Great Ormond Street Hospital has officiallyopened its state-of-the-art MR & CT ImagingCentre. The new facility has been developedto provide a high quality diagnostic imagingand interventional treatment service whilstensuring comfort for its young patients.The Siemens portfolio at Great OrmondStreet Hospital includes an independent MAG-NETOM Avanto Cardiac MR unit; a MAGNE-TOM Avanto MR combined with an ‘Artis dBC’Cardiac Angio suite incorporating Myabipatient transfer table and a SOMATOMDefinition Dual Source CT Scanner. A ‘SymbiaT2’ SPECT/CT Nuclear Medicine Scanner isalso due to be installed shortly. All equipmentis connected to a Siemens PACS and MedconCardiac system for fast image archiving andrecall.“Great Ormond Street Hospital is a recognisedcentre of excellence for paediatric diagnosisand treatment,” said Peter Harrison,Director of Imaging & Oncology Systems atSiemens. “We are delighted to have beeninvolved in the provision of new equipmentand in devising a unique and bespoke MRIand angiography solution. Collectively the newequipment will extend the provision of careoffered to patients and work towards improvingclinical outcomes well into the future.”The official opening event was held on 17thJanuary 2008 and involved key hospitalstakeholders. Dr Jane Collins, Chief Executiveof Great Ormond Street Hospital addressed theguests and assisted Oliver Barlin, a 9-year-oldpatient, to unveil the commemorative plaquemarking the opening of the new MR & CTImaging Centre.For more information contact: SiemensT. +44 (0)1276 696000,E. medmarketing.med.gb@siemens.comW. www.siemens.co.uk/medicalArtis zeego ® , the newly launched multi-axis C-arm for interventional imaging, has beeninstalled at the Institute for Clinical Radiologyat the University of Munich Hospital. The rotationtechnology enables the physician to viewvessels more easily from various sides, especiallywhen evaluating tumours or vasculardiseases.Peter Harrison, Director of Imaging &Oncology Systems at Siemens, claims that“The zeego heralds the introduction of automotiveindustry precision robotics in angiographysystems. The flexibility of the mechanicsaffords clinicians unprecedented flexibility andvessel visibility. The system also significantlyincreases image volume coverage and simplifiesworkflow during intervention,”The engineering and development of thisnew angiography system has transferred fromindustrial robotics. The Artis zeego has 8 pivotpoints extending imaging capabilities throughvirtually unrestricted C-arm positioning, givingunprecedented flexibility in catheter labs andoperating rooms. The extra positioning flexibilityallows for advanced cross-sectional imagingnot achievable with traditional C-arm systemsand also enables off-centre rotational angiographyfor all areas of the body. The Artis zeegois part of the Siemens Artis zee family of interventionalcardiology and radiology systems.For more information contact: SiemensT. +44 (0)1276 696000,E. medmarketing.med.gb@siemens.comW. www.siemens.com/artis-zee.‘Just doodle it!’What do Joanna Lumley, Ricky Gervais andSuzanne Shaw all have in common? Theanswer, National Doodle Day 2008 of course!The nation’s doodlers are being encouraged tojoin these celebrities and put pen to paper andjoin the fifth National Doodle Day on March 7.The event raises vital funds for EpilepsyAction and The Neurofibromatosis Associationand with the support of Lloyds Pharmacy andBIC stationary. Both companies have generouslydonated large prizes for a number of thisyear’s competitions.With a theme of ‘Just doodleit’ it appears as though manycelebrities have done just that.We have already received doodlesfrom an array of celebritiesfrom Sir Ian McKellen to Sally Gunnell andfrom Sir Bobby Charlton to Nick Park!To celebrate, people can take part in thecompetition by picking up individual entrycards at branches of Lloydspharmacy for a £1donation. Judging will be carried outby Maureen Lipman, the Doodle Daypatron.Paul Tranter, Epilepsy Action’sfundraising manager, said: “We’renow on our fifth National Doodle Day,we're hoping that lots of people are going toget involved and let their creativity flow.”For further information visitwww.nationaldoodleday.org.uk orT. +44 (0)113 210 8800.ACNR • VOLUME 8 NUMBER 1 • MARCH/APRIL 2008 I 53

News ReviewHand-carried ultrasound benefits ICU and surgicalpatients(L to R) Tim Clarke, Rudi Brits and Stephen Holgate withtheir MicroMaxx ultrasound system.Intensive care consultants and anaesthetists atthe East Lancashire NHS Hospitals Trust, UK,rely on SonoSite hand-carried ultrasound systemsfor placing central lines, and for performingnerve blocks during upper and lower limbsurgery at the Royal Blackburn and Burnleyhospitals.“We use our MicroMaxx ® ultrasound systemon a daily basis for interscalene, femoral andsciatic nerve blocks, as well as for vascularaccess,” said Dr Rudi Brits, Consultant inIntensive Care and Anaesthesia at the RoyalBlackburn Hospital. “Being able to visualisethe nerve as well as the anaesthetic duringthe injection has a number of advantages andin time we hope to see greater success rates,reduced risk of complications and less requirementfor anaesthetic.”“The MicroMaxx system is very compactand easy to carry around, and its clear imageresolution also makes it a really good teachingaid,” Dr Brits continued. “Several of our staffare attending ultrasound training courses andcan just pick up the system whenever a blockis being performed, so they are constantlylearning.”For more information,T. +44 (0)1462 444 800,F. +44 (0)1462 444 801E. europe@sonosite.comW. www.sonosite.comOvercoming challenging delivery of MRI magnetsNew access road built especially for the bulky and heavy deliveryLondon’s National Hospitalfor Neurology andNeurosurgery has recentlytaken delivery of three largeMRI magnets for machinesfrom the Total Imaging Matrix(Tim) family, as part of theongoing project to completethe building of the hospital’snew imaging centre.Gary Cook, London SalesManager at Siemens states,“The delivery of large MRImagnets can sometimes presentproblems due to theirweight and dimensions, especiallyto older hospital sitesthat have unknown groundworkor underground vaults.However, by working in partnership with hospitalestate managers, constructioncompanies and projectmanagers all situations canbe overcome. The end of anequipment sale is just the startof the delivery and installationprocess.”Further technology will bedelivered to London’s NationalHospital new imaging departmentin due course. Thisincludes a biplane neurologysystem, CT scanner and anotherMRI scanner.For more information contact:SiemensT. +44 (0)1276 696000,E. medmarketing.med.gb@siemens.comW. www.siemens.co.uk/medicalWiley-Blackwell book offer to all ACNR readersWiley-Blackwell is one of theworld’s foremost academicand professional and thelargest society publisher, providingmust-have contentand services to customers worldwide. With anextensive collection of journals and books publishedin a variety of print and electronic formats,you are sure to find something invaluablewithin your area of expertise.Wiley-Blackwell is delighted to offer allACNR readers an exclusive 20% book discount.Browse our extensive collection ofNeuroscience titles onwww.wiley.com/go/lifesciences and takeadvantage of this fantastic offer now!To receive your discount, simply quote promotioncode ACNR when you purchase abook. It’s that easy!Answering questions for lifein the 21st centurySiemens debuts its MR & CTinnovations to satisfy UK clinicaland cost expectationsGunter Dombrowe, Managing Director of Siemens Medical,welcomes guests to the launch evening at the ScienceMuseum in London.The latest innovations in the field of CT andMRI imaging have been formally launched inthe UK by Siemens at the Science Museum inLondon.A high-field 3T MRI system, the MAGNE-TOM Verio and an adaptable single source CT,the SOMATOM Definition AS, have both beendesigned to offer advanced imaging functionalityfor routine and specialised clinical proceduresat a much more viable capital cost forthe UK health marketplace.With the NHS and private diagnostic centresdemanding higher throughput rates and areturn on investment, the new systems meetclinical and cost expectations.The MAGNETOM Verio is a 3T field strengthMRI and can be used in neurology and functionalneuro evaluation, orthopaedic and cartilageassessment, breast, vascular and cardiacimaging. It has a wider than normal open bore(70cm) and features Tim (Total imagingmatrix) in one powerful system. This offersadvanced imaging capabilities with thepatient’s comfort in mind. Furthermore, it isan affordable capital purchase and efficient tooperate.The SOMATOM Definition AS and DefinitionAS+ break with the normal conventions of CTas the world’s first adaptive scanners. Thissimply means they can adapt to any patient orclinical need in routine diagnostic work andcomplex examinations including cardiology,neurology and oncology.For more information contact: SiemensT. +44 (0)1276 696000,E. medmarketing.med.gb@siemens.comW. www.siemens.co.uk/medicalThe SOMATOM Definition AS on show.54 I ACNR • VOLUME 8 NUMBER 1 • MARCH/APRIL 2008

News ReviewNews ReviewPartnerships in Care opens its first facility in ScotlandPartnerships in Care (PiC), the UK’s leadingindependent provider of specialist mentalhealth care and related services, is pleased toannounce the purchase of its first hospital inScotland, The Ayr Clinic in Ayrshire.The Ayr Clinic is a 24 bed low secure, purposebuilt psychiatric unit providing secure inpatientcare and treatment for men andwomen suffering from mental illness, personalitydisorder or a mild learning disability.On completion of the purchase, MylesPaterson, Regional Executive Director forPartnerships in Care in Scotland said, “Welook forward to working in partnership withThe Scottish Forensic Network and the localhealth boards to extend our first class mentalhealth services to new purchasers, enhancingthe quality of existing services and building onthe good relationships that have already beenestablished.”Andreana Adamson, Chair of the ForensicNetwork in Scotland, welcomes the arrival ofPiC to Scotland: “PiC has a well respectedreputation in the field. Clinicians are experiencedin referring patients to the services PiCoffer in specialist forensic services, particularlyin their units in the North of England.”For more information:T. +44 (0) 20 8327 1818E. LHamblin@partnershipsincare.co.ukPartnerships in Care launches its brand new websitePartnerships in Care (PiC), the UK’s leadingindependent provider of specialist mental healthcare and related services, is pleased to announcetoday the launch of its brand new companywebsite at www.partnershipsincare.co.ukThe new site provides commissioners, healthcareprofessionals and other audiences interested inPiC with:• increased functionality, including easier andmore intuitive site navigation• more in-depth information on the local serviceswe provide• further assistance for referrals• an online job application processThe launch ties in with PiC’s latest hospitalacquisition, The Ayr Clinic in Scotland,announced separately today.Fred Sinclair-Brown, Group Chief Executive ofPartnerships in Care said: “We now have 23hospitals providing services to over 180 primarycare trusts, commissioning consortia and socialservices. We are excited to launch a new websitethat reflects the size and depth of our organisationand hope the new website provides customersand other interested parties with easyaccess to all the information they need.”For more information:T. +44 (0)20 8327 1818,E. LHamblin@partnershipsincare.co.ukPresident of the Motor Neurone Disease (MND)Association, Lembit Opik MP, was presented with acheque for £5,000 from The Hospital SaturdayFund (HSF), the charitable trust associated withHSF health plan. The cheque was presented toLembit at the House of Commons and is to beinvested in research into MND.After receiving the cheque Lembit said: “TheHSF has always been a life saver and today they’veput their money behind this noble intent by givingAwards and AppointmentsCheque presented to president of MND Associationa hugely generous £5,000 to the cause of curingMND.“Every penny of the money given by HSF will bematched by the Government. So, in effect, this is a£10,000 contribution to the search for a cure.“On behalf of all those living with MND, andthose who won’t suffer it one day in the not-toodistantfuture, I thank HSF, their staff and theirvision of a world free of MND. It’s a vision we allshare.”The Encephalitis Society proudly welcomes their first presidentActors Martin Kemp, Patron of the EncephalitisSociety and Mathew Bose, Ambassador for theEncephalitis Society welcomed the first President ofthe Encephalitis Society, Professor Barbara Wilson,OBE. The event took place on 17 October 2007during a cruise along the river Thames in London.The Encephalitis Society is the only resource of itskind in the world providing direct support, informationand education to people affected by encephalitisand the professionals involved in their care. Onbehalf of the Society, Martin Kemp welcomedProfessor Barbara Wilson, OBE,‘I am delighted to welcome Professor Wilson andlook forward to working with her in our quest tosupport people affected by encephalitis and to raiseawareness of this very grave syndrome,’. ProfessorWilson has been a long standing clinical advisor toAva Easton, Development Manager,Encephalitis Society, Martin Kemp andProfessor Barbara Wilson, OBE.the Society and on her forthcoming retirement from theMedical Research Council, accepted the position ofPresident of the Society. Professor Wilson is a clinical neuropsychologistand international expert on memory problemsfollowing acquired brain injury: ‘It is a great honourto be invited to accept this position with the EncephalitisSociety,’ said Professor Wilson. ‘In my own field of braininjury rehabilitation, the patients most frequently referredfor cognitive rehabilitation are those with traumatic braininjury but after that the diagnostic group most seen aresurvivors of encephalitis. The professionalism and innovationshown by the Society in their quest to support andinform is quite breathtaking.’For further information contact: The EncephalitisSociety, 7b Saville Street, Malton, YO17 7LL,Tel. +44 (0)1653 692 583,E. ava@encephalitis.info W. www.encephalitis.infoACNR • VOLUME 8 NUMBER 1 • MARCH/APRIL 2008 I 55

COPAXONE ® (glatiramer acetate)PRE-FILLED SYRINGEPRESCRIBING INFORMATIONPresentation - Glatiramer acetate 20mgsolution for injection in 1ml Pre-filled Syringe.Indication - Reduction of frequency ofrelapses in relapsing-remitting multiplesclerosis in ambulatory patients who have hadat least two relapses in the preceding twoyears before initiation of therapy. Dosage andadministration - 20mg of glatiramer acetate(one pre-filled syringe) administered subcutaneouslyonce daily. Children (1%: Nausea,anxiety, rash, sweating, chills, face oedema,syncope, vomiting, lymphadenopathy, oedema,nervousness, tremor, herpes simplex, skinbenign neoplasm, eye disorder, vaginalmoniliasis. Rarely: Anaphylactoid reactions,convulsions, shifts in white blood cell counts,elevated liver enzymes (with no evidence ofclinical significance) and skin necrosis atinjection sites. Please refer to the SPC for afull list of adverse events. Overdose - Monitor,treat symptomatically. PharmaceuticalPrecautions - Store Copaxone in refrigerator(2ºC to 8ºC). If the pre-filled syringes cannotbe stored in a refrigerator, they can be storedat room temperature (15ºC to 25ºC) once forup to one month. Legal Category - POM.Package Quantity and Basic NHS Cost - 28pre-filled syringes of Copaxone: £545.59.Product Licence Number - 10921/0023.Further Information - Further medicalinformation available on request from TevaPharmaceuticals Limited, The Gate House,Gatehouse Way, Aylesbury, Bucks, HP19 8DBDate of Preparation - September 2007.Your decisiontodaycan make a differencetomorrowInformation about adverse eventreporting can be found atwww.yellowcard.gov.uk.Adverse events should also be reported toTeva Pharmaceuticals Ltd ontelephone number: 01296 719768.Reference: Ford C. et al. Multiple Sclerosis 2006; 12: 309-320.(glatiramer acetate)Long-term activeDate of preparation: October 2007Code: C0807/428a