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ISSN 1473-9348 Volume 5 Issue 1 March/April 2005ACNRAdvances in Clinical Neuroscience & RehabilitationREVIEW ARTICLESEmbryonic Stem Cells, Meng LiPost-Polio Syndrome – Diagnosis andManagement, Elisabeth FarbuConference and Society News • Journal Reviews • Diary of EventsMANAGEMENT TOPIC - The Management of Intracranial AbscessesCOGNITIVE PRIMER - ApraxiaREHABILITATION ARTICLE - Sacral Nerve Stimulation (Neuromodulation) for theTreatment of Lower Urinary Tract Symptoms in Adult Patientswww.acnr.co.uk

Female : 26Primary GeneralisedTonic-Clonic seizuresMale : 26Primary GeneralisedTonic-Clonic seizuresMuch of what makesLamictal an appropriatechoice for her……also makes it anappropriate choicefor himlamotrigine

ContentsMarch/April 20058 Review ArticleEmbryonic Stem CellsMeng Li10 Review ArticlePost-Polio Syndrome - Diagnosis and ManagementElisabeth Farbu12 Management TopicThe Management of Intracranial AbscessesPeter Whitfield16 Cognitive PrimerApraxiaSebastian Crutch20 Special FeatureA Topograhical Anatomy of False-Localising SignsAndrew Larner22 Neuropathology ArticleThe Neuropathology of Head InjuryColin Smith26 Book Reviews30 Events31 Conference NewsTraumatic Brain Injury - The Road to Recovery;15th International ALS/MND Symposium;American Epilepsy Society Annual Meeting35 Rehabilitation ArticleSacral Nerve Stimulation (Neuromodulation) for theTreatment of Lower Urinary Tract Symptoms in AdultPatientsStephanie Symons, Justine Barnecott and Simon Harrison38 Special FeatureDeep Brain Stimulation for Post Traumatic TremorAlex Green and Tipu Z Aziz40 Drugs in NeurologyThe Use of Tetrabenazine in Movement DisordersWendy Phillips and Roger Barker42 Reviews46 NewsAdditional web content www.acnr.co.ukSee www.acnr.co.uk/ case%20report.htm for a case of post-polio syndrome.ACNR • VOLUME 5 NUMBER 1 • MARCH/APRIL 2005 I 3

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Editorial Board and contributorsRoger Barker is co-editor of ACNR, and is Honorary Consultant inNeurology at The Cambridge Centre for Brain Repair. His main area ofresearch is into neurodegenerative and movement disorders, in particularparkinson's and Huntington's disease. He is also the university lecturer inNeurology at Cambridge where he continues to develop his clinicalresearch into these diseases along with his basic research into brain repairusing neural transplants.Alasdair Coles is co-editor of ACNR. He has recently been appointed tothe new position of University Lecturer in Neuroimmunology at CambridgeUniversity. He works on experimental immunological therapies in multiplesclerosis.Stephen Kirker is the editor of the Rehabilitation section of ACNR andConsultant in Rehabilitation Medicine in Addenbrooke's NHS Trust,Cambridge. He trained in neurology in Dublin, London and Edinburghbefore moving to rehabilitation in Cambridge and Norwich. His mainresearch has been into postural responses after stroke. His particular interestsare in prosthetics, orthotics, gait training and neurorehabilitation.David J Burn is the editor of our conference news section and Consultantand Reader in Movement Disorder Neurology at the RegionalNeurosciences Centre, Newcastle upon Tyne. He runs Movement Disordersclinics in Newcastle upon Tyne. Research interests include progressivesupranuclear palsy and dementia with Lewy bodies. He is also involved inseveral drugs studies for Parkinson's Disease.Andrew Larner is the editor of our Book Review Section. He is aConsultant Neurologist at the Walton Centre for Neurology andNeurosurgery in Liverpool, with a particular interest in dementia and cognitivedisorders. He is also an Honorary Apothecaries' Lecturer in theHistory of Medicine at the University of Liverpool.Alastair Wilkins is our Case Report Co-ordinator. He is Specialist Registrarin Neurology in Cambridge. His main research interests are the study ofaxon loss in multiple sclerosis and the molecular biology of axon-glia interactionsin the central nervous system.Roy O Weller is ACNR’s Neuropathology Editor. He is Emeritus Professorof Neuropathology, University of Southampton. His particular researchinterests are in the pathogenesis of Multiple Sclerosis, Alzheimer’s diseaseand Cerebral Amyloid Angiopathy.International editorial liaison committeeProfessor Riccardo Soffietti, Italy: Chairman of the Neuro-OncologyService, Dept of Neuroscience and Oncology, University and S. GiovanniBattista Hospital, Torino, Italy. President of the Italian Association of Neuro-Oncology, member of the Panel of Neuro-Oncology of the EFNS andEORTC Brain Tumour Group, and Founding member of the EANO(European Association for Neuro-Oncology).Professor Klaus Berek, Austria: Head of the Neurological Department ofthe KH Kufstein in Austria. He is a member of the Austrian Societies ofNeurology, Clinical Neurophysiology, Neurological and NeurosurgicalIntensive Care Medicine, Internal and General Intensive Care Medicine,Ulrasound in Medicine, and the ENS.Professor Hermann Stefan, Germany: Professor of Neurology /Epileptology in the Department of Neurology, University Erlangen-Nürnberg, andspecialises in the treatment of epilepsies, especially difficultto treat types of epilepsy and presurgical evaluation, including Magneticsource imaging (MEG/EEG) and MR-Spectroscopy.Professor Nils Erik Gilhus, Norway: Professor of Neurology at theUniversity of Bergen and Haukeland University Hospital. Research Dean atthe medical faculty, and Chairman for the Research Committee of theNorwegian Medical Association. He chairs the scientist panel of neuroimmunology,EFNS, is a member of the EFNS scientific committee, the WorldFederation of Neurorehabilitation council, and the European School ofNeuroimmunology board. His main research interests are neuroimmunologyand neurorehabilitation.ACNR • VOLUME 5 NUMBER 1 • MARCH/APRIL 2005 I 5

EditorialWelcome to the fifth year of ACNR. Once morethis issue has a variety of articles written byauthorative experts both from within the UKand abroad.The first of our review articles is on the post-polio syndromeby Dr Elisabeth Farbu from Bergen in Norway. Thiscondition is now relatively rare and despite being firstdescribed by Raymond and Charcot in 1875, has alwaysbeen a controversial area. I certainly remember as an SHOthe debates that used to rage on the Phipps (now Lane-Fox)respiratory unit at St Thomas’ Hospital as to whether thiswas a true disorder, or simply the natural ageing of a bodywith weak muscles. In her article, Dr Farbu lays to rest thiscontroversy by setting out in beautiful clarity the diagnosis(including the strict diagnostic criteria in table 1) andmanagement of this condition. This article is complimentedby a case report on the web site prepared by AlastairWilkins of a patient with this syndrome.Meng Li in her review article reveals the truth about embryonic stem(ES) cells, without any of the hype that often accompanies articles onthese, the most versatile, of stem cells. These stem cells have attractedmuch publicity not only in terms of the ethical issues they raise but theirbiological utility to reveal answers to normal development as well as theirpotential therapeutic use in neurological disorders. In this last respect theneed to engineer controlled differentiation of ES cells into neuronsremains a high priority, as does the need to prevent them from proliferatingin an uncontrolled tumourigenic fashion. Meng Li deals with theseissues along with the broader topic of using mouse ES cells to make transgenicanimals, which has so revolutionised modern biology. This article issuccinct, packed with information and a marvellous condensation of thisexpanding field – an area of neurobiology that will have relevance to allthose working in neuroscience and neurology.Neurosurgery in this issue takes on the subject of intracranial abscesses.Peter Whitfield takes us through this relatively rare condition with itsrange of presentations and therapies – many of which are surgical andbased on the approach of MacEwen from 1881 of “debridement anddrainage”. This article, as with all in these series, is steeped in commonsense and beautifully illustrated with plenty of relevant radiographicimages. This article is a superb accompaniment to the neuropathologyarticle by Daniel du Plessis in ACNR 4(6).The management of lower urinary tract symptoms is encountered bymost neurologists and rehabilitationists, and is typicallytreated using anti-cholinergic drugs and/or some form ofcatheterisation. In the article by Simon Harrison and colleaguesin this issue, we are given a state of the art discussionon the use of sacral nerve stimulators - a procedure that isnot without difficulties, but which also appears to be ofgreat value to some selected groups of patients. Althoughthis technique is expensive and still being developed, thearticle should at least raise the profile of this procedurewhich was certainly new to me.Neuropathology considers head injury (HI), and ColinSmith takes us through the different types of HI and howthey evolve over time. This touches upon other topics we havecovered in the past, including states of persistently alteredconsciousness (see Zeman ACNR 3(3)) and dementia. Thisarticle contains the usual educational plethora of histologicalimages.Andrew Larner tells us that no sign in neurology is to be believed!! Hediscusses the topographical anatomy of false-localising signs, startingwith Colliers paper in Brain in 1904, in which he observed that 12.4% ofpatients with brain tumours had false-localising signs. This short accountby Andrew is, as always, beautifully written (unlike most of my editorials)and is a real education.In the cognitive primer series, Sebastian Crutch discusses Apraxia. Thisinability to perform purposeful voluntary movements in the presence ofintact motor and sensory systems is one of the most fascinating andmemorable deficits in neurological practice. This article comprehensivelytakes us through the range of different types of dyspraxia, and how theycan be recognised and tested for along with their neural basis.In drugs in neurology, Wendy Phillips and myself discuss tetrabenazine– the drug most commonly prescribed for chorea and related movementdisorders. This drug, with its long history of use in neurology and psychiatry,is still not especially well-known to many practitioners because ofits relatively selective indications.As usual there are the journal, conference and book reviews. So asACNR enters 2005, do keep the feedback coming and thanks for all yoursupport and encouragement over the last 4 years with this exciting andevolving project.Roger Barker, Co-Editor,Email: roger@acnr.co.ukA new drug has been licensed in the USThere is a new potential treatment for multiple sclerosis: natalizumab,given by IV infusion once a month. We know this drug better by thename Antegren, although for some extraordinary reason the owners(Biogen) have renamed it Tysabri. It is a monoclonal antibody that targetsan adhesion molecule (VLA-4) on lymphocytes and so preventsthem from latching onto CNS endothelium and crossing the bloodbrain-barrier.Its approval is based on the 12 month data from twolarge, two-year phase III trials. The AFFIRM trial (n> 900) peopleshowed natalizumab reduced the relapse rate by 66 per cent comparedto placebo and the SENTINEL trial (n=1,200) showed that natalizumaband interferon-beta reduce relapse rate by 54% compared to interferonalone. However, before getting too excited, we need to see the trialdata. Astonishingly, the only information available at present is directlyfrom the manufacturing pharmaceutical company. The results have notyet been published in a peer-reviewed journal. Furthermore, the criticaldata -on whether natalizumab impacts on the accumulation of disabilityin multiple sclerosis - has not been released at all. An application forthe European licensing of natalizumab was submitted to the EuropeanMedicines Agency (EMEA) in June 2004 and a marketing authorisationis expected towards the end of 2005. Even if it is licensed, NICE willhave to be satisfied that natalizumab offers value for money, a testwhich the interferons failed. And if that is successful, neurology centresare going to have to face the daunting task of administering a monthlyinfusion to everyone who is suitable for the treatment. For the sake ofpeople with multiple sclerosis, who may have a lot to benefit from thisexciting treatment, we need to ensure natalizumab is efficiently andcritically assessed at each hurdle. Exciting times!Alasdair Coles, Co-Editor, Email: alasdair@acnr.co.ukACNR is published by Whitehouse Publishing, 7 Alderbank Terrace, Edinburgh EH11 1SX.Tel: 0131 477 2335 / 07989 470278, Fax: 0131 313 1110, Email: Rachael@acnr.co.ukPublisher: Rachael Hansford, Design & Production Email: production@acnr.co.ukPrinted by: Warners Midlands PLC, Tel. 01778 391000.Copyright: All rights reserved; no part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means,electronic, mechanical, photocopying, recording or otherwise without either the prior written permission of the publisher or a license permitting restrictedphotocopying 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 from action as a result ofmaterial in or omitted from this magazine. Any new methods and techniques described involving drug usage should be followed only in conjunction withdrug manufacturers' own published literature.This is an independent publication - none of those contributing are in any way supported or remunerated by any of the companies advertising in it, unlessotherwise clearly stated. Comments expressed in editorial are those of the author(s) and are not necessarily endorsed by the editor, editorial board orpublisher. The editor's decision is final and no correspondence will be entered into.Cover picture:Courtesy of PsychologyPress, taken fromDyslexia, Reading and theBrain by Alan Beaton.See page 45 for moreinformation.6 I ACNR • VOLUME 5 NUMBER 1 • MARCH/APRIL 2005

For adjunctive treatmentof partial onset seizuresin adults with epilepsy.Now availableKeppra ® oral solutionOne to build with.Strong.■ Clinically significant long-term seizure freedom 1Simple.■ No known pharmacokinetic interactions 2Solid.■ Very well tolerated 3Building powerful AED therapyKEPPRA ® Prescribing Information:Please read summary of product characteristics (SPC) before prescribing.Presentation: Keppra 250, 500, 750 and 1,000 mg film-coated tablets containing 250,500, 750 and 1,000 mg levetiracetam respectively. Keppra oral solution containing100mg levetiracetam per ml. Uses: Adjunctive therapy in the treatment of partial onsetseizures with or without secondary generalisation in patients with epilepsy.Dosage and administration: Oral solution should be diluted prior to use. Adults andadolescents older than 16 years: The initial therapeutic dose is 500 mg twice dailywhich can be started on the first day of treatment. Depending upon clinical responseand tolerability can be increased up to 1,500 mg twice daily. Dose changes can be madein 500 mg twice daily increments or decrements every two to four weeks. Elderly:Adjustment of the dose is recommended in patients with compromised renal function.Children (under 16 years): Not recommended. Patients with renal impairment:Adjust dose according to creatinine clearance as advised in SPC. Patients with hepaticimpairment: No dose adjustment with mild to moderate hepatic impairment.With severe hepatic impairment (creatinine clearance 10%): asthenia,somnolence. Common (between 1%–10%): GI disturbances, anorexia, accidental injury,headache, dizziness, tremor, ataxia, convulsion, amnesia, emotional lability, hostility,depression, insomnia, nervousness, vertigo, rash, diplopia. For information on postmarketingexperience see SPC. Legal category: POM. Marketing authorisationnumbers: 250 mg x 60 tabs: EU/1/00/146/004. 500 mg x 60 tabs: EU/1/00/146/010. 750 mgx 60 tabs: EU/1/00/146/017. 1,000 mg x 60 tabs: EU/1/00/146/024. Solution x 300ml:EU/1/146/027. NHS price: 250 mg x 60 tabs: £29.70. 500 mg x 60 tabs: £52.30. 750 mg x60 tabs: £89.10. 1,000 mg x 60 tabs: £101.10. Solution x 300ml: £71.00.Further information is available from: UCB Pharma Ltd., 3 George Street, Watford,Herts WD18 0UH. Tel: 01923 211811. medicaluk@ucb-group.comDate of preparation: September 2004.References:1. Krakow K, Walker M, Otoul C, Sander JWAS. Long-term continuation ofLevetiracetam in patients with refractory epilepsy. Neurology. 2001; 56: 1772-1774.2. Patsalos PN. Pharmacokinetic profile of Levetiracetam: toward ideal characteristics.Pharmacol Ther. 2000; 85: 77-85. 3. French J, Edrich P, Cramer JA. A systematic reviewof the safety profile of levetiracetam: a new antiepileptic drug. Epilepsy Res. 2001;47: 77-90.© 2004 UCB Pharma Ltd.UCB-K-04-49

Review ArticleEmbryonic Stem CellsKey properties of ES cellsEmbryonic stem (ES) cells are karyotypically normal continuouscell lines isolated directly from the inner cell massof the blastocyst embryo. ES cells are unique stem cells asthey retain the developmental potency of foetal foundercells even after extended propagation and manipulationin culture. When transferred to a preimplantation mouseembryo, ES cells incorporate to the inner cell mass andgenerate mice that are chimeric both in somatic and germtissues 1 (Fig 1).ES cells were initially isolated and maintained by cocultureon feeder layers of mitotically inactivated mousefibroblasts. 2,3 It was identified later that the fibroblastfeeders express the stem cell regulator leukaemia inhibitoryfactor (LIF) which actively suppress differentiation. 4,5LIF is able to completely replace feeder layers, not only inthe maintenance of previously established ES cell lines,but also in the de novo establishment of karyotypicallynormal and germ line competent ES cell lines. 5 This propertyhas enabled the culture of homogeneous populationof pluripotent ES cells in the absence of contaminatingfibroblasts.Recently, it was discovered that bone morphogenic proteins(BMPs) act in combination with LIF to sustain selfrenewaland preserve multilineage differentiation of EScells in serum-free condition. 6 This fully defined cultureparadigm also supports the generation of germ line competentES cell lines. In the absence of LIF, however, BMPstimulates differentiation, suggesting that a very delicatebalance of different signalling pathways regulate ES cellself-renewal versus differentiation.Creation of designer mouse modelsThe capacity for germ-line colonisation means that EScells can be exploited as vehicles for transgenic manipulationof the mouse genome, via introduction of new geneticinformation or the alteration of the host genesequences. Indeed, the major use of ES cells to date is as acellular tool for the production of mice carrying predeterminedgenetic modification generated by homologousrecombination or gene targeting. The planned alterationof a gene is first generated in genome of ES cells in tissueculture. Genetically modified ES cells can then be injectedinto recipient blastocysts, where they contribute differentiatedprogeny to their host, resulting in the birth ofgenetically modified chimeric pups. Following germlinetransmission, mice that carry a defined mutation of agene are generated. The genetic modification can now bedesigned in a sophisticated manner such that the mutationcan be temporally and spatially regulated (conditionalknock-out), by exploiting the Cre-loxP system andcell/tissue specific regulatory elements. Over the pastdecade, gene targeting by homologous recombination hasrevolutionised the field of mouse genetics and allowed theanalysis of diverse aspects of gene function in vivo.Cellular model for developmental studiesThe integration of ES cells into normal embryonic developmentdemonstrates their capacity to respond to arepertoire of developmental regulatory signals. Therefore,ES cells provide an invaluable in vitro system for theexperimental identification and characterisation of factorsthat control early embryonic growth and differentiation.In particular the system is well suited to investigatingthe capacity of genes through ‘gain of function’ studies,since they permit the study of specific gene overexpressionin a given differentiation lineage without havingto worry about the effects of such an overexpression onthe overall embryonic development. We have successfullyapplied this approach in determining Sox B transcriptionfactors in neural fate choice from pluripotent stem cells,and in a functional screen of candidate neural genes followinga microarray transcriptome analysis. 7,8,9Conversely, ES cells also provide an ideal system for ‘lossof function’ studies either via siRNA technology (knockdown)or gene targeting of specific gene.Therapeutic potential of ES cellsThe establishment of human ES cells has sparked muchinterest in both the scientific and general communityregarding their potential in regenerative therapies. 10,11 Celltransplantation can in principle be applied to manyMeng Li completed her medicaldegree in Beijing University andher PhD at the University ofEdinburgh. She established herown laboratory in 2000following a Career DevelopmentAward from the UK MRC.Meng’s research is focused onelucidating the cellular andmolecular mechanisms thatcontrol dopaminergic neuronspecification and axon connectivity,using embryonic stemcells and modern transgenictechnologies.Correspondence to:Meng Li,Institute for Stem Cell Research,University of Edinburgh,King’s Buildings,West Mains Road,Edinburgh EH9 3JQ.Email: meng.li@ed.ac.ukFig 1: Diagram summarises the propagation and use of ES cells. Photograph of self-renewing mouse ES cells cultured in the presence of LIF in serum ongelatine coated plastics. Upper panel depicts the inter relationship between ES cells, the inner cell mass (ICM) cells of the blastocyst embryos, andchimeric mice. In the absence of LIF under suitable culture condition, ES cells can give rise to many differentiated somatic cell types. Photograph of theES cells provided courtesy of QL Ying.8 I ACNR • VOLUME 5 NUMBER 1 • MARCH/APRIL 2005

Review Article* Mesoderm ** Endoderm***Fig 2: Neural lineage selectionstrategy. The approach involvesfirstly the generation of ES cellsin which a reporter (GFP orlacZ) and/or a drug selectionmarker (e.g. neo) is targeted intothe Sox1 or Sox2 locus viahomologous recombination.Following in vitro differentiationof ES cells, either drug selectionor fluorescence-activated cellsorting (FACS) can be applied toisolate cells of interest, in thisapplication, neuralstem/progenitor cells.human diseases such as leukaemia, diabetes and someneural degenerative diseases. Many protocols have beendeveloped to differentiate ES cells, so far mostly of mice,into a variety of cell types which includes neurons, 12adipocytes, 13 skeletal myocytes and hematopoietic cells 14and cardiomycytes. 15 Transplantation studies havedemonstrated a certain degree of functional repair in animalmodels of multiple sclerosis 16 and spinal cord injury. 17However, our abilities to direct ES cells into specificpathways and then to support the viability and maturationof individual differentiated phenotypes in vitroremains limited. Consequently, the differentiating ES cellcultures constitute heterogeneous types of differentiatedES cell progeny with unknown phenotypes. In the absenceof knowledge to instruct ES cells into a specific fate,strategies have been developed to enrich or isolate phenotypesof interest from the mix cell population. This can beachieved through selective culture condition 14 or fluorescence-activatedcell sorting (FACS). 18 In addition, drugresistance or cell sorting capacity conferred by geneticmanipulation in ES cells provides another way of isolatinga particular cell lineage or cell types. 19,20 We have successfullyapplied this approach in purifying ES cell derivedneural stem/progenitors based on specific expression ofSox1 and Sox2 in developing neuroepithelium 20,21 (Fig 2).Recently, we have investigated the ability of SoxB proteinsin influencing ES cell lineage choice. We found thatforced expression of Sox1 or Sox2 does not impair propagationof undifferentiated ES cells, but upon release fromself-renewal by LIF withdrawal promoted differentiationinto neuroectoderm at the expense of mesoderm andendoderm. The efficient specification of a primary lineageby transcription factor manipulation or their downstream signalling cascade may provide a general paradigmfor instructing differentiation of ES cells for biopharmaceuticalscreening and cell therapy applications. 9ConclusionsThe mouse ES cells have provided us with an unprecedentedopportunity to understand mammalian developmentand molecular mechanisms that lead to pathologicalsituations. The development of human ES cells now offersthe foundation of applying ES cell technology to the treatmentof human diseases. However, much remains to beaccomplished with regards to human ES cell technologybefore they can be used as a new form of human medicine.References1. Bradley A, Evans MJ, Kaufman MH, Robertson E. Formation of germ-line chimaeras fromembryo-derived teratocarcinoma cell lines. Nature 1984;309:255-6.2. Evans MJ, Kaufman M. Establishment in culture of pluripotential cells from mouse embryos.Nature 1981;292:154-6.3. Martin GR. Isolation of a pluripotent cell line from early mouse embryos cultured in mediumconditioned by teratocarcinoma stem cells. Proc Natl Acad Sci USA 1981;78:7634-8.4. Gearing PD, Gough NM, King JA, Hilton DJ, Nicola NA, Simpson RJ, Nice EC, Kelso A,Metcalf D. Molecular cloning and expression of cDNA encoding a murine myeloid leukemiainhibitory factor (LIF). EMBO J 1987;6:3995-4002.5. Smith AG, Heath JK, Donaldson DD, Wong GG, Moreau J, Stahl M, Rogers D. Inhibitionof pluripotential embryonic stem cell differentiation by purified polypeptides. Nature1988;336:688-90.6. Ying QL, Nichols J, Chambers I, Smith A. BMP induction of Id proteins suppresses differentiationand sustains embryonic stem cell self-renewal in collaboration with STAT3. Cell2003a ;115:281-92.7. Aubert J, Dunstan H, Chambers I, Smith A. Functional gene screening in embryonic stemcells implicates Wnt antagonism in neural differentiation. Nat Biotechnol 2002;20:1240-45.8. Aubert J, Stavridis MP, Tweedie S, O'Reilly M, Vierlinger K, Li M, Ghazal P, Pratt T,Mason JO, Roy D, Smith A. Screening for mammalian neural genes via fluorescence-activatedcell sorter purification of neural precursors from Sox1-gfp knock-in mice. Proc Natl AcadSci U S A 2003;Suppl:11836-41.9. Zhao S, Nichols J, Smith A, Li M. SoxB Transcription Factors Specify NeuroectodermalLineage Choice in ES Cells. Mol Cell Neurosci 2004;332-342.10. Reubinoff BE, Pera MF, Fong CY, Trounson A, Bongso A. Embryonic stem cell lines fromhuman blastocysts: somatic differentiation in vitro. Nat Biotechnol 2000;18:399-404.11. Thomson JA, Odorico JS (2000) Human embryonic stem cell and embryonic germ cell lines.Trends Biotechnol 18:53-57.12. Bain G, Kitchens D, Yao M, Huettner JE, Gottlieb DI. (1995) Embryonic stem cells expressneuronal properties in vitro. Dev Biol 168:342-357.13. Dani C, Smith AG, Dessolin S, Leroy P, Staccini L, Villageois P, Darimont C, Ailhaud G(1997) Differentiation of embryonic stem cells into adipocytes in vitro. J Cell Sci 110:1279-1285.14. Wiles MV, Keller G (1991) Multiple haematopoietic lineages develop from embryonic stem(ES) cells in culture. Development 111:259-267.15. Wobus A, Wallukat G, Hescheler J (1991) pluripotent mouse embryonic stem cells are ableto differentiate inot cardiomyocytes expressing chronotropic responses to adrenergic andcholinergic agents and Ca2+ channel blockers. Differentiation 48:173-182.16. Brustle O, Jones KN, Learish RD, Karram K, Choudhary K, Wiestler OD, Duncan ID,McKay RD (1999) Embryonic stem cell-derived glial precursors: A source of myelinatingtransplants. Science 285:754-756.17. Liu S, Qu Y, Stewart TJ, Howard MJ, Chakrabortty S, Holekamp TF, McDonald JW(2000) Embryonic stem cells differentiate into oligodendrocytes and myelinate in culture andafter spinal cord transplantation. Proc Natl Acad Sci U S A 97:6126-6131.18. Nishikawa SI, Nishikawa S, Hirashima M, Matsuyoshi N, Kodama H (1998) Progressivelineage analysis by cell sorting and culture identifies FLK1+VE-cadherin+ cells at a divergingpoint of endothelial and hemopoietic lineages. Development 125:1747-1757.19. Klug MG, Soonpaa MH, Koh GY, Field LJ (1996) Genetically selected cardiomyocytes fromdifferentiating embronic stem cells form stable intracardiac grafts. J Clin Invest 98:216-224.20. Li M, Pevny L, Lovell-Badge R, Smith A (1998) Generation of purified neural precursorsfrom embryonic stem cells by lineage selection. Curr Biol 8:971-974.21. Ying QL, Stavridis M, Griffiths D, Li M, Smith A (2003b) Conversion of embryonic stemcells into neuroectodermal precursors in adherent monoculture. Nat Biotechnol 21:183-86.ACNR • VOLUME 5 NUMBER 1 • MARCH/APRIL 2005 I 9

Review ArticlePost-Polio Syndrome – Diagnosis and ManagementPost-polio syndrome is characterised by muscularweakness, pain, and fatigue several years after theacute polio. The first known clinical descriptiondates back to 1875 when Raymond and Charcot reporteda 19-year old tanner with previous infantile paralysis whopresented with new paresis and atrophy in his shoulder.The subject was not investigated further during the nextdecade, as paralytic polio was considered to be a threephaseillness with acute pareses followed by a recoveryperiod, and then a life-long stable phase. However, manypatients with previous polio experienced a functionaldecline later on with new symptoms like pain, fatigue,muscle weakness, sleeping problems, and cold intolerance.Halstead introduced the term post-polio syndromein 1986, describing the symptoms experienced by manypolio survivors after decades with stable function.Halstead revised his criteria in 1991 1 (Table 1) where newmuscle weakness was included as an obligatory criterion,with or without other symptoms like pain, cold intolerance,and fatigue.The background and exact pathogenesis for the postpoliosyndrome is still not known, although several theorieshave been explored. Ongoing viral replication orvirus reactivation was suggested, but has not been confirmed.2 An ongoing inflammation has been found in thespinal cord, and recent studies have shown elevated levelsof inflammatory cytokines in the spinal fluid. 3 The ageingprocess may be a contributing factor but does not explainall clinical aspects as post-polio syndrome has been foundin patients before the age of 50 years. 4 At higher age, lossof motor neurones and diminishing motor units takeplace at a higher rate in post-polio patients compared topatients with normal neuromuscular function. 5 Hence,the increased muscle weakness seems to be a result ofboth an ongoing loss of motor neurones and a diminishedability to maintain their neurogenic supply toenlarged muscle fibres.The prevalence of post-polio syndrome has beenreported to be between 20-80% depending on the poliopopulation being studied and the diagnostic criteriabeing used.DiagnosisPost-polio syndrome is an exclusion diagnosis (Table 1).A careful medical history and clinical examination arenecessary to rule out all other conditions that may causethe same symptoms. At clinical examination, signs oflower motor neurone involvement should be present withflaccid muscle weakness or atrophy and diminished tendonreflexes. However, patients who have lost 50% oftheir motor neurones within one segment can still have anormal clinical picture. 6 This means that subclinicalmotor neurone involvement may be present, and newmuscle weakness may occur in apparently non-affectedmuscles. EMG can be of help to sort out other neurologicaland muscular illnesses, and can also establish a motorneurone involvement compatible with previous paralyticpolio. However, EMG cannot distinguish between stablepolio sequelae and new muscle weakness, and the majorrole of neurophysiology is to confirm previous polio andexclude other neuromuscular disorders. 7 Disorders notrelated to the patient’s previous polio may be co-existing:neurological and rheumatological disorders, cardiovascularand thyroid disorders, and depression. A thoroughinvestigation to sort out such co-existing disorders is necessary,as these disorders need specific treatment. Theyshould be treated in the same way as in patients withouta history of previous polio.ManagementMuscular weakness and fatigueEven though post-polio syndrome affects only between20-50% of polio survivors, it is important to have this inmind as polio patients in general report more pain,fatigue, sleeping problems and muscle weakness thanhealthy controls, and they rate their health lower. 8-10 Thisis irrespective of the presence of a post-polio syndrome ornot. For all practical purposes today’s management andtreatment will be similar for patients with and withoutpost-polio syndrome (PPS).Elisabeth Farbu is a consultant inthe Department of Neurology,Stavanger University Hospital,Norway. She has a PhD in clinicalneurology from the University ofBergen. Her clinical and scientificinterests are in neuromusculardisorders and post-polio syndrome.No specific medical treatment for PPS has been proven tobe effective;• Pyridostigmine and steroids have been tried in randomisedstudies without any positive effect withrespect to muscle strength and fatigue; 11,12• Muscle training at aerobic levels without maximum Correspondence to:exercise is useful to maintain muscular function and Elisabeth Farbu,ameliorate fatigue 13Deptartment of Neurology,and muscular training in warm Stavanger University Hospital,water seems to be particularly useful. 14 Systematic trainingprogrammes in a warm climate are more effectiveNorway.Email: elfa@sir.nothan identical training programmes in a cold climate; 15• Reorganisation of daily life activities with short breaksAdditional(thereby conserving energy expenditure) may help toweb contentcounteract fatigue. In addition, properly fitted assistivewww.acnr.co.ukdevices (i.e. intermittent use of wheel chair) can help See www.acnr.co.uk/in this respect;case%20report.htm for a• Inactivity increases the risk of obesity, diabetes, cardiovascular,and muskuloskeletal problems and so poliosyndrome.case of post-poliopatients who take part in physical activity have significantlyless symptoms than physically inactive patients. 16All polio patients with or without post-polio syndromeshould therefore be advised to take part in physicalactivity, but they should not be performing static musculartraining at maximum effort (anaerobic level) andthey should allow intermittent breaks.Disorders related to previous polioPatients with previous polio are more prone to developingoveruse symptoms and disorders like soft tissueinflammation, arthrosis, spinal degenerative disorders,and nerve entrapment due to asymmetric weight bearing.Carefully fitted orthoses, casts, splints, and otherassisting devices may prevent or delay these symptoms.If severe arthrosis is present, surgical treatmentwith hip or knee replacement should be considered in asimilar fashion as to that done for patients without previouspolio, but the post-operative rehabilitation periodTable 1: Criteria for the diagnosis of post-polio syndrome 11. A prior episode of paralytic polio confirmed by history, physical exam, and typical findings on EMG2. Standard EMG evaluation demonstrates changes consistent with prior anterior horn cell disease:increased amplitude and duration of motor unit action potentials, increased percentage ofpolyphasic potentials and, in weak muscles, a decrease in the number of motor units on maximumrecruitment. Fibrillations and sharp waves may or may not be present.3. A period of neurologic recovery followed by an extended interval of functional stability precedingthe onset of new problems. The interval of neurologic and functional stability usually lasts for 20 ormore years.4. The gradual or abrupt onset of new neurogenic (non-disuse) weakness in previously affected and/orunaffected muscles. This may or may not be accompanied by other new health problems such asexcessive fatigue, muscle pain, joint pain, decreased endurance, decreased function, and atrophy.5. Exclusion of medical, orthopaedic, and neurologic condition that might cause health problems listed above.10 I ACNR • VOLUME 5 NUMBER 1 • MARCH/APRIL 2005

Review Articlemay be prolonged and require particular training programmes. Severescoliosis or degenerative spine changes should be considered for surgeryif the neurological and/or respiratory function is threatened. Sleepingproblems can be related to the frequency and intensity of pain, and properpain management may improve sleep. 10 Sleeping problems can also bea part of nocturnal hypoventilation and patients with chest wall deformitiesand respiratory muscle weakness are at risk of developing respiratoryinsufficiency. 17 Co-existing obesity increases the risk. Symptoms onrespiratory insufficiency can manifest as daytime sleepiness, morningheadache, sleeping problems, fatigue, dyspnea, recurrent respiratorytract infections, and if not treated properly, secondary right sided heartfailure (cor pulmonale). If the respiratory insufficiency is due to amechanical deficit only (i.e. muscle weakness) with intact lung tissue, theeffect and prognosis for using artificial ventilatory aids is excellent. Inmost cases, artificial ventilation is only needed during nighttime, andnon-invasive ventilators are the first choice. Biphasic positive-pressureventilators (BIPAP) and nasal intermittent positive-pressure ventilators(NIPPV) are often used in polio-related respiratory insufficiency withgood results. General precautions like stopping smoking, a reduction inweight if obese, the use of influenza- and pneumoccocal vaccines, andaggressive treatment of respiratory tract infections are particularlyimportant for these patients.In conclusion, PPS is an exclusion diagnosis based on a thoroughinvestigation in a patient with a previous history of polio. Proper treatmentof other disorders, both polio-related and non-polio-related, isimportant with the management of PPS being primarily based on physicaltherapy and muscular training along with intermittent ventilatorysupport if necessary.References1. Halstead LS. Assessment and differential diagnosis for post-polio syndrome. Orthopedics1991;14(11):1209-1217.2. Melchers W, de Visser M, Jongen P, van Loon A, Nibbeling R, Oostvogel P et al. The postpoliosyndrome: no evidence for poliovirus persistence. Ann Neurol 1992;32(6):728-732.3. Gonzalez H, Khademi M, Andersson M, Wallstrom E, Borg K, Olsson T. Priorpoliomyelitis-evidence of cytokine production in the central nervous system. Journal of theNeurological Sciences 2002;205(1):15.4. Chang CW, Huang SF. Varied clinical patterns, physical activities, muscle enzymes, electromyographicand histologic findings in patients with post-polio syndrome in Taiwan.Spinal Cord 2001;39(10):526-531.5. Grimby G, Stalberg E, Sandberg A, Stibrant SK. An 8-year longitudinal study of musclestrength, muscle fiber size, and dynamic electromyogram in individuals with late polio.Muscle Nerve 1998; 21(11):1428-1437.6. Stalberg E, Grimby G. Dynamic electromyography and muscle biopsy changes in a 4-yearfollow- up: study of patients with a history of polio. Muscle Nerve 1995;18(7):699-707.7. Ravits J, Hallett M, Baker M, Nilsson J, Dalakas M. Clinical and electromyographic studiesof postpoliomyelitis muscular atrophy. Muscle & Nerve 1990;13(8):667-674.8. Farbu E, Gilhus NE. Former poliomyelitis as a health and socioeconomic factor. A pairedsibling study. J Neurol 2002;249(4):404-409.9. Farbu E, Gilhus NE. Education, occupation, and perception of health amongst previouspolio patients compared to their siblings. Eur J Neurol 2002;9(3):233-241.10. Farbu E, Rekand T, Gilhus NE. Post polio syndrome and total health status in a prospectivehospital study. Eur J Neurol 2003;10(4):407-413.11. Dinsmore S, Dambrosia J, Dalakas MC. A double-blind, placebo-controlled trial of highdoseprednisone for the treatment of post-poliomyelitis syndrome. Annals of the New YorkAcademy of Sciences 1995;753:303-313.12. Horemans HLD, Nollet F, Beelen A, Drost G, Stegeman DF, Zwarts MJ et al.Pyridostigmine in postpolio syndrome: No decline in fatigue and limited functional improvement.Journal of Neurology, Neurosurgery & Psychiatry 2003;74(12):1655-1661.13. Agre JC, Rodriquez AA, Franke TM. Strength, endurance, and work capacity after musclestrengthening exercise in postpolio subjects. Archives of Physical Medicine & Rehabilitation1997;78(7):681-686.14. Willen C, Sunnerhagen KS, Grimby G. Dynamic water exercise in individuals with latepoliomyelitis. Arch Phys Med Rehabil 2001;82(1):66-72.15. Strumse YAS, Stanghelle JK, Utne L, Ahlvin P, Svendsby EK. Treatment of patients withpostpolio syndrome in a warm climate. Disability & Rehabilitation 2003;25(2):77-84.16. Rekand T, Korv J, Farbu E, Roose M, Gilhus NE, Langeland N et al. Lifestyle and lateeffects after poliomyelitis. A risk factor study of two populations. Acta NeurologicaScandinavica 2004;109(2):120-125.17. Kidd D, Howard RS, Williams AJ, Heatley FW, Panayiotopoulos CP, Spencer GT. Latefunctional deterioration following paralytic poliomyelitis. QJM 1997;90(3):189-196.HEAD INJURYPathophysiology & ManagementSecond editionThe EditorsPeter L Reilly, Director of Neurosurgery,Royal Adelaide Hospital, AustraliaRoss Bullock, Division of Neurological Surgery,Medical College of Virginia, USA£150.00 • 0 340 80724 5 • February 2005Hardback • 544 pages • 200 b/w & 70 col illustrations• Increased clinical emphasis whilst also maintaining thebook's strengths in basic sciences• Wider range of contributors to bring in expertise frommajor international head injury centres• Integrated colour illustrations in pathology and imagingchaptersThis updated and revised edition of Head Injury retains thedetailed coverage of basic mechanisms and investigations ofits predecessor, but also has increased the clinical content ofthe first edition, with particular emphasis on the fast-movingareas of neuro-monitoring and neuro-protection. This newedition also contains a more representative range of authorsfrom major trauma centres - many from North America; andis fully illustrated with colour as well as b&w half-tones.To orderPlease order from your medical bookseller or preferred webretailer. In case of difficulty, please contact Health SciencesMarketing Dept., Hodder Arnold, 338 Euston Road, London,NW1 3BH.e: healthsci.marketing@hodder.co.uk /w: www.hoddereducation.comACNR • VOLUME 5 NUMBER 1 • MARCH/APRIL 2005 I 11

Management TopicThe Management of Intracranial AbscessesMost UK neurosurgeons treat 1-4 patients with anintracranial abscess each year. Intracranialabscesses can occur at any age. Contiguousspread to the intracranial cavity may occur directly or viaemissary veins from infected paranasal sinuses, the middleear and the mastoid. Such abscesses are usually locatedin the frontal or temporal lobes, or in the cerebellum.Haematogenous spread of infection can occur from theskin, dental sources and the lungs. Sixty percent ofpatients have a pre-disposing condition including aninfective source (ear, sinus, teeth, lung), diabetes or animmunocompromised state. Patients with cyanotic heartdisease are also at risk since circulating blood bypasses thepulmonary bacterial filter. Abscesses with a haematogenousorigin are frequently located in the middle cerebralartery territory, presumably due to haemodynamic factors.Such abscesses are sometimes multiple.PresentationThe clinical features in patients with an intracranialabscess evolve with time and depend upon the hostpathogeninteractions. From a brain perspective patientshave one or more of the following clinical scenarios:1. Symptoms and signs of raised intracranial pressure(headache, impaired level of consciousness, slow mentation,nausea, vomiting, papilloedema).2. Focal neurological deficits due to compression of neuronalpathways (e.g. hemiplegia, dysphasia, frontalsymptoms and signs, cerebellar syndrome).3. Seizures. These may by focal, Jacksonian or Grand Mal.Constitutional symptoms and signs (pyrexia, rigors, dehydration,neck stiffness) and clinical features due to aninfected source elsewhere in the body are surprisinglyuncommon at the time of presentation.PathologyBritt and Enzmann described a canine model ofStreptococcal abscess evolution with pathological phasesthat correlate with the clinical presentation in man. 1 Aninitial acute inflammatory cerebritis (days 1-9) is followedby hyperaemic capsule formation (days 10-14) andfibroblastic maturation (after day 14). Necrotic liquifactionand inflammatory exudate accumulate in the abscesscavity. During expansion of the abscess, the medial wall isusually thinner and less resistant and may result in ventriculitis.This is a poor prognostic indicator.MicrobiologyThe majority of intracranial abscesses contain severalmixed pathogens. In many patients, particularly thosewith sinus or ear infections a variety of aerobic andmicroaerophilic Streptococcal species are found (e.g.Strep millari; Strep pneumoniae, Strep pyogenes), often incombination with Haemophilus influenzae andPseudomonas aeriginosa and anaerobes such asBacteroides. In patients with a primary skin infection oran abscess complicating recent neurosurgery,Staphylococcus aureus is prevalent.InvestigationsSerial white blood cell counts, ESR and CRP levels provideuseful parameters to monitor response to treatment –although not infrequently such investigations may be normaland can result in a delayed diagnosis. Blood culturesmay help determine the likely pathogen. However, a CT orMRI scan of the brain +/- contrast secures the diagnosisand should always be performed before a lumbar punctureis considered. An abscess appears as a ring-enhancing,space demanding process. The ring of enhancement isusually quite linear without the heterogeneous appearancescharacteristic of a malignant glioma. The most frequentabscess locations are frontal, temporal or cerebellar.They are usually sub-cortical, but small abscesses mayabut the grey-white matter interface in the middle cerebralartery territory. A CT or MRI scan may also reveal aninfected source such as a paranasal sinus infection or anear infection. The diagnosis is confirmed by examinationof pus obtained directly from the abscess. Once an abscesshas been identified, broad-spectrum antibiotics should becommenced and urgent neurosurgical referral made.Surgical OptionsSurgery is required to obtain pus from a solitary abscess.Sometimes this is non-diagnostic particularly if antibioticshave been administered. Surgery also reduces thebulk of an abscess providing symptomatic relief and minimisingthe risks of abscess growth (intraventricular rupture,herniation, venous sinus thrombosis). The surgicaloptions include aspiration, craniotomy and completeexcision or craniotomy and marsupialisation.AspirationImage guided (CT or MRI) frameless stereotactic aspirationhas recently become the most commonly utilised surgicaltechnique to treat an abscess. For small and deepabscesses (< 2cm) a stereotactic frame increases the accuracyof the localisation technique. In patients with multipleabscesses, the largest lesion is usually aspirated andother lesions monitored with post-operative imaging. 2,3CraniotomyA craniotomy can be performed as a primary procedureor if abscess re-growth occurs after initial aspiration. Inthe majority of patients brain swelling is prominent andmannitol should be administered intraoperatively to minimisethis problem. If the abscess is located in non-eloquentbrain the abscess wall is dissected from the surroundingbrain permitting enucleation of the lesion. If theabscess is in an eloquent region a trans-cortical approachcan be made through a 2 cm incision. An intersulcalapproach shortens the distance to the lesion comparedPeter Whitfield is a ConsultantNeurosurgeon at the South WestNeurosurgical Centre in Plymouth.He has previously worked inGlasgow and Aberdeen in additionto his higher surgical training inCambridge. Peter has a PhD in themolecular biology of cerebralischaemia. His clinical interestsinclude vascular neurosurgery,image guided tumour surgery andmicrosurgical spinal surgery. Hehas a practical interest in medicaleducation and is involved in implementationof the Phase 2 teachingin neurosciences at the PeninsulaMedical School.Correspondence to:Peter Whitfield,South West Neurosurgery Centre,Derriford Hospital,Plymouth PL6 8DH.Email:Peter.whitfield@phnt.swest.nhs.ukImage guided (CT or MRI) frameless stereotactic aspirationhas recently become the most commonly utilised surgicaltechnique to treat an abscess12 I ACNR • VOLUME 5 NUMBER 1 • MARCH/APRIL 2005

Awakeand alertThe first and only wakefulnesspromotingagent is now indicatedfor the treatment of excessivesleepiness associated with chronicpathological conditions, includingnarcolepsy, OSAHS and moderateto severe chronic shift worksleep disorder.MODAFINILDon , t let them miss a momentUK ABBREVIATED PRESCRIBING INFORMATION: PROVIGIL ® 100mg/200 mg TabletsPlease refer to UK Summary of Product Characteristics (SmPC) before prescribing.Presentation: White to off-white tablets containing modafinil 100 mg or modafinil 200 mg(debossed with “Provigil” on one side and “100 mg” or “200 mg” on the other). Indication:Excessive sleepiness associated with chronic pathological conditions, including narcolepsy,obstructive sleep apnoea/hypopnoea syndrome and moderate to severe chronic shift work sleepdisorder. Dosage: Adults: Narcolepsy and Obstructive Sleep Apnoea/Hypopnoea Syndrome:200 – 400 mg daily either as two divided doses in the morning and at noon or as a singlemorning dose according to response; Shift Work Sleep Disorder: 200 mg daily taken as a singledose approximately 1 hour prior to the start of the work shift. Elderly: Treatment should start at100 mg daily, which may be increased subsequently to the maximum adult daily dose in theabsence of renal or hepatic impairment. Severe renal or hepatic impairment: Reduce dose by half(100 – 200 mg daily). Children: Not recommended. Contra-indications: Use in pregnancy andlactation, uncontrolled moderate to severe hypertension, arrhythmia, hypersensitivity to modafinilor any excipients used in Provigil. Warnings and precautions: Patients with major anxiety should onlyreceive Provigil treatment in a specialist unit. Sexually active women of child-bearing potentialshould be established on a contraceptive programme before taking Provigil. Blood pressure andheart rate should be monitored in hypertensive patients. In patients with obstructive sleepapnoea, the underlying condition (and any associated cardiovascular pathology) should bemonitored. Patients should be advised that Provigil is not a replacement for sleep and good sleephygiene should be maintained. Provigil is not recommended in patients with a history of leftventricular hypertrophy, cor pulmonale, or in patients who have experienced mitral valveprolapse syndrome when previously receiving CNS stimulants. This syndrome may present withischaemic ECG changes, chest pain or arrhythmia. Studies of modafinil have demonstrated a lowpotential for dependence, although the possibility of this occurring with long - term use cannot beentirely excluded. Provigil tablets contain lactose and therefore should not be used in patients withrare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucosegalactosemalabsorption. Drug interactions: Modafinil is known to induce CYP3A4/5 (and to alesser extent, other) enzymes and so may cause clinically significant effects on other drugsmetabolised via the same pathways. The effectiveness of oral contraceptives may be impairedthrough this mechanism. When these are used for contraception, a product containing at least50 mcg ethinylestradiol should be taken. Certain tricyclic antidepressants and selective serotoninreuptake inhibitors are largely metabolised by CYP2D6. In patients deficient in CYP2D6(approximately 10% of the Caucasian population) a normally ancillary metabolic pathwayinvolving CYP2C19 becomes more important. As modafinil may inhibit CYP2C19 lower doses ofantidepressants may be required in such patients. Care should also be observed withco-administration of other drugs with a narrow therapeutic window, such as anticonvulsant oranticoagulant drugs. Side effects: Very common (>10%) – headache. Common (>1%) –nervousness, insomnia, anxiety, dizziness, somnolence, depression, abnormal thinking,confusion, paraesthesia, blurred vision, nausea, dry mouth, diarrhoea, decreased appetite,dyspepsia, constipation, tachycardia, palpitation, vasodilatation, asthenia, chest pain, abdominalpain and abnormal liver function tests. Dose related increases in alkaline phosphatase andgamma glutamyl transferase have been observed. (See SmPC for uncommon side effects).Basic NHS cost: Pack of 30 blister packed 100 mg tablets: £60.00. Pack of 30 blister packed200 mg tablets: £120.00 Marketing authorisation numbers: PL16260/0001 Provigil 100 mg Tablets,PL 16260/0002 Provigil 200 mg Tablets. Marketing authorisation holder: Cephalon UK Limited.Legal category: POM. Date of preparation: March 2004. Provigil and Cephalon are registeredtrademarks. Full prescribing information, including SmPC, is available from Cephalon UK Limited,11/13 Frederick Sanger Road, Surrey Research Park, Guildford, Surrey UK GU2 7YD,Medical Information Freefone 0800 783 4869 (ukmedinfo@cephalon.com). PRO809/Mar 04

Management TopicFigure 1a:This 20 year old female presented to the neurologists withheadaches and vomiting. An MRI scan showed frontal lobecerebritis and ethmoid congestion. Note the extensive changeson this T2W image. She was treated with intravenousantibiotics for 3 weeks, improved and was discharged.Figure 1b:She represented 5 weeks later with similar symptoms. HerCRP and white cell count were normal. This contrastenhanced CT scan shows the characteristic appearances of anintracerebral abscess with a thin walled cavity surrounded bycerebral oedema. She underwent an emergency craniotomy tomarsupialise the abscess. She also underwent bilateralsphenoidectomies and a partial ethmoidectomy to treat theinfective source.Figure 1c:This Gadolinium enhanced MRI scan taken 4 weeks latershows involution of the abscess cavity. Intravenousceftriaxone and metronidazole were continued for a further 3weeks followed by 3 weeks of oral Augmentin. A repeat scan 1month later showed further involution of the cavity.with the more traditional transgyral corticotomy. Theoperative microscope is used to visualise and preserve corticalvessels within the sulcus. The abscess wall is thenencountered and opened widely (marsupialisation) topermit complete aspiration of all pus (Figure 1a). Thecavity is thoroughly irrigated with saline (some surgeonsuse a dilute solution of hydrogen peroxide). The use ofhaemostatic matrices (e.g. Surgicel) is limited to avoidcolonisation of such materials. Following evacuation oropen drainage the brain swelling has usually improvedconsiderably permitting replacement of the bone flapduring closure.Peri-Operative CareSeveral factors need to be addressed. These include thechoice and duration of antibiotic treatments, the role of surveillanceimaging, the treatment of any primary focus, theuse of steroids and the use of prophylactic anticonvulsants.Antibiotic TreatmentThe choice of antibiotics is governed by several factorsincluding the appearances on an initial Gram stain, thepotential for mixed aerobic and anaerobic pathogens, andantibiotic penetration. Expert microbiological advice isinvaluable when selecting antimicrobials. For the majorityof primary abscesses initial intravenous treatment witha third generation cephalosporin and metronidazole isappropriate. Cultures may subsequently refine the choiceof antibiotics.Some antibiotics can be safely instilled during surgery(e.g. Gentamicin 10mg), but direct instillation of penicillinis unsafe and can cause seizures. The duration ofantibiotic treatment is controversial. If antibiotics areadministered for a short period (e.g. 2 weeks) there doesappear to be an increased risk of recurrence. Provided surveillanceimaging is satisfactory a 4-week course of intravenousantibiotics, supplemented by a further 2 weeks oforal treatment is recommended.Surveillance ImagingMRI is preferred to CT scanning to abolish the risks ofradiation exposure. A post-operative MRI scan performedwithin 48 hours of surgery serves as a useful baseline forsubsequent imaging. Provided the patient remains stable,repeating the scan at weekly intervals for 2 weeks and thenat fortnightly intervals for a further 1-month enables reaccumulationof the abscess to be detected at a pre-clinicalphase (Figures 1b, 1c).Treatment of Primary FocusTo minimise the risk of recurrent or non-responsiveintracranial infection any identifiable primary sourcerequires aggressive treatment. 4 This may include surgeryfor paranasal, middle ear or dental sepsis, physiotherapyand antibiotics for pulmonary infection and surveillanceechocardigrams in patients with a cardiac source. Thetiming of such interventions does not need to coincidewith intracranial surgery but should be undertaken in anexpert, timely fashion.Steroid TherapyIn general steroids are not used in brain abscess patientsdue to the immunosuppression associated with thesedrugs. However, extensive oedema may surround theabscess and contribute to raised intracranial pressure. In adeteriorating clinical situation steroids can improve theclinical status of patients when there appear to be fewoptions remaining. This is probably due to a reduction inthe inflammatory process reducing concomitant oedema.Prophylactic AnticonvulsantsBetween 40-50% of patients who suffer from an intracranialabscess will develop epilepsy. Prophylactic anticonvulsantsshould therefore be seriously considered. Patientsshould contact the DVLA and refrain from driving.PrognosisIn the pre-CT era the mortality of cerebral abscesses wasin the region of 30-40%. CT scanning and improvedlocalisation techniques have reduced this to less than 5%.The use of modern treatment regimes with image-directedneurosurgery may reduce this further. Risk factors fora poor outcome include deep-seated location, intraventricularabscess rupture causing ventriculitis and a poor14 I ACNR • VOLUME 5 NUMBER 1 • MARCH/APRIL 2005

Management TopicFigure 2a:Axial CT scan showing opacification ofthe right maxillary sinus in a patientwith a subdural empyema. This sourceof infection requires treatment.Figure 2b:Axial CT scan + contrast showing aright parasagittal subdural empyema inthe same patient as figure 2a. Thisrequires surgical drainage and is bestperformed through a parasagittalcraniotomy taking care to preserveveins bridging from the cortex to thesuperior sagittal sinus.neurological status. 5 Many patients with a neurologicaldeficit achieve significant recovery during the rehabilitativephase of care.Rare Intracranial InfectionsSubdural empyema and extradural abscessesThese are both rare. They are usually associated with contiguousotological or sinus pathology and are identified onCT scans (Figure 2a). While extradural abscesses are readilydetected, subdural empyemas typically have a subtleappearance on CT scans (Figure 2b). They are characterisedby a relatively thin, low attenuation mass with minimalenhancement associated with a profound clinical picture(impaired level of consciousness, neurological deficitand fits). Symptoms and signs of infection may not be present.Early aggressive surgery targeted at the intracranialmass and any source of infection is recommended. A craniotomyis the preferred option for an empyema due to theviscous nature of the pus that is not readily washed out ofthe subdural space. Indeed, a fibrinous layer of tissue usuallyadheres to the arachnoid and is best left undisturbedafter thorough irrigation under direct vision. The risk of aneurological deficit and epilepsy in patients with a subduralempyema exceeds 60%, probably due to multiplesmall cortical venous infarctions. 6TuberculosisTB remains common in the Indian sub-continent andcases of intracranial TB are seen in the UK. Symptoms ofraised ICP and/ or epilepsy should lead to the suspicion ofa tuberculoma. This is a calcified parenchymal lesion withcentral caeseating necrosis. TB only rarely causes a typicalbrain abscess appearance. Treatment options depend onthe clinical status of the patient and lie between clinicalsurveillance, empirical anti-tuberculous treatment withfollow-up scans, image-guided aspiration combined withmedical treatment and rarely surgical excision.NeurocysticercosisThis disease is endemic in most developing parts of theworld. The larvae of this ingested intestinal tapewormhatch from eggs in the intestine and migrate to a varietyof tissues including brain parenchyma, muscles, subcutaneoustissues and the eye. In many cases the host immunesystem eliminates the parasite expeditiously. However, CTand MRI indicate that small-calcified parenchymal cysticlesions can persist. These may be multiple and may containa mural “scolex” of larvae. Neurocysticercosis may beasymptomatic, cause epilepsy or result in a focal neurologicaldeficit. Management is directed at seizure control. 7Empirical treatment with the anti-helminthic agentsalbendazole or praziquantel is not mandatory in the late“burnt-out” phase of the disease. Surgery is only requiredif seizures are not controlled medically or in rare instanceswhen space occupation is problematic.SummaryAlthough the incidence of intracranial abscesses hasdecreased over the past 100 years the surgical principlesexpostulated by MacEwen in 1881, namely debridementand drainage, remain of paramount importance.Advances in neuronavigation techniques make stereotacticdrainage a simple procedure that can be performedexpeditiously for the majority of abscesses. The appropriateuse of effective antibiotic therapy adds to the therapeuticarmamentarium. Surveillance imaging with MRIscans is now the follow-up modality of choice. Thesechanges in management have seen a significant reductionin the mortality of brain abscesses in the last 20 years.References1. Britt RH, Enzmann DR. Clinical stages of human brain abscesses onserial CT scans after contrast infusion. J.Neurosurg. 1983;59:972-989.2. Boviatsis EJ, Kouyialis AT, Stranjalis G, Korfias S, Sakas DE. CT-guidedstereotactic aspiration of brain abscesses. Neurosurgical Review2003;26:206-209.3. Barlas O, Sencer A, Erkan K, Eraksoy H, Sencer S, Bayindir C.Stereotactic surgery in the management of brain abscess. SurgicalNeurology 1999;52:404-410.4. Sennaroglu L, Sozeri B. Otogenic brain abscess: review of 41 cases.Otolaryngology - Head and Neck Surgery 2000;123:751-755.5. Takechita M, Kagawa M, Izawa M, Takakura K. Current treatmentstrategies and factors influencing outcome in patients with bacterialbrain abscess. Acta Neurochirurgica 1998;140:1263-1270.6. Cowie R, Williams B. Late seizures and morbidity after subduralempyema. J.Neurosurg. 1983;58:569-573.7. Sotelo J. Neurocysticersosis. Br Med J 2003;326:511-512.ACNR • VOLUME 5 NUMBER 1 • MARCH/APRIL 2005 I 15

Cognitive PrimerApraxiaThe term apraxia refers to a wide variety of high-levelmotor disorders, characterised by an impairment ofpurposeful voluntary movement skill. Apraxia is onlyindicated if aberrant motor behaviour cannot be accountedfor fully by pyramidal, extrapyramidal, cerebellar or peripheralmotor deficits or sensory loss, but may be observed inassociation with a number of low level motor disorders (e.g.weakness, rigidity, tremor, dystonia). Equally, an apraxicdeficit cannot be inferred without excluding associated cognitivedeficits, for example of language or perception, as primaryand sufficient explanations for the observed behaviour.The occurrence of apraxic errors is mediated greatly bythe context in which the action is elicited (e.g. clinical settingor natural environment), the stimulus prompting theaction (e.g. real object or verbal command), the nature ofthe action (e.g. meaningful or meaningless gesture), thehand with which the action is performed, and the difficultyof the action procedure (e.g. single gesture or as part of asimple or complex action sequence). Apraxic deficits mayalso be body-part specific; accordingly, a greater specificationof upper limb, gait and trunk, and orofacial apraxias isprovided below. Susequently, disorders which controversiallycarry the term ‘apraxia’ and the role of praxis in naturalisticaction are considered.Upper limb apraxiaThe most commonly drawn distinction in upper limbapraxia is that between ideomotor apraxia and ideationalapraxia. Individuals with ideomotor apraxia (IM) commonlyshow disruption in the spatial and temporal form ofstored and novel gestures, which is associated with damageto the left inferior parietal operculum. Patients withideational apraxia (IA) on the other hand tend to makewell-formed movements but show a disruption of the conceptualcontent of action production, resulting in tool misuse,production of complete but inappropriate gestures anddisorganisation of movements in an action sequence. IAtypically results from left parieto-occipital lesions (just posteriorto areas associated with IM), but the localising valueof IA has been questioned because the condition is rarelyseen in isolation. Indeed, the clinical usefulness of the distinctionhas been undermined by the frequent co-occurrenceof IM and IA; in a study of apraxic left hemispherebrain damaged patients, 60% showed symptoms of both IMand IA. 1Contemporary models of upper limb praxis mirror modelsof language processing, with voluntary motor actioninvolving a series of cognitive processing stages (e.g. input,output, transcoding and conceptual knowledge). 2 Suchmodels support the notion that IM and IA actually comprisea constellation of dissociable deficits. A variety of techniquesmay be used to assess the integrity of differing componentsof the action system (for examples, see Table 1).Furthermore, given the number of terminological difficultiesin this area, upper limb apraxia may be more accuratelydefined by the type and quality of action productionerrors (for a breakdown of error types, see Table 2). In evaluatingthe significance of praxic errors however, the specificityof gestural errors in a given context must be considered.For example, body-part-as-object errors (e.g. using theindex finger to pantomime brushing teeth) have beenshown to occur equally often in healthy controls as left andright hemisphere brain damaged subjects, and, in left hemispherepatients, not to be associated with severity of apraxia.3 The modality of stimulus presentation (e.g. verbal, visualor both) for gesture production tasks must be carefullyselected to maximise the likelihood that any action productionerrors reflect praxic dysfunction rather than concomitantcognitive deficits (e.g. misperceiving a complex, meaninglesshand posture demonstrated by the clinician).Sebastian Crutch is a ResearchPsychologist in the DementiaResearch Centre at the Departmentof Neurodegeneration, Institute ofNeurology, University CollegeLondon, and the Department ofNeuroscience and Mental Health,Imperial College London. Hisresearch concerns disorders of language,literacy and action.Correspondence to:Sebastian Crutch,Dementia Research Centre,Box 16,National Hospital for Neurologyand Neurosurgery,8 – 11 Queen Square,London,WC1N 3BG.Tel: 0207 837 3611,extension 3113,Fax: 020 7209 0179,Email:s.crutch@dementia.ion.ucl.ac.ukTable 1. Techniques employed in the assessment of upper limb apraxia.Praxic domain Cognitive domain Task type ExampleReception Praxis input Gesture naming Examiner performs gesture:“Tell me what I am doing”Gesture decisionExaminer performs real/unreal gesture:“Is this the correct way to turn a key?”Gesture recognitionExaminer performs a series of three gestures (one target, two foils):“Which one of these gestures is correct for using a trowel in the garden?”Production Praxis output Gesture to verbal command Examiner says:“Show me how you use a hammer to pound a nail into a wall in front of you.”Gesture to visual tool Examiner shows patient a tool:“Show me how you use this [hammer].”Gesture to tactile tool With eyes closed/covered, patient is asked:“Show me how to use this tool [hammer] I am placing in your hand.”Imitation Lexical/non-lexical Gesture imitation Examiner says:imitation system“I will produce a gesture and I want you to do it the same way I do it.”Nonsense imitationExaminer says:“I will produce a gesture and I want you to do it the same way I do it. It is not a real gesturelike the other ones you have been doing”Action semantics Conceptual system Tool selection Patient views an object representing an incomplete action (e.g. half sawn piece of wood)and three tools (1 target e.g. saw; 2 foils): “Point to the tool which goes with the object.”Alternative tool selection Patient views an object representing an incomplete action (e.g. partially banged in nail) andthree tools (none ideal but one with appropriate features for the task e.g. brick).Multiple step tasksExaminer provides letter, envelope, stamp and pen:“Show me how to prepare a letter for posting.”16 I ACNR • VOLUME 5 NUMBER 1 • MARCH/APRIL 2005

Cognitive PrimerTable 2. A classification of praxic error types. 4Error ClassSpatialTemporalContentOtherExample subtypes and descriptionsInternal configuration – incorrect spatial relationship between different body parts (e.g. fingers in incorrect arrangement)External configuration – incorrect spatial relationship between body part and imagined tool (e.g. brushing teeth with hand too far away from the face)Movement – e.g. twisting pretend screwdriver from the shoulder rather than elbowBody part as tool – e.g. when pretending to smoke cigarette, puffing end of fingerAmplitude – increase, decrease or irregularity in typical amplitude of a movementSequencing – adding, deleting or transposing a movement in a multi-stage sequenceTiming – abnormally increased, decreased or irregular rate of action productionOccurrence – repetitive production of characteristically single movements (e.g. turn key) or reduced production of typically repetitive movements(e.g. screwdriver)Perseverative – response includes all or part of a previously produced pantomimeRelated – e.g. pantomime playing a trombone for the target of a bugleNon-related – e.g. pantomime playing a trombone for the target of shavingHand – performing the action without a real or imagined tool (e.g. ripping paper by hand when asked to demonstrate use of scissors)Concretisation – performing pantomimed act on an inappropriate real object (e.g. when asked to saw some wood, pantomiming sawing on their leg)No responseUnrecognisable – not recognisable and with no spatial or temporal features of the targetGait, leg and trunk apraxiaGait apraxia refers to an impaired ability to executethe highly practised, co-ordinated movementsof the lower legs required for walking, butremains rather poorly specified and probablyincludes a number of different complex gait syndromes.5 Disturbances of voluntary, non-routinemovements of the lower limbs (leg apraxia) havealso been reported in patients with gait apraxia. 6However, it remains unclear whether leg apraxiaand gait apraxia should be considered manifestationsof damage to a common lower limb praxiccentre, or whether leg apraxia is more closelyrelated to the ideomotor apraxia more typicallydescribed in the upper limbs. A clearer dissociationhas been described between limb apraxiasand axial or trunk apraxia, in which patients mayhave difficulty generating body postures (e.g.stand like a boxer), rising from a lying position,rolling over or adopting a sitting position.Orofacial apraxiaPatients with orofacial (or buccofacial) apraxiaexhibit difficulties with performing voluntarymeaningful and meaningless movements withfacial structures including the cheeks, lips, tongueand eyebrows. Attempting to perform a pantomimeto verbal command may result either in noresponse or often a characteristic verbal repetitionof the target action (e.g. “Could you show me howto cough?”“Cough”). For some patients, imitationof an examiner’s pantomime may be achievedmore accurately. Orofacial apraxia may occur independentlyof limb apraxia, and should also be distinguishedfrom apraxia of speech which is a disorderof articulatory integration associated with nonfluentaphasia. Orofacial apraxia is commonlyassociated with damage in the left frontal operculumand insula, although the left hemisphere isparticularly implicated in lower face movementswhilst the right hemisphere may play a role in bothupper and lower face actions. 7Controversial apraxiasIn addition to the body part-specific apraxiasdescribed above, the term apraxia has also beenapplied more controversially to a range of othermotor disorders. Limb-kinetic (or melokinetic)apraxia refers to an inability to make precise,smooth, fine and independent movement ofthe fingers. The observation that the disordercan affect all types of gesture in any contextirrespective of hemispheric lateralisation ofdamage has led to suggestions that limb-kineticapraxia is in fact primarily a deficit of themotor system. 8 Other specialists maintain limbkineticapraxia is truly apractic in nature,resulting from premotor cortex damage. 9,10 Theappropriateness of terms such as constructionalapraxia and dressing apraxia has also beenquestioned, where a combination of perceptual,spatial and motor deficits may explain at leastsome of the action disorder. 11Naturalistic action disordersNaturalistic action refers to well-establishedsequences of movements aimed at achievingpractical goals such as food consumption orgrooming activities. Naturalistic action isorganised by goal hierarchies which structurebehaviour over long periods of time, and is criticallydependent upon cognitive processeslargely subserved by the frontal lobes (e.g. planning,attention, working memory.) 12 The termfrontal apraxia describes a breakdown in thissequential organisation of behaviour, and ischaracterised by object substitutions and misuse(e.g. spooning butter into coffee, using thewrong implements to eat or stir). 9,13 Althoughevidence of limb apraxia is elicited typically ina clinical setting, studies of the real worldbehaviour of ideomotor apraxic patients reveala reduced frequency of tool-related action productionand an increased number of toolactionerrors relative to other patient groups. 14References1. De Renzi E, Pieczuro A, & Vignolo LA. Ideationalapraxia: a quantitative study. Neuropsychologia1968;6: 41-52.2. Rothi LG, Ochipa C & Heilman KM. A cognitive neuropsychologicalmodel of limb praxis and apraxia. In L.G.Rothi &K. M. Heilman (Eds). Apraxia: the neuropsychology ofaction. Psychology Press, Hove, UK 1997.3. Duffy RJ, & Duffy, JR. An investigation of body part asobject (BPO) responses in normal and brain-damagedadults. Brain Cogn 1989;10:220-236.4. Rothi LG, Raymer AM, Ochipa C, Maher LM,Greenwald ML, & Heilman KM. Florida ApraxiaBattery. Unpublished Work 1998.5. Nutt JG, Marsden CD, & Thompson PD. Humanwalking and higher level gait disorders, particularly in theelderly. Neurology 1993; 43:268-279.6. Meyer JS & Barron D. Apraxia of gait: a clinico-pathologicalstudy. Brain 1960; 83:61-84.7. Bizzozero I, Costato D, Della Sala S, Papagno C,Spinnler H, & Venneri A. Upper and lower face apraxia:role of the right hemisphere. Brain 2000;123:2213-2230.8. De Renzi E. Apraxia. In F.Boller & J. Grafman (Eds).Handbook of Neuropsychology; 2:245-263.Amsterdam: Elsevier 1989.9. Luria AR. Higher cortical functions in man. (2nd ed.)New York: Basic Books 1980.10. Freund HJ. The apraxias. In AK Asbury, GMMcKhann & WI McDonald (Eds), Disease of thenervous system: clinical neurobiology: 751-767.Philadelphia: W.B. Saunders 1992.11. McCarthy RA & Warrington EK. CognitiveNeuropsychology:a clinical introduction. London:Academic Press 1990.12. Schwartz MF, & Buxbaum LJ. Naturalistic action. InL.G.Rothi & K. M. Heilman (Eds). Apraxia: the neuropsychologyof action. Hove, UK: Psychology Press1997.13. Schwartz MF, Reed ES, Montgomery MW, Palmer C& Mayer MH. The quantitative description of action disorganizationafter brain damage: a case study. CognitiveNeuropsychology 1991;8:381-414.14. Foundas AL, Macauley BL, Raymer AM, Maher LM,Heilman KM, & Gonzalez-Rothi LJ. Ecological implicationsof limb apraxia: evidence from mealtime behavior.J Int.Neuropsychol.Soc.1995;1:62-66.18 I ACNR • VOLUME 5 NUMBER 1 • MARCH/APRIL 2005

Special FeatureA Topographical Anatomy of False-Localising SignsOne hundred years ago, Dr James Collier published apaper in Brain entitled The false localising signs ofintracranial tumour. Based on his experience of 161clinically and pathologically examined cases of intracranialtumour seen at the National Hospital, Queen Square,London, he observed false-localising signs in 20 (12.4%). 1The term was coined to indicate clinically observed signsthat violated the expected clinico-anatomical concordanceon which clinical examination is predicated. 2Since 1904, many examples of false-localising signshave been described. They may occur in the clinical contextof raised intracranial pressure (RICP) which is symptomaticof intracranial pathology (tumour, haematoma,abscess) or idiopathic (idiopathic intracranial hypertension:IIH), and with spinal cord lesions. Associated lesionsmay be intra- or extraparenchymal. The course of theassociated disease may be acute (cerebral haematoma) orchronic (IIH, tumour). 3The pathogenesis of false-localising signs remainsuncertain, but their importance from a clinical standpointis not in doubt, since they may lead to inappropriate imagingand even interventions on the wrong side (althoughthe risk of such errors of commission is less now that neuroimagingis widely available). This article gives a brieftopographical overview of false-localising signs.Motor systemKernohan’s notch syndrome: false-localising hemiparesisA supratentorial lesion, such as acute subdural haemaotoma,may cause transtentorial herniation of the temporallobe, with compression of the ipsilateral cerebralpeduncle against the tentorial edge; since this is above thepyramidal decussation a contralateral hemiparesis results.Occasionally, however, the hemiparesis may be ipsilateralto the lesion, and hence false-localising; this occurs whenthe contralateral cerebral peduncle is compressed by thefree edge of the tentorium. This is the Kernohan-Woltman notch phenomenon, or Kernohan’s notch syndrome.4 There may be concurrent homolateral thirdnerve palsy, ipsilateral to the causative lesion. 5occur contralateral, and hence false-localising, tointracranial pathology. 8 The exact mechanism for thisclinical observation is not currently known.Divisional third nerve palsy is usually associated withlesions at the superior orbital fissure or anterior cavernoussinus, where the superior division of the oculomotornerve passes to the superior rectus and levator palpabrae,and the inferior division to the medial and inferiorrecti and inferior oblique muscles. Divisional thirdnerve palsies may sometimes occur with more proximallesions, presumably as a consequence of the topographicarrangement of the fascicles within the nerve, for examplewith intrinsic brainstem disease (e.g. stroke) 9 or withpathology in the subarachnoid space where the nerverootlets emerge from the brainstem (e.g. malignant infiltration).10Trochlear nerveFalse localising fourth nerve palsies, causing diplopia ondownward and inward gaze, have occasionally beendescribed in the context of IIH. 11,12Trigeminal nerveTrigeminal nerve hypofunction (trigeminal sensory neuropathy)or hyperfunction (trigeminal neuralgia) may onoccasion be false-localising, for example in associationwith IIH 13 or with contralateral pathology, often atumour. 14 For example, trigeminal neuralgia has beenassociated with a contralateral chronic calcified subduralhaematoma which caused rotational displacement of thepons, with resolution after removal of the haematoma. 15Abducens nerveSixth nerve palsies are the most common false-localisingsign of raised intracranial pressure. In one series of 101cases of IIH, 14 cases were noted, 11 unilateral and 3 bilateral.16 Stretching of the nerve in its long intracranialcourse or compression against the petrous ligament orridge of the petrous temporal bone have been suggestedas the mechanism for false-localising sixth nerve palsy. 3Andrew Larner is the editor ofour Book Review Section. Heis a Consultant Neurologist atthe Walton Centre forNeurology and Neurosurgeryin Liverpool, with a particularinterest in dementia andcognitive disorders. He is alsoan Honorary Apothecaries'Lecturer in the History ofMedicine at the University ofLiverpool.Correspondence to:AJ LarnerConsultant Neurologist,Walton Centre for Neurologyand Neurosurgery,Lower Lane,Fazkerley,Liverpool,L9 7LJ,United Kingdom.Fax: 0151 529 5513,Email: a.larner@thewaltoncentre.nhs.ukCerebellar syndromeFrontocerebellar pathway damage, for example as a resultof infarction in the territory of the anterior cerebralartery, may result in incoordination of the contralaterallimbs, mimicking cerebellar dysfunction. Suboccipitalexploration to search for cerebellar tumours based onthese clinical findings was known to occur before theadvent of brain imaging. 6Brainstem compression: false-localising diaphragmparalysisHemidiaphragmatic paralysis with ipsilateral brainstem(medullary) compression by an aberrant vertebral arteryhas been described, in the absence of pathology localisedto the C3-C5 segments of the spinal cord where phrenicmotor neurones originate, hence a false-localising sign. 7Cranial nervesOculomotor nerveUnilateral fixed dilated pupil (Hutchinson’s pupil) mayoccur with an ipsilateral intracranial lesion such as anintracerebral haemorrhage, due to transtentorial herniationof the brain compressing the oculomotor nerveagainst the free edge of the tentorium. Because of the fascicularorganisation of fibres within the oculomotornerve, the externally placed pupillomotor fibres are mostvulnerable. Very occasionally, fixed dilated pupil mayFacial nerveLower motor neurone type facial weakness has beendescribed in the context of IIH, 17 sometimes occurringbilaterally to cause facial diplegia, 18 usually with concurrentsixth nerve palsy or palsies. Hemifacial spasm hasrarely been described with contralateral posterior fossalesions. 14Vestibulocochlear nerveHearing loss has on occasion been reported as a complicationof IIH, 19 although the commonest otological complicationof IIH is tinnitus. 16The pathogenesis of false-localising signsremains uncertain, but their importance froma clinical standpoint is not in doubt, sincethey may lead to inappropriate imaging andeven interventions on the wrong side20 I ACNR • VOLUME 5 NUMBER 1 • MARCH/APRIL 2005

Special FeatureMultiple and lower cranial nerve involvementConcurrent false-localising involvement of multiple cranialnerves has been noted on occasion, for exampletrigeminal, abducens and facial nerves with a contralateralacoustic neuroma, 20 and trigeminal, glossopharyngealand vagus nerves with a contralateral laterally-placed posteriorfossa meningioma. 21Spinal cord and rootsFalse localising signs within the spinal cord are well attestedto. Broadly, these may be said to occur with lesionsaround the foramen magnum, or lower cervical/upperthoracic spinal cord.Foramen magnum/upper cervical cordParaesthesia in the hands with intrinsic hand musclewasting and distal upper limb areflexia, with or withoutlong tract signs, suggestive of a lower cervical myelopathymay occur with lesions at the foramen magnum or uppercervical cord (“remote atrophy”). 22Lower cervical/upper thoracic cordCompressive lower cervical or upper thoracic myelopathymay produce spastic paraplegia with a mid-thoracic sensorylevel (or “girdle sensation”). 23,24 For example, in onecase a spastic paraplegia with a sensory level at T10 wasassociated with cervical compression from a herniateddisc at C5/C6. 25RadiculopathyFalse-localising radiculopathy may occur in the context ofIIH and cerebral venous sinus thrombosis, manifesting asacral paraesthesias, backache and radicular pain, and lessoften with motor deficits, 26 which on occasion may be sufficientlyextensive to mimic Guillain-Barré syndrome(flaccid-areflexic quadriplegia). 27 The postulated mechanismfor such radiculopathy is mechanical root compressiondue to elevated CSF pressure.Higher cognitive functionHemineglect is much commoner with right rather thanleft parietal lobe lesions. An example of false-localisingneglect has been encountered: in a patient with a posteriorfossa meningioma causing left pontine compression,long tract signs and hydrocephalus, ipsilesional neglectwas found, despite normal structural imaging of the cerebralhemispheres. The neglect resolved promptly aftershunting and did not recur despite progressive brainstemcompression (PC Nachev & IH Jenkins, personal communication).CommentAs false-localising signs most often occur in the context ofRICP, this seems likely to be the most important factor inthe pathogenesis of these signs. Suggested mechanismsinclude mechanical distortion of cranial nerves withintracranial pathology and venous and/or arterialischaemia with spinal cord pathology. 3 It is worth rememberingthat RICP itself may be a false localising sign whenassociated with spinal tumours, even in the thoracolumbarregion, perhaps related to elevated CSF protein concentration.28Of the various false-localising signs described, sixthnerve palsies are the most commonly observed. However,the possibility of false localisation should be borne inmind when any of the above-mentioned signs occur withoutobvious clinical-anatomical or clinical-radiologicalcorrelate. 2References1. Collier J. The false localising signs of intracranial tumour. Brain1904;27:490-508.2. Larner AJ. A dictionary of neurological signs. Clinical neurosemiology.Dordrecht: Kluwer Scientific Publications, 2001.3. Larner AJ. False localising signs. J Neurol Neurosurg Psychiatry2003;74:415-418.4. Kernohan JW, Woltman HW. Incisura of the crus due to contralateralbrain tumor. Arch Neurol Psychiatry 1929;21:274-287.5. Cohen AR, Wilson J. Magnetic resonance imaging of Kernohan’s notch.Neurosurgery 1990;27:205-207.6. Gado M, Hanaway J, Frank R. Functional anatomy of the cerebral cortexby computed tomography. J Comput Assist Tomog 1979;3:1-19.7. Schulz R, Fegbeutel C, Althoff A, Traupe H, Grimminger F, Seeger W.Central sleep apnoea and unilateral diaphragmatic paralysis associatedwith vertebral artery compression of the medulla oblongata. J Neurol2003;250:503-505.8. Marshman LAG, Polkey CE, Penney CC. Unilateral fixed dilation ofthe pupil as a false-localizing sign with intracranial hemorrhage: casereport and literature review. Neurosurgery 2001;49:1251-1255.9. Ksiazek SM, Repka MX, Maguire A et al. Divisional oculomotor nerveparesis caused by intrinsic brainstem disease. Ann Neurol1989;26:714-718.10. Larner AJ. Proximal superior division oculomotor nerve palsy frommetastatic subarachnoid infiltration. J Neurol 2002;249:343-344.11. Lee AG. Fourth nerve palsy in pseudotumor cerebri. Strabismus1995;3:57-59.12. Speer C, Pearlman J, Phillips PH et al. Fourth nerve palsy in pediatricpseudotumor cerebri. Am J Ophthalmol 1999;127:236-237.13. Arsava EM, Uluc K, Nurlu G, Kansu T. Electrophysiological evidence oftrigeminal neuropathy in pseudotumor cerebri. J Neurol2002;249:1601-1602.14. Matsuura N, Kondo A. Trigeminal neuralgia and hemifacial spasm asfalse localizing signs in patients with a contralateral mass of the posteriorcranial fossa. J Neurosurg 1996;84:1067-1071.15. Kandoh T, Tamaki N, Takeda N, Shirataki K, Matsumoto S.Contralateral trigeminal neuralgia as a false localizing sign in calcifiedchronic subdural hematoma: a case report. Surg Neurol 1989;32:471-475.16. Round R, Keane JR. The minor symptoms of increased intracranialpressure. 101 cases with benign intracranial hypertension. Neurology1988;38:1461-1464.17. Davie C, Kennedy P, Katifi HA. Seventh nerve palsy as a false localisingsign. J Neurol Neurosurg Psychiatry 1992;55:510-511.18. Kiwak KJ, Levine SE. Benign intracranial hypertension and facialdiplegia. Arch Neurol 1984;41:787-788.19. Dorman PJ, Campbell MJ, Maw AR. Hearing loss as a false localisingsign in raised intracranial pressure. J Neurol Neurosurg Psychiatry1995;58:516.20. Ro LS, Chen ST, Tang LM et al. Concurrent trigeminal, abducens, andfacial nerve palsies presenting as false localizing signs. Neurosurgery1995;37:322-324.21. Maurice-Williams RS. Multiple crossed false localizing signs in a posteriorfossa tumour. J Neurol Neurosurg Psychiatry 1975;38:1232-1234.22. Sonstein WJ, LaSala PA, Michelsen WJ et al. False localizing signs inupper cervical spinal cord compression. Neurosurgery 1996;38:445-448.23. Adams KK, Jackson CE, Rauch RA, Hart SF, Kleinguenther RS,Barohn RJ. Cervical myelopathy with false localizing sensory levels.Arch Neurol 1996;53:1155-1158.24. Ochiai H, Yamakawa Y, Minato S, Nakahara K, Nakano S, Wakisaka S.Clinical features of the localized girdle sensation of mid-trunk (falselocalizing sign) appeared [sic] in cervical compressive myelopathypatients. J Neurol 2002;249:549-553.25. Pego-Regiosa R, Trobajo de las Matas JE, Brañas F, Martinez-VázquezF, Cortés-Laíño JA. Dorsal sensory level as a false localizing sign in cervicalmyelopathy [in Spanish]. Rev Neurol 1998;27:86-88.26. Moosa A, Joy MA, Kumar A. Extensive radiculopathy: another falselocalising sign in intracranial hypertension. J Neurol NeurosurgPsychiatry 2004;75:1080-1081.27. Obeid T, Awada A, Mousali Y et al. Extensive radiculopathy: a manifestationof intracranial hypertension. Eur J Neurol 2000;7:549-553.28. Ridsdale L, Moseley I. Thoracolumbar intraspinal tumour presentingfeatures of raised intracranial pressure. J Neurol Neurosurg Psychiatry1978;41:737-745.ACNR • VOLUME 5 NUMBER 1 • MARCH/APRIL 2005 I 21

Neuropathology ArticleThe Neuropathology of Head InjuryAcute head injuryEpidemiologyIn the United Kingdom more than 150,000 patients areadmitted to hospital each year with an acute head injury.Of this group more than 80% are classified as having amild head injury, as defined by the Glasgow Coma Scale(GCS). 1 Approximately 1-2% of patients admitted to hospitalafter traumatic brain injury die as a consequence oftheir injuries with the majority of fatalities being withinthe severe head injury group.In the acute phase the neuropathology of blunt forcehead injury can be divided into two principal categories:1) focal; and 2) diffuse 2 (see table).HaematomasIntracranial haemorrhage is the most common cause ofclinical deterioration and death in patients who experiencea lucid interval after head injury. Haematomas mayact as a mass lesion and produce secondary effects.Extradural (EDH), subdural (SDH) and intracerebral(ICH) haematomas can all be associated with traumaticbrain injury. 3EDH’s are seen in some 10% of severely head injuredpatients, 80% being associated with skull fractures andthe majority involve the middle meningeal artery withfractures of the squamous temporal bone.SDH’s tend to be more extensive than extradurallesions as blood can spread more freely within the subduralspace (Figure 1). The majority are due to disruptionof parasagittal bridging veins.ICH’s may be superficial, usually associated with contusions,or they may be more deeply seated, usually withinthe basal ganglia. When an intracerebral lesion is incontinuity with a subdural haematoma the term “burstlobe” is used.ContusionsThese are seen in approximately 90% of fatal cases oftraumatic brain injury, although they may be absent insome 6% of fatal cases. They are more commonly seen atthe crests of the frontal and temporal gyri than withinsulci and occur principally at sites where the brain comesin contact with the uneven bony surfaces of the base ofthe skull. Contre-coup lesions on the opposite side of thebrain to the site of impact are thought to be due to negativepressures built up as the brain moves in relation tothe skull at the moment of impact. Patients with contusionsmay show sudden clinical deterioration, particularlythose with extensive bifrontal lesions.Diffuse injuryThree forms of diffuse brain injury are seen as a consequenceof trauma; diffuse ischaemic injury, whichinvolves grey matter, diffuse traumatic axonal injury(TAI), which involves white matter, and brain swelling.While focal infarcts are commonly seen after fatal traumatichead injury (91% in one study), usually as a consequenceof raised intracranial pressure (ICP), global cerebralischaemia is less common. Global cerebral ischaemiamay be related to hypotension, e.g. after multiple injuries,or secondary to raised ICP resulting in reduced cerebralblood flow. Ischaemic neurons are widely distributed, initiallyfollowing a pattern of selective vulnerability.Diffuse traumatic axonal injury (TAI) describes a diffuseprocess in which there is disruption to axons in anumber of white matter bundles throughout the cerebrumand brainstem (Figure 2). Axons are damaged as aconsequence of rotational forces being applied to thebrain, and is most frequently seen in high velocityimpacts such as road traffic accidents. TAI is not a staticprocess. A small proportion of axons may be damaged atthe time of head injury (primary axotomy), but animalexperiments suggest this is not the case for most of thedamaged axons, which degenerate over a period of timeafter the head injury (secondary axotomy). The clinicalimpact of TAI ranges from mild diffuse injury being associatedwith short spells of unconciousness and possiblyconcussion, through to extensive diffuse TAI associatedwith irreversible coma and death. The structural basis ofconcussion is poorly defined. However, TAI has beendescribed in mild head injury 5 and may form the basis ofconcussion. Post-concussive sequelae are commonlydescribed in mild head injury and axonal damage hasbeen demonstrated in animal models of concussion.Brain swelling can develop either locally, such as inrelation to contusions, or can be diffuse involving one orboth hemispheres. In diffuse brain swelling ischaemia isthe most common underlying pathology, althoughswelling can be associated with diffuse TAI.Long term outcomeThe outcome is modified by the type and severity ofinjury and may be influenced by the pre-morbid statesuch as age, nutritional status and pre-existing disease.Among survivors of traumatic brain injury of all gradesFocal injuriesScalp lacerationsSkull fracturesContusionsIntracranial haemorrhagesLesions secondary to raised intracranial pressureDr Colin Smith trained in neuropathologyin Glasgow and is currentlya Senior Lecturer inPathology in Edinburgh. His mainresearch interests are related totraumatic brain injury, both adultand paediatric. In particular he isinvolved in studies of mechanismswhich may contribute to the ongoingneurodegeneration in survivorsof head injury.Correspondence to:Dr C Smith,Neuropathology Laboratory,Department of Pathology,University of Edinburgh,Western General Hospital,Edinburgh, EH4 2XU.Email: col.smith@ed.ac.ukDiffuse InjuriesGlobal ischaemiaDiffuse traumatic axonal injuryBrain swellingFigure 1: Subacute subdural haematoma identified at autopsy. This individual had a blunt force head injury asthe result of a fall. The patient survived for two weeks post injury. The lesion extends over the surface of theright cerebral hemisphere and shows some degree of organisation.22 I ACNR • VOLUME 5 NUMBER 1 • MARCH/APRIL 2005

For some, epilepsy still means being out of control. LYRICAis a new and effective 1 stchoice adjunctive therapy foradults with partial seizures. 1–3LYRICA has demonstrated that up to 50% of refractorypatients have at least 50% fewer seizures at 12 weeks. 1In addition, in patients treated with LYRICA in open-labelstudies for 12 months, 6% remained seizure-free. 4Bringing stability, taking controlSo, with no known pharmacokinetic drug interactions,*simple dosing, and a favourable tolerability profile, 5 LYRICAis a rational next step when monotherapy is insufficient,enabling you to bring control to partial seizures.*Despite no PK interactions, LYRICA appears to be additive in the impairment of cognitiveand gross motor function when co-administered with oxycodone. LYRICA may potentiatethe effect of lorazepam and ethanol 5 LYR379 Sept 2004NewNew possibilities for partial seizure controlLyrica ® (pregabalin) Prescribing Information.Refer to Summary of Product Characteristics (SmPC) before prescribing.Presentation: Lyrica is supplied in hard capsules containing 25mg, 50mg, 75mg,100mg, 150mg, 200mg or 300mg of pregabalin. Indications: Treatment of epilepsy, asadjunctive therapy in adults with partial seizures with or without secondarygeneralisation. Dosage: Adults: 150 to 600mg per day in either two or three divideddoses taken orally. Treatment may be initiated at a dose of 150mg per day and, basedon individual patient response and tolerability, may be increased to 300mg per day afteran interval of 7 days, and to a maximum dose of 600mg per day after an additional 7-day interval. Treatment should be discontinued gradually over a minimum of one week.Renal impairment/Haemodialysis: dosage adjustment necessary; see SmPC. Hepaticimpairment: No dosage adjustment required. Elderly: Dosage adjustment required ifimpaired renal function. Children and adolescents: Not recommended. Contraindications:Hypersensitivity to active substance or excipients. Warnings andprecautions: Patients with galactose intolerance, the Lapp lactase deficiency orglucose-galactose malabsorption should not take Lyrica. Some diabetic patients whogain weight may require adjustment to hypoglycaemic medication. Occurrence ofdizziness and somnolence could increase accidental injury (fall) in elderly patients.Insufficient data for withdrawal of concomitant antiepileptic medication, once seizurecontrol with adjunctive Lyrica has been reached, in order to reach monotherapy withLyrica. May affect ability to drive or operate machinery. Interactions: Lyrica appears tobe additive in the impairment of cognitive and gross motor functioncaused by oxycodone and may potentiate the effects of ethanol andlorazepam. Pregnancy and lactation: Lyrica should not be used duringpregnancy unless benefit outweighs risk. Effective contraception mustbe used in women of childbearing potential. Breast-feeding is not recommended duringtreatment with Lyrica. Side effects: Adverse reactions during clinical trials were usuallymild to moderate. Most commonly (>1/10) reported side effects in placebo-controlled,double-blind studies were somnolence and dizziness. Commonly (>1/100,

Neuropathology ArticleFigure 2 Figure 3chronic disability may have a physical componentalthough it is predominantly the cognitive and behaviouralproblems which provide the greatest challenge.Outcome may be assessed by the extended GlasgowOutcome Scale (GOS) which defines four outcome states;death/ vegetative state, severe disability, moderate disability,and good recovery. 6Neuropathological basis of outcome after headinjuryIn studies of the brains of patients who entered a vegetativestate after blunt force head injury 7 diffuse pathologywas common and, in particular, diffuse traumatic axonalinjury was seen in more than 60% of the cases. In severedisability 8 there was a relatively equal distribution of focaland diffuse pathology between cases, while in moderatedisability 9 focal lesions, particularly evacuated intracranialhaematomas, accounted for the bulk of the pathologywith diffuse injury being uncommon. Neuronal loss fromthe dorsomedial thalamic nucleus was seen in all grades ofdisability while additional damage to the ventral posteriornucleus was also seen in severely disabled and vegetativecases. 10Neurodegeneration and Dementia after headinjuryRecent studies have indicated that the incidence of moderateand severe disability in young people and adults oneyear after mild head injury is similar to that seen in survivorsof moderate and severe head injury. 11 This raisesthe possibility of ongoing brain damage in long-term survivorsof head injury such that their cognitive functionand motor function continues to deteriorate for monthsand possibly years after the initial injury. 12 The clinicalentity of dementia pugilistica is well recognised in the settingof repetitive head injury. Epidemiological evidencelooking at an association between a single episode of headinjury and subsequent neurodegeneration is conflictingalthough meta-analysis of both retrospective andprospective studies does suggest an association. 13 Headinjury and Alzheimer’s disease (AD) have similarities inrelation to protein and cellular responses and in geneticinfluences, particularly the influence of APOE polymorphisms.14 Both cytoskeletal pathology and amyloid depositionare key pathological features of AD and have beendescribed in animal models of head injury and studies ofboth fatal head injury and repetitive head injury inhumans. Cholinergic dysfunction has been described inboth AD and head injury: damage to key cholinergicpathways (nucleus basalis of Meynart) has been reportedat autopsy in head injury and imaging studies of survivorsof head injury have demonstrated damage to basal forebrainstructures. Chronic neuroinflammation has beenpostulated as a mediator of neuronal loss in many chronicneurological diseases, including AD, and is a feature ofthe response to head injury (Figure 3). 15References1. Teasdale G, Jennett B. Assessment of coma and impaired consciousness:A practical scale. Lancet 1974,304:81-4.2. Graham DI, Smith C. (2001) The pathology of head injury. CPDBulletin- Cellular Pathology 2001,3:148- 51.3. Smith C, Graham DI. Subdural and extradural hemorrhages. In:Olsson Y, ed. Pathology and Genetics Cerebrovascular disease. Basel:ISN Neuropath Press, 2005.4. Graham DI, Gennarelli TA, McIntosh TK. Trauma. In: Graham DI,Lantos PL, eds. Greenfield’s Neuropathology. London: Arnold, 2002:823-98.5. Blumbergs PC, Scott G, Manavis J, Wainwright H, Simpson DA,McLean AJ. Staining of amyloid precursor protein to study axonal damagein mild head injury. Lancet 1994,344:1055-6.6. Teasdale GM, Pettigrew LE, Wilson JT, Murray G, Jennett B.Analyzing outcome of treatment of severe head injury: a review andupdate on advancing the use of the Glasgow Outcome Scale. JNeurotrauma 1998,15:587-97.7. Adams JH, Graham DI, Jennett B. The neuropathology of the vegetativestate after an acute brain insult. Brain 2000,123:1327-38.8. Jennett B, Adams JH, Murray LS, Graham DI. Neuropathology in vegetativeand severely disabled patients after head injury. Neurology2001,56:486-90.9. Adams JH, Graham DI, Jennett B. The structural basis of moderatedisability after traumatic brain damage. J Neurol NeurosurgPsychiatry 2001,71:521-4.10. Maxwell WL, Pennington K, MacKinnon MA, Smith DH, McIntoshTK, Wilson JT, Graham DI. Differential responses in three thalamicnuclei in moderately disabled, severely disabled and vegetative patientsafter blunt head injury. Brain 2004,127:2470-8.11. Thornhill S, Teasdale GM, Murray GD, McEwen J, Roy CW, PennyKI. Disability in young people and adults one year after head injury:prospective cohort study. BMJ 2000,320:1631-5.12. Smith C, Nicoll JAR, Graham DI. Head Injury and Dementia. In: EsiriMM, Lee V M-Y, Trojanowski JQ, eds. The Neuropathology ofDementia, Cambridge University Press, Cambridge, 2004:457-71.13. Fleminger S, Oliver DL, Lovestone S, Rabe-Hesketh S, Giora A. Headinjury as a risk factor for Alzheimer's disease: the evidence 10 years on;a partial replication. J Neurol Neurosurg Psychiatry. 2003,74:857-62.14. Teasdale GM, Nicoll JA, Murray G, Fiddes M. Association ofapolipoprotein E polymorphism with outcome after head injury. Lancet1997,350:1069-71.15. Gentleman SM, Leclercq PD, Moyes L, Graham DI, Smith C, GriffinWS, Nicoll JA. Long-term intracerebral inflammatory response aftertraumatic brain injury. Forensic Sci Int 2004,146:97-104.Figure 2: Immunocytochemistryfor Amyloid Precursor Protein(b-APP)demonstrates swollendamaged axons (stained brown)within the corpus callosum froma case of diffuse traumatic axonalinjury.Figure 3: Microglial activationdemonstrated in the whitematter of an individual whosurvived for several weeks afteran episode of blunt force headinjury. The activated microgliaare immunostained by anantibody which recognises MHCclass II expression. Most cells arestill ramified, the characteristicmorphology of quiescentmicroglia, but are hypertrophied.24 I ACNR • VOLUME 5 NUMBER 1 • MARCH/APRIL 2005

Mestinon in Myasthenia Gravis:Prescribing InformationPresentation: Each tablet contains 62.5mg pyridostigminebromide (equivalent to 60.0mg of the base). Indications:Myasthenia Gravis, paralytic ileus and post-operative urinaryretention. Dosage and Administration: MyastheniaGravis – Adults – Doses of 30 to 120mg are given atintervals throughout the day. The total daily dose is usually inthe range of 5-20 tablets. Children – Children under 6 yearsold should receive an initial dose of half a tablet (30mg) ofMestinon; children 6-12 years old should receive one tablet(60mg). Dosage should be increased gradually, in incrementsof 15-30mg daily, until maximum improvement is obtained.Total daily requirements are usually in the range of 30-360mg. The requirement for Mestinon is usually markedlydecreased after thymectomy or when additional therapy isgiven. When relatively large doses of Mestinon are taken bymyasthenic patients, it may be necessary to give atropine orother anticholinergic drugs to counteract the muscariniceffects. It should be noted that the slower gastro-intestinalmotility caused by these drugs may affect the absorption ofMestinon. In all patients the possibility of "cholinergic crisis",due to overdose of Mestinon, and its differentiation from"myasthenic crisis" due to increased severity of the disease,must be borne in mind. Other indications: Adults –The usual dose is 1 to 4 tablets (60-240mg). Children –15-60mg.The frequency of these doses may be variedaccording to the needs of the patient. Elderly – No specificdosage recommendations. Contra-indications, Warningsetc: Contra-indications – Gastro-intestinal or urinaryobstruction, known hypersensitivity to the drug and tobromides. Extreme caution is required when administeringMestinon to patients with bronchial asthma. Warnings –care should also be taken in patients with bradycardia, recentcoronary occlusion, hypotension, vagotonia, peptic ulcer,epilepsy or Parkinsonism. Lower doses may be required inpatients with renal disease. Use in pregnancy: The safetyof Mestinon during pregnancy or lactation has not beenestablished. Experience with Mestinon in pregnant patientswith Myasthenia Gravis has revealed no untoward effects.Negligible amounts of Mestinon are excreted in breast milkbut due regard should be paid to possible effects on thebreast-feeding infant. Side effects: These may includenausea and vomiting, increased salivation, diarrhoea andabdominal cramps. Drug interactions – None known.Pharmaceutical Precautions: Storage – Recommendmaximum storage temperature 25ºC. Protect from light andmoisture. Legal Category: POM. Package Quantities:Amber glass bottles with aluminium screw caps anddesiccant, containing 200 tablets. Basic NHS Price: £48.12Product Licence Number: PL 15142/0006. ProductLicence Holder: Valeant Pharmaceuticals Limited.Cedarwood, Chineham Business Park, Crockford Lane,Basingstoke, Hampshire RG24 8WD Telephone: +44 (0)1256 707744e-mail: sales@valeant.com Internet: www.valeant.comDate of Preparation: August 2004.Are your patients getting the most out of Mestinon?• Mestinon is known as the 1st-line symptomatictreatment for Myasthenia Gravis 1-4References:1. Hart I. Myasthenia Gravis – the essentials. Eurocommunicapublications.2. Buckley C. Diagnosis and treatment of myasthenia gravis.Prescriber 2000;193. Sharma KR. Myasthenia gravis: a critical review. Internal Med 1996;August:47-694. Drachman DB. Myasthenia gravis. N Eng J Med 1994;330:1797-18105. Vincent A, Drachman DB. Myasthenia Gravis. In: eds Pourmand R,Harati Y, Neuromuscular Disorders, Lippincott, Williams & Wilkins,Philadelphia 2001: p159®However:• Optimum efficacy can only be achieved if yourpatient takes Mestinon FREQUENTLY throughoutthe day 2,5pyridostigmine bromideStrength in ActionHalf-life = 3-4 hoursDosing = 5-6 times a dayFREQUENCY MATTERS

Book ReviewsIf you would like to review books for ACNR, please contact Andrew Larner, Book Review Editor, c/o rachael@acnr.co.ukSPECT in Dementia (Advances in Biological Psychiatry Vol. 22)This slim tome gives details of a study entitled “SPECT indementia”, a collaborative European initiative designed toimprove the use of single photon emission computedtomography in the diagnosis of dementia, involving centresin Scotland, France, Germany, Italy and Israel.Many of the chapters are quite technical in their orientation,e.g. combining images from different clinical settings,voxel-based approaches to imaging (statisiticalparamateric mapping apparently improves rater accuracyof scan reading), comparison of HMPAO-SPECT withFDG-PET, and use of novel receptor ligands. There is nospecific discussion of the functional imaging signatures ofdifferent dementia syndromes (frontotemporal dementia,dementia with Lewy bodies, vascular cognitive impairment,prion disease), the focus being principally onAlzheimer’s disease (AD), in which context an exhaustivesystematic review (taking up more than a quarter of thebook) that finds 99mTc-HMPAO-SPECT can successfullydiscriminate between normal controls and AD is reassuringthough hardly earth-shattering.Of perhaps greater clinical impact are chapters on theuse of SPECT to correlate specific cognitive and psychiatricphenomena in AD with specific patterns of regionalcerebral perfusion, and, particularly topical, assessing theefficacy of cholinestrase inhibitor (ChEI) therapy in AD.Donepezil seems to preserve regional cerebral blood flowpatterns in comparison to untreated AD patients, and inresponders vs. non-responders. In the future, use ofacetylcholine receptor ligands may also provide a surrogatemeasure of ChEI efficacy.A cost-effectiveness study of SPECT in the diagnosis ofAD rounds off the text, and makes interesting reading forthose of us unfamiliar with the methodology of suchstudies. Some of the assumptions, for example monthlyfollow up of AD patients for 3 months before decidingwhether ChEI is continued, and transfer of responders toa GP who will then prescribe the drug, caused some raisingof eyebrows.Thus, this book’s appeal is largely to the cognoscenti offunctional brain imaging, rather than to the clinical neurologist,but nonetheless is worth dipping into by thosewith an interest in dementia.AJ Larner; Cognitive Function Clinic, WCNN, Liverpool.Editors: KP Ebmeier (ed.)Published by: Karger 2003ISBN: 3-8055-7595-5Price: EUR80.00Neuropsychological Assessment (Fourth Edition)This is an update of what for almost three decades hasbeen the classic textbook of clinical neuropsychologicalassessment. The first edition appeared back in 1976, followedby updates in 1983 and 1995. The volume of whatis covered in this textbook has grown significantly, perhapsreflecting the exponential developement of knowledgein this exciting field.As before, the basic scientific knowledge underpinningthe practice of neuropsychological assessment is coveredin great depth before discussing implications for clinicalpractice. It is both striking and reassuring that often thereis not a single, definitive answer to clinical dilemmas. Agood example of this is the question of how to determinepre-morbid ability (Chapter 4) where a critical appraisalof the different methods is followed by providing a pragmaticsolution to this perennial problem in neuropsychologicalassessment. A general theme emphasising the needto be “clinically streetwise” permeates the text. Indeed, thepoint is made that it is now harder than ever to be a goodclinician (page 102).In general, there is now more on neuro-imaging and abetter integration of insights from cognitive neuropsychology.The limitations of findings from neuro-imagingstudies are however highlighted throughout (For example,page 287). A particular strength remains the provisionof strong links between research findings and clinicalpractice. There is also more on the implications of neuropsychologicalassessment for the practice of neuropsychologicalrehabilitation, in effect removing the ratherartificial barrier between assessment and rehabilitation.The basic structure of the book is, as before, that thefirst few chapters address the core, scientific basis of clinicalneuropsychological assessment (Chapters 1 – 8),before proceeding to review a truly wide range of tests,rating scales and inventories (Chapters 9 – 19). Finally, anew chapter on response bias has been added (Chapter20). The application of computers in neuropsychologicalassessment is not covered. It is likely that the first eightchapters will as before be the “must know” part of thebook, while the section on tests will probably be usedmore as a reference source.A vast array of tests are comprehensively reviewed,including some of the new versions of existing, widelyused tests such as the Wechsler Adult Intelligence Scale –III, the Wechsler Memory Scale – III and the RivermeadBehavioural Memory Test - E. Newer tests that are nowbeing used in practice, for example the Delis-KaplanExecutive Function System and the BehaviouralAssessment of the Dysexecutive Syndrome, as well as teststhat have been around for several decades, for example thePorteus mazes, are reviewed. The tests are criticallyreviewed regarding reliability, validity and other neuropsychologicalfindings, providing essential guidance tothe practitioner. As is often the case in neuroscience, a lotof the answers are not straightforward. Indeed, the pointis made that it remains unclear what many tests measure(page108).Are there any gaps in this truly phenomenal textbook?The short answer is no. Perhaps bedside cognitive assessmentand psychopharmacology could have been coveredin a bit more depth, but there are textbooks specificallydedicated to these topics. The chapters on rating scales,inventories and questionnaires used in neuropsychologicalassessment (Chapters 18 & 19) could possibly haveincluded more instruments, for example the EuropeanBrain Injury Questionnaire and the Brain InjuryCommunity Rehabilitation Outcome scale, but thenagain, it is simply not possible to include every test orquestionnaire currently in use. NeuropsychologicalAssessment (Fourth Edition) represents a monumentalachievement by the authors and remains the most importanttext on clinical neuropsychological assessment. Nopractitioner or researcher should be without it.Rudi Coetzer, North Wales Brain Injury Service,Conwy & Denbighshire NHS Trust.Authors: Lezak, MD; Howieson,DB & Loring, DW; with Hannay,HJ & Fischer, JSPublisher: Oxford UniversityPress, 2004ISBN: 0-19-511121-4Price: £59.5026 I ACNR • VOLUME 5 NUMBER 1 • MARCH/APRIL 2005

Society NewsThe Multiple SclerosisSociety of Great Britain andNorthern IrelandMS is the most common disabling neurological disorder affecting youngadults. It is estimated that around 85,000 people in the UK have MS.Approximately 50 people are diagnosed with MS every week.The MS Society is the UK’s largest charity dedicated to supporting everyonewhose life is affected by MS. It is dedicated to funding the very bestresearch into the cause, cure and care of people affected by MS, and is currentlythe largest funder of MS research in the UK. Research is essential to allaspects of the Society's work. It ensures those affected are provided with evidence-basedinformation, enabling them to make informed decisions andmanage their condition. It also helps professionals to develop their servicesand to provide effective treatment and care.MS Society Research ProgrammeThe MS Society currently funds around 55 research projects with aims offinding the causes of MS, investigating ways to stop progression, alleviatingsymptoms, and also improving services to better meet the needs of peopleaffected by MS. In addition to short-term innovative projects, PhD studentships,Fellowships, and Project grants, the MS Society currently supportsthree Programme grants. These long-term commitments include the UK MSTissue Bank at Imperial College, the NMR MRI Unit at University CollegeLondon, and the MS Society Cambridge Centre for Myelin Repair atCambridge University.Consumer InvolvementThe MS Society has a policy of involving consumers at every stage of itsresearch programme to ensure Society funded research is relevant, andreflects the needs and interests of those who live with the condition. So far,150 people affected by MS have been integrated into the research programme,taking part in activities ranging from grant review, reporting on the progressof funded research, raising awareness about MS, and contributing to the MSSociety’s research strategy.After consultation with people affected by MS and researchers in 2002, theMS Society has agreed some research priorities to run alongside its opengrant round, to ensure funds are focused further. Initial priorities include aSymptom Research Programme with the first symptom to be addressed beingfatigue, and research into nerve damage and repair.MS Professional NetworkThe MS Society Professional Network is a group of health and social care professionalswith a common interest in sharing good practice and informationto improve services for people affected by MS. Membership is free andincludes regular newsletters, conferences and learning events. To join emailmsnetwork@mssociety.org.uk or call 020 8438 0765.MS Frontiers 2005MS Frontiers is the Society’s key research conference, which aims to bringtogether researchers and healthcare professionals within the MS field to shareideas and identify key challenges for the future. It is also a great opportunity forstudents and younger researchers currently studying MS to take part in whathas consistently proven to be an extremely interesting and enjoyable event. Thisyear’s programme focuses on neuroprotection, and sessions covering:● a UK MS clinical trial network● evolving MS services● epidemiology● translational research in neurologyThe event in 2005 will be held in Edinburgh on the 25th & 26th May atHeriot-Watt University. For further details or to obtain a booking form pleasecontact frontiers@mssociety.org.uk or tel: 020 8438 0809.For further information about the MS Society’s research programme,email researchadmin@mssociety.org.uk, call 020 8438 0770, or visitthe Society’s website http://www.mssociety.org.uk/research/index.html28 I ACNR • VOLUME 5 NUMBER 1 • MARCH/APRIL 2005

ACNR • VOLUME 5 NUMBER 1 • MARCH/APRIL 2005 I 29

Events DiaryTo list your event in this diary, e-mail brief details to: Rachael@acnr.co.uk2005MarchThe Visual System - RSM ClinicalNeurosciences Section3 March, 2005; London, UKTel. 20 7290 2984/2982, E. cns@rsm.ac.ukRoyal College of Psychiatry: Old Age Psychiatry3-4 March, 2005; UK. http://www.rcpsych.ac.uk/conferences/diary/index.htm13th Annual Conference - Association ofCognitive Analytic Therapy: Body, Brain andBeyond CAT4-5 March, 2005, London, UKTel. 020 7188 0692, E. conference@acat.me.ukStandardised Assessment in OccupationalTherapy with special emphasis on Dementia,Part 2March, 2005; London, UK. Tel. 020 7834 31819th International Congress of Parkinson'sDisease and Movement Disorders5-8 March, 2005; New Orleans, USE. congress@movementdisorders.orgGCNN 2, 2nd Global College ofNeuroprotection and NeuroregenerationAnnual Conference7-10 March, 2005; Innsbruck, AustriaE. info@gcnpnr.orgThe British Pain Society Annual Meeting8-11 March, 2005; Edinburgh, UKTel. 020 7631 8870,E. meetings@britishpainsociety.org7th International Conference on Progress inAlzheimer's and Parkinson's Disease9 - 13 March, 2005; Sorrento, ItalyFax. 08451 275 687, E. adpd@kenes.comThe Electrophysiological Technologists’Association Scientific Meeting10-12 March, 2005; Glasgow, UKE. epta@execbs.comAdvances in Otology and Neurotology11-12 March, 2005; Houston, USE. cme@bcm.tmc.eduAdvances in the Management of People in aVegetative and Minimally Conscious State16 March, 2005; Newcastle, UKLinda Eldred, Tel. 0870 1500 100,E. eldredl@irwinmitchell.co.ukTuberous Sclerosis Association: ProfessionalStudy Day17 March, 2005; Birmingham, UKTel. 01527 871898, Fax. 01527 579452.1st Joint International Meeting on Degos Disease18-19 March, 2005; Berlin, GermanyE. judith@degosdisease.comEssential Skills in Neurosurgery22 March, 2004; London, UK0207 4053 474, E. international@rcseng.ac.ukABN Spring Meeting30 March - 1 April; Belfast, UKTel. 020 7405 4060, E. info@theabn.orgBPS 2005 Quinquennial Conference30 March - 2 April, 2005; Manchester, UKwww.bps.org.uk/events/AC2005AprilPain Management: The Online Series,Assessing and Treating Neuropathic Pain1-30 April, 2005E. mark_evans@ama-assn.org7th Neurochemistry Winter Conference2-7 April, 2005; Sölden, Austriawww.sambax.com/nwc2005/18th National Meeting of the BNA3-6 April, 2005; Brighton, UKwww.bna.org.ukClinical Neurophysiology BSCN Course3-8 April, 2005; Oxford, UKE. robin.kennett@orh.nhs.ukInternational Psychogeriatric Association5-8 April, 2005; Rotorua, New ZealandFax. +1 847 663 0591, Tel. +1 847 663 0574,E. info@ipa-online.orgIndependent Living Scotland6-7 April, 2005; Glasgow, UKTel. 020 7874 0200.27th Advanced Clinical Neurology Course6-8 April, 2005; Edinburgh, UKE. events@acnr.co.ukDo Corticosteroids Damage the Brain?Symposium in honour of Prof Joe Herbert7 April, 2005; Cambridge, UKMichael Hastings, E. mha@mrc-lmb.cam.ac.uk,Tel. 01223 402307/402411.Introduction to NeuropsychologicalRehabilitation7-8 April; 2005; Ely, UKE.alison.gamble@ozc.nhs.ukNeurology for Neuroscientists XI7-8 April, 2005; Oxford, UKE. nneurosc@ion.ucl.ac.ukInsight Following Brain Injury8 - 9 April, 2005; Gatwick Hilton, SussexBrain Tree Training,E. enquiries@BrainTreeTraining.co.ukTel. 01276 472 369.American Academy of Neurology (AAN)Annual Meeting9-16 April, 2005; Florida, UShttp://am.aan.com/Cognitive Neuroscience Society (CNS) Meeting10-12 April, 2005; New York, USE. cnsinfo@cogneurosociety.orgwww.cogneurosociety.org/content/meeting3rd World Congress Of The ISPRM10-14 April, 2005; San Paulo, BrazilE. ispmr2005@isprm.orgUK MS Week 200510-17 April, 2005, UK. E. info@msif.orgInternational Parkinson’s Disease Conference11 April, 2005; LuxembourgRegister by 11 March - FREE.www.epda.eu.com/worldPDDay-2005.shtmCertificate Course in NeurologicalRehabilitation11-29 April, 2005, Newcastle, UKTel/Fax. 0191 2195695,E. traceymole@actionfordisability.co.ukNeuro-Ophthalmology Clinical Course11-15 April, 2005; Dubline, IrelandTel. +353 1 809 2609 or +353 1 803 28762005 International Conference on Posture &Wheeled Mobility11-15 April 2005; Exeter, UKE. info@mobility2005.org, Tel: 0845 1301 674Neurodegeneration - RSM ClinicalNeurosciences Section14 April, 2005; London, UKTel. 20 7290 2984/2982, E. cns@rsm.ac.ukTuberous Sclerosis Association: ProfessionalStudy Day - the adult perspective14 April, 2005; Birmingham, UKE. support@tuberous-sclerosis.org,Tel. 01527 871898RCP Live: Current Issues in the Management ofParkinson’s Disease14 April, 2005; OnlineE. conferences@rcplondon.ac.uk,www.rcplondon.ac.ukBritish Sleep Society Spring Meeting14-15 April, 2005; Newcastle, UKJane Orgill, Lung Function Unit, St George'sHospital, Tooting SW17 0QT.BGS Spring Meeting14-15 April, 2005; Birmingham, UKBritish Geriatric Society, Tel. 0207 6081369Evolving MS Services15 April, 2005; Wales. E. CBray@mssociety.org.ukESH-EBMT-EUROCORD Euroconference onStem Cell Research15-18 April, 2005; Cascais, PortugalE. ghyslaine@chu-stlouis.fr73rd Annual Meeting of the AmericanAssociation of Neurological Surgeons16-21 April, 2005; New Orleans, USwww.aans.org/annual/2005/Second International NeuroacanthocytosisSymposium "Expanding the Spectrum ofChoreatic Syndromes"17-20 April, 2005; Montreal, CanadaTel. 0207 937 2938; E. gingerirvine@usa.netThe Management of Blackouts andMisdiagnosis of Epilepsy and Falls19 April, 2005; London, UKTel. 0207 9351 174, Fax. 0207 4875 218,E. conferences@rcplondon.ac.ukAction in Neuro-Rehab21 April, 2005; Newbury, UKTel. 01635 202 605, E. neuroconf@aol.comNeuroanaesthesia Society of Great Britain andIreland, Annual Update21-22 April, 2005; Bristol, UKE. John.carter@north-bristol.swest.nhs.uk /samantha.shinde@north-bristol.swest.nhs.ukIII International Conference on Metals and theBrain: From Neurochemistry toNeurodegeneration20-22 April, 2005; Cape Town, South Africawww.unistel.co.za/neuro2005Understanding Brain Injury22 April, 2005; Ely, UKE. alison.gamble@ozc.nhs.ukOtoneurologia 200523-24 April, 2005; Azores Portugalotoneuro2005@mail.pt, www.otoneuro.ptNeurological Rehabilitation: Past, Present &Future27 April, 2005; Manchester, UKTel. 0161 295 7014, E. j.fletcher@salford.ac.ukMayShort Courses : Neuro-Medical / Surgical NursingMay, 2005; Cambridge, UKE. wood@health-homerton.ac.uk6th World Congress on Brain Injury1 - 4 May, 2005; Melbourne, AustraliaE. braininjury@icms.com.auAspects of the Neurological Examination -RSM Clinical Neurosciences SectionTel. 20 7290 2984/2982, E. cns@rsm.ac.ukAnnual Meeting of the German, Austrian, Swisssection of the International League AgainstEpilepsy5-7 May, 2005; Innsbruck, AustriaTel. +43 512 5043879,E: iris.unterberger@uibk.ac.at2nd quadrennial meeting of the WorldFederation of Neuro-Oncology EANO VI5-7 May, 2005; Edinburgh, UKE. EANO6@fecs.be, Tel. 32 27 750 205,Fax. 32 27 750 200.4th BASP Thrombolysis Training Day6 May, 2005; Nottingham, UKPamela Nicholson, sec to Professor Lees,E. pcn1w@clinmed.gla.ac.uk, Tel. 0141 211 2176.Neurochirurgie 20057-11 May, 2005; Strasbourg, FranceFax. +49 3 028 449 911,E. nch2005@porstmann-kongresse.de12th European Congress of ClinicalNeurophysiology8-12 May, 2005; Stockholm, SwedenE. secretary@ec-ifcn.org /weerd@ipe.nlInaugural Meeting of the VocationalRehabilitation Special Interest Group13 May, 2005; London, UKE. admin@bsrm.co.ukAlzheimer’s Disease: Update on Research,Treatment, & Care19-20 May, 2005; San Diego, USE. jcollier@ucsd.edu30 I ACNR • VOLUME 5 NUMBER 1 • MARCH/APRIL 2005

Traumatic Brain Injury – The Road to Recovery6 December, 2004; London, UK.This was a one-day conference organised by the Royal College ofPhysicians and British Society of Rehabilitation Medicine held atthe Royal College of Physicians, London. The main theme of themeeting was to enable professionals involved in the care of patientswith brain injury to have a clear understanding of the scope as well asthe complexities involved in rehabilitation of this patient group.Professor Carol Black, President of the Royal College of Physicians gavethe welcome address and was pleased that so many people involved in braininjury rehabilitation, not only from the statutory services but also from thevoluntary and charitable sectors, had come to this meeting. She went on tosay that the meeting covered a topic that has not received the attention itdeserves in the past. The meeting was conducted in four sessions.1. Morning sessionsChair: Dr Vera Neumann,President of the British Society of Rehabilitation Medicine1.1. The patient journeyTitle:National Service Framework (NSF) for long term conditions:Guidance and evidence for traumatic brain injury (TBI)rehabilitationSpeaker: Professor Lynne Turner-Stokes,Vice-Chair – External Reference Group of the NSF forlong term conditionsTake home messages:1. There is an urgent need for further research in traumatic braininjury (TBI) rehabilitation2. Users’ and carers’ views must be fully taken into account in furtherdevelopment of TBI rehabilitation3. A new research typology has been developed with information onclassification of design, quality rating and grades of evidence andrecommendationsTitle: Robin’s story – one family’s experience of brain injurySpeakers: Steve and Ann Harris, Robin’s parentsTake home messages:1. Good practice in post brain injury rehabilitation has been rather patchy2. There needs to be better co-operation and co-ordination of servicesfor those with brain injury in the community1.2. Clinical conundrumsTitle: Management of agitation and challenging behaviourSpeaker: Dr Simon Fleminger, Consultant NeuropsychiatristTake home messages:1. Managing restless, agitated and aggressive patients following braininjury requires a team approach2. The medication to control these problems must be used judiciouslyin conjunction with psychological and behavioural managementprogrammesTitle: Profound brain damage: locked in or vegetative stateSpeaker: Dr Keith Andrews, Director – Institute of ComplexNeuro-disabilityTake home messages:1. There is still much confusion among the clinicians between lockedConference Reportin, minimally conscious and vegetative states2. It is important to be aware of potential pitfalls in diagnosis as well asproblematic presentations2. Afternoon sessionsChair: Professor Lynne Turner-Stokes2.1. Brain injury rehabilitation servicesTitle: Acute care and the interface with rehabilitationSpeaker: Professor John Pickard, Consultant NeurosurgeonTake home messages:1. The interface between acute care and rehabilitation services are farfrom ideal2. Head injury co-ordinators are essential in ensuring smooth movementof patients through acute care, rehabilitation and support inthe communityTitle: Specialist rehabilitation service networks – a model of careSpeaker: Dr Kyaw Nyein, Consultant in Rehabilitation MedicineTake home messages:1. Network of specialist rehabilitation services are essential to ensureappropriate and timely care for patients with brain injury2. There needs to be an ever closer collaboration between the specialistrehabilitation services and the district and community services indelivering a seamless service to patients with severe complex disabilityin the community2.2. Living with brain injuryTitle: Longer term community support and case managementSpeaker: Maggie Campbell, Brain Injury Co-ordinatorTake home message:1. Need to promote an interdisciplinary client centred approach inpractical service delivery2. Professionals should work in collaboration with service users toachieve realistic personalised goalsTitle: Back to work following brain injurySpeaker: Dr Andy Tyerman, Consultant Clinical NeuropsychologistTake home message:1. Supported work re-entry programmes are effective in reintegratingthe brain injury population to their workplace2. Need to develop local inter-agency protocolsHe then launched the inter-agency guidelines on vocational assessmentand rehabilitation after acquired brain injury, which was well received.There was widespread agreement among those who attended the one-dayconference that the highlight of the meeting was Steve and Ann Harris’spowerful presentation of their son Robin’s journey following his braininjury.The trials and tribulations that they encountered as well as the triumphsthat they achieved with able support from many of the professionalsinvolved in Robin’s care left a powerful and indelible impression on thosewho attended the meeting as to the importance of patient centred care.Dr Andrew Thu, Dr Charlie Nyein, Regional Rehabilitation Unit,Northwick Park Hospital, London.PD ACADEMY2005In association with theParkinson’s Disease Section,British Geriatrics Society &Parkinson’s Disease Society UKSupported by an unrestricted educational grant fromBoehringer Ingelheim LtdWho are these courses for? Consultants, staff grade physicians, and final year specialist registrars with an interest in Parkinson’sdisease wishing to advance their knowledge and skills in this area.What will it involve? The course will advance understanding of PD and related movement disorders through taught sessions andmentorship.What will it cost? £400 for a six month mentored course, (includes all course materials, portfolio and accommodation for the tworesidential modules). You are encouraged to apply to your employing Trust for Study Leave, and approval.Dates for Parkinson's Disease Masterclass 7Module 1, 14-16th Sept 2005, Carlyon Bay Hotel, Cornwall • Module 2, 15th -17th March 2006, Down Hall Hotel, Hatfield.Both Modules must be completed to pass the courseAdditional seminars and learning opportunities will be undertaken more locally with the mentor and through distance learning.Download an application form from www.bgsnet.org.uk/Notices/meetings/April05.htm or Email redpublishing@btopenworld.com for more information.ACNR • VOLUME 5 NUMBER 1 • MARCH/APRIL 2005 I 31

Conference Report15th International ALS/MND Symposium2-4 December 2004; Philadelphia, USADoctors, nurses and professionals allied tomedicine (PAM’s) gathering in a northerncity in a temperate weather zone inearly winter? – it must be the ALS/MND symposium.All those with a significant interest inmotor neurone disease (MND) or amyotrophiclateral sclerosis (ALS), gathered in Philadelphia.For a relatively uncommon condition, MNDgenerates disproportionate interest, probablybecause most health care workers recognise theawful truth of this disease.This year more that 750 delegates gathered topresent, discuss, debate and exchange the mostrecent advances in the fields of MND basic scienceresearch and clinical care. Each year the sizeof this meeting increases, reflecting the impactthat MND has upon patients, their families andprofessional carers alike. The symposium properwas preceded by several days of satellite sessionsand an allied professionals meeting for the dayimmediately preceding the opening plenary session.The format of opening and closing jointplenary sessions, separated by parallel sessionscovering basic science research and clinical care iswell established. Most clinical academics areforced to make difficult choices between key sessionscovering important areas of scientificadvance and those concentrating on importantissues of care provision.One of the major themes highlighted this yearwas the similarity of MND to many other neurodegenerativeconditions. Several keynotespeakers emphasised this point with reference toParkinson’s disease, Alzheimer’s disease andsome of the tri-nucleotide repeat disorders. It isnow more that ten years since the first report thatmutations in Cu/Zn superoxide dismutase(SOD1) are causal in approximately 20% offamilial MND cases. Finally, mutated SOD1 isstarting to give up its aetiological secrets. Severalelegant scientific presentations put forward evidencethat, in common with other neurodegenerativeconditions, mutant SOD1 associatedfamilial MND appears to be a disorder caused byprotein mis-folding, failed degradation and ultimatepathological aggregation. These problemsappear fundamental to motor neurone cell loss inmutant SOD1 associated MND, and may well beof great importance in sporadic MND, whereprotein aggregation was first reported andremains one of the most widespread neuropathologicalabnormalities.At last year’s symposium (in a cold and dankMilan) the first reports of the vascular endothelialgrowth factor (VEGF) gene acting as a risk factor(modifier) for the development of MND werepresented. This year several scientific presentationsshowed how this novel information is beingexploited in new therapeutic approaches to MND.VEGF administered to transgenic mice carryinghuman SOD1 mutations and which develop aform of MND, improved survival of these animals.Moreover, novel delivery systems using viralvectors, conveying VEGF genes to motor neuronswere also shown to slow the degenerative processin both in vitro and in vivo models of MND.Don CevelandDr CoxDr ChioA novel therapeutic option, again employingour understanding of the role of mutant SOD1was reported by Don Cleveland’s group (USA).They have developed anti-sense RNA oligonucleotidesto several SOD1 mutants, which downregulate those specific SOD1 RNAs in vitro. Thismay offer a therapeutic pathway for familialMND sufferers with identified SOD1 mutations.Although stem cell therapies in MND were notprominent at this year’s symposium, StanleyAppel’s group (USA) presented evidence thatbone marrow derived haematopoietic stem cellsmay be able to cross the blood brain barrier, withsustained levels of donor-derived DNA present inthe spinal cords of allogenic bone marrow transplantedMND patients. Caution in the interpretationof these very early and limited results mustremain, particularly given the use of a high-riskstrategy such as bone marrow transplantation.The clinical sessions included brief reports oftrials conducted in human MND patients. Threeof these reported trials were small and preliminaryin nature. Sadly, the two large and well conductedtrials presented, examining the drugs celecoxiband pentoxyfilline respectively, both reportednegative results in terms of improved survival.MND care centres around the world are stillwrestling with the problems associated with theappropriate timing of various interventions suchas gastrostomy and ventilation for MNDpatients. Increasing evidence supports the use ofsome form of pressure measurement as the mostaccurate monitor of respiratory function (maximuminspiratory or expiratory pressure, nasalsniff pressure, peak cough flow), with overnightoxygen saturation and forced vital capacity beingrelatively insensitive indicators of the need forsome form of ventilatory intervention.A clinical session was devoted to non-invasiveventilation (NIV). Several groups reported theresults of their experience in the use of NIV fortheir MND patients, and factors which influencedsuccessful and compliant use of NIV. TheNewcastle (UK) group reported the results of theonly positive therapeutic trial presented at thesymposium. More than 40 MND patients fulfillingpredetermined criteria for NIV were randomlyallocated to receive NIV or “standard”conservative management of their respiratoryinsufficiency. A significant overall survival benefit,but more importantly a highly significant andsustained improvement in quality of life wasdetected in patients receiving NIV.The symposium closed with two excellent presentationson differing epidemiological studies ofMND. Dr Chio (Italy) reported on the high incidenceof MND amongst professional footballersin Italy, supporting the widely held but largelyanecdotal view that MND is over represented inhigh performing sports men and women. Themechanisms behind this apparent finding remainelusive. Dr Cox (USA) presented what appears tobe the answer to a near 100-year-old conundrum– the very high incidence ALS / Parkinsonism /dementia complex (ALS/PDC) affecting theChamorro peoples of Guam. Nearly 20 years agothis disorder was linked to an environmentaltoxin ß-methyl-amino-L-alanine (BMAA),found in cycad seeds, a staple of the Chamorrodiet. However, the level of BMAA appeared tolow in the flour derived from these seeds. It nowappears that BMAA is concentrated in flyingfoxes (fruit bats), a delicacy highly sought after bythe Chamorro peoples, the ingestion of which ledto their toxic exposure to BMAA and the developmentof ALS/PDC. Intriguingly, Dr Cox presentedpreliminary data indicating the presenceof BMAA in the brain tissue of Alzheimer’s diseasepatients in Canada (who had no associationwith Guam) raising the possibility that such toxinsare present in other parts of the world andmay even contribute to neurodegeneration.Suitably enthused, and having had ampleopportunity to reinforce old collaborations andforge new ones, delegates left with plenty of newscientific and clinical information to digest, andthoughts of a temperate Dublin next Decemberin their minds.Dr Timothy Williams,Consultant Neurologist & MND Care CentreMedical Director, Newcastle.See www.acnr.co.uk/pdfs/volume2issue3/v2i3interview.pdf for an interview with Oliver Sacks, "Flying Bats in Guam - the cause of the complex".For a response to that article by Dr Huw Morris, see www.acnr.co.uk/pdfs/volume2issue3/v2i3specfeaturebats.pdf32 I ACNR • VOLUME 5 NUMBER 1 • MARCH/APRIL 2005

Conference ReportAmerican Epilepsy Society Annual Meeting3-7 December, 2004; New Orleans, USAFollowing the heavy snow in Boston lastyear, balmy New Orleans was a welcomechange. Genetics was the topic for theannual course. The number of single geneepilepsies identified continues to increase. As inother clinical areas, there is a “many-to-manyrelationship”; the same clinical syndrome maybe associated with different genes and abnormalitiesof the same gene may be associatedwith different clinical syndromes. For example,SCN1A truncating mutations cause severemyoclonic epilepsy of infancy and missensemutations cause generalised epilepsy withfebrile seizures plus (GEFS+), which may alsobe associated with mutations of the SCN1B,SCN2A and GABA receptor gene mutations.Lennox and Lennox demonstrated a concordanceof 80% in MZ twins for IGE syndromeshalf a century ago and this has been almostexactly replicated by Berkovic and colleagues.In rare IGE families with a dominant pedigree,abnormalities of the GABA receptor have beenidentified. However, the genetic bases of commoneridiopathic epilepsies remain elusive. Alate onset form of idiopathic generalisedabsence epilepsy has been recognised for someyears but recent studies have shown that up toa quarter of IGE has onset over the age of 20. Ifyour patient has tonic clonic seizures with noaura, triggered by fatigue or alcohol, and a familyhistory, think IGE.Another major session was devoted to neuronaldevelopment. Since the 1970’s it has beenknown that the cortical neurons arise from theependymal zone and then migrate along radialglial fibres. Arnold Kriegstein from SanFrancisco, used labelling methods to show howglial cells at the ventricular zone start to producetheir radial fibre then divide asymmetricallyto produce another glial cell and a neuronwhich then migrates up the glial fibre. Some ofthe molecules that help to determine the fate ofeither cell, are being identified. By contrastdivisions of cells slightly further along theirroute, in the subventricular zone, are symmetric,giving two neurons. Some radial cells haveGABAA receptors and studies show that GABAactive drugs can influence neurogenesis; of significanceas we consider antiepileptic drugs inpregnancy. When radial glial cells reach thecortex they change into astrocytes, which mayretain some stem cell activity. Pat Levitt fromVanderbilt University pointed out thatinterneurons are only 10% of neurons and sochanges in pathological states may be difficultto detect. He described how in the rat they arisefrom the ventral telencephalon and thenmigrate into the cortex by a mechanism dependenton hepatocyte growth factor (HGF). Aknockout mouse with reduced HGF has fewerinterneurons and increased susceptibility toseizures. They are also less social and more sensitiveto diazepam. He speculated that alteredfunctional anatomy of cortical columns maycause these changes and that they may be amodel for autistic spectrum disorders. AmyBrooks from Pennsylvania addressed the questionof why young animals are particularly susceptibleto seizures. In immature neurons thereis a higher intracellular chloride concentrationthan in mature neurons. Consequently, chloridefluxes controlled by GABA receptors movein the opposite direction and are depolarisingrather than hyperpolarising. She also describedhow A and B type GABA subunits switch duringdevelopment to alter their functional propertiessuch that young mice are particularlyprone to seizures in the postnatal period.Glutamate receptor function is also enhancedfrom postnatal day 5-15 in the mouse. In additionthe response of the brain to seizuresappears to be different at different ages. Afterstatus in neonatal mice there is an upregulationof GABAA with an increased sensitivity to benzodiazepines,which is not seen after status inadults. All adults in these studies developedspontaneous seizures within 4 days of statuswhereas neonates did not. If similar factorsoperate in humans, they may clearly be significantin designing and using drugs in youngchildren rather than in adultsIn the annual Lennox lecture, Dr Pitkänenfrom Denmark emphasised an increasingtheme that current therapies treat seizures andwe should be looking at factors that underly thedevelopment of epilepsy. She argued that currentmodels may not be representative ofhuman epilepsy and suggested different modelsand the use of surrogate markers in assessingthe severity of acute brain injury such as 14-3-3 protein levels in the CSF. She showed how theadrenergic blocker atipamezole may makeestablished seizures worse but is anti-epileptogenic;if given early after injury may reduce theseverity of subsequent epilepsy by 90%.One session was devoted to evidence-basedguidelines in the drug treatment of epilepsy.The background was set with a talk thatdescribed the evolution over 20-30 years fromexpert opinion through consensus statementsto evidence-based medicine, a process drivenpartly by cost considerations. Dr BenMenachem chaired an ILAE team whichanalysed all the existing drug trials in differentforms of epilepsy, used to inform the currentguidelines of the ILAE. In monotherapy studiesof focal epilepsy, only 1 trial (from 1985) wasconsidered to be of class 1a quality and only 10of 33 studies were in the top tier. The paneladopted the view that only where a good qualitytrial had been conducted could firm conclusionsbe drawn. So if you conduct a good studyon a mediocre drug it gets in the guidelines andif you conduct a bad study on a good drug itdoesn’t. Recommended first line treatment forfocal epilepsy in adults is carbamazepine,oxcarbazepine, topiramate and valproate(men) with alternative treatments gabapentin,lamotrigine, phenytoin (downgraded by toxicity)and valproate (women). There are no ILAErecommended drugs for childhood absenceepilepsy because there are no good trials andsulthiame (not available for decades in the UK)is the only recommended drug for benignrolandic epilepsy as it is the only one subjectedto a decent clinical trial. This approach emphasisesthe need for more carefully conducted trials.But where none is available, taking the evidence-basedprinciple to extremes denies awealth of clinical experience, implies that opinionand consensus are worthless and results inguidelines that are frankly bizarre – better noguidelines at all. As the leading internationalepilepsy organisation the voice of the ILAE hasan authority which it risks losing if it generatesguidelines to which nobody will adhere.The issues around pregnancy and epilepsycontinue to figure largely. Whether maternalseizures contribute to major foetal malformationsremains uncertain but the various registersgive useful and sometimes disturbinginformation about AED’s, with valproateremaining the villain of the piece.Carbamazepine and lamotrigine data are morereassuring.A recent Cochrane review concluded thatDancing in the street in New Orleans.ACNR • VOLUME 5 NUMBER 1 • MARCH/APRIL 2005 I 33

Conference ReportSingle gene mutations and epilepsy syndromes have amany-to-many relationshipthere is insufficient evidence of the benefit ofspecialist nurse intervention. Insufficient evidenceof efficacy does not imply absence of efficacyand a US study using the QOLIE-89demonstrated that nurses do provide significantquality of life improvements for their patients.It is always somewhat mind-numbing to workround 1000 posters in two sessions. There was ofcourse basic science that we didn’t understandand the usual posters telling how different newdrugs really do work quite well in this or thatform of epilepsy in which they haven’t been triedbefore. Here is a baker’s dozen highlights thatstruck us: 1) intravenous furosemide or mannitolsuppressed interictal spike activity as measuredby intraoperative EEG spike recordingduring epilepsy surgery. 2) Over 90% of 75patients with JME identified lifestyle as seizuretriggers (sleep deprivation 77%, stress 83%,menstruation 33%, alcohol 11% - an underestimateI think – and various cognitive tasks in asmall number each), important factors to considerin your patients. 3) Late-onset nontumoraltemporal lobe epilepsy in 20 patientswas associated with very high antithyroid antibodies,18 of whom did not fulfil criteria fordiagnosis of Hashimoto’s encephalopathy. Thismay need to be added to the list of autoimmunecauses including paraneoplastic and voltagegated-potassiumchannel antibodies. 4) Pre-ictalheadache affected 11 of 100 consecutive patientsand lasted more than 30 minutes in 4. In 9patients it was ipsilateral to the seizure focus (nbheadache is often a prodrome of psychogenicnon-epileptic seizures. 5) There is always a littlehesitancy in using baclofen in patients withepilepsy but in one study of 42 children withcerebral palsy, intrathecal baclofen at least, didnot increase seizures. 6) When do you decidewhen to abandon trial of a new drug in yourpatient? A study from Alabama suggests that thestrategy varies from drug to drug; they foundtopiramate has a ceiling response at around400mg and gabapentin at 2400mg per day.Higher doses yielded few new responders. Bycontrast, oxcarbazepine had a more linear doseresponse,all the way to the maximum recommended2400mg. 7) Lamotrigine levels start tofall only 3 days after withdrawing concomitantvalproate. In women with catamenial epilepsylamotrigine levels peak at ovulatory day 10-13,with up to 31% reduction premenstrually. 8)One study reported good efficacy but poor tolerabilityof bromides in 17 patients with refractoryepilepsy. Plus ça change! 9) Beware stoppingAED in seizure-free patients; in an analysis of 12studies where treatment was reinstituted, it tookup to 1 year for half of patients to becomeseizure free and 10% never regained seizurefreedom.10) Confusion is such a common presentationin the elderly that it is easy to forget theoccasional patient presenting with non-convulsivestatus. Even those who had previously suffereda bout were not diagnosed for 29 hours onaverage. 11) Of 10 patients in one study withunexplained syncope, 9 had psychogenic pseudosyncope;“swoons” are rarely organic. 12)Rapidly titrated levetiracetam has been used successfullyin the treatment of refractory focal status.MRAM also has found it valuable in thisindication and would be interested to hear fromothers with similar experience. 13) Depressionin TLE patients was associated with inferiorfrontal hypometabolism on FDG-PET.Hypometabolism developed in similar areas inthose who developed depression after temporallobectomy; an organic cause is implied.Dr Mark Manford,Consultant Neurologist,Cambridge.34 I ACNR • VOLUME 5 NUMBER 1 • MARCH/APRIL 2005

Rehabilitation ArticleSacral Nerve Stimulation (Neuromodulation) forthe Treatment of Lower Urinary Tract Symptoms inAdult PatientsSacral nerve stimulation (SNS) has become establishedin recent years as a treatment option for two groups ofpatients seen within urological practice. Firstly, it can beused for patients with idiopathic detrusor over-activity leadingto symptoms of urinary frequency, urgency and urgeincontinence. 1 The second group are women with urinaryretention due to either an unknown cause or abnormalitiesof the distal urethral sphincter (Fowler’s syndrome). Otherindications are now being evaluated as interest and researchinto this exciting treatment modality gains momentum.Origins of the techniqueElectrical stimulation of the peripheral nervous system haslong been known to influence lower urinary tract symptoms(LUTS) and perception of pelvic pain, whether deliveredtranscutaneously or by implanted devices. Historically,stimulation has been applied using anal, vaginal, bladderwall and cutaneous electrodes. In the modern era, anal andvaginal stimulation probes have been used to treat stressincontinence, while transcutaneous electrical nerve stimulation(TENS) has been successfully used to treat chronicpain. While treating such patients, investigators observedthat electrical stimulation also had a beneficial effect onurinary urgency and urge incontinence. 2,3 Both anogenitaland transcutaneous stimulation techniques have since beenused to treat bladder overactivity. However, the short hangovereffect, combined with the intensity of the treatmentschedules themselves, have prevented widespread acceptanceof these non-invasive techniques.A more invasive approach using direct electrical stimulationof the third (and sometimes fourth) sacral nerveswas first described experimentally in 1988 4 and is now themost prominent and well established of the so-called neuromodulationtechniques. In contrast to the non-invasivemethods, sacral nerve neuromodulation uses continuousstimulation and close nerve contact. This requires surgicalimplantation of a pulse generator and electrode.Theoretical basis of sacral neuromodulationThe aim of sacral neuromodulation is to relieve bladdersymptoms by rebalancing micturition control. However,the exact neurophysiological basis for this action is stillunclear. Everyday clinical experience shows that bladdercontractions can be suppressed by external sphincter andpelvic floor contractions, and therefore it is not surprisingthat electrical stimulation of the sacral nerves causes bladderinhibition in both animals and man. 2,5 However, whenmixed S3 nerves are stimulated at the level of the sacralforamina it is not always clear whether therapeutic neuromodulationis the result of direct activation of the sensorynerves, or indirectly by activation of the striated externalsphincter and pelvic floor muscles leading to reflexdetrusor relaxation. Both mechanisms have been consideredand researchers now conclude that it is the afferentpathways, causing inhibition at either spinal orsupraspinal level, which play the crucial role. 6-8 The mostdirect evidence supporting an afferent mechanism comesfrom the fact that neuromodulation effects can bedemonstrated with stimulation of the (purely sensory)dorsal penile and clitoral nerves. 2IndicationsThe main indications for SNS are detrusor overactivityand female urinary retention as mentioned above.However, there is also some evidence that neuromodulationmay be useful in patients with voiding disorders ofneurological origin: it has been used successfully inpatients with multiple sclerosis and incomplete spinal cordlesions. 9,10 However, the numbers of such reported cases aresmall. Painful bladder disorders, notably interstitial cystitis,have also been studied in small case series with some,but not all, investigators finding favourable responses. 11S3 sacral neuromodulation received FDA approval inthe USA for the treatment of urge incontinence in 1997and for urgency/frequency and non-obstructive urinaryretention in 1999. However, within the UK currentNational Institute for Clinical Excellence (NICE) guidelinesexist only for patients with urge/frequency syndromeand urge incontinence. 1Pre-operative patient work-upAll patients who are considered for sacral neuromodulationshould have their diagnosis defined as clearly as possibleby urodynamic assessment. They should have undergonerigorous trials of conservative treatments such aslifestyle modification, pelvic floor exercises and anticholinergictherapy. It is also important to document theseverity of patient symptoms using frequency/volumecharts which document fluid intake and urine output overseveral days.Not every patient will gain benefit from sacral neuromodulationand it is now accepted practice that everypatient considered for this technique should undergo atrial period of temporary stimulation known as percutaneousnerve evaluation (PNE). The test electrode is placedin either the right or left S3 posterior sacral foramen usinglocal anaesthesia. Surface markings identify the site of theposterior sacral foramen and a hollow needle is used toallow the electrode to be threaded into position. Correctpositioning of the electrode is determined by both motorand sensory responses. Once well positioned, the temporaryelectrode is held in place with an adhesive dressingand an external pulse generator provides stimulation forthree to five days. The patient provides subjective informationregarding their response to the PNE, while objectivedata comes from accurately completed frequency/volumecharts.Only those patients who gain significant benefit fromthe PNE proceed to neuromodulator implantation. ThePNE is generally considered successful when there is atleast 50% improvement in the main voiding symptom.Although results vary between studies in the literature ingeneral approximately 50% of patients will respond wellto the trial stimulation and go on to receive a definitivesacral neuromodulator implant.The implant techniqueImplantation of a sacral neuromodulator is performedunder either general or local anaesthesia. The originalopen surgical approach to the sacrum 12 has been supersededby a minimally invasive percutaneous alternative. 13A quad electrode with four independent stimulation electrodesis positioned under radiological control. Once inplace, an outer sheath is removed and plastic tines springout and fix the assembly in place (Figure 1). The electrodeis tunnelled to a subcutaneous pocket in the upper outerquadrant of the buttock area where the pulse generator isimplanted (Figure 2).Stephanie Symons worked as aResearch Registrar in Urology atPinderfields Hospital, Wakefield. Sheis now a Urology Specialist Registrarin the North Thames region.Justine Barnecott is a ClinicalTechnologist within MedicalPhysics, based at PinderfieldsHospital, Wakefield. Her primaryarea of work is within Urology.Simon Harrison is a ConsultantUrologist at Pinderfields Hospital,Wakefield. He has a special interestin neuro-urology and has anattachment to the Regional SpinalInjuries Unit at Pinderfields.Correspondence to:Stephanie Symons,Department of Urology,Edith Cavell Hospital,Bretton Gate,Peterborough, PE3 9GZ.Email:stephisymons@yahoo.co.ukACNR • VOLUME 5 NUMBER 1 • MARCH/APRIL 2005 I 35

Rehabilitation ArticleFig 2aFig 1aFig 1bFig 2aFigure 1. (a) The tined lead.(b) X-ray showing the tined lead in position.A key feature of the technology is that the pulse generatorcan be adjusted using an external computer andtelemetry link. The system is extremely flexible and familiaritywith its options and capabilities is essential; successfulinitial programming and subsequent adjustment iscritical to the success of an implant programme.Figure 2: (a)The sacral neuromodulation circuit.(b) X-ray showing the neuromodulation circuit in situ.Results and complicationsEfficacy data from both randomised controlled trials andcase series studies show that about 70% of the patientswho received sacral neuromodulators for urge/frequencyand urge incontinence became dry or showed improvementin their main incontinence symptoms. 1,14-16 Thiscompared with 4% in the control groups in randomisedstudies. Fewer episodes of leakage, fewer pads used andfewer voids per day were also reported post-implantation.The data concerning female patients with non-obstructiveurinary retention are less extensive but shows that 69%eliminated catheterisation at six months and a further14% had a 50% or greater reduction in the catheter volumeper catheterisation. 17There is no evidence that the safety profile for sacral neuromodulationdiffers according to patients’ clinical indicationsfor implantation. Overall surgical revision rate isapproximately 33%. The most common complications arepain (24%), lead migration (16%), wound problems (7%),adverse effect on bowel function (6%), infection (5%), andgenerator problems (5%). 15% of patients require replacementor relocation of the implanted pulse generator andsome (9%) have required permanent explantation. 1Over the past eight years 55 patients with a variety oflower urinary tract dysfunctions have received permanentSNS implants at our centre. Our experience in thesepatients largely mirrors that reported in the literature,although we believe that medium and long-term benefitwill be achieved in about 60% of patients if one is dealingwith highly symptomatic subjects. One of the major problemsthat we encounter is that there is a group of patientswhose symptoms return within the first few months afterimplantation; this relapse occurs despite the system continuingto produce typical sensory and motor responsesfor S3 stimulation and is resistant to reprogrammingefforts. It is our belief that this picture represents centralnervous system adaptation to the stimulus and this mightbe analogous to the loss of efficacy that can be seen whenneural stimulators are used to treat chronic pain.36 I ACNR • VOLUME 5 NUMBER 1 • MARCH/APRIL 2005

Rehabilitation ArticleConclusionSacral neuromodulation is an exciting and valuable techniquewhich has the ability to transform the quality of lifeof some patients with severe LUTS which are refractory tomore conservative measures. The simplicity of the surgicaltechnique and its associated safety are key issues forpatients who are considering this form of treatment andset it apart from alternative approaches such as augmentationcystoplasty. The widespread adoption of SNS in theUK remains hampered by funding and cost issues (eachimplant costs in the order of £6,750). However, we feelthat its proven utility and the lack of acceptable alternativetreatment options should lead to the establishment ofregional centres which would provide a neuromodulationimplant service.There is every indication that neural stimulation willbecome an important modality in the treatment of somepatients with LUTS. However, future research and technologicaldevelopments are likely to demonstrate thatcurrent practice will come to be seen as the beginning ofan era rather than the definitive delivery of this form oftherapy.References1. Brazzelli M, Murray A, Fraser C, Grant A. Systematic review of theefficacy and safety of sacral nerve stimulation for urinary urge incontinenceand urgency-frequency. Aberdeen: Review Body forInterventional Procedures; 2003. Commissioned by the NationalInstitute for Clinical Excellence. Available from:www.nice.org.uk/ip082systematicreview2. Craggs M, McFarlane J. Neuromodulation of the lower urinary tract.Experimental Physiology 1999;84:149-160.3. Thon WF, Baskin LS, Jonas U et al. Neuromodulation of voiding dysfunctionand pelvic pain. World J Urol 1991;9:138-141.4. Tanagho EA, Schmidt RA. Electrical stimulation in the clinical managementof the neurogenic bladder. J Urol 1988;140:1331-1339.5. Bemelmans BLH, Mundy AR, Craggs MD. Neuromodulation byimplant for treating lower urinary tract symptoms and dysfunction. EurUrol 1999;36:81-91.6. Malaguti S, Spinelli M, Giardiello G et al. Neurophysiological evidencemay predict the outcome of sacral neuromodulation. J Urol 2003;170(6,Part 1 of 2):2323-2326.7. Groen J, Bosch JLHR. Neuromodulation techniques in the treatment ofthe overactive bladder. BJU Int 2001;87:723-731.8. Brubaker L. Electrical stimulation in overactive bladder. Urology2000;55(supp 5A):17-23.9. Bosch JLHR, Groen J. Treatment of refractory urge urinary incontinencewith sacral spinal nerve stimulation in multiple sclerosis patients.Lancet 1996;348:717-719.10. Bosch JLHR, Groen J. Neuromodulation: urodynamic effects of sacral(S3) spinal nerve stimulation in patients with detrusor instability ordetrusor hyperflexia. Behav Brain Res 1998;92:141-150.11. Comiter CV. Sacral neuromodulation for the symptomatic treatment ofrefractory interstitial cystitis: a prospective study. J Urol2003;169(4):1369-1373.12. Siegel SW. Management of voiding dysfunction with an implantableneuroprosthesis. Urol Clin North America 1992;19(1):163-170.13. Spinelli M, Giardiello G, Gerber M et al. New sacral neuromodulationlead for percutaneous implantation using local anaesthesia: descriptionand first experience. J Urol 2003;170(5):1905-1907.14. Schmidt RA, Jonas U, Oleson KA. Sacral nerve stimulation for thetreatment of refractory urge incontinence. J Urol 1999;162:352-357.15. Hassouna MM, Siegel SW, Lycklama a Nijeholt AAB et al. Sacral neuromodulationin the treatment of urgency-frequency symptoms: a multicentrestudy on efficacy and safety. J Urol 2000;163:1849-1854.16. Spinelli M, Bertapelle P, Cappellano F et al. Chronic sacral neuromodulationin patients with lower urinary tract symptoms: results from anational register. J Urol 2001;166:541-545.17. Jonas U, Fowler CJ, Chancellor MB et al. Efficacy of sacral nerve stimulationfor urinary retention: Results 18 months after implantation. JUrol 2001;165(1):15-19....WIN BOOKS...WIN BOOKS...WIN BOOKS...Enter our competition to win the following books:SaturdayIan McEwanSaturday is a novel setwithin a single day inFebruary 2003. HenryPerowne is a contentedman – a successfulneurosurgeon, happilymarried to a newspaperlawyer, andenjoying good relationswith his children,who are young adults. What troubles him isthe state of the world – the impending waragainst Iraq, and a general darkening and gatheringpessimism since the New York andWashington attacks 2 years before. On this particularSaturday morning, Perowne makes hisway to his usual squash game with his anaesthetist,trying to avoid the hundreds of thousandsof marchers filling the streets of London,protesting against the war. A minor accident inhis car brings him into a confrontation with asmall-time thug called Miller. To Perowne’s professionaleye, something appears to be profoundlywrong with this young man. Miller, in histurn, believes the surgeon has humiliated him,and visits the opulent Perowne home thatevening, during a family reunion – with savageconsequences that will lead Henry Perowne todeploy all his skills to keep this doomed figurealive.See www.Randomhouse.co.uk formore information.Head Injury: Pathophysiology & Management –2nd edition P Reilly, R BullockThis updated and revised edition of Head Injury retains the detailed coverage of basic mechanismsand investigations of its predecessor, but also has increased the clinical content of the first edition,with particular emphasis on the fast-moving areas of neuro-monitoring and neuro-protection. Thisnew edition also contains a more representative range of authors from major trauma centres -many from North America, and is fully illustrated.See advert on page 11 for more details.Clinical Disorders of Balance, Posture and GaitA Bronstein, T Brandt, H Woollacott, J NuttThis is the second edition of this text, covering all clinical aspects of human locomotion and its disorders.Multidisciplinary in authorship and approach, it covers all the important clinical areas.Updated and revised throughout, the book has been expanded to allow for increased knowledgeon the subject. Important changes for the second edition include: new chapters on techniques forgait analysis, peripheral neuropathies and dizziness.See www.hoddereducation.com for more informationHow to enter:All you have to do is submit a short editorial on neurology and literature. We are looking for around 500 words on anovel which has a neurological aspect to it (e.g. Amsterdam by Ian McEwan). The best entrant, as judged by theeditors, will win Saturday by Ian McEwan and Head Injury, by Reilly & Bullock. The second prize winner will receiveClinical Disorders of Balance, Posture and Gait. The best entries will be published in future issues of ACNR.Email your entry to Rachael@acnr.co.uk by 30th April, 2005.ACNR • VOLUME 5 NUMBER 1 • MARCH/APRIL 2005 I 37

Special FeatureDeep Brain Stimulation for Post Traumatic TremorIntroductionAfter severe head injury a significant number of survivorswill suffer from crippling movement disorders of whichtremor is particularly disabling. In a survey of 289 severelyhead injured children significant tremor was noted in45% within 18 months of follow up. However, in half thecases the tremor improved with time. 1In those patients with severe post traumatic tremor onecommon finding is of lesions in the projections from thecerebellum to the thalamus typically in the mid brain. 2The tremors are of a violent nature and often affect theshoulder and arm. The shoulder tremor is usually of awide displacement rendering the patient unable to doanything and can also make nursing virtually impossible.Medical therapy is rarely helpful but it is worth tryingL Dopa in all such patients as occasionally there are someresponders. 3 However, in such patients surgery is the besthope of alleviation.In the past, lesioning the thalamus was the therapy ofchoice. 4 Although the results reported have been goodthere are many disadvantages. In an injured brain, tocause further damage by a lesion runs the risk of high sideeffects, also many such patients may have bilateral tremorand bilateral lesions would be at high risk particularly tospeech and swallowing. We therefore feel that deep brainstimulation is the treatment of choice.Patient selectionPeople with head injuries will also quite commonly haveproblems with ataxia or inco-ordination in addition totremor. This will affect the response to surgery which willonly help tremor. To better select candidates for surgerywe have used visually guided tasks.VISUALLY GUIDED WRIST RAMP TRACKING TASKCase reportWe illustrate this with the case of a man aged 26 years. At theage of 18 years he was hit by a car suffering severe head andchest injuries. He was left with a right hemiparesis althoughthe left side was functional. 12 months after his injuries hebegan to develop tremor of his left arm which progressed toa severe almost ballistic movement disorder, at which time,he was referred for consideration of deep brain stimulation.An MRI scan of his brain showed a lesion of the left cerebellarpeduncle consistent with his symptoms.He underwent visual guided tracking which showedthere was a tremor with frequency of 5 Hz (Fig 2). He wasthen offered surgery and a right VOP/ZI electrode wasimplanted stereotactically (Fig 3) with good suppressionof the tremor during the operation (Fig 2).He remains well, with functional use of his left arm. Heis able to feed himself, drink but unable to perform finetasks two years after surgery.ConclusionsPost traumatic tremor is an extremely disabling conditionand is generally resistant to medical therapy. We feel thatcarers of such patients should seek help from specialistcentres for consideration of deep brain stimulation.Figure 2: Above - Preoperative tracking. Below - Post-operative tracking.The traces from the visual guided tracking task illustrates the virtual lossof tremor after deep brain stimulation.Alex Green, MBBS, BSc, MRCS isa Specialist Registrar in Neurosurgeryat the Radcliffe Infirmary,Oxford. He is currently undertakingresearch into the effects ofDeep Brain Stimulation.Professor Tipu Z Aziz is a ConsultantNeurosurgeon at the RadcliffeInfirmary, Oxford and CharingCross Hospital London. He is anexpert in functional neurosurgeryand has a special interest in thesurgical treatment of movementdisorders.Correspondence to:Alex Green,Oxford Movement DisorderGroup,Department of Neurosurgery,Radcliffe Infirmary,Woodstock Road,Oxford, OX2 6HE.Email: alex.green@physiol.ox.ac.ukFigure 1: Wrist tracking (top), shoulder tracking belowAs illustrated (Fig 1), patients are sat comfortably in front of a screen anduse a joy stick to track a target moving across the screen. Movements ofthe forearm for distal tremor and whole arm for shoulder tremor can berecorded. We found that patients with a distal tremor with a singlefrequency responded better to thalamic surgery targeted at the VOPnucleus than patients with irregular jerky movements. Proximal singlefrequency tremor responds to stimulation deeper in the zona incerta.38 I ACNR • VOLUME 5 NUMBER 1 • MARCH/APRIL 2005Figure 3: A coronal MRI showing the deep brainelectrode in situ.References1. Johnson SL, Hall DM. Posttraumatictremor in headinjured children. Arch DisChild. 1992 Feb;67(2):227-8.2. Harmon RL, Long DF, ShirtzJ. Treatment of post-traumaticmidbrain resting-kinetictremor with combined levodopa/carbidopaand carbamazepine.Brain Inj. 1991Apr-Jun;5(2):213-8.3. Krauss JK, Wakhloo AK,Nobbe F, Trankle R,Mundinger F, Seeger W.Lesion of dentatothalamicpathways in severe post-traumatictremor. Neurol Res.1995 Dec;17(6):409-16.4. Marks PV. Stereotactic surgeryfor post-traumatic cerebellarsyndrome: an analysis of sevencases. Stereotact FunctNeurosurg. 1993;60(4):157-67.AcknowlegdgementsTZA is supported by the MRCand the Norman CollissonFoundation.

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Drugs in NeurologyThe Use of Tetrabenazine in Movement DisordersIntroductionTetrabenazine (TBZ) is a relatively safe and effective treatmentfor a wide variety of hyperkinetic movement disorders,particularly tardive dyskinesia (TD) and chorea. Ithas been subject to a number of studies including doubleblind placebo controlled crossover trials, although therehave been no randomised controlled trials and no studiesin patients with pre-existing depression.The mechanism of action of tetrabenazineTBZ is a synthetic benzoquinolizine derivative 1 whichbinds to vesicular monamine transporters (VMATs).Monoamines are concentrated from the cytoplasm intovesicles by VMATs (Figure). The transporters exchangeprotons for monoamines, using a proton electrochemicalgradient generated by a vacuole ATP-dependent H +pump. 2,3 Many compounds bind to VMATs but threedrugs bind selectively: TBZ, reserpine (from the IndianRauwolfia plant) and ketanserin. 4 Two human isoforms5of VMAT exist and have been cloned; VMAT 1 andVMAT 2. 6 VMAT 2 is located predominantly in the brainand in sympathetic neurones, and VMAT 1 in peripheralendocrine and paracrine cells. 7 TBZ binds with highaffinity to VMAT 2 but with low affinity to VMAT 1. 8Reserpine binds with different characteristics and, onthe basis of displacement studies, it has been proposedthat they bind to the same site on the VMAT but to differentconformations. 9 Reserpine binds irreversiblywhereas TBZ displays reversible binding. TBZ thusinhibits the uptake of monoamines into synaptic vesiclesand so diminishes their output at synapses.TBZ additionally blocks postsynaptic dopaminereceptors. 10,11 Despite this, there have been no reports ofTD, thus conferring significant advantages over neurolepticsin the treatment of hyperkinetic movementdisorders.PharmacokineticsTBZ has a low and erratic bioavailability and ismetabolised by first pass metabolism. 12Clinical use and adverse effectsIndicationsTBZ has been used in a wide range of movement disordersand more recently as a positron emission tomography(PET) ligand. 13,14,15,16Case reports and open label studiesMany case reports and open label studies have reportedbenefits of TBZ. 17,18,19,20 For example, Ondo and colleaguesin 1999, showed that scores on the AbnormalInvoluntary Movement Scale (AIMS) were reduced by54% in twenty patients with TD post TBZ administration.26 Others, however, have described adverse effects,including oculogyric crises, retrocollis 21 and neuroleptic22, 23, 24malignant syndrome.Retrospective studiesA recent, retrospective study showed that TBZ was moderatelyeffective for a large variety of hyperkinetic movementdisorders and highly effective for Huntington’s disease(HD) chorea, and patients with facial dystonia anddyskinesia. 25 A retrospective chart review was conductedin three tertiary care centres and 118 patients were followedup for a mean of twenty-two months with theClinical Global Impression of Change (CGIC) scale usedto assess response to TBZ.Cross-over studiesSeveral placebo controlled cross over studies have beendescribed. McLellan, Chalmers and Johnson 27 in 1974published the first double blind crossover trial of TBZ,thiopropazate and placebo, using ten patients withchorea, nine of whom had HD. Each phase of treatmentlasted two weeks and assessment was clinical, cinematographic(videos watched by eight neurologists) andwith manual dexterity tasks. The authors found thatTBZ produced the most effective improvement ofchorea. They noted that side effects could occur for thefirst time after several weeks of treatment.Jankovic 28 in 1982 published a double blind crossovertrial of TBZ versus placebo using nineteen patients witha variety of movement disorders. The trial design wassimilar and again, TBZ significantly reduced thepatient’s score on the hyperkinesia scale, particularly inpatients with TD.Long term dataJankovic and colleagues have published open labellong-term data on the use of TBZ. 29,30 In the more recentlarger study, 29 526 patients were treated with TBZ and400 analysed. Among those who were not analysed, seventeendiscontinued TBZ within the first two weeks oftreatment due to intolerable adverse effects and fourteendiscontinued due to lack of efficacy. Most patientshad been tried on a variety of other medication buttheir symptoms were poorly controlled. The drug wasFigure: An ATP-dependent H + pump on the vesicle membrane generatesa proton electrochemical gradient. This gradient drives the entry ofcytoplasmic monoamines into the vesicle via the VMAT(monoamine/2H + exchange). TBZ binds reversibly and reserpine,irreversibly, to the VMAT, preventing the vesicular accumulation ofmonoamines. TBZ also blocks postsynaptic dopamine receptors. TheVMAT has 12 transmembrane domains, with the C and N terminals inthe cytoplasm, and three putative glycosylation sites in the vesicularlumen. TBZ binds to transmembrane domains I and II, and X and XII.Wendy Phillips graduated fromGlasgow university in 1999. She didan intercalated degree inpharmacology in 1996, SHOrotation in Addenbrookes, and isnow a Neurology ResearchRegistrar in the second year of herPhD studying neurogenesis inHuntingtons disease at theCambridge Centre for Brain Repair.Roger Barker is co-editor ofACNR, and is HonoraryConsultant in Neurology at TheCambridge Centre for BrainRepair. His main area of researchis into neurodegenerative andmovement disorders, in particularParkinson's and Huntington'sdisease. He is also the universitylecturer in Neurology atCambridge where he continues todevelop his clinical research intothese diseases along with his basicresearch into brain repair usingneural transplants.Correspondence to:wp212@cam.ac.uk40 I ACNR • VOLUME 5 NUMBER 1 • MARCH/APRIL 2005

Drugs in Neurologystarted at 25 mg once a day and increased until themovement disorder was controlled or adverse effectsappeared. Most patients determined their long-termresponse within the first six weeks of treatment.Responses were graded on a 5-point scale, evaluated bythe same neurologist, patient and relatives, 1 being anexcellent response. Mean follow up was 28.9 +/- 31.1months. Patients with TD responded best (89.3% with agrade of 1) although in all groups but the HD patients,the score had reduced slightly at the end of evaluation(e.g. to 84.9% in the case of TD). 82.8% of HD patientsscored 1, as did 62.9% of dystonia patients; but patientswith Tourette’s syndrome responded least well (57.4%scored grade 1).Side effects were common (81.8%) although this mayhave reflected the author’s strategy of increasing thedose to the maximum recommended, or until sideeffects were experienced, or complete control achieved.36.5% of patients experienced drowsiness, 28.5%Parkinsonism, 15% depression, 11% insomnia, 10.3%anxiety, 2.3% acute dystonic reaction and lesser numbersof side effects including confusion, orthostatichypotension, and hallucinations. Seventy-three patientsreported no side effects at all, and all the side effectswere dose related, reversible upon reduction of the doseor cessation of the drug (which occurred in 23% ofpatients). Interestingly, lithium enhanced the action ofTBZ in 67.6% of the thirty-four patients in whom it wastried.Kazamatsuri, Chien and Cole 17 noted in a long-termstudy in 1973, that the beneficial effect of TBZ maydecline within a few days or weeks. Other long termstudies have been published and, for example, shown18, 25benefit from TBZ with mild infrequent side effects.Use of TBZ in HDMost of the published evidence has shown that TBZ significantlyimproves TD and the chorea in HD. Over 90%of patients with HD will display chorea at some stage ofthe illness, particularly in the early phase but other moredisabling movement disorders are common, and tend todevelop later in the illness, displacing chorea. 31 The decisionto treat chorea with TBZ must be balanced againstthe risk of developing more disabling Parkinsonism(albeit at high doses) and depression, both of which arecommon in HD. These effects can be ameliorated byTBZ withdrawal. Pragmatically, TBZ should be avoidedin patients with pre-existing depression.Anti-choreic medication, if indicated at all, should betailored to the individual patient and antipsychotic medication,for example, may be a more appropriate choicein patients with concomitant psychiatric disorders.References1. Pletscher A, Brossi A, Gey KF. Benzoquinoline derivatives: a newclass of monoamine depleting drug with psychotropic action. Int Rev.Neurobiol. 1962;4:275-306.2. Kanner BI, Schuldiner S. Mechanism of storage and transport ofneurotransmitters. CRC Crit. Rev. Biochem,1987;22:1-38.3. Johnson RG. Accumulation of biological amines into chromaffingranules: a model for hormone and neurotransmitter transport.Physiol. Rev, 1988;68:232-307.4. Scherman D, Henry JP. Effect of drugs on the ATP-induced and pHgradient-drivenmonoamine transport by bovine chromaffin granules.Biochem Pharmacol. 1980 Jul 1;29(3):1883-90.5. Liu Y, Peter D, Roghani A, Schuldiner S, Prive GG, Eisenberg D,Brecha N, Edwards RH. A cDNA that suppresses MPP+ toxicityencodes a vesicular amine transporter. Cell. 1992 Aug 21;70(4):539-51.6. Erickson JD, Eiden LE, Hoffman BJ. Expression cloning of a reserpine-sensitivevesicular monoamine transporter. Proc. Natl. Acad.Sci. USA. 1992;89:10993-7.7. Erickson JD, Schafer MKH, Bonner TI, Eiden LE, Weihe E. Distinctpharmacological properties and distribution in neurones andendocrine cells of two isoforms of the human vesicular monoaminetransporter. Proc. Natl. Acad. Sci. USA. 1996;93:5166-71.8. Henry JP, Scherman D. Radioligands of the vesicular monoaminetransporter and their use as markers of monoamine storage vesicles.Biochem Pharmacol. 1989 Aug 1;38(15):2395-404.9. Darchen F, Scherman D, Henry JP. Reserpine binding to chromaffingranules suggests the existence of two conformations of themonoamine transporter. Biochemistry. 1989 Feb 21;28(4):1692-7.10. Login IS, Cronin MJ, MacLeod RM. Tetrabenazine has properties ofa dopamine receptor antagonist. Ann Neurol.1982 Sep;12(3):257-62.11. Reches A, Burke RE, Kuhn CM, Hassan MN, Jackson VR, Fahn S.Tetrabenazine, an amine-depleting drug, also blocks dopamine receptorsin rat brain. J Pharmacol Exp Ther. 1983 Jun;225(3):515-21.12. Roberts MS, McLean S, Millingen KS, Galloway HM. The pharmacokineticsof tetrabenazine and its hydroxy metabolite in patientstreated for involuntary movement disorders. Eur J Clin Pharmacol.1986;29(6):703-8.13. Scherman D, Desnos C, Darchen F, Pollak P, Javoy-Agid F, Agid Y.Striatal dopamine deficiency in Parkinson's disease: role of aging.Ann Neurol. 1989 Oct;26(4):551-7.14. DaSilva JN, Kilbourn MR, Domino EF. In vivo imaging ofmonoaminergic nerve terminals in normal and MPTP-lesioned primatebrain using positron emission tomography (PET) and[11C]tetrabenazine. Synapse. 1993 Jun;14(2):128-31.15. Frey KA, Koeppe RA, Kilbourn MR, Vander Borght TM, Albin RL,Gilman S, Kuhl DE. Presynaptic monoaminergic vesicles inParkinson's disease and normal ageing. Ann Neurol. 1996Dec;40(6):873-84.16. Gilman S, Frey KA, Koeppe RA, Junck L, Little R, Vander BorghtTM, Lohman M, Martorello S, Lee LC, Jewett DM, Kilbourn MR.Decreased striatal monoaminergic terminals in olivopontocerebellaratrophy and multiple system atrophy demonstrated with positronemission tomography. Ann Neurol. 1996 Dec;40(6):885-92.17. Kazamatsuri H, Chien CP, Cole JO. Long-term treatment of tardivedyskinesia with haloperidol and tetrabenazine. Am J Psychiatry.1973 Apr;130(4):479-83.18. Mikkelsen BO. Tolerance of tetrabenazine during long-term treatment.Acta Neurol Scand. 1983 Jul;68(1):57-60.19. Bartels M, Zeller E. Tetrabenazine (Nitoman) therapy of chronicspontaneous oral dyskinesia. A video- and EMG-controlled study. EurArch Psychiatry Neurol Sci. 1984;234(3):172-4.20. Watson MW, Skelton D, Jamali F. Treatment of tardive dyskinesia:preliminary report on use of tetrabenazine. Can J Psychiatry. 1988Feb;33(1):11-3.21. Burke RE, Reches A, Traub MM, Ilson J, Swash M, Fahn S.Tetrabenazine induces acute dystonic reactions. Ann Neurol. 1985Feb;17(2):200-2.22. Petzinger GM, Bressman SB. A case of tetrabenazine-induced neurolepticmalignant syndrome after prolonged treatment. Mov Disord.1997 Mar;12(2):246-8.23. Mateo D, Munoz-Blanco JL, Gimenez-Roldan S. Neuroleptic malignantsyndrome related to tetrabenazine introduction and haloperidoldiscontinuation in Huntington's disease. Clin Neuropharmacol.1992 Feb;15(1):63-8.24. Ossemann M, Sindic CJ, Laterre C. Tetrabenazine as a cause of neurolepticmalignant syndrome. Mov Disord. 1996 Jan;11(1):95.25. Paleacu D, Giladi N, Moore O, Stern A, Honigman S, Badarny S.Tetrabenazine treatment in movement disorders. ClinNeuropharmacol. 2004 Sep-Oct;27(5):230-3.26. Ondo WG, Hanna PA, Jankovic J. Tetrabenazine treatment for tardivedyskinesia: assessment by randomized videotape protocol. Am JPsychiatry. 1999 Aug;156(8):1279-81.27. McLellan DL, Chalmers RJ, Johnson RH. A double-blind trial oftetrabenazine, thiopropazate, and placebo in patients with chorea.Lancet. 1974 Jan 26;1(7848):104-7.28. Jankovic J. Treatment of hyperkinetic movement disorders with tetrabenazine:a double-blind crossover study. Ann Neurol. 1982Jan;11(1):41-7.29. Jankovic J, Orman J. Tetrabenazine therapy of dystonia, chorea, tics,and other dyskinesias. Neurology. 1988 Mar;38(3):391-4.30. Jankovic J, Beach J. Long-term effects of tetrabenazine in hyperkineticmovement disorders.Neurology. 1997 Feb;48(2):358-62.31. Bates G, Harper P, Jones L. Huntington’s disease (third edition).2002.Wendy Philips receivedan honorarium fromCambridgeLaboratories forwriting this article.However, the viewsexpressed are those ofthe authors.ACNR • VOLUME 5 NUMBER 1 • MARCH/APRIL 2005 I 41

Journal ReviewsEDITOR’S CHOICEAlcoholism is linked to disruption of thebiological clockAlcohol and drug addiction are complex disorders with environmental,drug-induced and genetic components. It is likely that multiplegenes contribute to the development of an addictive disease. There isa growing body of evidence implicating circadian clock genes inmechanisms of drug-abuse related behaviours. The clock genes,including, Per1, Per2, Cry1 and Cry2, underlie the ability of the biologicalclock to provide endogenous rhythms of physiological functionswith a periodicity of 24 hours, without any environmental cues.These genes regulate oscillations in the levels of the transcription factorcomplex, CLOCK-BMAL1, in the suprachiasmatic nucleus of thehypothalamus. Such oscillations are generated by inhibitory feedbackloops, in which the protein products of the clock genes down-regulatetheir own transcription. This study by Spanagel focuses on one suchclock gene, Per2, and its role in alcoholism. They investigated aPer2 Brdm1 mutant mouse, in which the Per2 protein is rendered nonfunctional.As a result, neurochemically these mutant mice exhibitedserious disturbances in the glutamatergic system. A significant reductionin the astrocytic expression of the EAAT1 glutamate transporter,which clears glutamate from the synaptic cleft, produced a three-foldincrease in extracellular glutamate in the ventral striatum. On a behaviourallevel, the Per2 Brdm1 mutant mice voluntarily consumed morealcohol compared to wild-type mice. On administration of acamprosate,an anti-relapse drug, the Per2 Brdm1 mutants showed a reductionin augmented extracellular glutamate levels in the nucleus accumbensand their alcohol consumption was normalised to below wild-typelevels. This latter finding lends support to the theory that acamprosateacts by reducing the hyperglutamatergic state in alcohol-dependents.In humans Spanagel found that the Per2 gene had an analogous function inthe regulation of alcohol consumption. By sequencing the Per2 gene ofalcohol-dependents, they identified a haplotype of four gene variants associatedspecifically with the subjects with low alcohol consumption. In summary,Spanagel identifies glutamate to be the link between disruptionof the Per2 and increased alcohol consumption. It is proposed thatglutamate alters the alcohol reinforcement processes in the brain,most likely via modulation of the dopamine reward pathways. In theclinic, acamprosate increases abstinence rates in just 10-20% of casescompared to placebo. Further research is required to determine if certainpolymorphisms in the Per2 gene confer a positive acamprosateresponse. Thus it would be possible to predict if a patient would benefitfrom this therapy. - LMS & SJTSpanagel R, Pendyala, Abarca C, Zghoul T, Sanchis-Segura C,Magnone M, Lascorz J, depner M, Holzberg D, Soyka M, Schreiber S,Matsuda F, Lathrop M, Schumann G, Albrecht U.The clock gene Per 2 influences the glutamatergic system andmodulates alcohol consumption.NATURE MEDICINE2005;11:35-42.MOTORNEURON DISEASE: VEGF treatment of ALS★★★ RECOMMENDEDAmyotrophic lateral sclerosis (ALS) is a paralysing progressive disorder that killswithin five years of onset. It can present in one of two forms: the first is limbonsetALS, which is characterised by initial muscle weakness of extremities andthe second, more aggressive form is bulbar-onset ALS, in which patients havedifficulty swallowing and breathing. This disease results from selective loss ofmotor neurons in the spinal cord and brainstem but the underlying pathogenicmechanism has not yet been identified. Furthermore, there is currently nocure for this devastating illness. To date, neurotrophin treatment of motor neurondegeneration, although rational, has proved unsuccessful in prolonging survivalof ALS patients. Storkebaum and colleagues have now published veryencouraging data indicating that vascular endothelial factor (VEGF) may be aneffective therapy for ALS. In a mutant SOD1 transgenic rat model, which mimicsthe more severe bulbar-onset disease, they have found that continuousintracerebroventricular (i.c.v) delivery of recombinant VEGF improves motorperformance compared to controls. When administered before onset of symptoms,onset of paralysis was delayed by 17 days and survival was improved by 22days. They demonstrate that through their novel mode of delivery VEGF diffusesfrom the site of delivery in the CSF to spinal motorneurons, where it isanterogradely transported in axons. Whilst they show that VEGF prolongsmotorneuron survival via a direct neurotrophic action, it is proposed that VEGFis a more effective therapy compared to other neurotrophic factors due to itsadditional angiogenic activity whereby increasing blood flow to the microenvironmentsof the brain and spinal cord. I.c.v. VEGF administration offers protectionto cervical neurons in particular and thus represents an ideal therapy forbulbar-onset ALS and final stage limb-onset disease. This route of administrationoffers advantages, in that dosing and duration of treatment can be controlled.Whilst these results are highly promising, it must be noted that only amodest improvement in survival was observed when i.c.v VEGF was administeredat the time of disease onset. - LMS & SJTStorkebaum E, Lambrechts D, Dewerchin M, Moreno-Murciano M-P,Appelmans S, Oh H, Van Damme P, Rutten B, Man W, De Mol M, Wyns S,Manka D, Vermeulen K, Van Den Bosch L, Mertens N, Schmitz, RobberechtW, Conway EM, Collen D, Moons L, Carmeliet P.Treatment of Motorneuron Degeneration by Intracerebroventricular deliveryof VEGF in rat model of ALS.NATURE NEUROSCIENCE2005;8:85-92.COGNITIVE IMMUNOLOGY: The cortical control ofthymic function★★★ RECOMMENDEDThere is a lot of very poor science in the field of neuro-endocrine-immuneinteractions and, accordingly, it is given a wide berth by most respectable laboratories.But no less a figure than Norman Geschwind drew attention in the1980s, with Peter Behan, to the possible lateralisation of neocortical controlover the immune system. Vahe Amassian, in New York, has been working upthis story for more than a decade and now has produced a compelling animalstudy. Amassian’s group studied rats in whom a permanent stimulatingelectrode had been placed over either tempero-parietal cortex. A permanentcatheter in the right atrium allowed frequent blood sampling. A four hourstimulation of the left cortex increased circulating T and B lymphocyte numbers;whilst exactly the opposite occurred with stimulation of the right tempero-parietalcortex. This difference was most marked during periods ofincreased behavioural activity, such as at night. The effect of cortical stimulationwas abolished by thymectomy or lesions of the cord above T7. Thesedata suggest there is an anatomical pathway from the cortex through thePanel of ReviewersRoger Barker Honorary Consultant in Neurology,Cambridge Centre of Brain RepairRichard Body Lecturer, Department of Human CommunicationSciences, University of SheffieldAlasdair Coles Lecturer, Cambridge UniversityRhys Davis Research Registrar, Addenbrooke’s Hospital,CambridgeDan Healy Neurology SPR, National Hospital,Queens Square, LondonLucy Anne Jones Research Associate (Cognitive Neuroscience)Mark Manford Consultant Neurologist, Addenbrooke's Hospital,Cambridge, and Bedford HospitalAndrew Michell Neurology Research Registrar,Addenbrooke’s Hospital, CambridgeWendy Phillips Research Registrar, Addenbrooke’s Hospital,CambridgeLiza Sutton UCL PhD Student, Institute of NeurologySarah J Tabrizi DoH Clinician Scientist and Clinical SeniorLecturer, Institute of NeurologyAilie Turton Research Fellow, Burden Neurological Institute,BristolWould you like to join ACNR's reviewer's panel?We have complimentary subscriptions to Karger's Neuroepidemiologyand Neurodegenerative Diseases available for a reader who would like tocontribute regular journal reviews to ACNR. For more information,Email Rachael@acnr.co.uk or telephone 0131 477 2335.42 I ACNR • VOLUME 5 NUMBER 1 • MARCH/APRIL 2005

Journal Reviewsupper thoracic spinal cord to the thymus which controls lymphocyte generation.Furthermore, there is cortical lateralisation of function of this pathway….But, what on earth does this mean? Frustratingly, the authors have notrevealed whether there is any difference in phenotype of the newly generatedlymphocytes. (I am sure they will have looked). Nor do they say if the alteredlymphocyte numbers lead to any difference in immune responses. - AJCMoshel YA, Durkin HG, Amassian VE.Lateralized neocortical control of T lymphocyte export from the thymus I.Increased export after left cortical stimulation in behaviorally active rats,mediated by sympathetic pathways in the upper spinal cord.JOURNAL OF NEUROIMMUNOLOGY2005;158:3-13.NEUROIMMUNOLOGY: Inflammation in the brain isgood for youMuch effort is spent suppressing inflammation in the brains of people withmultiple sclerosis. Yet there has always been a kernel of sceptics who havecautioned that this may be throwing out the baby with the bathwater, becauseinflammation promotes remyelination. It is true that, in the 1990s, it wasshown that remyelination is often found close to inflammatory lesions. And,experimentally, remyelination is impaired in the absence of T cells, Class IIexpression or the cytokines IL-1 and TNF-a. Yet who can really argue that thedominant effect of cerebral inflammation in multiple sclerosis is bad? RobinFranklin at the Vet School in Cambridge has studied the beneficial effects ofinflammation by using a model in which demyelination is induced by a toxin,with any inflammation therefore being a secondary response. He has previouslyshown that depletion of macrophages from the animals, using clodronate-liposome,impaired oligodendrocyte remyelination. Now his grouphas adopted a different approach. They studied the effect of minocyclinetreatment on the repair of demyelinated cerebellar lesions induced by ethidiumbromide. Minocycline is an antibiotic, but it also has multiple antiinflammatoryactions. These were confirmed in this study by the reducedactivation of microglia (as shown by reduced Class II and Ox42 expression)in the minocycline-treated animals. The crucial results were that oligodendrocyteprecursor numbers in the lesion were also reduced in these animals,accompanied by reduced histological remyelination. What makes this studyso interesting is that minocycline is being trialled in the treatment of multiplesclerosis, having shown promising efficacy in suppressing EAE. Whilstminocycline might effectively reduce the immune attack on myelin (which ofcourse is deliberately missing from the Franklin model), it might also reducerepair. Indeed might suppressed remyelination be a generic problem withanti-inflammatory treatments of multiple sclerosis? Having said which, anhour or two in a MS clinic soon brings home the indisputable point that leavinginflammation unchecked in the brain is not a good thing. Clearly the wayforward is to dissect from the complex mechanisms of inflammation thosethat promote repair and those that are harmful. - AJCLi WW, Setzu A, Zhao C, Franklin RJ.Minocycline-mediated inhibition of microglia activation impairs oligodendrocyteprogenitor cell responses and remyelination in a non-immunemodel of demyelination.JOURNAL OF NEUROIMMUNOLOGY2005;158:58-66.REHABILITATION: Functional electrical stimulation forstroke recoveryTreatment methods in rehabilitation can take decades to develop, test andbecome part of clinical practice. Functional Electrical Stimulation (FES) hasbeen advocated by a passionate few as a method for improving walking sincethe 1960s. Over the last decade support has become more widespread.Sophisticated stimulating systems being researched for the benefit of peoplewith spinal cord injuries have received attention in the press and it is becomingmore common for therapists to use simple systems in clinical practice asa gait training tool after stroke. 2005 sees evidence, from a good randomisedcontrolled trial, of the benefit of FES used as a treatment early after stroke.Yan, Hui-Chan and Li recruited 46 patients from a single centre in HongKong. The patients were within 3 weeks of stroke (mean 9 days) and only 5were able to walk before the treatment. They were randomly allocated usinga minimisation method to either standard rehabilitation plus FES, 30 minutesa day, 5 days a week for 3 weeks, or to a placebo group who had shamstimulation for 60 minutes a day plus standard rehabilitation, or to a controlgroup who received standard rehabilitation only. The stimulation was carriedout not during gait training but with the patient positioned on their sidelying with the affected leg in a sling. Quadriceps, hamstrings, tibialis anteriorand gastrocnemius were stimulated using an activation sequence thatmimicked the gait cycle. Spasticity, isometric strength of the ankle dorsiflexorsand plantar flexors and the amount of their co-contraction was measuredalong with walking ability weekly during the treatment period and also at afollow up 8 weeks after stroke. The assessor was blinded to the individualsubject’s intervention. Significantly greater improvements in impairmentlevel outcomes were found in the FES group compared with the other twogroups. Significantly more subjects in the FES group were able to walk aftertreatment than in the other two groups. These differences were evident atweek 2, 3 of the treatment and 8 weeks after stroke. Patients in the FES groupwere also able to start walking in the hospital an average of two days earlierthan those in the other two groups. This trial shows that sensorimotor stimulationrequiring no active participation on the part of the patient but whichmimics the gait cycle can help prepare patients for walking early after stroke.The adoption of FES as a treatment in clinical practice is restricted in part bythe cost of stimulators and of training therapists in their use, but also by lackof evidence of its effect from good quality randomised controlled trials. Theresults of this study should increase the support for a treatment that has beenforty years in the making. - AJTYan T, Hui-Chan CWY, Li LSW.Functional Electrical Stimulation improves motor recovery of the lowerextremity and walking ability of subjects with first acute stroke.STROKE2005:36:80-5.COGNITION: Better than one for the phrenologistsMost people acquire a ‘collection’ of one sort or another during their lives.Animals ranging from crows to hamsters may also accumulate non-fooditems, often shiny ones. Experimental lesion studies implicate a number ofsubcortical sites in this behaviour. In humans, however, it is thought that thedrive to collect is modulated by cognitive processes presumably occurring inthe cortex. Several clinical conditions are associated with maladaptive collectingbehaviour including schizophrenia, obsessive-compulsive disorderand various dementias. Famously, after suffering frontal lobe trauma,Phineas Gage developed a ‘great fondness’ for animals and souvenirs.Collectors of cortical areas to which a function has been ascribed will enjoythe study by Anderson and colleagues in the January issue of Brain. The keydata-sets are profiles of collecting behaviour, and maps of static corticallesions in a group of 63 subjects. Nine were deemed to have abnormal collectingbehaviour. Perhaps surprisingly, in view of the varied nature of collectionsin general, independent raters showed 100% agreement when decidingon the normality or otherwise of an individual’s collecting behaviour.General neuropsychological testing confirmed that global impairment wasnot present; the ‘collectors’ scored somewhat better on tests of executivefunction and worse on tests of memory. The study draws upon an importantresource, already used in a language study (Damasio et al, 2004). StructuralMR images of all patients have been reconstructed such that the lesions aremapped to allow voxel-by-voxel comparison of overlaps. The resultinganatomical data can be analysed alongside any cognitive or behaviouralindices. In this instance, maximal lesion overlap in ‘collectors’ versus ‘noncollectors’was the mesial and inferior prefrontal region bilaterally, whichincluded anterior cingulate cortex and extended to involve the frontal poleon the right. There was no evidence of damage in subcortical structures associatedwith acquisition behaviour in rodents. The inference is that activity inmesial prefrontal structures is necessary for regulation of collecting tendenciesthat originate in subcortical bioregulatory nuclei and that the normaloperation of this multitiered system underlies the ubiquitous tendency ofhumans to create socially acceptable collections. Comparison of Anderson’spaper and a single case study that showed impairment of mentalising abilitieswith bilateral anterior cingulate lesions (Bird et al, Brain 2004, alsoreviewed in ACNR) highlights the burgeoning literature on localisation ofcerebral function and the need for care in its assimilation. - RRDAnderson SW, Damasio H, Damasio AR.A neural basis for collecting behaviour in humans.BRAIN2005;128:201-12.PARKINSON’S DISEASE: A stimulating new approachThe surgical treatment of Parkinson’s disease (PD) has concentrated oneither neural transplantation (see ACNR 2(6)) or deep brain stimulation(ACNR 2(6)). However there is an emerging realisation that many of the featuresof PD may occur through alterations of synchronised oscillatory neuronalactivities in corticostriatal circuits. With this in mind, Drouot et alACNR • VOLUME 5 NUMBER 1 • MARCH/APRIL 2005 I 43

Journal Reviewsposed the unusual hypothesis that direct interference of the basal gangliaassociated motor cortical areas, by using implanted electrodes adjacent to thecortex, may actually lead to functional recovery in PD. This they investigatedusing the chronic MPTP primate model of PD, and a high frequency stimulatingepidural electrode placed unilaterally on the motor cortex, but at anintensity below that required for producing muscle twitching in the contralateralmuscles. Amazingly this approach worked, with a significant bilateralimprovement in bradykinesia, in association with an increase in metabolicactivity in the supplementary motor area (SMA) using FDG-PET – anarea that is known to be underactive in the bradykinesia of PD. In additionthere was a normalisation of firing rates from neurons within the outputnuclei of the basal ganglia and a reduction in synchronised oscillatory activitiesbetween the cortex and basal ganglia. All of this was achieved withoutside-effects. Of course whether this is the whole story behind its actions is notknown, but the authors attribute the success of their approach to the normalisationof aberrant neuronal activity downstream of the striatum.Whatever the mechanism, this approach is exciting and may lead to a radicalrethink of the surgical treatment of movement disorders as well as the role ofcortical stimulation in other basal ganglia related disorders. - RABDrouot X, Oshino S, Jarraya B, Besret L, Kishima H, Remy P, Dauguet J,Lefaucheur JP, Dolle F, Conde F, Bottlaender M, Peschanski M, Keravel Y,Hantraye P, Palfi S.Functional recovery in a primate model of Parkinson’s disease followingmotor cortex stimulation.NEURON2004;44:769-78.EPILEPSY: Out of AfricaIn a region with a population approaching 1 billion, there are 75 EEGmachines and 25 CT scanners, roughly equivalent to 1 scanner for the populationof England and at any one time many are broken. Half the populationare under the age of 15 and life expectancy is 45. Mortality below age 5 is16.4%. Against this setting, with little health care infrastructure, simple epidemiologicalquestions are difficult to answer. This review of epidemiologyrelied only on door-to-door surveys. The prevalence of epilepsy in two studiesof villages 20km apart in Nigeria, with similar ethnic and age structures were0.5% and 3.7% - population sizes were admittedly small. Reviewing all thestudies from this part of the world the prevalence ranges from 0.5-7.4% withmost studies falling out at 1-2% (cf Western populations around 0.5%). Someof these may be underestimates as young women especially have to hide theirepilepsy in order to get married. There are less data on the mortality of epilepsybut in a small study in Ethiopia it has been estimated to be 3.16% (cf 1.64%without epilepsy) with status epilepticus and burns being the modes of deathattributed directly to seizures. I imagine that SUDEP goes unrecognised in thissociety. Seizures start below the age of 20 in 60% of the population, but thismay reflect the population structure of the region. Treatment (usually phenobarbital)is effective in this environment, but compliance is poor and may contributeto later relapse. In small studies where investigation has allowed epilepsyclassification, 40% have focal seizures, half generalised seizures, usuallyfrom a focal onset and 9% were unclassifiable. Perinatal factors are importantin the aetiology of epilepsy in all countries but are difficult to evaluate in thisregion as studies rely on personal recall by patients’ mothers. The real significanceof cysticercosis is difficult to establish as few patients will have a CTscan, but prevalence of seropositivity ranges is 0.3% in predominantly Muslimareas but much more in other regions. In a case control study from Burundi,an association was found with seizures but seropositivity was 35.1% of controlsas well. Other postulated but unproven associations include malaria (thecommonest cause of febrile seizures), filariasis and onchocerciasis. Eradicationof Taenia solium could give a 50% reduction of epilepsy in this region. As inthe history of health care in the developed world, a single public health caremeasure can do much more than thousands of doctors and prescriptions andis probably cheaper, but requires a more coordinated effort. - MRAMPreux PM and Druet-Cabanac M.Epidemiology and aetiology of epilepsy in sub-Saharan Africa.LANCET NEUROLOGY2005;4:21-31.MULTIPLE SCLEROSIS & DEVIC’S DISEASE: Defined by anew antibody★★★ RECOMMENDEDA monophasic neurological disease characterised by bilateral optic nerveinvolvement and myelitis occurring in rapid succession was first describedby Eugene Devic in the late 19th century. Since then a relapsing form of theillness has been identified and there has been much philosophising aboutwhether this represents a variant of multiple sclerosis, or whether it is a distinctdisease. To the cynics’ “so what?” came the important rebuttal in thelate 1990s from the Mayo clinic, that attacks of Devic’s disease, but not multiplesclerosis, may respond to plasma exchange (Keegan, M. Neurology2002;58:143-6). This discovery led the hunt for an antibody that mightmediate Devic’s… and here it is. Brian Weinshenker’s group at the Mayohas managed the extraordinary feat of collecting serum from 45 patientswith Devic’s disease and 35 with “forme frustes” of the disease: recurrenttransverse myelitis or optic neuritis. They compared these to serum from 22people with classical multiple sclerosis, found an antibody and then testedit out in two other cohorts. They discovered that serum from most Devic’spatients (33/45) contains a distinct immunoglobulin they called “NMO-IgG”, that was found in only 2/22 multiple sclerosis controls and in higherproportions of those with recurrent transverse myelitis (14/27) or opticneuritis (2/8). NMO-IgG bound to mouse pia and subpia, outlined theVirchow-Robin space and microvessels in white and grey matter, and alsoto subependymal white matter and the subpial layer of midbrain. Colabellingshowed that the antibody bound to the abluminal face ofmicrovessels and in extracellular matrix protein in pial and perivascularlocations. These findings correlate nicely with the vasculocentric pattern ofimmunoglobulin and complement deposition seen in the spinal cords ofpeople with Devic’s. The crucial questions are: what is the molecular targetof the antibody and why does it pick on the optic nerves and spinal cord? Ifthe Mayo team know the answers, they are certainly not telling… - AJCLennon VA, Wingerchuk DM, Kryzer TJ, Pittock SJ, Lucchinetti CF,Fujihara K, Nakashima I, Weinshenker BG.A serum autoantibody marker of neuromyelitis optica: distinction frommultiple sclerosis.LANCET2004 Dec 11;364(9451):2106-12.PARKINSON’S DISEASE: What you eat is importantThere is no doubt that modifying the environment can have effects on neurologicaldisorders and this has perhaps been most explored clinically inrehabilitation therapy and in the laboratory with enrichment of the animalenvironment. However whilst attempts to manipulate the environment forthe good of the individual are well known, how this is achieved at the cellularlevel has been less well explored. In this paper, Maswood et al have shownthat in MPTP treated monkeys, dietary caloric restriction (CR) had a significanteffect on the toxicity of the MPTP on the nigrostriatal dopaminergicnetwork such that it afforded a degree of protection which was accompaniedby an improvement in motor deficits. These investigators then demonstratedthat this CR had a significant effect of the levels of GDNF in the caudatenucleus – implying that this may be the explanation for the observed recovery.However, in PD the greatest area of dopaminergic loss is the putamenrather than the caudate nucleus – a structure that is more associated with thecognitive, than motor, deficits of PD. Furthermore patients with PD oftenhave difficulty maintaining their weight because of the difficulties with swallowingcoupled to the increased metabolic rates induced by the movementdisorder of this condition. Thus recommending CR in this patient group isnot straightforward. However this study once more highlights the complexrelationship that exists between our environment (including diet) and thestate of our brain in health and disease. A relationship that is worth rememberingwhen you are trying to lose those extra pounds from 2004, throughyour 2005 New Year resolutions. - RABMaswood N, Young J, Tilmont E, Zhang Z, Gash DM, Gerhardt GA,Grondin R, Roth GS, Mattison J, Lane MA, Carson RE, Cohen RM, MoutonPR, Quigley C, Mattson MP, Ingram DK.Caloric restriction increases glial cell line derived neurotrophic factor levelsand attenuates neurochemical and behavioral deficits in a primate modelof Parkinson’s disease.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, USA.2004;101:18171-6.EPILEPSY: Stepping attacksUnusual cases of epilepsy are curiosities but also give insights into the functionof the brain. A 33-year-old man had a history of sudden falls. These wereoften precipitated by distractions such as unexpected loud noises or seeing achange in the floor material. His only symptom during the attacks was thesensation of loss of connection with his left lower limb. During the attacks,which were videoed, he would try to step over an obstacle with his right foot,but never his left foot, and then fall. Ictal scalp EEG revealed a midline 10-12Hz frontocentral discharge, lasting 1-3 seconds. He underwent intracranial44 I ACNR • VOLUME 5 NUMBER 1 • MARCH/APRIL 2005

Journal ReviewsEEG and simultaneous EMG. The EMG showed no alteration in muscleactivity or resting tone during attacks. Attacks were reproduced by stimulationof the right posterior parietal region and spontaneous discharges werealso recorded from this area. The patient decided against resective surgery butunderwent multiple pial transection, which was unsuccessful. The clinicalmanifestations of epilepsy never cease to amaze. I always ask myself in thesesort of cases whether I would have thought of the diagnosis. - MRAMSo EL and Schaüble BS.Ictal asomatoagnosia as a cause for epileptic falls. Simultaneous video,EMG and invasive EEG.NEUROLOGY2004;63:2153-4.EPILEPSY: Anticonvulsants in the gardenValerian is a perennial, widely distributed inEurope and North America. It is distinctive by itsunpleasant smell and taste, so should make a goodmedicine. It was probably first used in the treatmentof epilepsy by Fabio Colonna (1567-1650) ofNaples, who himself suffered from epilepsy. Hesearched for a herb to help him and wrote a classicwork “Phytobasanos” in which he describedthe efficacy of Valerian for his own condition.Willis only cited Valerian as an ingredient in oneof his anticonvulsant concoctions in his work“Pathology of the Brain and Nervous stock: Onconvulsive diseases”. Tissot in the 1770’s described it as the best drug availablefor epilepsy and other European noteworthies also used it with success, suchthat it was in popular usage in the 18th and 19th centuries. John Cooke ofLondon wrote in 1823 that valerian had “very little power” but Robert BentleyTodd (1849) thought more highly of it. Soon after it was superseded by thebromides and was not mentioned by Gowers in his monograph in 1885. It wasused in WWII to relieve the stress of air-raids in London and is now used as anocturnal sedative. In this role there have been a number of clinical trials,including one comparing it favourably with oxazepam but none of these isvery satisfactory technically. Among the chemical ingredients of the plant arevalepotriates, which may yield isovaleric acid, chemically related to valproicacid. Valerian extracts contain GABA and also valerenic acid, which inhibitsGABA transaminase. So when the nth AED fails and you and your patientdon’t know where to go, you might try the garden. - MRAMEadie MJ.Could Valerian have been the first anticonvulsant?EPILEPSIA2004;45:1338-1343.(with help from http://ods.od.nih.gov/factsheets/Valerian.asp)EPILEPSY: Fracture riskIn Denmark all fractures are recorded on a central register, providing a uniqueopportunity to identify risk factors. From 1977 only inpatients were recordedbut from 1995 outpatients were included. Medications prescribed and boughtare also registered centrally to enable reimbursement of patients. For AEDsthe amount taken by each patient from 1996-2000 could also be calculated.This study was conducted as a case-control study with fractures as the outcomeand AED use as the variable. A further analysis was conducted to takeaccount of different seizure types including generalised tonic clonic and focalseizures, IGE absences and status epilepticus. From Jan 01 2000 to Dec 312000 there were 124,655 fractures and for each case, three age and gendermatchedcontrols were selected from a national database. The following factorswere associated with a slight but significantly increased risk of fracture:lower income; divorced or unmarried status; being out of work or retired;more regular GP visits or ever having taken corticosteroids. Not surprisinglyfactors associated with a considerably higher risk were previous fracture oruse of any treatment for osteoporosis such as HRT or biphosphonates. 2.5%of patients who had sustained a fracture had epilepsy, and 5.7% were takingAEDs compared with 1.3% of controls with epilepsy and 2.9% taking AEDs;these were particularly spine (10.3%) and hip fractures (9.9%). Odds ratiosfor specific drugs were calculated and a dose-response was sought. Anincreased risk of fracture was associated with carbamazepine, oxcarbazepine,clonazepam, valproate and phenobarbitone, but only phenobarbitone wasassociated with an increased risk of spine fracture. The increased risk, as measuredby an adjusted odds ratio, was modest (1.18 for carbamazepine and 1.79for Phenobarbital, which had the greatest effect). A clear dose-response effectwith duration of drug exposure (P

News ReviewMotorised Stage and Ergo Controller forEclipse 90iResearchers cannow view, manipulateand digitallycapture their samplesfrom a remotelocation with theMotorised Stageand Ergo Controlleraccessories for theNikon Eclipse 90i.When combinedwith Nikon’s Digital ImagingHeads and Digital Sight Camerasystems, the user can adjust thefocus, move the stage, switchobservation techniques and captureimages, as if they were seatedin front of the microscope.This could be extremely beneficialif it is necessary to simultaneouslyperform other tasks at the PC,particularly if the microscope isto be sited in an isolated area.Preference settings can also berecorded for each individual user.For simplicity and efficiency ofoperation, buttons on the frontpanel of the Ergo Controller canbe assigned to the control functionsthat are most frequentlyused.For more information Emaildiscover@nikon.co.ukNew Standards in DIC ImagingNikon Instruments Europe iscompletely redesigning itsDIC system for the EclipseTE2000, 90i and 80iresearch microscopes. Withenhanced resolutionresearchers can visualiseminute structures withsuperb clarity and contrast.Three types of DIC are nowavailable providingresearchers a choice of standard,high contrast or high resolution DIC,allowing them to tailor imagingcapabilities depending on theirapplication.The DIC prism is the key to creatingthe 3-D effect in DIC imaging.By making changes to the materialcomposition of the prism, Nikonhave been able to generate uniformlycrisp images that demonstratehigh contrast and high resolution –even at low magnifications.The 3-D effect of DIC imagingcan also be adjusted and optimisedon Eclipse 90i and 80i uprightmodels equipped with a rotatablestage by altering the shear directionof the DIC image. The result issharper imaging revealing morestructural information about thespecimen under observation.For more information Emaildiscover@nikon.co.ukNew Era of Flexibility and Performance to Digital Fluorescence MicroscopyThe Carl Zeiss Axio Imager is an innovative modularsystem for digital fluorescence microscopy, featuringadvanced flexibility and application versatility.New IC2S objectives (Infinity Contrast &Colour Corrected System) optimise image qualityand maximise contrast in all techniques while specialfluorescence filters reduce exposure and imageacquisition time by up to 50% for superior 3Dimaging.The ‘Intelligent Stand’ is the basis for each ofthe four models, ranging from manual entrylevelto fully automated high-end systems. Itincorporates an award-winning complex of softwareelements that automatically recognisecomponents as they are added, such as filterwheels and objectives. Inaddition, the embedded“contrast manager” ensuressimple changes betweencontrasting techniques.Standard interfaces permitcommunication via USBand TCP/IP, making integrationinto a network or completeremote control quick and simple. For thefirst time, defined interfaces in the reflected andtransmitted-light beam paths allow coupling ofadditional optical components.The vibration-free Imaging Cell is isolatedwithin the stand for stable observation andunparalleled precision. Anapochromatic fluorescencebeam path ensures optimumcolour correction overthe entire wavelength range.Axio Imager also introducesspecial fluorescence filterswith a significantlyimproved signal-to-noiseratio, which permit excitation intensity up to70% higher than normal to reduce exposuretimes by up to 50%.For further information, contact Carl ZeissLtd., PO Box 78, Woodfield Road, WelwynGarden City, Hertfordshire, AL7 1LU.British Journal of Neuroscience NursingThis new journal,launching in April2005, bringstogether clinicalupdates, researchreports and policydevelopments inthe rapidly evolvingfield of neurosciencenursing. Itis an invaluabletool for nurseswho want to keepup to date and improve theirpractice. Other members of thehealth care team will also find itof great benefit.The journal addresses allaspects of neuroscience nursingin an intelligent, helpful andaccessible way. Prevention, primarycare, acute and criticalcare, rehabilitationand palliative careare all covered.For informationon how to subscribeto the onlyUK journal dedicatedto neurosciencenursing please callthe Freephone0800 137 201.To register aninterest in contributingto the journal pleasecontact the editor-in-chief, SueWoodward, programme leaderfor critical care and post-registrationeducation at KingsCollege London(sue.woodward@kcl.ac.uk) orthe editor, Ruth Laughton(ruth@markallengroup.com).Handheld Pulse Oximeter from TycoHealthcareThe Critical CareDivision of TycoHealthcare has launchedthe OxiMAX NPB40, anenhanced version of theexisting handheldNellcor NPB-40 oximeter.The OxiMAX NPB40 handheldpulse oximeter encompasses fifthgeneration OxiMax technology andis intended for non-invasive spotcheck measurement of functionalarterial oxygen saturation (SpO2)and the pulse rates of adults, paediatricand neonatal patients. It canbe used for attended monitoring inhospital, emergency, transport andmobile environments, as well as athome. It is compatible with allOxiMax sensors, and its event datais readable on otherOxiMax monitors with theability to display eventdata.Compared to the earlierNPB-40 oximeter, theOxiMAX NPB40 features a 7-buttonconfiguration membrane panel, areal-time clock and a bi-directionalIrDA capability. It is launched withan LCD display for SpO2 and BPM(beats per minute) readings, togetherwith tactile feedback membranebuttons and a number of LCD indicators.These include alarm silence,pulse search, low battery, motionand print indicators.For information please telephonethe Tyco Healthcare customer careteam on 01329 224306.46 I ACNR • VOLUME 5 NUMBER 1 • MARCH/APRIL 2005

News ReviewResidential Units for People withAcquired Brain InjurySpecialist care provider Voyage is to open the third oftheir residential units for people with acquired braininjury in May 2005. The purpose-built, eight placehome in Dudley in the West Midlands offers a spacious,homely environment, and features ensuite rooms withkitchenette facilities.The home is equipped to be able to support individualswith significant physical disabilities, including a specialistbathroom and the use of ceiling tracking, but willalso admit people who only have cognitive needs. Theemphasis of the care and support that will be providedwill be on enabling people to increase their independenceand pursue an individual programme of activitiesin the community, and there will be a high level ofstaffing to facilitate this.Voyage’s other units are in Gloucester and Burnley.The contact to discuss referrals is Steve Ball, AssociateDevelopment Director, on Tel. 01543 442540.Tyco Healthcare ECG Electrodesserve all applicationsThe Critical Care Divisionof Tyco Healthcare manufacturersa range ofsolid hydrogel, stresstesting, multipurposeand long-term monitoringelectrodes, plus the liquidgel electrodes for upto 24-hour, short termmonitoring.The complete range ofTyco Healthcare ECGelectrodes incorporate:● A range of round, ovaland square electrodes for easy application to a varietyof anatomical sites.● A broad scope of backing materials to suit all patientskin types, including foam, cloth, micropore, andvinyl.● Patented gel formulas which exceed AAMI electricalstandards.● Non-sensitising and non-irritating adhesives, designedto be ‘kind’ to patients skin and minimise allergicreactions.● Individual packaging and a two-year shelf life.A comprehensive brochure on all the Tyco HealthcareECG electrodes is available. It also features an indicationchart, full list of monitoring accessories and a look atthe latest TAB/SNAP Universal Connector.Complementary skin preparation products are also listed.For more information please telephone 01329 224187.Greater Dose Flexibility for Treatment of SchizophreniaBristol-Myers Squibb Pharmaceuticals Ltdand Otsuka Pharmaceuticals (UK) Ltdlaunched a 5mg dose of Abilify (aripiprazole)for the treatment of schizophrenia.Dr Helen Millar, consultant psychiatristat the Carseview Centre, Dundee said,“The availability of a 5mg dose of Abilifyallows more flexibility in prescribing for theclinician and therefore treatment can betailored to meet the needs of sensitive populationssuch as the elderly.”Abilify works in a new way to currentlyavailable antipsychotics. It is thought thatan imbalance in dopamine may accountfor the symptoms of schizophrenia. Abilifyis a dopamine system stabiliser. Thismeans that it preserves or enhancesdopaminergic neurotransmission where itis too low and reduces dopaminergic transmissionwhere it is too high. This results insustained efficacy against the positiveDyslexia, Reading And TheBrain: Despite the wealth ofliterature available on thesubject of dyslexia, there islittle that explores the subjectbeyond a single theoreticalframework. The need for acomprehensive review of theliterature by both researchersand practitioners from differentfields and theoreticalbackgrounds is the central motivationbehind Dyslexia, Reading and the Brain. Bycombining the existing fragmented and onesidedaccounts, Alan Beaton has created a(delusions, hallucinations and hostility),negative (lack of motivation and socialinteraction) and cognitive (memory lossand poor attention) symptoms of schizophrenia.Clinical trials have demonstratedthe short- and long-term efficacy of Abilifyin acute psychosis.Clinicians now have the choice of furtherdose flexibility, with the availability of a5mg once-a-day tablet.For more information contact BMS onTel. 020 8754 3519.A Sourcebook of Psychological and Biological Researchsourcebook that provides themuch-needed basis for a moreintegrated and holisticapproach to dyslexia.The comprehensive coverageand impartial approach meanthat this sourcebook will provean invaluable resource for anyoneinvolved in study, researchor practice in the fields of readingand dyslexia.To order please contactThomson Publishing Services,Tel. 01264 343 071,Email book.orders@tandf.co.ukCarl Zeiss purchases P.A.L.M. Microlaser TechnologiesCarl Zeiss has announced the acquisitionof German-based P.A.L.M. MicrolaserTechnologies (PALM). The move bringstogether PALM’s proprietary LaserMicrodissection and Pressure Catapulting(LMPC) technology and Carl Zeiss’ awardwinninglaser scanning microscopes.“Carl Zeiss laser scanning microscopesare setting new standards in researchimaging instrumentation,” says Dr UlrichSimon, head of the microscopy businessgroup at Carl Zeiss and Chairman of thePALM supervisory board. “Our microscopestands are not just the keystone ofour own integrated imaging solutions butthe preferred choice for many partners,including PALM. The uniting of Carl Zeissand PALM will open the way to new,highly integrated biomedical applicationsolutions.”“Adding the superior global infrastructureof Carl Zeiss to the technologicalleadership of the PALM products will doubleour size over the next three years,even within a strongly competitive market,”says Reinhard Müller-Späth, CEO ofPALM. “This union is the logical consequenceof a very successful partnership.”For further information, contactCarl Zeiss Ltd, PO Box 78,Woodfield Road, Welwyn Garden City,Hertfordshire, AL7 1LU.ACNR • VOLUME 5 NUMBER 1 • MARCH/APRIL 2005 I 47

AriceptSignificantlyImprovesBehaviouralSymptoms 1-3Compared to untreated AD patientsdonepezil hydrochloride®Dr. Alois AlzheimerBefore Him,The Disease Didn’t Have A NameBefore Aricept,It Didn’t Have A Realistic Treatmentdonepezil hydrochlorideContinuing Commitment To Alzheimer’s®ABBREVIATED PRESCRIBING INFORMATIONARICEPT ® (donepezil hydrochloride)Please refer to the SmPC before prescribing ARICEPT 5 mg or ARICEPT 10 mg.Indication: Symptomatic treatment of mild to moderately severeAlzheimer's dementia. Dose and administration: Adults/elderly; 5 mgdaily which may be increased to 10 mg once daily after at least onemonth. No dose adjustment necessary for patients with renalimpairment. Dose escalation, according to tolerability, should beperformed in patients with mild to moderate hepatic impairment.Children; Not recommended. Contra-Indications: Pregnancy.Hypersensitivity to donepezil, piperidine derivatives or any excipientsused in ARICEPT. Lactation: Excretion into breast milk unknown.Women on donepezil should not breast feed. Warnings andPrecautions: Initiation and supervision by a physician with experience ofAlzheimer's dementia. A caregiver should be available to monitorcompliance. Regular monitoring to ensure continued therapeutic benefit,consider discontinuation when evidence of a therapeutic effect ceases.Exaggeration of succinylcholine-type muscle relaxation. Avoid concurrentuse of anticholinesterases, cholinergic agonists, cholinergic antagonists.Possibility of vagotonic effect on the heart which may be particularlyimportant with “sick sinus syndrome”, and supraventricular conductionconditions. There have been reports of syncope and seizures - in suchpatients the possibility of heart block or long sinusal pauses should beconsidered. Careful monitoring of patients at risk of ulcer diseaseincluding those receiving NSAIDs. Cholinomimetics may cause bladderoutflow obstruction. Seizures occur in Alzheimer's disease andcholinomimetics have the potential to cause seizures and they may alsohave the potential to exacerbate or induce extrapyramidal symptoms.Care in patients suffering asthma and obstructive pulmonarydisease. As with all Alzheimer’s patients, routine evaluation of ability todrive/operate machinery. No data available for patients with severehepatic impairment. Drug Interactions: Experience of use withconcomitant medications is limited, consider possibility of as yetunknown interactions. Interaction possible with inhibitors or inducers ofCytochrome P450; use such combinations with care. Possible synergisticactivity with succinylcholine-type muscle relaxants, beta-blockers,cholinergic or anticholinergic agents. Side effects: Most commonlydiarrhoea, muscle cramps, fatigue, nausea, vomiting, and insomnia.Common effects (>1/100, 1/1,000, 1/10,000,