ISSN 1473-9348 Volume 5 Issue 3 July/August 2005 ACNR july august 2005.pdf · ACNRISSN 1473-9348...

ACNRISSN 1473-9348 Volume 5 Issue 3 July/August 2005

Advances in Clinical Neuroscience & Rehabilitation

Nick Gutowski, Sian EllardThe Congenital Cranial Dysinnervation Disorders (CCDDs)

Adolfo M BronsteinBenign Paroxysmal Positional Vertigo (BPPV): Diagnosis and Physical Treatment

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ACNR • VOLUME 5 NUMBER 3 • JULY/AUGUST 2005 I 3

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 inter-ests are 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 cog-nitive disorders. 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 inter-actions in 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 neuroim-munology, 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 neuroimmunol-ogy and neurorehabilitation.

4 I ACNR • VOLUME 5 NUMBER 3 • JULY/AUGUST 2005

Congenital cranial dysinnervation disorders(CCSDs) cover a range of conditions whichare now starting to be understood at the gene

level, and as such have been instructive in helping toput basic embryological processes into clinically rel-evant neurology and vice versa. It is this topic whichNick Gutowski and Sian Ellard discuss in their excel-lent review article, which takes us from the familiarsyndromes of Duane and Mobius to a range of less-er known conditions. These authors are still activelyrecruiting CCDD cases, so do feel free to contactthem if you encounter such cases.

In the second review article, Adolfo Bronsteintreats us to a terrific account on benign paroxysmalpositional vertigo (BPPV) which is distilled from hisvast experience of all things neuro-otological. Thiscommon disorder accounts for 20-30% of all casesreferred to specialist vestibular clinics and is readilytreatable with either the Epley or Semont manoeuvre. This lattermanoeuvre is easily remembered as “take your patient quickly in a bigswing from the symptomatic ear down to the opposite eye down”. Thisreview is nicely illustrated with links to video websites of the proce-dures, and as one would expect from such an author is a great educa-tion.

The succinct account on cerebrovascular disease by Allder andMukonoweshuro continues our neuropathology series. This reviewlists the common, as well as rarer causes of this disorder and againcomes with clear illustrations. The discussion also includes a section onlacunar infarction, which has its neurological origins in the work of DrCM Fisher. This great neurologist will be describing his variant of theGuillain-Barre syndrome in a future issue of ACNR.

In the neurosurgery series of articles, we remain in the realm of thecerebral vasculature, as Pawan Minhas deals with intracerebral haem-orrhage. In this account the causes, presentation, medical and surgicalmanagement of this condition are laid out with great clarity, and thearticle includes references to several recent important trials. Theseinclude the value of early surgical intervention (the STICH trial) which

concludes that this is probably not a useful manoeu-vre, in contrast to the use of recombinant activatedFactor VII administration. Both these studies high-light how this field is moving forward, although it issobering to remember that patients presenting with aGlasgow Coma Score of 8 or less have “an almost uni-versally poor outcome”.

John Shneerson is well recognised as the UK experton sleep, and in his rehabilitation article he discussesthe causes of excessive daytime somnolence followingbrain injury. This includes a discussion on the rare(e.g. Kleine-Levine syndrome) to the more common(e.g. sedative drug side effects). This list of causes isframed by a discussion on the physiology of sleep-wake cycling in the human brain and drugs known tobe of therapeutic value in its management of sleepdisorders. This clear account is a wonderful summaryof a complex field by a renowned expert.

Journal reviews this issue concentrate on the amygdala and noveltherapeutic strategies in neurological disease, especially with respect tomotorneuron disease and Alzheimer’s dementia. This issue of ACNRalso features an article on ‘Neuromarketing’ by David Lewis andDarren Bridger. This is the emerging (pseudo-)science which uses newimaging type techniques, especially fMRI, to gauge themarketing/effect/success of products. This has now evolved to thepoint where new fMRI facilities are being built purely for marketingresearch - reported at 8 in the US last year. The rationale for thisapproach is clearly outlined in this provocative article, and includesdiscussion on the paper from Neuron last year on what happens in thebrain when you are given the choice between Coke and Pepsi.

Finally thanks for all your support and feedback. Do keep letting usknow what you think and what you like to see in ACNR - including rel-evant case reports organised by Alastair Wilkins (Email:[email protected]).

Roger Barker, Co-Editor,Email: [email protected]

Editorial

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unless clearly necessary. Breast-feeding not recommended. Driving, etc: Cautionrecommended when performing skilled tasks, e.g. driving vehicles or operatingmachinery. Undesirable effects: Incidence of undesirable effects considered to be atleast possibly related in controlled clinical studies: Very common (>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 post-marketing experience 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. [email protected] 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.

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Contents

8 Review ArticleThe Congenital Cranial Dysinnervation Disorders(CCDDs)Nick Gutowski & Sian Ellard

12 Review ArticleBenign Paroxysmal Positional Vertigo (BPPV): Diagnosis and Physical TreatmentAdolfo Bronstein

17 Rehabilitation Article Excessive Sleepiness After Brain InjuryJohn Shneerson

20 Neuropathology ArticleCerebrovascular DiseaseSteven Allder &Pinias Mukonoweshuro

22 Management TopicIntracerebral HaemorrhagePawan Minhas

25 Book Reviews

26 Events

27 Conference NewsBritish Neuroscience AssociationPreview: United in Care

32 Reviews

36 Special FeatureMarket Researchers make Increasing use of Brain ImagingDavid Lewis and Darren Bridger

38 News

July/August 2005

Cover picture:Front cover image courtesy ofVisitBrighton. For a full report onthe recent Annual Meeting of theBritish Neuroscience Association,held in Brighton, see page 27.

ACNR is published by Whitehouse Publishing, 7 Alderbank Terrace, Edinburgh EH11 1SX.Tel: 0131 477 2335 / 07989 470278, Fax: 0131 313 1110, Email: [email protected]: Rachael Hansford, Design & Production Email: [email protected] 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 anymeans, electronic, mechanical, photocopying, recording or otherwise without either the prior written permission of the publisher or a licensepermitting restricted photocopying issued in the UK by the Copyright Licensing Authority. Disclaimer: The publisher, the authors and editors accept no responsibility for loss incurred by any person acting or refraining from action as aresult of material in or omitted from this magazine. Any new methods and techniques described involving drug usage should be followed onlyin conjunction with drug manufacturers' own published literature.This is an independent publication - none of those contributing are in any way supported or remunerated by any of the companies advertisingin it, unless otherwise clearly stated. Comments expressed in editorial are those of the author(s) and are not necessarily endorsed by the edi-tor, editorial board or publisher. The editor's decision is final and no correspondence will be entered into.


The Congenital Cranial Dysinnervation Disorders (CCDDs)

The term ‘congenital cranial dysinnervation disor-ders’ or CCDDs was derived in 2002 at a EuropeanNeuromuscular Centre (ENMC) international

workshop for a group of congenital neuromuscular dis-eases reflecting the belief that these disorders resultedfrom developmental errors in innervation.1 The condi-tions under consideration were characterised by abnor-mal eye, eyelid, and/or facial movement. The groupincludes Duane syndrome, congenital fibrosis of theextraocular muscles (CFEOM), congenital ptosis, hori-zontal gaze palsy, congenital facial palsy and Möbius syn-drome, but this is not an exhaustive list. The current list ofclinical phenotypes, genetic loci and genes is certainlyincomplete. It is envisaged that other congenital dysinner-vation disorders such as Marcus Gunn Jaw winking (pto-sis accompanied by elevation of the ptotic eyelid onmovement of the lower jaw, due to aberrant trigeminalnerve innervation of levator palpebrae superioris) andCrocodile tears (food provokes excessive tearing, due toaberrant facial salivary fibres innervating the lacrimalgland) and disorders of afferent pathways will also beincluded. The purpose of this classification is to study thegenes underlying the CCDDs which should enhance ourunderstanding of human brain stem and cranial nervedevelopment, with common functional pathways likely toemerge, as well considering potential treatments for thesedisorders.

The concept from muscular fibrosis to dysinnervationIsolated strabismus is relatively common affecting 1-5%of the general population. A subset of sporadic and famil-ial congenital, non-progressive ophthalmoplegia withrestriction of globe movement was initially referred to asthe “congenital fibrosis syndromes” because the primarypathologic process was thought to be in the eye muscles.Further data challenged this view. It was suggested thatDuane syndrome, the most common of these disorders,may be primarily neuropathic rather than myopathic andat least five autopsy reports of Duane syndrome have doc-umented anatomic absence of the abducens nerve. Inaddition, electromyography revealed paradoxical innerva-tion of the lateral rectus by the oculomotor nerve thatprobably occurs in the absence of normal innervation bythe abducens nerve (reviewed in reference 1). Duane syn-drome also occurs in the setting of other conditions withanomalous axonal guidance.2

Genetic and neuropathologic studies in CFEOM alsosupport a neurogenic cause for these disorders; an autop-sy study of one affected member of a large CFEOM type 1family showed the absence of the superior division of theoculomotor nerves bilaterally.3 Subsequently CFEOMtype 2 was shown to result from mutations in thePHOX2A gene,4 the absence of which in mouse andzebrafish results in loss of the nuclei of the oculomotorand trochlear nerves in addition to other neuropatholog-ic changes.

Recently familial horizontal gaze palsy with progressivescoliosis (HGPPS) has been shown to be associated withROBO3 gene mutations. These patients also haveuncrossed corticospinal and dorsal column projectionsdue to disruption of axonal hindbrain pathway crossing.5

CCDDs current concepts (Figure 1)• Congenital, non-progressive, sporadic or familial

abnormalities that result from developmental abnor-malities of one or more cranial nerves/nuclei with pri-mary or secondary dysinnervation.

• Primary dysinnervation - absence of normal innervation.• Secondary dysinnervation - aberrant innervation dur-

ing development by branches of other nerves.• Dysinnervation may be associated with secondary

muscle pathology and/or other orbital and bony struc-tural abnormalities.

• Predominantly vertical ocular motility defects resultfrom abnormalities in development of oculomotorand trochlear nerves and/or nuclei (CFEOM variantsand congenital ptosis).

• Predominantly horizontal ocular motility defects resultfrom abnormalities in the development of the abducensnerve and/or nucleus (Duane syndrome and HGPPS).

• Predominantly facial weakness resulting from abnor-mal development of facial nerve and/or nucleus (con-genital facial weakness, and with associated ocularmotor abnormalities or Möbius syndrome).

A practical approach: genetic loci, genes andphenotypesSee Figures 2 and Table 1, a brief overview is given here.

A) Predominantly vertical disorders of ocular motilityCongenital fibrosis of the extraocular muscles (CFEOM)and congenital ptosis result from abnormalities in devel-opment of oculomotor and trochlear nerves and/or nuclei(there are several oculomotor sub-nuclei).

1. CFEOM. Various forms of CFEOM result from prima-ry dysinnervation of oculomotor and/or trochlearinnervated extraocular muscles. The genetic loci forCFEOM phenotypes are referred to as FEOM.Currently, three CFEOM phenotypes (mild facialweakness has been reported to occur sometimes in allphenotypes) and four FEOM loci have been defined.

a. KIF21A (FEOM1, 12p11.2-q12)6 The KIF21A geneencodes a kinesin motor protein, with most mutationslocated within the coiled-coil structure of the stalk.CFEOM1 phenotype. Most common CFEOM phe-notype: bilateral ptosis, infraducted globes in pri-mary position, limited supraduction, chin-up headposture and variably restricted horizontal gaze.Inheritance is autosomal dominant with full pene-trance. Neuropathology shows a primary defect ofthe superior division of oculomotor nerve.CFEOM3 phenotype. See FEOM3 below, rareCFEOM3 families are due to KIF21A mutationswhich can be non-penetrant.

b. PHOX2A (FEOM2, 11q13.2)4 The PHOX2A gene(previously known as ARIX) encodes a home-odomain transcription factor protein.

Nick Gutowski is a ConsultantNeurologist at the Royal Devon andExeter Foundation Hospital andSenior Lecturer in the PeninsulaMedical School. Besides his interestin the CCDDs he also maintains hisscientific interest in several aspectsof biochemistry, cell and molecularbiology in central nervous systemdisorders particularly relating toastrocytes and endothelial cells.

Sian Ellard is a Consultant ClinicalScientist, Head of the Departmentof Molecular Genetics at the RoyalDevon & Exeter NHS FoundationTrust and Senior Lecturer in thePeninsula Medical School. Herresearch aims to identify geneticaetiologies for a range of inheriteddiseases (monogenic types ofdiabetes and vertebraldysegmentation disorders inaddition to CCDDs) in order tounderstand the underlyingpathophysiology and providegenetic testing for affected families.

Correspondence to:Dr Nick Gutowski,Department of Neurology,Royal Devon and Exeter Hospital,Barrack Road,Exeter. EX4 4JQTel: 01392 402492Fax: 01392 402721Email: [email protected]

Review Article

Figure 1. CCDDs the main features

• Congenital, non-progressive• Sporadic or familial• Developmental abnormalities of one or more cranial

nerves/nuclei • Primary dysinnervation

- absence of normal innervation- neurons do not develop or are misguided

• Secondary dysinnervation- aberrant innervation during development by branches of another nerve

Additional web contentwww.acnr.co.uk

A case on Duane’s syndrome will beappearing shortly onwww.acnr.co.uk


CFEOM2 phenotype. Rare form ofCFEOM, bilateral ptosis and a large angleexotropia with severely limited horizon-tal and vertical eye movements.Inheritance is autosomal recessive. Thereis a primary developmental defect ofboth oculomotor and trochlear nuclei.

c. FEOM3 (16q24.2-q24.3)7

CFEOM3 phenotype. A variable pheno-type in which at least one affected familymember does not meet CFEOM1 crite-ria. CFEOM3 results from a variabledefect in the oculomotor nucleus devel-opment. Inheritance is autosomal domi-nant with incomplete penetrance.CFEOM1 phenotype. See KIF21A(FEOM1) above, rarely CFEOM1 fami-lies map to the FEOM3 locus.8

d. FEOM4CFEOM3 phenotype. See FEOM3 above.One family has been identified with achromosomal translocation, co-inheritedin an autosomal dominant pattern.1

2. Isolated congenital ptosis. Some forms ofcongenital ptosis may result from aberrantdevelopment of the unpaired caudal centraloculomotor sub-nucleus. Two congenitalptosis loci are reported.

a. PTOS1 (1p32-p34.1)9

PTOS 1 phenotype. Variable degree con-genital unilateral or bilateral ptosis.Inheritance is autosomal dominant withincomplete penetrance of 90%.

b. PTOS2 (Xp24-27.1)10

PTOS2 phenotype. Congenital bilateralsymmetrical and severe ptosis almostimpinging on the visual axis in the prima-ry position of gaze, with chin-up headposture. Inheritance is X-linked dominant(male and females are equally affected).

B) Predominantly horizontal disorders ofocular motilityThese disorders include the various forms ofDuane syndrome and horizontal gaze palsy andare proposed to result from primary dysinner-vation abnormalities in the development of theabducens nerve and/or nucleus.

1. Duane syndrome. The prevalence is 1:10000(1-4% of strabismus cases), 10% are famil-ial.2,11 Abducens motorneurons are reducedin number or are absent; there is aberrantinnervation of lateral rectus by the oculo-motor nerve (Figure 3). Congenital limita-tion of horizontal globe movement andsome globe retraction on attempted adduc-tion is required to make this diagnosis. Thebalance between the amount of aberrantinnervation and the reduction/absence ofabducens motor neuron function (and con-sequent muscle fibrosis) leads to a limitationof horizontal globe movement. Most com-monly (~80%) abduction is affected withnormal or minimally defective adduction,type 1 Duane syndrome (Figure 4); in type 3Duane syndrome both abduction andadduction are limited and in type 2 adduc-tion is limited. From case series the left eye(2:1) and females are more frequently affect-ed although the reason for this is notknown.2,11 At least three Duane syndromegenetic loci have been defined.

a. DURS1 (8q13)DURS1 Phenotype. Duane syndrome isusually bilateral and may be associatedwith other features such as mental retar-dation, branchio-oto-renal syndromeand genital tract anomalies in patients

with cytogenetically visible deletions. Apeptidase gene, CPAH, has been high-lighted as a candidate gene as it is dis-rupted by a balanced translocationbreakpoint at 8q13 in a single patient.12

b. DURS2 (2q31)13,14

DURS2 Phenotype. Duane syndrome isunilateral or bilateral with decreasedabduction with or without decreasedadduction (in bilateral cases the left eyetends to be more severely affected). Therecan be a variety of vertical deviations.Amblyopia is common. Inheritance isautosomal dominant.14,15

c. SALL4 (DRRS, [Duane radial ray syn-drome or Okihiro syndrome], 20q13).16,17

The SALL4 gene encodes a putative zincfinger transcription factor.DRRS Phenotype. There is Duane syn-drome (unilateral or bilateral) and radialdysplasia (unilateral or bilateral) rangingfrom most commonly thumb hypoplasiato most severely a phocomelic limb (sim-ilar to that seen in thalidomide cases).Other features include deafness, renaland ocular manifestations. Inheritance isautosomal dominant. Truncating muta-tions and SALL4 deletions have beenidentified in DRRS families.16,17 NoSALL4 mutations were found in 25 spo-radic cases of isolated Duane syndrome.18

d. Other potential Duane syndromegenetic loci. These have been found at22pter->22q11.2 and at 4q27-31 and aredefined cytogenetically (reviewed in ref-erence 1).

Review Article

Figure 2. The main CCDDs currently recognised and subdivided

Predominantly vertical disorder of ocularmotility

• Congenital fibrosis of the extraocular muscles (CFEOM)

• Congenital ptosis

Predominantly horizontal disorder of ocularmotility• Duane syndrome (DS)• DS + radial ray (DRRS)• Horizontal gaze palsy with progressive

scoliosis (HGPPS)

Disorder of facial motility• Congenital facial palsy

Disorder of facial motility and ocular abduc-tion deficit• Möbius syndrome

CRANIAL SYNDROME GENETIC LOCUS PHENOTYPE GENE LOCATION GENENERVE/NUCLEI

Oculomotor CFEOM FEOM1 CFEOM1 12p11.2-q12 KIF21A(CFEOM3)

FEOM3 CFEOM3 16q24.2-q24.3(CFEOM1)

FEOM4 CFEOM3

Congenital PTOS1 PTOS1 1p32-p34.1ptosis PTOS2 PTOS2 Xp24-27.1

Oculomotor CFEOM2 FEOM2 CFEOM2 11q13.2 PHOX2A& trochlear

Abducens Duane DURS1 Duane 8q13

DURS2 Duane 2q31

Other potential Duane+ 22pter->22q11.2

loci Duane+ 4q27-31

DRRS Duane with 20q13 SALL4radial ray

HGPPS HGPPS HGPPS with 11q23-25 ROBO3absent long-tract crossing

Facial Congenital FNP1 (MBS2) FNP1 3q21-22

facial palsy FNP2 (MBS3) FNP2 10q21.3-22.1

Facial & Möbius MBS1 MBS1 13q12.2-13abducens syndrome MBS4 MBS4 1p22

Table 1. A summary of the current CCDD classification


2) Horizontal gaze palsy. Horizontal gazepalsy is suggested to result from hypoplasiaof the abducens nucleus with interneurondysinnervation (medial longitudinal fasci-culus and pontine paramedian reticular for-mation). It differs from the other disordersas the extraocular nerves and innervatingmuscles seem normal.

a. ROBO3 [HGPPS (Horizontal gaze palsywith progressive scoliosis), 11q23-25.The ROBO3 gene encodes a transmem-brane receptor required for hindbrainaxon midline crossing.5

HGPPS phenotype. There is congenitalcomplete absence of conjugate horizon-tal gaze and childhood onset progressivescoliosis. Inheritance is autosomal reces-sive.5 The uncrossed corticospinal anddorsal column pathways are not associat-ed with an obvious neurological deficit.

C) Disorders with abnormalities of facialmotilityThis includes congenital non-traumatic facialweakness in isolation or in association withocular dysmotility.

1. Facial nerve palsy (FNP). Isolated congenitalfacial weakness is usually an autosomaldominant disorder which is proposed toresult from facial nuclei and/or nervemaldevelopment. Two genetic loci have beendefined.

a. FNP1 (previously known as MBS2, 3q21-22)19

FNP1 phenotype. Non-progressive, con-genital isolated facial weakness, mostlybilateral, often asymmetrical. Inheritanceis autosomal dominant with penetranceof 95%.

b. FNP2 (previously known as MBS3,10q21.3-22.1)20

FNP2 phenotype. Non-progressive, con-genital isolated facial weakness, unilater-al or bilateral, often asymmetrical. Therecan be hearing loss and rarely congenitaldeafness. Inheritance is autosomal domi-nant with penetrance of 60%.

2. Möbius syndrome. This is defined as facialweakness combined with an ocular abduc-tion deficit. It is almost always sporadic, fre-

quently accompanied by lingual and/or pha-ryngeal dysfunction at birth, craniofacialdysmorphisms, and limb malformations.1,21

A low recurrence risk of 2% is quoted. Insuch cases it is thought to be due to a vascu-lar insult in early pregnancy and misopros-tol, ergotamine, cocaine and thalidomidehave been implicated. Rarely cytogeneticabnormalities have been reported in associ-ation with Möbius syndrome, the pheno-types are variable but can additionallyinclude ptosis, two loci are suggested.a. MBS1 (13q12.2-13 defined cytogeneti-

cally) reviewed in reference 1.b. MBS4 (1p22 defined cytogenetically)

reviewed in reference 1.

RecruitmentWe are still actively recruiting CCDD cases,especially Duane syndrome (both familial andsporadic), for genetics studies and would bepleased to hear of cases.

AcknowledgementsWe would like to thank the European NeuromuscularCentre (ENMC), its sponsors and the participants at theworkshop for their support.

Review Article

References

1. Gutowski NJ, Bosley T, Engle E. The Congenital Cranial Dysinnervation Disorders(CCDDs). Neuromuscular Disorders 2003;13:573-8.

2. Gutowski N. Duane's syndrome. Eur J Neurol 2000;7:145-9.

3. Engle E, Goumnerov B, McKeown C, Schatz M, Johns D, Porter J, Beggs A. Oculomotornerve and muscle abnormalities in congenital fibrosis of the extraocular muscles. AnnNeurol 1997;41:314-25.

4. Nakano M, Yamada K, Fain J, Sener E, Selleck C, Awad A, Zwaan J, Mullaney P, Bosley T,Engle E. Homozygous mutations in ARIX (PHOX2A) result in congenital fibrosis of the extraocular muscles type 2. Nat Genet 2001;29:315-20.

5. Jen J, Chan W, Bosley T, Wan J, Carr J, Rub U, et al. Mutations in a human ROBO genedisrupt hindbrain axon pathway crossing and morphogenesis. Science 2004;304:1509-13.

6. Yamada K, Andrews C, Chan W, McKeown C, Magli A, de Berardinis T, et al.Heterozygous mutations of the kinesin KIF21A in congenital fibrosis of the extraocular mus-cles type 1 (CFEOM1). Nat Genet 2003;35:318-21.

7. Doherty E, Macy M, Wang S, Dykeman C, Melanson M, Engle E. CFEOM 3: A NewExtraocular Congenital Fibrosis Syndrome that Maps to 16q24.2-q24.3. Invest OphthalmolVis Sci 1999;40:1687-94.

8. Engle E, McIntosh N, Yamada K, Lee B, Johnson R, O'Keefe M, Letson R, London A,Ballard E, Ruttum M, Matsumoto N, Saito N, Collins M, Morris L, Del Monte M, MagliA, de Berardinis T. CFEOM1, the classical form of congenital fibrosis of the extraocular mus-cles, is genetically heterogeneous but does not result from mutations in ARIX. BMC Genetics2002;3:3.

9. Engle E, Castro A, Macy M, Knoll J, Beggs A. A gene for Isolated Congenital Ptosis Maps toa 3-cM Region within 1p32-p34.1. Am J Hum Genet 1997;60:1150-7.

10. McMullan T, Collins A, Tyers A, Robinson D. A Novel X-Linked Dominant Condition: X-Linked Congenital Isolated Ptosis. Am J Hum Genet 2000;66:1455-60.

11. Gutowski NJ. Duane's syndrome. In: E.S. Gruson, Editor. The NORD (NationalOrganisation for Rare Diseases) Guide to Rare Disorders. Philadelphia: Lippincott,Williams and Wilkins, 2003, 645.

12. Pizzuti A, Calabrese G, Bozzali M, Telvi L, Morizio E, Guida V, Gatta V, Stuppia L, Ion A,Palka G, Dallapiccola B. A peptidase gene in chromosome 8q is disrupted by a balancedtranslocation in a Duane syndrome patient. Invest Ophthalmol Vis Sci 2002;43:3609-12.

13. Appukuttan B, Gillanders E, Juo S-H, Freas-Lutz D, Ott S, Sood R, Auken A, Bailey-Wilson J, Wang X, Patel R, Robbins C, Chung M, Annett G, Weinberg K, Borchert M,Trent J, Brownstein M, Stout J. Localization of a Gene for Duane Retraction Syndrome toChromosome 2q31. Am J Hum Genet 1999;65:1639-46.

14. Evans J, Frayling T, Ellard S, Gutowski N. Confirmation of linkage of Duane's syndromeand refinement of the disease locus to an 8.8cM interval on chromosome 2q31. Hum Genet2000;106:636-8.

15. Chung M, Stout JT, Borchert MS. Clinical diversity of hereditary Duane's retraction syn-drome. Ophthalmol 2000;107:500-3.

16. Al-Baradie R, Yamada K, St Hilaire C, Chan W, Andrews C, McIntosh N, Nakano M,Martonyi E, Raymond W, Okumura S, Okihiro M, Engle E. Duane Radial Ray Syndrome(Okihiro Syndrome) Maps to 20q13 and Results from Mutations in SALL4, a New Memberof the SAL Family. Am J Hum Genet 2002;71:1195-9.

17. Kohlhase J, Heinrich M, Schubert L, Liebers M, Kispert A, Laccone F, Turnpenny P,Winter R, Reardon W. Okihiro syndrome is caused by SALL4 mutations. Hum Mol Genet2002;11:2979-87.

18. Wabbels B, Lorenz B, Kohlhase J. No evidence of SALL4-mutations in isolated sporadicduane retraction "syndrome" (DURS). J Med Genet 2004;131A:216-18.

19. Kremer H, Kuyt L, van der Helm B, van Reen M, Leunissen J, Hamel B, Jansen C,Mariman E, Frants R, Padberg G. Localisation of a gene for Möbius syndrome to chromo-some 3q by linkage analysis in a Dutch family. Hum Mol Genet 1996;5:1367-71.

20. Verzijl H, van der Helm B, Veldman B, Hamel B, Kuyt L, Padberg G. A second gene forautosomal dominant Möbius syndrome is localized to chromosome 10q, in a Dutch family.Am J Hum Genet 1999;65:752-6.

21. Verzijl H, van der Zwaag B, Cruysberg J, Padberg G. Möbius syndrome redefined: a syn-drome of rhombencephalic maldevelopment. Neurology 2003;61:327-33.

Figure 3: Pathophysiology of Duane Syndrome. Figure 4: Left eye type 1 Duane Syndrome.


Benign Paroxysmal Positional Vertigo (BPPV):Diagnosis and Physical TreatmentAbstractBenign paroxysmal positional vertigo (BPPV) is one of themost common causes of vertigo. It is easily diagnosed andtreated. BPPV is due to the presence of otoconial debris with-in the semicircular canals, usually the posterior canal. Thevertigo is intense but brief, usually triggered by seating, lyingdown and turning over in bed. The diagnosis can only bemade by observing the typical nystagmus during positionalmanoeuvres such as the Hallpike manoeuvre or equivalent.The nystagmus occurs when the affected ear is in the sidedown position and is mostly torsional (rotatory) beatingtowards the undermost ear. On observing the typical nystag-mus in a patient with a typical history one can proceed imme-diately to physical treatment with one of the repositioningmanoeuvres. The Semont manoeuvre is described here,essentially consisting of one big swing whereby the patient istaken from one end of the couch (the ear down side) to theother (the eye down side). These manoeuvres ‘reposition’ thedebris back to the utricle and cure patients of their currentBPPV in 70-90% of cases. Links to a webpage showing videosof the diagnostic and treatment manoeuvres are provided.

Introduction Up to 10 or 20 years ago the diagnosis of vertigo was just anacademic exercise. Identification of the various causes of ver-tigo was largely irrelevant as all patients ended up with thesame antivertiginous drugs and with little benefit. Physicaltherapy and rehabilitation have been at the centre of arefreshing change in dizziness treatment.

We now understand that the centre piece for the treatmentof the patient with a single episode of vertigo (eg vestibularneuritis or ‘labyrinthitis’) and the patient with long termdizzy symptoms is rehabilitation.1 Setting up a vestibularrehabilitation service does not require complex equipmentor prolonged training. A physiotherapist, particularly aneuro-physiotherapist, or an audiologist, particularly onewith an interest in vestibular disorders, can quickly acquirethe necessary skills. Indeed, a recent study has shown that aGP practice nurse, with an appropriate one-day training ses-

sion, can make a significant difference to the outcome ofdizzy patients in primary care.2

In this review, however, we will concentrate on the diag-nosis and physical treatment of one specific condition,benign paroxysmal positional vertigo or BPPV. BPPV isone of the most common causes of vertigo. Both the diag-nosis and treatment are straight forward and yet manypatients have many drugs and expensive investigationsinstead of what they really need, namely a Hallpikemanoeuvre for diagnosis and an Epley or Semontmanoeuvre for treatment.

SymptomsBPPV is by far the most common cause of positional vertigo,accounting for about 90% of patients. Moreover, BPPV is thenumber one vestibular disorder, causing 20-30% of referrals tospecialised dizziness clinics.3,4 The prevalence of BPPV increas-es with advancing age; women are affected almost twice asoften as men. BPPV may involve each semicircular canal, withBPPV of the posterior canal being by far the most commonvariant.All subtypes of BPPV can be diagnosed on the basis ofclinical observation during the positional manoeuvre.

Patients with BPPV complain of brief episodes (<1 min)of vertigo that appears in specific head positions, e.g. on lyingdown or sitting up, after turning in bed from one side toanother, with head extension or bending forward.Frequently, however, the positional and brief nature of thevertigo is not recognised by the patient, even after directquestioning. Therefore, positional tests should be performedin all patients with recurrent or episodic vertigo.

Patients are usually aware that certain head movementsprecipitate attacks of vertigo. They often develop strategies toavoid vertiginous attacks, e.g. sleeping upright or holdingtheir neck stiff, which may lead to immobility and prolonga-tion of the natural course of the disease. Indeed many BPPVpatients with stiff neck and head movement-induced vertigoare often told that the problem originates in the neck – themyth of ‘cervical vertigo’.5 Another presentation is the patientwith BPPV who, due to the terrifying nature of the vertigo inBPPV, develops a secondary anxiety disorder – the myth ofthe ‘it’s all in your mind’ syndrome.

Each single BPPV attack lasts a few seconds but after aseries of attacks, patients may complain of prolonged dizzi-ness and imbalance lasting from hours to days. Typically,BPPV manifests itself with symptomatic episodes lastingfrom a few days to several months, which are interspersed byasymptomatic intervals of several months to years duration.Most cases of BPPV are idiopathic, but about 25% developafter head trauma or on the background of a pre-existinglabyrinthine disorder such as vestibular neuritis orMenière´s disease. Bilateral BPPV is more common in post-traumatic patients.

ExaminationConventional clinical examination as performed by GPs, neu-rologists or ENT surgeons is negative in BPPV. Provocation ofvertigo by positional testing and observation of typical nys-tagmus is the only way to make a diagnosis of BPPV. Patientsmust have this clearly explained to them before the position-al manoeuvres. Positional vertigo is terrifying but brief - if thepatient closes his/her eyes in response to the vertigo the exam-iner will not be able to make a diagnosis.

The most popular test for provocation and confirmationof BPPV is the Hallpike manoeuvre (Figure 1A). With thisprocedure the head is rotated with respect to gravity in theplane of the affected posterior canal. Alternatively, a lateral

Adolfo Bronstein is Professor ofClinical Neuro-otology at ImperialCollege London and a ConsultantNeurologist at Charing CrossHospital and at the NationalHospital for Neurology andNeurosurgery, Queen Square,London. He heads the Departmentof Movement and Balance in theDivision of Neuroscience at ImperialCollege and is the lead Editor of thefirst and second (2004) edition of thebook ‘Clinical Disorders of Balance,Posture and Gait’.www.imperial.ac.uk/medicine/dizziness

Correspondence to:Prof Adolfo M Bronstein MDPhD FRCP,Professor of Clinical Neuro-otology and ConsultantNeurologist,Head, Department of Movement& Balance,Division of Neuroscience &Psychological Medicine,Imperial College London,Charing Cross Hospital,London W6 8RF.Tel: 020 8846 7285,Fax: 020 8846 7577,Email: [email protected]

Review Article

A B

Figure 1: Two positional manoeuvres for eliciting positional vertigo andnystagmus. In this case the right ear is being investigated. Bothmanoeuvres are equally successful in inducing positional nystagmus andshould be conducted briskly. Note how the clinician can help the patientkeep the eyes open for full visibility of a positional nystagmus. A: theHallpike manoeuvre in which the head finishes in a head hangingposition. B: a trunk-sideways positional manoeuvre.

Clinical Disorders of Balance, Posture and Gait

A Bronstein, T Brandt, H Woollacott, J Nutt

This is the second editionof this text, covering allclinical aspects of humanlocomotion and its disorders.

Seewww.hoddereducation.com

for more information

tilt of the trunk and head from a sitting positioncan be performed with the head turned 45° to theopposite side, which positions the head with thelateral aspect of the occiput onto the couch (Figure1B). This latter manoeuvre is the only one that canbe performed when the couch is placed betweenwalls or cupboards and the patient’s head cannotreach the head hanging position. In any case, withboth manoeuvres, the final position of the posteri-or semicircular canal is identical (compare Figures1A & B). The patient is instructed to keep theireyes open, to watch the examiner’s forehead oreyes and to stay in the final position even if verti-go occurs. It is useful to help the patient keep theireyes open with your own fingers, as some patientsfind it difficult to keep their eyes open when thevertigo develops. Frenzel´s glasses are not neces-sary for observation of the nystagmus.

The nystagmus in posterior canal BPPV ismostly torsional (often called ‘rotatory’), with theupper pole of the eye beating towards the under-most ear (Figure 2). In addition, there is a smallervertical skewing upbeating nystagmus compo-nent, most prominent on the uppermost eye.Typically, nystagmus and vertigo start a few sec-onds after the precipitating head position isreached (latency). Nystagmus intensity increasesrapidly and then decays (adaptation), usually last-ing 10 to 20 seconds. On returning to the sittingposition, a transient nystagmus of lesser intensitybeating in the opposite direction can be observed(reversal). With repeated testing, vertigo and nys-tagmus decrease with repeated positioning inmost cases (fatigability).

A patient with a typical history of brief rotation-al vertigo on lying, seating or turning over in bedand with a transient torsional nystagmus asdescribed above does not require any further inves-tigations. One should proceed to repositioningtreatment straight away. A similar clinical historycan be due to the rarer horizontal or anterior canalvariants of BPPV. The former has horizontal nys-tagmus and the latter downbeat nystagmus with atorsional component. However, unless the clinicianis conversant with positional nystagmus, an MRI isadvisable to rule out cerebellar-brainstem diseasewhenever a positional manoeuvre induces a nys-tagmus atypical for posterior canal BPPV.

PathophysiologyBPPV appears when dislodged calcium rich par-ticles from the utricular otoconia fall into theposterior semicircular canal. These debris, due togravitational forces, move within a semicircularcanal and cause inadequate endolymph flow

after changes of head position (canalolithiasis).There are five factors predisposing to BPPV,namely advanced age, head trauma, a precedinginner ear disease, migraine, and general anaes-thesia. These predisposing factors act by a com-bination of age related or ischemic utriculardegeneration and head reclination (for intuba-tion during anesthesia).

Figure 3 shows how these otoconial debrismove within the posterior canal. Once otoconiahave entered the posterior canal they tend to sinkto the most dependent point. When the patient isupright, they are located at the base of the cupulaand do not have any effect. During the Hallpiketest, the head is rotated backwards in the plane ofthe posterior canal, inducing movement of theparticles within the canal away from the cupulaand thus activation of the canal’s hair cells. Thenystagmus subsides after the particles havereached the most dependent point of the canaland the cupula has returned to the resting posi-tion. Agglomerates of otoconia may disperse withrepeated positional manoeuvres which mayexplain BPPV fatigability. Although thecanalolithiasis concept is supported by several his-tological and intraoperative findings, the mostconvincing proof for canalolithiasis comes fromthe efficacy of positioning manoeuvres, whichclear the affected canal from mobile particles.

TreatmentThe rationale of the treatment is to redirect theotoconial particles back to the utricle where theydo not cause BPPV symptoms. First of all thepatient is informed about the benign course ofBPPV, its mechanism and rationale for reposi-tioning treatment. Patient cooperation is vitalduring the treatment as further vertigo isunavoidable during the manoeuvres. There areessentially two repositioning treatments, Epley´sand Semont´s manoeuvre. Patients should keeptheir eyes open for observation of nystagmus,since a positional nystagmus beating in the samedirection with respect to the head indicates suc-

cessive movement of the particles towards theutricle and predicts a favourable outcome to someextent. Both these therapies are highly effective interminating an acute episode of BPPV but recur-rences after several months or years are notuncommon.

Epley has introduced the canalith repositioningprocedure, in which the posterior canal is rotatedbackwards close to its planar orientation. Themanoeuvre consists of a series of successive headpositionings each of about 90° displacement andseveral reviews illustrate clearly how to carry itout3,4. My personal impression is that, unless thedoctor or therapist applies this manoeuvre fre-quently, Epley’s manoeuvre is more difficult toremember than Semont’s, so the latter will bedescribed and illustrated here.

The Semont manoeuvre involves a 180° swing ofthe head in the plane of the posterior canal (Figure3). The examiner guides the manoeuvre by stand-ing in front of the patient who is seated on a couchwith the head rotated 45° away from the affectedear. Then the patient is brought with a fast move-ment to a lying position on the side of the provoca-tive ear (Figure 3 - 1,2). This initial part of themanoeuvre is in fact the diagnostic phase equiva-lent to a Hallpike manoeuvre or, more precisely, thesideways variant Hallpike manoeuvre describedunder Examination and illustrated in Figure 1B. Inthis position vertigo is triggered and torsional nys-tagmus beats toward the affected (undermost) ear.After being kept in this position for approximatelya minute (so all debris falls to the bottom), thepatient is swung rapidly onto the opposite side ofthe couch (and stays there for another minute)(Figure 3 - 2,3). The manoeuvre should be execut-ed quickly in one single movement step and so, ifthe patient is frail, old or overweight, an assistantcan help the therapist achieve this from behind thepatient. In order to memorise this manoeuvre, it isuseful to think that the plane of the posterior semi-circular canal lies vertically in the head at 45degrees, midway between the sagittal and coronalplanes. In order to move the head diagonally at 45

Review Article

Figure 2: The nystagmus observed in a case of right sidedBPPV in the right ear down position. The arrows indicatethe predominant beat (fast phase) direction: torsionalbeating towards the right ear with a minor upbeatingcomponent. This nystagmus pattern is the result of theexcitation of the right posterior semicircular canal.

Figure 3: Pathophysiology and treatment of right sided BPPV. The cartoon illustrates canalolithiasis of the right posteriorcanal. On the left, the debris move down during the diagnostic positional manoeuvre (as illustrated in Figure 1B). On theright, the particles are swung out of the posterior canal back into the utricle by way of the fast head acceleration producedduring the repositioning treatment (Semont manoeuvre).



degrees all you have to remember is to “go from one ear down to the opposite eyedown”. That is, to do a Semont manoeuvre on a patient with right BPPV (i.e. ver-tigo/nystagmus evoked by right ear down positional manoeuvre) swing thepatient from right ear down all the way to a left eye down position (Figure 3).

Vibration of the mastoid during these repositioning treatments has been rec-ommended but does not improve treatment outcome. Similarly, keepingupright for 48 hours after treatment has proven unnecessary. In a few patientswith unusual anxiety, vertigo or nausea medication with sedatives or antiemet-ics before the repositioning treatment is required.

Both the Epley and Semont manoeuvres are highly effective when performedproperly. After a single application complete recovery is achieved in approxi-mately 70% of patients and 90% after a second session.6 Randomised, controlledtrials have shown that repositioning manoeuvres are clearly more effective thana sham procedure or no treatment.7,8 For patients who do not respond to thesemanoeuvres or suffer from frequent recurrences, several useful procedures forself-treatment at home are available, eg Brandt-Daroff exercises or a modifiedEpley procedure.9 It is advisable to visit the original publications or visitWebPages illustrating these self-treatments and prepare handouts for patientswho require them.

Surgery of the posterior canal can be considered in those rare patients withlongstanding BPPV who have not responded to appropriate and repeated ther-apeutic positionings, but this is very rarely required nowadays.

Differential diagnosisPosterior canal BPPV must be differentiated from other forms of BPPV (hori-zontal and rarely anterior canal) and from central positional vertigo due to alesion of the vestibular nuclei or caudal cerebellum. The distinction is mainlybased on nystagmus features and a patient with atypical nystagmus shouldalways be imaged. A purely vertical (either downbeat or upbeat) nystagmusstrongly suggests a central positional nystagmus whereas a history of recur-rences and remissions is in favour of BPPV and against a central lesion.Migrainous vertigo is often aggravated by changes of head position and mayoccasionally present with pure positional vertigo. The following factors help todistinguish migrainous positional vertigo from BPPV: short-duration sympto-matic episodes and frequent recurrences, manifestation early in life, migrainoussymptoms during episodes with positional vertigo.10 A trial with antimigraineprophylactic agents is often required in a patient with migraine and recurrentvertigo, whether positional or not.

ConclusionBPPV is one of the most common causes of vertigo. Diagnosis is straightfor-ward if clinicians develop the healthy habit of doing positional manoeuvres(Hallpike or equivalent) as the single most important step in the diagnosis ofpatients with positional and recurrent vertigo. Treatment with repositioningprocedures is effective and clinicians should get familiar with at least one ofthese manoeuvres (either Epley or Semont). The Semont manoeuvre is easilyremembered: take your patient quickly in a big swing from the symptomatic eardown to the opposite eye down. You can see videos of these manoeuvres inwww.imperial.ac.uk/medicine/dizziness

Review Article

References1. Pavlou M, Shumway-Cook A, Horak F, Yardley L, Bronstein A. Rehabilitation of balance dis-

orders in the patient with vestibular pathology. In: Bronstein A, Brandt T, Woolacott M, NuttJG, eds. Clinical Disorders of Balance and Gait Disorders. London: Edward Arnold;2004:317-43.

2. Yardley L, Donovan-Hall M, Smith HE, Walsh BM, Mullee M, Bronstein AM. Effectiveness ofprimary care-based vestibular rehabilitation for chronic dizziness. Ann Intern Med.2004;141(8):598-605.

3. Lempert T, Gresty MA, Bronstein AM. Benign positional vertigo: recognition and treatment.BMJ. 1995;311(7003):489-91.

4. Furman JM, Cass SP. Benign paroxysmal positional vertigo. N Engl J Med.1999;341(21):1590-6.

5. Brandt Th, Bronstein AM. Controversial Topics in Neurology: Cervical Vertigo. J of NeurolNeurosurg Psychiatry. 2001;71:8-12.

6. Bronstein AM. Benign paroxysmal positional vertigo: some recent advances. Curr OpinNeurol. 2003;16(1):1-3.

7. Lempert T, Wolsley C, Davies R, Gresty MA, Bronstein AM. Three hundred sixty-degree rotationof the posterior semicircular canal for treatment of benign positional vertigo: a placebo-controlledtrial. Neurology. 1997;49(3):729-33.

8. Woodworth BA, Gillespie MB, Lambert PR. The canalith repositioning procedure for benignpositional vertigo: a meta-analysis. Laryngoscope. 2004;114(7):1143-6.

9. Radtke A, Neuhauser H, von Brevern M, Lempert T. A modified Epley’s procedure for self-treatment of benign paroxysmal positional vertigo. Neurology 1999;53(6):1358-60.

10. von Brevern M, Radtke A, Clarke AH, Lempert T. Migrainous vertigo presenting as episodicpositional vertigo. Neurology 2004;62(3):469-72.

The National Hospital forNeurology and Neurosurgery,

Queen Square, London

DIZZINESSA Multi-Disciplinary Approach

Assessment, Clinical Diagnosis and Management

11th – 14th October 2005

Following the success of the previous Dizziness Courses, theDepartment of Neuro-otology has expanded its course tofour full days, which will include:

• Mechanisms of dizziness• Evidence based vestibular testing• Opportunity for ‘hands-on’ experience with the

department’s equipment• Developments in genetics and radiology• The range of medical diagnoses• Diagnostic strategy• BPPV and Particle Repositioning Manoeuvres• Role of physiotherapy• Psychological aspects including the role of cognitive

behavioural therapy• The future of pharmacological therapy• Failed management and role of surgery• Theoretical basis of vestibular compensation

The course will include three full days on the diagnosis andmanagement of balance disorders with case histories, videosand quizzes and an optional fourth practical day. There willbe a course dinner on the Wednesday evening.Cost: £125/day or £420 for 4 days.

The course will be suitable for clinicians, scientists, audiologists and therapists involved in the care of the dizzypatient and will be run by Professor Linda Luxon, Dr Rosalyn Davies, Mr Albert Coelho and Mrs Karen Cox.The faculty will include renowned national and internationalspeakers.

CME accreditation will apply and CPD points will be awarded.

For details contact:

Dr Rosalyn Davies / Mr Albert Coelho / Mrs Karen CoxDepartment of Neuro-otologyThe National Hospital for Neurology and NeurosurgeryQueen SquareLondon WC1N 3BG

Tel: 020 7837 3611 ext. 3386 or 3274Fax: 020 7829 8775


Excessive Sleepiness after Brain InjuryIntroductionThe areas controlling sleep and wakefulness in the brain arewidely distributed so it is not surprising that brain injuriescan disturb sleep in many ways. While many aspects of braininjury have been well researched, there is remarkably littleinformation regarding sleep disorders, the mechanisms ofchanges in sleep/wake patterns or the factors that determinethe prognosis of the sleep disorder.

Physiological mechanisms of sleep/wake control(Figure 1)There are three control systems,1 all of which can be dam-aged by brain injuries.

a) Homeostatic drive to sleep. The drive to enter sleepincreases exponentially with the duration since the endof the previous sleep episode and declines exponential-ly once sleep is initiated. The most important sleep-promoting centre is the ventrolateral pre-optic nucleus(VLPO) in the anterior hypothalamus.2 This inhibits allthe main arousal systems especially those in the brainstem such as the locus coeuruleus and raphe nuclei,which form part of the ascending reticular activatingsystem, and the tuberomammillary nuclei in the hypo-thalamus.

b) Circadian rhythms. These are generated in the suprachi-asmatic nuclei which are responsible for the intrinsiccircadian rhythm of around 24.2 hours. This entrainsseveral important systems including sleep/wake control,temperature, feeding, motor behaviour and endocrinefunction to the local environmental time. Exposure tolight fine tunes the circadian rhythms and is sensed, notby rods and cones, but by the retinal ganglion cells.Information from these passes especially to thesuprachiasmatic nuclei which connect to the pinealgland. In the absence of light this secretes melatoninwhich promotes sleep.

c) Adaptive drive. This includes a variety of mechanismsthat adapt sleep and wakefulness to the external environ-ment independently of the homeostatic and circadiandrives. They include behavioural responses, psychologi-cal aspects and reflex factors, including the influence ofexertion and temperature on sleep and wakefulness.

Excessive daytime sleepiness after brain injuriesExcessive daytime sleepiness is a common result of braininjuries but can have several causes.

a) Post traumatic hypersomnia. This is thought to be due towidespread damage to the sleep/wake control mecha-nisms. The initial coma is often followed by a stage ofcontinuous sleepiness with a reduction of REM sleepwhich is interrupted by increasingly frequent awaken-ings. Improvement in cognitive function is associatedwith an increase in the duration of REM sleep after theinjury although there is usually poor dream recall.NREM sleep and REM sleep may be poorly differentiat-ed which makes accurate sleep staging difficult.The excessive daytime sleepiness may continue toimprove for around a year but recovery may be incom-plete. There is often a prolonged nocturnal sleep episodetogether with frequent and prolonged naps during theday and subalertness between these.3 The clinical featuresof this post traumatic hypersomnia are similar to thoseof idiopathic hypersomnia apart from the history of abrain injury.

b) Sleep apnoeas. Obstructive sleep apnoeas are frequentlyseen after brain injuries4,5 but there is little evidence toindicate whether they result from the brain injury orwere present before the incident and only diagnosedafterwards. Secondary effects of the brain injury such asweight gain may predispose to obstructive sleep apnoeas.Central sleep apnoeas may be induced by damage to res-piratory control mechanisms but little is known of theirprevalence after brain injuries.

c) Narcolepsy. Narcolepsy is occasionally associated withbrain injuries. Loss of consciousness at the time of theinjury is usual but not invariable. Narcolepsy may followinjuries to any part of the head and usually appearsimmediately afterwards or within a few weeks ormonths.6 The characteristic HLA type (DQB1*0602) ispresent in only around 50% of those with post-traumat-ic narcolepsy7 whereas it is found in around 95% ofCaucasians with idiopathic narcolepsy.While post traumatic narcolepsy might be due to directinjury to the structures controlling REM sleep, it mayalso result from damage to the blood/brain barrier or toan inflammatory response within the pons or hypothal-amus.

d) Kleine-Levin syndrome. This syndrome usually occursin adolescence or early adult life and is more common inmales than females. It is characterised by episodic day-time sleepiness which is often severe and associated witha voracious non-selective appetite (megaphagia) and, inaround 25% of patients, sexual disinhibition.Psychological changes such as anxiety, depression, con-fusion and hallucinations are also seen. These featuresare probably the result of fluctuating hypothalamicinflammation which follows the brain injury.8 The con-dition usually runs a fluctuating course with a tendencyto gradual improvement.

e) Periodic limb movements in sleep. These have been asso-ciated with brain injuries but, like obstructive sleepapnoeas9 they may have been present before the accidentbut unrecognised.

f) Circadian rhythm disorders. Brain injuries can disruptthe circadian control of sleep. A delayed sleep phase syn-drome is seen after neck and also brain injuries probablydue to damage to the tortuous pathway between thesuprachiasmatic nuclei through the cervical spinal cord

Dr John Shneerson is ConsultantPhysician and Director of theRespiratory Support and SleepCentre at Papworth Hospitalwhich is the largest unit of its kindin the UK. His specialist interestsare the physiology and treatmentof respiratory failure in neuro-muscular disorders and the man-agement of sleep disorders in neu-rological conditions.

Correspondence to:Dr John Shneerson,Consultant Physician,Papworth Hospital,Papworth Everard,Cambridge,CB3 8RE.Tel: 01480 830541,Fax: 01480 364558.

Rehabilitation Article

Figure 1: Mechanisms of sleep-wake control. SCN, suprachiasmatic nuclei, VLPO,ventrolateral preoptic nuclei,TMN, tuberomammillary nuclei, LC, locus coeuruleus, RN, raphe nuclei.


to the pineal gland.10 Impairment in vision after braininjuries frequently leads to a non-24 hour sleep/wakerhythm because of the failure of light to entrain the cir-cadian rhythm. This becomes independent of the envi-ronment (free running) so that its relationship to theenvironment changes slightly each day.11 At one point inthe cycle the two may be in phase but the sleep rhythmthen moves progressively forward leading initially to adelayed sleep phase and then through a period whenthere is insomnia at night and sleepiness during the dayto an advanced sleep phase pattern before temporarilyreturning to synchrony with the environment again.

g) Drugs. Drugs used to treat, for instance, epilepsy or psy-chiatric disorders following brain injuries may causesedation.

Treatmenta) Sleep hygiene. Maladaptive behaviour patterns are com-

mon in those with sleep disorders following brain injury.The loss of physical activity and exposure to bright lightpromotes subalertness during the day and impairs sleepat night. Excessive caffeine intake in the evenings andirregular sleep/wake schedules often contribute.Routines imposed in residential and nursing homes andsimilar institutions may also worsen sleepiness duringthe day and lead to insomnia at night and agitation.

b) Drugs. Treatment of excessive daytime sleepiness shouldbe targeted at the cause of the symptoms. Periodic limbmovements, for instance, may respond to a dopaminer-gic agent and a non 24-hour sleep/wake rhythm due tovisual impairment can usually be corrected by 0.5mgmelatonin at around 9pm, which entrains the circadianrhythms.Several of the older stimulant medications such as selegi-line and amantadine have been used but with little suc-cess. Amphetamines, particularly dexamphetamine, aremore effective but are generalised central nervous systemstimulants with important side effects.The most effective wakefulness promoting drug ismodafinil (Table 1). This is chemically unrelated to theamphetamines and is currently licensed for treatment ofexcessive daytime sleepiness due to chronic pathologicalconditions.12 Its peak blood level is reached within 2-3hours and it has a half life of 10-15 hours. It ismetabolised in the liver and the initial dose of 100-200mg daily often needs to be increased to 400mg dailyand occasionally beyond this. Around two-thirds of thedose should be given on waking and one-third in themiddle of the day. It increases the activity of the hista-minergic neurones in the tuberomammillary nuclei13

which promote wakefulness, and inhibits the VLPO. Itsmain side-effects are headaches, nausea and dry mouth

but it is usually well tolerated. Mental hyperactivity, anx-iety and nervousness occur with high doses. Tolerancehas not been documented and it has little potential fordependency. It can be used if necessary in combinationwith amphetamines and related drugs.

ConclusionsExcessive sleepiness frequently impedes rehabilitation afterbrain injuries but often remains unrecognised or underesti-mated. It can be due to a variety of specific sleep disordersand its causes should be carefully analysed. While sleephygiene may be of help drug therapy may need to be addedto treat specific disorders such as periodic limb movementsin sleep. A wakefulness promoting drug is, however, oftenrequired and modafinil has several advantages over theolder central nervous system stimulants.

Rehabilitation Article

Table 1. Comparison of amphetamines and modafinil. Reproduced with permission1

Amphetamines Modafinil

Efficacy + +Duration of action Short LongSpecificity of action Low HighDependency Moderate risk Low riskWithdrawal symptoms Common AbsentTolerance 30% narcoleptics UnknownSide-effects Multiple, often serious Few, mildContraindications Multiple FewDrug interactions Occasional RareEffects of overdose May be fatal Insomnia

References1. Shneerson JM. Sleep Medicine: A Guide to Sleep and its Disorders. Blackwell Publishing Oxford 2005.2. Saper CB, Chou TC, Scammell TE. The Sleep Switch: Hypothalamic control of sleep and wakefulness. Trends

in Neurosci 2001;24:726-731.3. Guilleminault C, Faull KF, Laughton M, van den Hoed J. Posttraumatic excessive daytime sleepiness: A review

of 20 patients. Neurology 1983;33:1584-1589.4. Webster JB, Bell KR, Hussey JD, Natale TK, Lakshminarayan S. Sleep Apnea in Adults with Traumatic Brain

Injury: A Preliminary Investigation. Arch Phys Med Rehabil 2001;82:316-321.5. Castriotta RJ, Lai JM. Sleep Disorders Associated with Traumatic Brain Injury. Arch Phys Med Rehabil

2001;82:1403-1406.6. Maccario, M, Ruggles KH, Meriwether MW. Post-traumatic narcolepsy. Military Medicine 1987, 152:370-3717. Lankford DA, Wellman JJ, O’Hara C. Posttraumatic Narcolepsy in Mild to Moderate Closed Head Injury. Sleep

1994;17:S25-288. Will RG, Young JPR, Thomas DJ. Kleine-Levin Syndrome: Report of Two Cases with Onset of Symptoms

Precipitated by Head Trauma. Br J Psych 1988; 152:410-412.9. Masel BE, Scheibel RS, Kimbark T, Kuna ST. Excessive Daytime Sleepiness in Adults with Brain Injuries. Arch

Phys Med Rehabil 2001;82:1526-1532.10. Patten SB, Lauderdale WM. Delayed Sleep Phase Disorder after Traumatic Brain Injury. J Am Acad Child

Adolesc Psych 1992; 31:100-102.11. Boivin DB, James FO, Santo JB, Caliyurt O, Chalk C. Non 24-hour sleep-wake syndrome following a car acci-

dent. Neurology 2003; 60:1841-1843.12. Shneerson JM. Modafinil (Provigil), a new treatment for excessive sleepiness. Prescriber 2005;16:16-22.13. Scammell TE, Estabrooke IV, McCarthy MT, et al. Hypothalamic arousal regions are activated during

modafinil-induced wakefulness. J Neurosci 2000;20:8620-8.

Sleep Medicine: A Guide to Sleep and its DisordersBy John Shneerson

Published by: Blackwell Publishing • Published: July 2005 • ISBN: 1405123931Format: Hardback • Pages: 336 • Illustrations: 75 • Price: £65.00

Written by one of the UK’s leading authorities on sleep medicine, Sleep Medicine: A Guide to Sleep and itsDisorders presents a practical guide to the clinical problems related to sleep disorders. The book is divided intothree sections covering: The fundamentals of sleep, the effects of drugs on sleep and how to assess sleep complaints. Individual sleep disorders, Insomnia, excessive daytime sleepiness, awareness during sleep andbehavioural abnormalities. Respiratory consequences of upper airway dysfunction, changes in the control ofbreathing during sleep and the social implications of sleep problems.

To order your copy visit www.blackwellpublishing.com/1405123931


Cerebrovascular DiseaseIntroductionCerebrovascular diseases (CVD) are common and serious,ranking worldwide as the third largest cause of morbidityand mortality. The outlook for patients with the recognisedclinical presentations of CVD is improving. Clinical trialshave delivered effective treatments for patients with acuteischaemic stroke and transient ischaemic attack.1 Progressin CVD will continue as further research is enhancing ourunderstanding of pathophysiology of carotid atherosclero-sis,2 lacunar infarction,3 cerebral amyloid related haemor-rhage4 and the role of cerebrovascular disease in dementia.5

Neuropathology is proving central to our understanding ofeach of these areas. In this article we review the basic pathol-ogy of cerebrovascular disease.

Cerebrovascular disease - OverviewCerebrovascular disease encompasses two main categories;cerebral ischaemia and haemorrhage. Cerebral ischaemicinjury results from the occlusion of a major cerebral artery,a small perforating cerebral artery or a venous sinus.Cerebral haemorrhage results from rupture of a cerebralartery, arterial aneurysm, arterio-venous malformation orcapillaries. The clinical term ‘stroke’ refers to the acute clin-ical manifestation of any one of these processes. However,the full clinical spectrum of CVD is broad including acutebehavioural disturbance, progressive cognitive impairment6

and parkinsonism.7

Cerebral IschaemiaCerebral infarction is the endpoint of cerebral ischaemicinjury wherever it occurs in the brain. Pathologically this isdefined as a region of brain tissue in which all the cellularelements have undergone necrosis i.e. cell death. Infarctscan be divided into acute, subacute (2-4 days) and chronic(days to months). An infarct that has occurred 5-8 hoursbefore death is often characterised by petechial haemor-rhages in the grey matter but may be almost undetectableon gross examination in the white matter; microscopic fea-tures are usually minimal at this stage. Changes that devel-op within 12-36 hours include blurring of the grey/whitematter interface and slight softening of the brain parenchy-ma. The chronic infarct shows liquefactive and cysticchanges. The histology of infarcts ranges from earlyeosinophilic neurones (hypoxic neurones - Figure 1a) and aminimal number of neutrophils 6-12 hours after theischaemic episode to macrophage infiltration in the suba-cute phase at 5 days leading to liquefactive necrosis and cystformation with atrophy of surrounding brain in the chron-ic infarct (Figure 1b). The differential diagnosis for the radi-ological and macroscopic appearances of cerebral infarctionor haemorrhage includes; primary cerebral tumours,metastatic tumours, cerebral abscess and demyelinating

conditions such as acute multiple sclerosis.It is rational to classify cerebral ischaemic injury into

large and small vessel, as they are associated with differentclinical syndromes, clinical outcomes and aetiologies.

Large vessel ischaemiaLarge vessel infarction results from occlusion of a majorcerebral artery within the carotid or vertebrobasilar circula-tion. They present with severe clinical strokes and are com-monly fatal because of extensive brain swelling in days afterstroke onset and have a poor long-term outcome.2,8 Largevessel occlusive strokes are most commonly a result ofthrombo-embolism from extracranial atheroma or cardiacemboli. Other less common large artery conditions that cancause brain infarction are listed in Table 1.

Since the description of the ischaemic penumbra identi-fying a region of potentially reversible ischaemic tissuewithin the terrority of the occluded large cerebral artery,much of the research in stroke has exploited functionalimaging techniques rather than neuropathology.Neuropathological techniques have traditionally been limit-ed in defining the penumbra, however, new pathologicaltechniques are being developed. These techniques entail theuse of animal models with a combination of imaging andpathology and they are increasing our understanding of fac-tors involved in the development of infarction.9 Althoughnot entirely refined, the concept of the ischaemic penumbrahas proved a very powerful stimulus to develop treatmentfor large vessel ischaemic injury.10 It has recently beendemonstrated that salvaging the ischaemic penumbra ishow thrombolytic therapy improves clinical outcomes11 andthis should allow the time-window for therapy of strokes to

Steven Allder is a ConsultantNeurologist, Plymouth HospitalTrust. He graduated fromNottingham University and com-pleted a research fellowship in MRIof acute stroke in the departmentsof Clinical Neurology andAcademic Radiology at UniversityHospital, Nottingham. He complet-ed specialist training in Neurologyat Sheffield.

Dr Pinias Mukonoweshuro,MBCHB, is a Specialist Registrar inHistopathology at DerrifordHospital, Plymouth.

Correspondence to:Dr Steven AllderConsultant NeurologistDerriford HospitalDerriford RoadPlymouthPL6 8DHEmail:[email protected]

Neuropathology Article

Premature atherosclerosis

Dissection (spontaneous or traumatic)

Inherited metabolic diseases (homocystinuria, Fabry’s, pseu-doxanthoma elasticum, MELAS syndrome)

Fibromuscular dysplasia

Infection (bacterial, fungal, tuberculosis, syphilis, Lyme)

Vasculitis (collagen vascular diseases - systemic lupus ery-thematosus, rheumatoid arthritis, Sjögren’s syndrome, pol-yarteritis nodosa; Takayasu’s disease, Wegener’s syndrome,cryoglobulinemia, sarcoidosis, inflammatory bowel disease,isolated central nervous system angiitis)

Moyamoya disease

Radiation

Table 1. Less common large artery conditions causing brain infarction

Figure 1a. Histology of an acute cerebral infarct showing neuronaleosinophilia (hypoxic/ischaemic neurones) and vacuolation of theneuropil. (Hematoxylin and eosin x20).

Figure 1b. Histology of a chronic cerebral infarct showing macrophageswith foamy or granular cytoplasm. Some of the macrophages containhaemosiderin pigment. (Hematoxylin and eosin x20).


be significantly increased.12

Atherosclerosis is the commonest cause oflarge vessel stroke. It is most severe at the originsof the vertebral arteries and the carotid bifurca-tion. Pathological study of atherosclerosis hasbeen deemed sufficiently important that an inter-national pathological classification has beendevised. This originally comprised six types whenpresented in 1995. This was modified in 2000 totake in to account further developments in thefield (See Table 2). This is another area whereimaging and pathology are now being used intandem to define the actual pathological process-es within atheroma in vivo. Figure 2 shows thecorrelation between MRI finding andintraplaque haemorrhage, a hallmark of clinical-ly symptomatic atheroma (type VI). In additionto atheromatous emboli, infarction can be causedby emboli from cardiac valve vegetations, cardiacthrombi associated with myocardial infarcts, fat,air, malignancies, parasites or material intro-duced during vascular surgery, interventionalprocedures or during angiography.

Small vessel ischaemiaThe concept of small vessel stroke (lacunarinfarction) was proposed by Fisher in 1965.13 Hedescribed lesions caused by occlusion of perfo-rating cerebral arteries secondary to lipohyali-nosis within the artery walls. Research into smallvessel ischaemia is undergoing a renaissance. Ithas recently been shown that the aetiology ofclinical syndromes associated with lacunarinfarction are not homogeneous and the short orlong term prognoses are not benign.14 A new pro-posal suggests that in most lacunar strokes, thevascular abnormality is pathologically diffuse,even if the clinical manifestations are focal and

result from small vessel endothelial damage. Thisin turn leads to a subtle increase in blood-brainbarrier permeability, and leakage of substancestoxic to the brain into the perivascular tissue.3

Support for this proposal comes from pathologi-cal and imaging data. A recently described variantof a small, microvessel-associated basal ganglialesion with histopathological features distinctfrom those of classical Types I, II and III lacunessuggests a state of incomplete infarction mayexists prior to infarction.15 This has gained fur-ther support from studies using a combination ofimaging with computed tomography and mag-netic resonance imaging. This has allowed delin-eation of structures with the density or signal fea-tures consistent with an occluded (or at leastabnormal) perforating artery associated with therelevant lacunar infarct.16

Cerebral haemorrhageIntraparenchymal cerebral haemorrhage is lesscommon than cerebral ischaemia, but has aworse prognosis. Specific treatments are still lack-ing for this condition although it is hoped thatthis will change now cerebral haemorrhage isbeing systemically investigated.17 Intra-parenchymal haemorrhage can be classified intosubcortical and lobar haemorrhage. In manycases the underlying pathological conditions thatlead to both types of haemorrhage are the sameand there is significant overlap with the causes ofcerebral ischaemia i.e. arteriolosclerosis and lipo-hyalinosis in many cases. Anticoagulation, trau-ma and underlying vascular abnormalities aremore specific aetiological factors of cerebralhaemorrhage. In young patients cerebral haem-orrhage can be associated with the use of recre-ational drugs such as cocaine and amphetamines.

Cerebral amyloid angiopathy related haemor-rhage (CAA-H) is another area where new patho-logical insights are emerging. CAA-H is charac-terised by extracellular deposition of amyloid incortical and leptomeningeal vessels (Figure 3). Itis the most common cause of lobar haemorrhageparticularly in elderly normotensive individuals.Risk factors for CAA include mutations of theamyloid precursor protein (APP) gene and pos-session of the epsilon 4 allele of apolipoprotein E.The deposition of amyloid in blood vessel wallsresults in rigid and fragile blood vessels that are

prone to haemorrhage. Path-ological studies have highlighted anadditional factor. In some patientsthe clinical expression of the diseaserelates to an associated vasculitic

reaction.4 Pathological studies also suggest thatCAA may have a relevance that extends beyondcerebral haemorrhage as it may be central to howCVD and Alzheimer’s pathology interact to pro-duce dementia.5

SummaryThe sheer size and spectrum of the clinical burdenof CVD continues to evolve. This is stimulatingresearch and clinical services for patients with CVD.Neuropathology remains central to this effort.

References1. Schellinger PD, Hacke W. Stroke: advances in therapy.

Lancet Neurol 2005;4(1)2.2. Albers GW, et al. Transient ischemic attack—proposal for a

new definition. N Engl J Med 2002;347(21):1713-6.3. Wardlaw JM. What causes lacunar stroke? J Neurol

Neurosurg Psychiatry 2005;76(5):617-9.4. Scolding NJ, et al. Abeta-related angiitis: primary angiitis of

the central nervous system associated with cerebral amyloidangiopathy. Brain 2005;128(Pt 3):500-15. Epub 2005 Jan 19.

5. Nicoll JA, et al. Cerebral amyloid angiopathy plays a directrole in the pathogenesis of Alzheimer’s disease. Pro-CAAposition statement. Neurobiol Aging 2004;25(5):589-97;discussion 603-4.

6. Bowler JV. Vascular cognitive impairment. Stroke, 2004.35(2):p386-8.

7. Sibon I, and Tison F. Vascular parkinsonism. Curr OpinNeurol 2004;17(1):p49-54.

8. Heuschmann PU, et al. Predictors of in-hospital mortalityand attributable risks of death after ischemic stroke: theGerman Stroke Registers Study Group. Arch Intern Med,2004;164(16):1761-8.

9. Fisher M. Characterizing the target of acute stroke therapy.Stroke 1997;28(4):866-72.

10. Baron JC. Mapping the ischaemic penumbra with PET:implications for acute stroke treatment. Cerebrovasc Dis1999;9(4):193-201.

11. Chalela JA, et al. Early magnetic resonance imaging findingsin patients receiving tissue plasminogen activator predictoutcome: Insights into the pathophysiology of acute stroke inthe thrombolysis era. Ann Neurol 2004;55(1):105-12.

12. Hacke W, et al. The Desmoteplase in Acute Ischemic StrokeTrial (DIAS): a phase II MRI-based 9-hour window acutestroke thrombolysis trial with intravenous desmoteplase.Stroke 2005;36(1):66-73. Epub 2004 Nov 29.

13. Fisher CM. Lacunes: Small, Deep Cerebral Infarcts.Neurology 1965;15:774-84.

14. de Jong G, Kessels F, and Lodder J. Two types of lacunarinfarcts: further arguments from a study on prognosis.Stroke 2002;33(8):2072-6.

15. Lammie GA, Brannan F, and Wardlaw JM. Incompletelacunar infarction (Type Ib lacunes). Acta Neuropathol(Berl) 1998;96(2):163-71.

16. Wardlaw JM, et al. Imaging appearance of the symptomaticperforating artery in patients with lacunar infarction: occlu-sion or other vascular pathology? Ann Neurol2001;50(2):208-15.

17. Priorities for clinical research in intracerebral hemorrhage:report from a National Institute of Neurological Disordersand Stroke workshop. Stroke 2005;36(3):e23-41. Epub 2005Feb 3.

Neuropathology Article

Type I Isolated macrophage foam cellsType II Multiple foam cells layers formedType III Isolated extracellular lipid pools addedType IV Confluent extracellular lipid core formedType V Fibromuscular tissue layers producedType VI Surface defect, haematoma, thrombosisType VII Calcification predominatesTypeVIII Fibrous tissue predominates

Table 2: Stary classification of Atherosclerosis

Figure 2. A and B, Extensive area of intraplaque haemorrhage is demonstratedon coronal (arrow) and axial (arrowheads) views. C, Intraplaque haemorrhageis seen on histological specimen (arrow). Moody et al - publisher LWW.

Figure 3: CAA demonstratedusing an anti-Aβ antibody.Note the amyloid deposited inblood vessel walls.


Intracerebral HaemorrhageIntroductionSpontaneous intracerebral haemorrhage carries a highermortality and poorer functional outcome than ischaemicstroke or subarachnoid haemorrhage.1 The mortality at onemonth from intracerebral haemorrhage has been observedto range from 35% – 52%. After six months, only 20% ofpatients can be expected to be independent. The incidencevaries between different populations (15 – 35 per 100,000)but is generally twice that of subarachnoid haemorrhage.Despite the damaging impact of this condition, even thebasic surgical and medical management varies widelybetween centres with no good evidence base for best prac-tice. Intracerebral haemorrhage has been recently targetedas a high priority for further clinical stroke research andthere have been some recent advances in understanding thiscondition, and towards improving outcome in the future. Inparticular, the results of the STICH trial (InternationalSurgical Trial in Intra–Cerebral Haemorrhage) which ran-domised 1033 patients between early surgery and initialconservative therapy have recently been published;2 and newavenues of early treatment to prevent clot expansion usingactivated factor VII show promise.3

Differential diagnosisTable 1 outlines the different causes of intracerebralhaemorrhage. The majority of intracerebral haemorrhage(70 – 80%) is termed primary in nature and results fromchronic small vessel disease processes such as intra-parenchymal hypertensive small vessel microaneurysmsor amyloid angiopathy. Secondary intracerebral haemor-rhage can be due to a structural lesion (e.g tumour, arte-riovenous malformation, intracranial berry aneurysm),bleeding diathesis (e.g. warfarin, aspirin, alcohol inducedcoagulopathy), or a disease process causing acute andsevere hypertensive changes such as abuse of sympath-omimetic drugs (cocaine, ecstasy, amphetamines) oreclampsia in pregnancy (Figures 1a and 1b).

It is important to note that at a practical level, the dis-tinction between differential causes of intracerebralhaemorrhage is not always clear cut e.g: microaneurysmal

small vessel changes can occur (with increasing preva-lence in older patients) in the absence of clinical hyper-tension; an alcohol induced coagulopathy may exacerbatea bleed from other causes such as amyloid angiopathy.Secondary intracerebral haemorrhage can also occur intoan ischaemic cerebral infarct. This latter entity willbecome more frequent with the advent of widespread useof acute thrombolysis for reperfusion in ischaemic stroke.

Clinical presentation and radiologicalassessmentImportant clinical points to note are: -1. Any features of trauma that may confound the diagno-

sis of a spontaneous haemorrhage.2. The presence of co-morbidity that may predispose to

intracerebral haemorrhage (e.g. hypertension, antico-agulant history, use of illicit drugs or alcohol, andhaematological disorders).

3. Any recent history of headache, focal deficit or seizuresthat may indicate the presence of an underlying cere-bral lesion.

4. The presence of focal neurological deficit and the levelof consciousness as assessed objectively with a break-down of the Glasgow Coma Score.

Intracerebral haemorrhage classically presents with asudden onset neurological deficit and features of raisedintracranial pressure including headache, vomiting andmarkedly elevated blood pressure, whereas ischaemicstroke is more likely to present with a sudden onsetdeficit alone. Early progression of neurological symp-toms including deterioration in the level of conscious-ness within the first few hours is more common forintracerebral haemorrhage (over 50%) than forischaemic stroke or subarachnoid haemorrhage (5% -20%).1 This is thought to be due to the presence of earlycontinued bleeding and hence clot expansion, during theevolution of an intracerebral haematoma.

These clinical features may be helpful in indicatingwhich patients presenting with a sudden onset neurolog-ical deficit are likely to have suffered an intracerebralhaemorrhage, but they cannot be reliably used to differ-entiate ischaemic stroke from haematoma. Hence emer-gent, rapid access CT scanning is essential in the diagno-

Pawan S Minhas,Pawan Minhas is a consultantneurosurgeon in the AtkinsonMorley Wing of St George’sHospital, Tooting, South WestLondon. His sub-specialist inter-ests are in vascular and spinal neu-rosurgery.

Correspondence to:Mr P S Minhas,Consultant Neurosurgeon,Department of Neurosurgery,Atkinson Morley Wing,St George’s Hospital,Tooting,London SW17 OQT.Tel: 020 8725 4450.Email: [email protected]

Management Topic

PrimaryChronic hypertensionAmyloid angiopathy

Secondary to Structural abnormalityAneurysmArteriovenous malformation (AVM)Dural arteriovenous fistulaCavernous haemangiomaTumourHaemorrhage into ischaemic cerebral infarctMoya moya diseaseSagittal sinus thrombosisVasculitis/inflammatory vasculopathy

Secondary to coagulopathyIatrogenic (warfarin, aspirin, thrombolysis)Alcohol induced coagulopathyBlood dyscrasias e.g leukaemia, thrombocytopenia, Hepatic failure, renal failure

Secondary to severe acute hypertensionSympathomimetic drugs (cocaine, ecstasy, amphetamines)Pregnancy - eclampsia

Table 1: Causes of Spontaneous Intracerebral Haemorrhage

Figure 1a: Presentation CT scan of a 68 year oldpatient with sudden onset left/right agnosia andsymptoms of raised intracranial pressure. Anintracerebral haemorrhage was identified in the righttemporal region causing mass effect. He improvedwithout haematoma evacuation.

Figure 1b: Five weeks later he developed symptoms ofraised intracranial pressure. A repeat CT scan revealeda space-occupying lesion, confirmed at biopsy to be aglioblastoma multiforme.


sis and subsequent management. It allowsassessment of the size and location of haemor-rhage along with the features of mass effectsuch as the degree of midline shift and efface-ment of the basal cisterns indicating pendingtentorial herniation. The presence of intraven-tricular haemorrhage with resultant hydro-cephalus is also important in determining sur-gical treatment. CT will often give informationof underlying lesions causing secondary haem-orrhage. Aneurysmal haemorrhage is usuallyassociated with the presence of subarachnoidblood and typical bleed patterns extending tothe Sylvian fissure (for middle cerebral arteryaneurysms) or paramedian frontal lobe haem-orrhage extending to the interhemispheric fis-sure anteriorly (for anterior communicatingartery or pericallosal artery aneurysms).Arteriovenous malformations will usuallyshow calcified vessels in association with theAVM. Tumours may be suspected where thereappears to be a separate mass adjacent to theacute intracerebral haematoma (usually withcontrast enhancement) or a degree of sur-rounding cerebral oedema in excess to thatexpected for an acute haematoma. Malignantmelanoma is the most common metastasis topresent with intracerebral haemorrhage andhigh-grade intrinsic gliomas can infrequentlypresent with haemorrhage (Figures 1a and 1b).Intracerebral haemorrhage secondary to sagit-tal sinus thrombosis is often bilateral, parame-dian in location and associated with cerebraloedema arising from cerebral venous conges-tion. Following intravenous contrast, the‘empty delta’ sign may be evident in the supe-rior sagittal sinus.

Lobar, peripherally located haemorrhage inthe elderly is often attributed to amyloidangiopathy. More centrally located haemor-rhage originating in the putamen, globus pal-lidus, thalamus, or internal capsule is classical-ly assigned to chronic hypertension (as ishaemorrhage in the pons and cerebellum).However these assumptions can frequently beincorrect. In a study of 102 patients4 withintracerebral haemorrhage, 58 patients had noCT features of an underlying structural lesion(the presence of subarachnoid, Sylvian fissureor intraventricular haemorrhage, abnormalintracranial calcification, prominent vascularstructures). Of these, 42 underwent delayedcerebral angiography revealing 10 unsuspectedvascular lesions (8 AVM’s and 2 aneurysms).More recently, the high sensitivity of an MRI orCT scan with contrast once the haemorrhage isresolving (usually 4-6 weeks after the bleed)should resolve the need for conventional inva-sive cerebral angiography to exclude a vascularlesion such as an AVM. Angiography can thenbe confined to those patients with abnormalfindings indicative of an AVM or aneurysm.

Initial medical treatmentThe initial medical treatment is supportive.Patients suffering from intracerebral haemor-rhage frequently show respiratory or cardio-vascular instability and hence airway, breathingand circulation are the first priorities, even in apatient demonstrating significant neurologicaldecline. Ventilation will be required in patients

with a Glasgow Coma Score of less than 8, ifthe airway or oxygenation is not being main-tained, and in patients who are agitated orcombative to the point that a CT scan cannotbe performed. Ventilation may also be neededfor patients suffering repeated or prolongedseizures. Aspiration of gastric contents whilstthe airway is unprotected is a frequent risk inpatients who are showing significant neurolog-ical decline.

Blood pressure management is a controver-sial issue.1 Patients often have a history ofchronic hypertension and will thereforerequire higher than normal mean arterialblood pressures to maintain adequate cerebralperfusion. In the presence of a large intracere-bral haematoma, intracranial pressure may besignificantly raised and hence require a higherthan normal arterial blood pressure in orderto maintain an adequate cerebral perfusionpressure. Yet there is evidence that thosepatients with abnormally elevated blood pres-sures are more likely to deteriorate clinicallywithin the first few hours because of ongoingbleeding causing haematoma enlargement.5

There is a lack of good evidence regarding thebest blood pressure management strategy toemploy, and it may be beneficial to individu-alise blood pressure targets depending on thepatient’s clinical circumstances. Reco-mmendations have been made by the StrokeCouncil, American Heart Association1 thatpatients with chronic hypertension shouldhave mean arterial blood pressures notexceeding 130mm Hg, that if systolic arterialblood pressure falls below 90mm Hg thenpressors should be given, and where intracra-nial pressure monitoring is used, CPP shouldbe maintained at greater than 70mm Hg.

In patients who are warfarinised, thisshould be reversed immediately and fullyusing fresh frozen plasma and vitamin K. Therisk of extension of the intracerebralhaematoma remains very high whilst antico-agulation is not reversed, whereas the risk ofan adverse thromboembolic event even inthose patients who are most at risk (e.g. witha metal prosthetic heart valve replacement) isminimal within the first week.

A significant proportion of patients experi-ence ongoing haemorrhage within the first fewhours causing intracerebral haematomaexpansion and thus clinical deterioration. Arecently published randomised controlled trialhas shown improved survival and functionaloutcome from the early administration of acti-vated Factor VII to prevent haematoma propa-gation.3 This trial is significant in being theonly medical treatment to show a clinicalimprovement in outcome for intracerebralhaematoma. Practically, there will be difficul-ties in the widespread institution of this type oftreatment because patients must be treatedvery early in the evolution of their intracere-bral haematoma and because of the presentprohibitive cost of treatment with activatedFactor VII.

Surgical treatment of intracerebralhaemorrhageSurgical treatment of intracerebral haemor-

rhage includes intracranial pressure monitor-ing for guiding subsequent intensive care man-agement, ventricular drainage for the relief ofhydrocephalus, and partial or complete evacu-ation of the intracerebral haematoma. The lat-ter can be achieved by open craniotomy or byless invasive procedures such as stereotacticallyguided burr hole aspiration and endoscopical-ly guided aspiration. In addition, a throm-bolytic agent such as the plasminogen activa-tor, urokinase can be instilled into thehaematoma cavity to aid clearance of the clot.

The rationale for haematoma evacuation ispotentially twofold. Firstly it is effective inrelief of raised intracranial pressure when thereis significant mass effect. This may improveoutcome by preventing brainstem compressionand subsequent coning, improving global cere-bral perfusion to prevent ongoing ischaemia tothe brain, or indirectly by allowing control ofintracranial pressure so that patients can bemore rapidly weaned on the intensive care unitand hence be less susceptible to medical com-plications such as ventilator associated pneu-monia. Secondly haematoma evacuation maybe beneficial in minimising the surroundingbrain oedema and secondary neurotoxic injurythat occurs as a delayed reaction within thepenumbra surrounding the intracerebral bloodclot.6 The early retraction of blood clot, thepresence of thrombin and activation of thecoagulation cascade, and the presence ofhaemoglobin breakdown products is believedto be key in the development of cerebral oede-ma and secondary neurotoxicity. Balancedagainst these potential benefits is the addedcerebral trauma of surgical evacuation.Evacuation is often only partial and this maynot be sufficient to prevent secondary neuro-toxicity. Evacuation is more likely to be incom-plete (or even leave significant residualhaematoma causing mass effect) when less sur-gically invasive procedures such as endoscopicor stereotactic aspiration are employed. Themajority of large intracerebral haemorrhagesdestroy the internal capsule and hence patientsare likely to remain densely hemiplegic.Surgical evacuation of a haematoma largeenough to cause significant mass effect maytherefore achieve little more than to convertpatients who would not survive into patientswho will be left severely disabled.

McKissock et al. published the first ran-domised controlled trial for the surgical treat-ment of intracerebral haemorrhage in 1961,7

showing that outcome was worse in surgicallyas opposed to conservatively treated patients.Subsequent trials have generally shown con-flicting results with insufficient power. Toprogress from this, the STICH trial2 recruited1033 patients who were randomised to earlysurgery or initial conservative therapy. Patientswere eligible if they presented within 72 hoursof a supratentorial, non aneurysmal, non AVMbleed, if the treating neurosurgeon was uncer-tain which treatment was better for the patient(the clinical uncertainty principle) and if sur-gical treatment was intended within 24 hours.This was a trial for early surgery and sopatients in the medical arm could undergohaematoma evacuation at a later date (about a

Management Topic


quarter of patients did require this). Outcomeand mortality did not differ significantlybetween the two groups. Predefined subgroupanalysis showed benefit in early surgery whenthe haematoma was less than 1cm from thecortical surface, suggesting that surgery mightbe better when less surgical trauma is caused inreaching the haematoma, a possibility whichhas previously been raised from the benefitconferred in outcome from endoscopic evacu-ation of intracerebral haematoma in an earliertrial.8 One very important finding of STICHwas that patients presenting with a GlasgowComa Score of eight or less had an almost uni-versally poor outcome.

SummaryIntracerebral haemorrhage remains a frequentand devastating condition within the centralnervous system. The evidence base for consid-ering optimal treatment is lacking but recenttrials are beginning to rectify this. Progress inimproving outcome for the future will requirewidespread availability of good quality neuro-intensive care facilities and early referral sys-tems for acute stroke in general. In addition a

better understanding of the factors that pro-duce early clinical deterioration by haematomaenlargement (and particularly how this can becontrolled haematologically and with bloodpressure management), and delayed deteriora-tion by secondary neurotoxic processes will beimportant. Any future trials of surgery are like-ly to need to consider techniques that minimisetrauma to the brain, yet achieve consistentlygood haematoma evacuation.

References1. Broderick JP, Adams HP Jr, Barsan W, Feinberg W,

Feldmann E, Grotta J, Kase C, Krieger D, Mayberg M,Tilley B, Zabramski JM, Zuccarello M. Guidelines for themanagement of spontaneous intracerebral hemorrhage: Astatement for healthcare professionals from a special writ-ing group of the Stroke Council, American HeartAssociation. Stroke 1999Apr;30(4):905-15.

2. Mendelow AD, Gregson BA, Fernandes HM, Murray GD,Teasdale GM, Hope DT, Karimi A, Shaw MD, Barer DH;STICH investigators. Early surgery versus initial conserva-tive treatment in patients with spontaneous supratentorialintracerebral haematomas in the International SurgicalTrial in Intracerebral Haemorrhage (STICH): a ran-domised trial. Lancet. 2005;365(9457):387-97.

3. Mayer SA, Brun NC, Begtrup K, Broderick J, Davis S,Diringer MN, Skolnick BE, Steiner T, and theRecombinant Activated Factor VII IntracerebralHemorrhage Trial Investigators. Recombinant ActivatedFactor VII for Acute Intracerebral Hemorrhage.N. Engl. J. Med. 2005;352(8):777– 85.

4. Halpin SF, Britton JA, Byrne JV, Clifton A, Hart G,Moore A. Prospective evaluation of cerebral angiographyand computed tomography in cerebral haematoma. JNeurol Neurosurg Psychiatry 1994;57:1180–6.

5. Ohwaki K, E. Yano, Nagashima H, Hirata M, NakagomiT, and Tamura A. Blood Pressure Management in AcuteIntracerebral Hemorrhage: Relationship Between ElevatedBlood Pressure and Hematoma Enlargement. Stroke2004;35(6):1364-7.

6. Xi G, Keep RF, Hoff JT. Pathophysiology of brain edemaformation. Neurosurg Clin N Am. 2002;13(3):371-83.

7. McKissock W, Richardson A, Taylor J. Primary intracere-bral hemorrhage: a controlled trial of surgical and conser-vative treatment in 180 unselected cases. Lancet.1961;2:222–6.

8. Auer L, Deinsberger W, Niederkorn K, Gell G, KleinertR, Schneider G, Holzer P, Bone G, Mokry M, Korner E,et al. Endoscopic surgery versus medical treatment forspontaneous intracerebral hematoma: a randomized study.J Neurosurg 1989;70:530–5.

Management Topic

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This newly published fourth edition of the English ver-sion of the classic German neurology textbook aims, inthe authors’ own words, to be a comprehensive text ofneurology for practising physicians, but also not to be toounwieldy, and readable for both study and reference. Thebook is an unusual size. It is too big for most people’swhite coat pockets, but not big enough to intimidate orinspire on the shelf; it may have been designed for thebriefcase. Overall we thought it was a little (or mediumsized) gem, we highly recommend it, and any minorgripes are a reflection of how much we have used it ratherthan any real concerns about content.

We read through the book and then delved into it tolook up current problems on the ward. We then had todecide where it would live: the bin, the hospital library, thedesktop, or the briefcase.

It is subdivided into 15 sections covering a broad rangeof neurological subjects in both adult and paediatric neu-rology. On the whole, it achieves its aim of being compre-hensive, and readers looking for more detailed materialcan consult the reference list provided.

The read through was fun; the 438 illustrations and 210tables make for quick and easy reference and there aremany excellent neuroimaging studies of various modali-ties. The chapter on dementing disorders and neuropsy-chology, and the chapter on disturbances of cerebral per-fusion were superb with a helpful mix of microscopic andtelescopic perspectives. We were impressed by the spacegiven to syncope and other disorders which mimic epilep-tic seizures. Epilepsy and anti epileptic drugs are classifiedin useful tables although the discussion about terato-genicity is very short and does not appear in the otherwise

helpful list of ten principles for the treatment of patientswith epilepsy. Perhaps a subsection should be added deal-ing with the particular problems of epilepsy in women.Having the references available on line makes for a muchmore concise book and the scales and genetics in theappendix are a useful reference tool. At times the format-ting of the text could be easier on the eye (if the format-ting of the British National Formulary can make druginformation readable, anything is possible) but that maybe an inevitable problem in a book of this size. There area few errors, for example on page 9, in diagram g, ‘coc-cygeal’ is spelt ‘kokzygeal’, and on page 76, fig.2.13 a/b thelabels remain in German. On page 35, table 2.5, the phrase‘feeble mindedness’ may be more appropriately replacedby ‘learning disability’, and on page 41 it is stated that alarge head in a neonate often reflects familial ‘micro-cephaly’, which should surely be ‘macrocephaly’.

Specific problems we looked up included the diagnosisand treatment of autonomic dysreflexia in patients withspinal cord injury, Lambert Eaton Myaesthenic syndrome(LEMS), and the anatomy of the cerebral venous sinuses.Autonomic dysreflexia is not mentioned by name butparoxysmal hypertension is described in ten lines and themanagement is not discussed. As this is one of the com-mon life threatening problems after spinal cord injury thiswas a surprise. LEMS is described well and the descriptionof the anatomy of the venous sinuses was just what wewanted. Two out of three; not bad.

It’s in the briefcase.

Andrea Lowman, Tom Hughes,University Hospital of Wales, Cardiff & Vale NHS Trust.

Book Reviews

Neurology 4th Edition

Everything about this second edition is bigger than thefirst (of 1997): editors (3 vs. 2); chapters (24 vs. 19); pages(578 vs. 440; cf. blurb: “this new edition is almost twice thesize of its predecessor”; might possibly refer to wordcount?); contributors (45 vs. 19); and price (£195 vs. £75):hence the greatest proportionate increase, regrettably, is inthe latter.

The opening chapters deal with general issues such asthe definition of dementia, brain anatomy, safety precau-tions, and the practical approach to neuropathologicaldiagnosis. The latter is especially good in tackling thornydiagnostic issues such as mixed pathology, mild patholo-gy appropriate to age, no pathology to account for a clin-ical diagnosis of dementia, and pathology typical of adementia syndrome in the absence of a clinical diagnosis.Chapters devoted to the molecular diagnosis of dementiaand to neuroimaging in Alzheimer’s disease may surprise(could one imagine neuropathology chapters in textbooksdevoted to the neurogenetics or neuroimaging of demen-tia?) but reflect the inclusiveness of the approach to infor-mation gathering taken by neuropathologists whichshould sit well with clinicians.

Of the fifteen chapters dealing with specific clinico-pathological entities, appropriately the longest is devotedto Alzheimer’s disease, approximately one third of whichreviews the pathogenesis of this most prevalent dementiasyndrome (the final chapter on transgenic mouse models

of neurodegenerative disease also addresses this concernwith pathogenesis). However, as clinicians we were disap-pointed to find little on the neuropathological hetero-geneity associated with presenilin mutations (for exam-ple, there is no mention of cotton wool plaques), a situa-tion which contrasts with the chapter discussing thehereditary tauopathies.

It is difficult to think of particular omissions: vasculardementia, prion disease, Parkinson’s disease and dementiawith Lewy bodies, frontotemporal dementias,Huntington’s disease, multiple sclerosis, head injury, alco-hol-related cognitive decline are amongst the topics cov-ered, though from a clinical perspective there is no specif-ic discussion of primary progressive aphasia and semanticdementia. If you are seeking an account of progressivesubcortical gliosis of Neumann the index will not helpyou (try 261; also 168). There are few references datedlater than 2002 which presumably reflects a long gestationperiod. Hence, the E46K α-synuclein mutation is notmentioned (Zarranz et al., Ann. Neurol 2004; 55: 164-73).

Verdict: obviously a must for neuropathologists with aninterest in dementia; highly desirable (if budgets allow)for clinicians with an interest; and a possible for thedepartmental library.

AJ Larner, M Doran,Cognitive Function Clinic, WCNN, Liverpool.

The Neuropathology of Dementia

If you would like to review books for ACNR, please contact Andrew Larner, Book Review Editor, c/o [email protected]

M Esiri, VMY Lee,JQ Trojanowski (eds.)Published by: CambridgeUniversity Press 2004 (2nd edi-tion)Price: £195.00ISBN: 0-521-81915-6

Mark Mumenthaler,Heinrich Mattle with Ethan TaubPublished by: ThiemePrice: EUR 39,95ISBN: 3135239047


Events Diary

To list your event in this diary, e-mail brief details to: [email protected]

2005

JulyMS Professional Network7 July, 2005; Bristol, UKE. [email protected]

Society for Research in Rehabilitation7-8 July, 2005; Southampton, UKE. [email protected]

Conference on NeuropsychologicalRehabilitation11-12 July, 2005; Galway, Irelandwww.conference.ie/Conferences/index.asp?Conference=14

Multidisciplinary Care in Parkinson’s Disease:from science to practice12 July, 2005; London, UKE. [email protected], www.mepltd.co.uk

4th Congress of the International Society forAutonomic Neuroscience 12-16 July, 2005; Marseille, Francewww.atout-org.com/isan2005/

PSIGE Conference 200513-15 July, 2005; Chester, UKE. [email protected]. 0116 252 9555, Fax. 0116 252 7123

12th Meeting of the Neurosonology ResearchGroup of the World Federation of Neurology 13-15 July, 2005; Osaka, Japanwww.congre.co.jp/nsrg/

Bioscience 200517-21 July, 2005; Glasgow, UKwww.BioScience2005.org

Venice Epilepsy Summer School –International School of Neurological Sciencesof Venice International Course:Bridging Basic with Clinical Science-218-27 July 2005; Venice, ItalyE. [email protected]

Prognosis & Life Expectancy in ComplexNeurological Disabilities19 July, 2005; London, UKTel. 0208 780 4500, x 5140,E. [email protected]

6th ASNA Biennial Convention 21-23 July, 2005; Jakarta, Indonesiahttp://asna.perdossi.or.id/

COGSCI 2005: 27th Annual Meeting21-24 July, 2005; Stresa, Italywww.cognitivesciencesociety.org/cogsci.html

Introduction to NeuropsychologicalRehabilitation22 July, 2005; Ely, CambridgeE. [email protected]

AugustClinical Neuropsychology of Social Cognition19 August, 2005; Ely, UKTel. 01353 652173

14th National Neurotrauma Conference 19-21 August, 2005; Kolkata, IndiaContact: Dr GK Prusty Tel. 913 324 654 994 , Fax. 913 324 567 880,E. [email protected]

International Society for NeurochemistryAugust 21-26, 2005; Innsbruck, AustriaE. [email protected] [email protected]

World Congress on Pain21-25 August, 2005; Sydney, AustraliaE. [email protected]

European Conference on Visual Perception22-26 August, 2005; A Coruña, Spainhttp://ecvp2005.neuralcorrelate.com/E. [email protected]

8th Workshop on the Neurobiology of Epilepsy24-26 August, 2005; FranceE. [email protected]

26th International Epilepsy Congress28 August-1st September, 2005; Paris, FranceTel. +353 1 409 7796,E. [email protected]

Measuring Behaviour 2005 30 August - 2 September, 2005; Wageningen,The NetherlandsE. [email protected],www.noldus.com/mb2005

SeptemberChanging Gear: Working with Behaviour - aroad map for progress1-2 September, 2005; London, [email protected],Tel. 020 8748 1965

British Aphasiology Society (BAS)International Conference4-7 September, 2005; University of Essex, UKwww.bas.org.uk/symposia.htm

The Construction of the Social Brain.A seminar with Professor Jordan Grafman 5 September, 2005; Cardiff, UKE. [email protected]

Biomechanics of the Lower Limb in Health,Disease and Rehabilitation5-7 September, 2005; Manchester, UKE. [email protected]

Encephalitis Explored: Assessment,Rehabilitation and Therapies6-7 September, 2005; York, UKTel. 01653 692583, E. [email protected],www.encephalitis.info

Event Processing by the Human PrefrontalCortex. A seminar with Professor JordanGrafman 7 September, 2005; Cardiff, UKE. [email protected]

Joint ABN/SBNS meeting7 - 9 September, 2005; Torquay, UKTel. 020 7405 4060, E. [email protected]

Symposium: Genetics in Modern Medicine9 September, 2005; Edinburgh, UKE. [email protected], Tel. 0131 225 7324.

The Neurorehabilitation of Children andYoung Adults9 September, 2005; Ely, UKwww.easternrehabgroup.org.uk,[email protected]/[email protected]

European Paediatric Neurology Society14-17 September, 2005; Goteborg, SwedenTel. +46-31-708 60 00, Fax. +46-31-708 60 25,E. [email protected]

Behavioural Experiments in the rehabilitationof Acquired Brain Injury16 September, 2005; Ely, UKE. [email protected]

8th Congress of the European Federation ofNeurological Societies17-20 September, 2005; Athens, GreeceTel. 0041 22 908 0488, Fax. 0041 22 732 2850,E. [email protected], www.efns.org/efns2005

World Congress on Huntington’s Disease10-13 September, 2005; Manchester, UKE. [email protected],Fax. 0161 276 6145,www.hda.org.uk/congress/index.html

33rd Annual Meeting of the InternationalSociety for Pediatric Neurosurgery 11-15 September, 2005; Vancouver, BC, Canadawww.venuewest.com/2005/ispn/

Methods in Mind, BPPS Meeting12-16th September, 2005; Aston University, UKwww.hop.man.ac.uk/bpps/,E. [email protected]

fMRI experience VII 15-16 September, 2005 Birmingham, UKwww.fmrixp.com/7

Behaviour Experiments in the NeuroRehabilitation of Acquired Brain Injury16 September, 2005; Ely, UKTel. 01353 652173

9th Congress of the European Federation ofNeurological Societies (EFNS)17-20 September, 2005; Athens, GreeceE. [email protected]

Attention - Advanced Cognitive RehabilitationWorkshop17 September, 2005; Gatwick, UKTel. 01276 472369,E. [email protected]

Treatment of neurological diseases-an evi-dence-based approach. Cochrane NeurologicalNetwork workshop18 September, 2005; Athens, GreeceE. [email protected]

An International Educational Course:Pharmacological Treatment of Epilepsy18-25 September, 2005; Eilat, IsraelE. [email protected],Fax. 97-235-175-155

International Psychogeriatric AssociationAnnual Meeting20-24 September, 2005; Stockholm, SwedenE. [email protected]

78th Congress of the German NeurologicalSociety21-23 September, 2005; Wiesbaden, GermanyFax. +49 7621 78714E. [email protected]

European Brain & Behaviour Society (EBBS)37th Meeting24-28 September, 2005; Dublin, IrelandE. [email protected], www.ebbs-science.org

The second IBRO/FENS Summer School“Development and Plasticity of the HumanCerebral Cortex”24 September-1 October, 2005; CroatiaE. [email protected],http://www.hiim.hr/english/index.html

Scientific Symposium of the Multiple SclerosisInternational Federation (MSIF) and 7th GreekConference25-27 September, 2005; Thessaloniki, GreeceE. [email protected] , Tel. 302 310 250 927.

6th Meeting of the International Society forNeuroImmunoModulation 25-28 September, 2005; Athens, GreeceTel. +30 210 7257693, E. [email protected]

130th Annual Meeting of the AmericanNeurological Association25-28 September, 2005; San Diego, USwww.aneuroa.org/index.html,E. [email protected]

10th International Congress of the WorldMuscle Society28 September-1 October, 2005; Iguassu Falls,Brazilwww.wms2005.com/

34th Annual Meeting of the Child NeurologySociety 28 September-1 October, 2005; Los Angeles, USwww.childneurologysociety.org/events/evt_001.asp

ECTRIMS-ACTRIMS 200528 September-1 October, 2005; Thessaloniki,Greecewww.akm.ch/ectrims2005

The Conversation: MS Professional NetworkConference in Scotland30 September, Stirling, UKE. [email protected], or Tel. 0131 335 4050

OctoberBritish Geriatric Society Autumn Meeting4-7 October, 2005; Harrogate, UKTel. 020 7608 1369

1st Annual Meeting of the International SpineSociety 6-8 October, 2005; London, UKwww.spineinternational.org/iss-meetings.html,E. [email protected],Fax. 32 38 214 532.British Society of Neuroradiologists AnnualMeeting7-8 October, 2005; Edinburgh, UKE. [email protected]

Congress of Neurological Surgeons AnnualMeeting7-12 October, 2005; Boston, USTel. 001 630 323 5144, Fax. 001 630 323 6989,E. [email protected]

The 6th Euroyapmeet - conference forYounger People with Parkinson’s7–9 October, 2005; IrelandE. [email protected]


Conference Report

This year’s national BNA meeting was heldover four days at the beginning of April,in the sunny seaside town of Brighton.

Events took place within the Brighton Centreand adjacent Belgrave Hotel, and were as eclec-tic and exciting as promised. With the largenumber and wide range of plenary lectures,symposia, posters and exhibition stands, therewas barely time to sample the local fish andchips or take a stroll along the famous pier. Theconference was well attended as always, andfilled with the faces of those familiar and thoseyet to be acquainted. It was also noticeable thata number of delegates had previously attendedthe BNA Post-Graduate Symposium inManchester last September, and were nowmeeting again in Brighton; a measurable suc-cess of that particular symposium that its atten-dees were already crossing paths and network-ing less than a year down the line.

The meeting was opened on the afternoon ofSunday 3rd April by the President of the BNA,Richard Fracowiak, and the drinks reception inthe Brighton Centre that followed later thatevening ensured that all delegates felt very wel-come. The scientific programme of events alsobegan on Sunday, with The Wolstencroft Lecturedelivered by Pierre Magistretti from Lausanne.Entitled ‘Cellular Bases of NeurometabolicCoupling and its Relevance for Functional BrainImaging’, his presentation focused on develop-ments in our understanding of the couplingbetween neuronal activity and glucose utilisationby the brain, with particular reference to the‘astrocyte-neuron lactate shuttle’ model.

The theme of neuroimaging remained strongthroughout the meeting and continued on thesecond day, with a symposium exploringadvances in magnetic resonance (MR) method-ology. Speakers in this session gave an informa-tive overview of the progress being made in ourunderstanding and utilisation of MR imaging.David Thomas from the Wellcome Trust HighField MR Research Lab at UCL describedadvances in neuroimaging involving scanningat magnetic fields as high as 4.7 Tesla (conven-tional MR scanners typically operate at 1.5 or3.0 Tesla). His talk explored the pros and consof high field imaging, and the techniques beingdeveloped to improve spatial resolution withimpressive results. The use of array coil imag-ing, discussed by Dr Thomas, was also exam-ined in detail by the second speaker in this ses-sion. Joseph Hajnal from Imperial College gavea comprehensive explanation of the advantagesof using arrays of receiver coils and partiallyparallel imaging, which make use of morelocalised sensitivity and can improve acquisi-tion time and distortion artefacts during imag-ing. He also offered a valuable insight into howthese methods might be developed in thefuture. The next talk was from FernandoCalamante of ICH, who described develop-ments in the specific field of diffusion MRimaging. Diffusion MR, which relies on the dif-fusion properties of water molecules within dif-

ferent structures, is a relatively novel techniquethat allows the visualisation and investigationof fibre tracts within the brain. Also from ICH,Mark Lythgoe then spoke about other ways inwhich our knowledge and use of MR methodsare progressing, with a discussion covering anumber of topics including the use of high-throughput high resolution imaging in animalmodel systems and its applications. Finally,Raman Saggu from the University of Oxfordgave a specific insight into her work examiningthe effects of interleukin-1β on cerebral ener-getics, using MR spectroscopy in a model oflow-flow ischaemia in the rat.

Other symposia on this day covered topicsthat included progress in stem cell biology, sen-sory integration for cognition and action, andthe role of microglia in brain injury. In theafternoon, there was also a symposium tacklingthe important issue of human neuropathologyfor neuroscience research, with speakers fromthe CJD Surveillance Unit at the University ofEdinburgh (James Ironside), the Institute ofNeurology in London (Janice Holton), the UKMultiple Sclerosis Tissue Bank (RichardReynolds) and the University of Nottingham(James Lowe). These valuable talks highlightedthe importance of effective and open commu-nication with the public with regard to the useof human tissue for research purposes, andexplored the crucial matter of new regulationsfollowing The Human Tissue Act of 2004.There were also two plenary lectures on thissecond day of the meeting. In the morning,Peter Seeburg (Heidelberg) discussed the criti-cal properties of AMPA receptors, and their rolein olfaction and spatial memory, with referenceto mouse models. Mechanisms of endocannib-inoid signalling were introduced in the secondplenary lecture, which was given by TamasFreund. In his lecture he presented work fromhis group in Budapest, investigating the impor-tance of CB receptors and exploring potentialtherapeutic targets for the treatment of anxiety.

There were a number of special events on thesecond day of the meeting. The first of these wasa BNA Discussion Group debating currentissues in the teaching of neuroscience. Therewere also a series of short presentations aboutthe Foresight ‘Brain Science, Addiction and

Drugs’ Project. This Foresight Project, as part ofthe Government’s Office of Science andTechnology, has been set up to provide an evi-dence-based review of how science and technol-ogy may impact our understanding of addictionand the use of psychoactive substances. Theproject involves Government science advisors,the Home Office, the Police, drugs charities, thepharmaceutical industry and medical researchorganisations, with the aim that the ethical, legaland economic issues associated with its findingswill be considered (see the Foresight Projectwebsite www.foresight.gov.uk).

On Monday evening, there was another BNADiscussion Group, this time tackling the ever-important issue of Public Awareness of Science.Speakers for this event included BBC ScienceRadio Correspondent Pallab Ghosh, HuseyinMehmet from Imperial College, ScienceCommunicator Myc Riggulsford and ElaineSnell, Science Communicator and ExecutiveOfficer for the European Dana Alliance for theBrain (EDAB; www.edab.net). The event wasorganised in collaboration with EDAB, anorganisation designed to promote brain researchand one which has a very good relationship withthe BNA (indeed EDAB was recently presentedwith an Award for Public Service by the BNA).Following the event, Elaine confirmed that theworkshop had been a real success, and that thissuccess was made measurable by the fact thatseveral of the speakers were approached by dele-gates on separate occasions to discuss the issuesraised. It appears that science communicationremains a critical issue for scientists and themedia alike. Similarly, an example of anothermuch encouraged collaboration, that betweenscience and the arts, was evident in the fascinat-ing images on display in the foyer exhibition‘Thinking Science - Making Art’, a collectionprovided by Lizzie Burns and the MedicalReseach Council, and Catherine Draycott andThe Wellcome Photographic Library.

A brisk walk along the sea-front on Tuesdaymorning was an ideal way to start the third dayof the meeting. Symposia on this day again cov-ered a broad range of issues, from stem cell plas-ticity, to information coding in auditory cortexand neuroinflammation. One of the afternoonsessions was focused on promoting recovery

BNA National Meeting3-6 April, 2005; Brighton, UK

The BNA Committee.


after stroke, and chaired by Cathy Price fromUCL. Speakers in this session included RichardWise from the MRC Clinical Science Centre atthe Hammersmith Hospital, who describedfunctional neuroimaging research demonstrat-ing the converging pathways involved in lan-guage processing in both healthy individuals andaphasic stroke patients. The implications con-cerning targeted behavioural and drug therapiesto rehabilitate patients were discussed. In thesame session, Argye Hillis from Baltimore alsodiscussed mechanisms and stages of languagerecovery after stroke. Professor Paul Matthewsfrom the University of Oxford Centre for fMRIof the Brain explored evidence that commonmechanisms exist in the healthy and injuredbrain, with regard to motor learning and con-trol. He too made the point that future therapiesmay be specifically targeted and manipulated,based on strong biological rationale and infor-mative neuroimaging methods. The sessionended with a presentation from Jean-ClaudeBaron from the University of Cambridge, whogave a complementary overview of researchmapping motor recovery after stroke.

The plenary lecture on the third day of themeeting was delivered by James McCullochfrom the University of Edinburgh, who spokeabout the concern that although a significantinsight into the mechanisms of ischaemic celldeath had been gained in recent years, this suc-cess was yet to be translated into new drug treat-ments. He discussed the obvious importance ofresearch efforts to meet this challenge. On

Tuesday afternoon, there was also the Trends inNeurosciences Lecture, given by Trevor Robbinsfrom The University of Cambridge, and entitled‘Chemistry of the Adaptive Mind’. ProfessorRobbins gave an overview of research, in bothexperimental animals and humans, into theaction of drugs that affect the prefrontal cortexvia ascending neuromodulatory systems, andexplored the implications for our understand-ing and treatment of neuropsychiatric disor-ders. Special events of note on Tuesday were theBNA Annual General Meeting held atlunchtime, and of course the ‘legendary’ BNAConference Banquet and Party in the evening.

Another fairly early start saw the fourth andfinal day begin with the penultimate plenarylecture. Hugh Perry (University ofSouthampton) described work from his groupusing mouse models of prion disease. He pre-sented findings about the interactions betweenbrain inflammation and systemic inflammation,which may contribute to the progression ofchronic neurodegeneration. The final plenarylecture of the meeting, concerning axonalregeneration in the CNS, was delivered by MarieFilbin from New York. She presented researchfrom her lab, which shows that elevation ofcAMP can promote spinal axon regeneration inan otherwise inhibitory environment; an effectthat is transcription-dependent and requires theactivation of the transcription factor CREB.

Throughout the meeting in Brighton therewere a variety of themed poster sessions, whichshould also be mentioned. On the final day, for

example, investigators displayed their work ontopics including genes and behaviour, behav-ioural pharmacology, tumours, pain, cere-brovascular disease, trauma, infection, inflam-mation, gene therapy, neural networks and neu-roimaging, to name but a few. It is obviouslyimpossible to mention them all, but fair to saythat each poster session reflected the high stan-dard and scope of research presented through-out the meeting, which was brought to a closeon Wednesday afternoon leaving enough timefor a visit to the Royal Pavilion before a reflec-tive journey home.

The BNA National Meeting 2005 was sup-ported by GlaxoSmithKline, Eli Lilly, NatureReviews Neuroscience, the Trends Journals, theEuropean Dana Alliance for the Brain, theAssociation of British Neurologists, the BritishNeuropathology Society, the PhysiologicalSociety and the OST Foresight Project.

Helen L Jamison (DPhil Student),Dept. Experimental Psychology & Centre for

fMRI of the Brain (FMRIB),The University of Oxford.

See ACNR 3:5 for an interview with Professor Richard Frackowiak, and ACNR 4:3 for a review article on

The Impact of Systemic Inflammation on Brain Inflammation by Professor Hugh Perry

The second national United in Care conferenceis to be held at the Royal College of Physicianson Wednesday 23rd of November 2005, organ-ised by Medical Education Partnership (MEP)Ltd in association with the British GeriatricsSociety (BGS).

The practice of geriatric medicine involveshealthcare professionals from many differentdisciplines and the BGS is committed to pro-moting multidisciplinary approaches in thefield. The United in Care series of conferencesaim to identify ways in which interdisciplinarycollaboration can be improved among health-care professionals who are providing care forolder people. A highly successful inaugural con-ference was held in London in December 2004.

United in Care 2005 focuses on two importantthemes – End-of-life care and Mental healthissues of medically unwell older people.Speakers include experts who work in theseemotive areas and the programme includes:

• The needs of patients and patient safety –Mary Baker MBE, President of the EuropeanFederation of Neurological Associations andthe European Parkinson’s Disease Association.

• The meaning of futility: a clinical perspective– Dr Edmund Dunstan, ConsultantGeriatrician and Honorary Clinical Lecturer,University of Birmingham.

• Resuscitation in old age: what it means for

patients, their families and healthcare staff –Dr Kevin Stewart, Consultant Physician andMedical Director, Winchester and EastleighHealthcare NHS Trust.

• The role of hospital clinical ethics committees– Dr Jim Eccles, Consultant Geriatrician andChair of the Clinical Ethics Committee, LeedsTeaching Hospitals.

• End-of-life decisions in care homes – DrKatherine Froggatt, Senior Lecturer, Palliativeand End-of-Life Care Research Group, Schoolof Nursing & Midwifery, University ofSheffield.

• Flu immunisation for patients and staff –Professor Margot Gosney, Professor of ElderlyCare Medicine, Reading University.

• Community matrons: holistic care for the21st century – Aileen Fraser, ConsultantNurse, Bristol University Hospitals.

• Mobility, rehabilitation and cognitive impair-ment – Professor Val Pomeroy, Professor ofRehabilitation of Older People, St. George’sHospital Medicine School, London.

• Recognition and management of delirium inacute hospitals –– Dr Duncan Forsyth,Consultant Physician, Addenbrooke’sHospital, Cambridge.

• Who develops delirium and why – Dr DavidAnderson, Consultant Old Age Psychiatrist,Mossley Hill Hospital, Liverpool.

• What makes clinical guidelines work in the

clinical setting? – Professor Martin Eccles,Professor of Clinical Effectiveness and TheWilliam Leach Professor of Primary CareResearch, University of Newcastle upon Tyne.

• How specialist mental health nursing canhelp in general hospital wards – Clare Wai,Liaison Mental Health Nurse, Cambridge andPeterborough Mental Health PartnershipNHS Trust.

A report on the new British Geriatrics Societyguidelines for the recognition and managementof delirium in acute hospitals will also be givenby Dr Jim George, Consultant Physician andClinical Director, Cumberland Infirmary,Carlisle.

Abstracts relevant to the interdisciplinarycare of older people are also invited for posterpresentation. Preliminary results and audit arewelcome.

The programme has been devised to encour-age debate and full participation of all membersof the interdisciplinary team who are involvedin the management and care of older people.

For further information contact: MEP Ltd,53 Hargrave Road, London N19 5SH

Tel: 020 7561 5400Email: [email protected]: www.mepltd.co.uk

Conference Report

CONFERENCE PREVIEW: 2nd National United in Care Conference23rd November, 2005; Royal College of Physicians, Regent’s Park, London.


CDP approval has been granted by the Royal College of Physicians (17 points) and the Eurpoean Accreditation Council for CME (15 points).

www.hda.org.uk/congress


Journal Reviews

ACNR Reviews June 2005

PPARγ agonists for Alzheimer’s Disease?It is well-recognised from epidemiological studies that NSAIDs reducethe risk of developing Alzheimer’s disease (AD). The mechanism of thiseffect is uncertain; the possibility that it is mediated via cyclo-oxygenas-es (COX) must be weighed against the ineffectiveness of selective COX2inhibitors in treating established disease. Activation of the nuclear recep-tor peroxisome proliferation-activated receptor-γ (PPARγ), leading toinhibition of pro-inflammatory gene expression, is another possibility,examined in this paper. APPV717I transgenic mice, which develop amy-loid deposits and glia-mediated inflammatory responses typical of ADaround 10 months of age, were fed with rodent chow supplemented withibuprofen (62.5mg/kg/day) or pioglitazone (40mg/kg/day) for 7 daysbefore sacrifice. The latter is a thiazolidinedione, a highly specific PPARγagonist, used in the treatment of type 2 diabetes (although it had noeffect on blood glucose levels in these animals). Treated animals showed:• reduced number of activated microglia and reactive astrocytes in brain

cortex and hippocampus;• reduced expression of proinflammatory enzymes (COX2 in microglia,

iNOS in astrocytes);• reduced expression at both mRNA and protein level of BACE1, a key

enzyme in the APP processing pathway;• reduced Aβ1-42-immunopositive plaque area and staining intensity;• reduced soluble Aβ1-42 peptide (pioglitazone only).These findings suggest that brief oral treatment with these agents actsrapidly to inhibit inflammatory responses in brain, so modulating amy-loidogenesis. The authors suggest that PPARγ agonists might be exploredin the treatment of AD. Obviously, however, given the clinical experiencewith NSAIDs in AD, there must be misgivings about the efficacy ofPPARγ agonists in clinical practice. - AJLHeneka MT, Sastre M, Dumitrescu-Ozimek L, Hanke A, DewachterI, Kuiperi C, O’Banion K, Klockgether T, Van Leuven F, Landreth GE.Acute treatment with the PPARγ agonist pioglitazone and ibuprofenreduces glial inflammation and Aβ1-42 levels in APPV717I trans-genic mice.BRAIN 2005;128(6):1442-53.

HEAD INJURY: Roids no good Sometimes it takes a huge effort to answer a simple question, in this case doesearly treatment with corticosteroids improve the outcome of head injury?The answer is no. In fact they may make things worse…. Top marks for thetrial acronym, CRASH, which stands for corticosteroid randomisation aftersignificant head injury! In this MRC trial 10,008 adults with head injury anda Glasgow Coma Scale score of 14 or less, within 8 hours of injury, were ran-domised to a 48-h infusion of corticosteroid (methylprednisolone) or place-bo. The follow-up was impressive: at six months they had data from 9,673(96·7%) patients. The risk of severe disability and/or death was higher in thecorticosteroid groups by statistically significant, but rather small, differences.For those who like these things, the stats were: risk of death higher in the cor-ticosteroid group (1,248 [25·7%] vs 1,075 [22·3%]; relative risk 1·15, 95% CI1·07–1·24; p=0·0001); and the risk death or severe disability (1,828 [38·1%]vs 1,728 [36·3%] dead or severely disabled; 1·05, 0·99–1·10; p=0·079).Subgroup analysis by injury severity or time since injury did not reveal anyuseful differences. This is a very useful trial. I wonder if it will have any influ-ence on the use of corticosteroids for spinal cord injury, which seems to beprevalent. Or are we going to have to randomise 10,000 people with that con-dition in the CRASS trial?!? - AJCCRASH trial collaborators.Final results of MRC CRASH, a randomised placebo-controlled trial ofintravenous corticosteroid in adults with head injury-outcomes at 6 months.LANCET2005;365(9475):1957-9.

MOTOR NEURON DISEASE: Interfering with silencers

The identification of genetic causes of neurodegenerative disorders of theCNS has led to the development of therapeutic approaches which attemptto silence the disease causing gene product. This has perhaps been moststudied using small interfering RNA (siRNA), that promote specificendonucleolytic cleavage of the mRNA targets of the mutant gene/protein.Adopting this strategy has proven successful in vitro, although it has proveddifficult to completely silence the relevant element. Nevertheless the prob-lem in vivo is even more problematic, in that there are issues of delivery –how do you get siRNA into all relevant cells with long term silencing? Oneapproach around this has been to use viral vectors, which have a long his-tory in the experimental delivery of therapeutic agents (especially growthfactors) for CNS disorders. The favoured viral vector has changed overtime, but of late much interest has focused on lentiviruses, because of theefficiency with which these viruses can infect neural cells. In this paper,Patrick Aebischer and colleagues explore this approach in vitro and then invivo with the SOD1G93A transgenic mouse model of familial motor neurondisease/amyotrophic lateral sclerosis (ALS). Mutations in Cu/Zn superox-ide dismutase (SOD) have been known for over 10 years to cause rarefamilial forms of ALS, through a proposed toxic gain of function.Transgenic mice containing the mutant form of this gene develop a pro-gressive ALS like illness over about a 6 month period. Using these mice,Aebischer et al show that intraspinal lumbar injection of a lentiviral deliv-ery system for siRNA to SOD1, slows down the onset of disease and its pro-gression in hindlimb muscles and related behaviours. This is an excitingstudy and comes hot on the heels of a study last year using a similarapproach with transgenic SCA mice (see Caplan NJ (2004) NatureMedicine 10:775-776), which gives weight to the validity of this approach.There are though still a number of unresolved issues, including the mostappropriate target of the siRNA as many neurogenetic diseases have multi-ple causative mutations. In addition, issues of delivery are still very real. Inthis study only lumbar regions were injected, although in the case of ALSone could argue for targeted delivery as there are clearly some motorneu-ronal pools that are more important than others (such as those innervatingthe bulbar/respiratory musculature). Nevertheless this work once moreshows how far we have come in the treatment of neurological disordersthrough studies of rare genetic causes of common neurodegenerative dis-eases of the CNS - RAB.Raoul C, Abbas-Terki T, Bensadoun JC, Guillot S, Haase G, Szulc J,Henderson CE, Aebischer P.Lentiviral-mediated silencing of SOD1 through RNA interference retardsdisease onset and progression in a mouse model of ALS.NATURE MEDICINE 2005;11:423-8.

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EDITOR’S CHOICE

Panel of Reviewers

Roger Barker Honorary Consultant in Neurology, Cambridge Centre of Brain Repair

Richard Body Lecturer, Department of Human Communication Sciences, University of Sheffield

Alasdair Coles Lecturer, Cambridge UniversityRhys Davis Research Registrar, Addenbrooke’s Hospital,

CambridgeDan Healy Neurology SPR, National Hospital,

Queens Square, LondonDavid Lythgoe Centre for neuroimaging sciences,

Institute of Psychiatry, LondonMark Manford Consultant Neurologist, Addenbrooke's Hospital,

Cambridge, and Bedford HospitalAndrew Michell Neurology Research Registrar,

Addenbrooke’s Hospital, CambridgeWendy Phillips Research Registrar, Addenbrooke’s Hospital,

CambridgeRobert Redfern Consultant Neurosurgeon,

Morriston Hospital, Swansea.Liza Sutton UCL PhD Student, Institute of NeurologySarah J Tabrizi DoH Clinician Scientist and Clinical Senior

Lecturer, Institute of NeurologyAilie Turton Research Fellow, Burden Neurological Institute,

Bristol

Would you like to join ACNR's reviewer's panel and submit reviews to our popular journal reviews section?

For more information, Email [email protected] or telephone 0131 477 2335.


Journal Reviews

THE TEMPORAL LOBE: Musical OfferingThis paper in Brain takes as its topic the basis of scary music. This is an inter-esting topic as all film goers will testify…after all if you watch the predatorygiant shark in Jaws about to attack without the music (as was once shown onNationwide several decades ago!!), then the dramatic impact is greatlydiminished. So how does music do this - where in the brain could musicmediate such an effect? One obvious target would be the amygdala, given itsclose association with fearful stimuli – both experimentally in animals and inthe clinic. In this study, 16 right handed patients with either a right OR leftmedial temporal lobectomy were studied using an emotional recognitiontask involving instrumental music. The patients had all had surgery forintractable temporal lobe epilepsy, of non-tumour origin. This music wascategorised into fearful, peaceful, happy or sad and the subjects had to scorethese emotional impressions out of 10 – similar in many ways to the facialgrading tests of emotion. Each subject was tested with 56 stimuli and carefulattention was paid to ensure that any deficits were specific for the emotionalcontent of the music. Interestingly, the study showed a relatively selectivedeficit in the recognition of scary music, with the other musical emotionsbeing unaffected, irrespective of whether the patient had had a right or lefttemporal lobe resection. The authors therefore conclude that “These findingssuggest that the anteromedial temporal lobe (including the amygdala) playsa role in the recognition of danger in a musical context”. Although no evi-dence can be provided that the amygdala really is the source of this aspect ofmusical emotional processing, it would nevertheless seem the most likelycandidate given its known role in the processing of fearful stimuli throughother sensory modalities. Thus once more emphasising that structuresinvolved in these forms of high level sensory processing, do so for a specificemotion but independently of the exact mode of sensory stimulation….Nowwho has turned the sound down on my television and what is all the fussabout that man stabbing at the shower curtain. - RABGosselin N, Peretz I, Noulhiane M, Hasboun D, Beckett C, Baulac M,Samson S.Impaired recognition of scary music following unilateral temporal loberesection.BRAIN 2005;128: 628-640.

AMYGDALA: Look into my eyes… and be fearful

SM, a 38-year-old woman, has selective lesions of the amygdala bilaterally.She had previously been shown to lack normal fear responses and her inter-personal conduct is indiscriminately trusting and friendly. The experimentalparadigm here consisted of a remarkable 3000 presentations of faces express-ing either happiness or fear. However, only a small area (a random ‘bubble’)of any face was visible at each presentation, the remainder being obscured. Incomparison with controls, SM required more bubbles to identify facialexpressions reliably. Regression analysis of bubble locations contributing tofear recognition showed, in controls, the eye region to be most critical. Bycontrast, only bubbles around the mouth region seemed to influence SM’sresponses. Gaze monitoring, furthermore, found that SM consistently failedto fixate on the eyes of presented faces. Curiously, on the control task ofdeciding the sex of presented faces, not only did SM perform within the nor-mal range but her visual scanning of the presented images was also normal.The implication is that perception links into emotional processes and ordi-nary object recognition in different ways. Most strikingly, when SM wasinstructed specifically to look at the eyes of the presented faces she attainednormal fear recognition. This elegant case study therefore suggests that theamygdala engages in emotion recognition by influencing visual fixation andperception. The theory is both novel and intuitively plausible, given the prox-imity of the amygdala to multimodal sensory association cortices in the ante-rior temporal lobe and the increasing appreciation that perceptual processesmerge seamlessly with other neural functions as disparate as memory andmovement. Although the single instruction to SM that she should ‘look at theeyes’ failed to resolve permanently her impaired emotion recognition, thepossibility is raised of rehabilitating patients with similar behavioural prob-lems. As well as occasional patients with focal lesions, this might includepatients with neurodegenerative disease and those with autistic-spectrumdisorders. - RDAdolphs R, Gosselin F, Buchanan TW, Tranel D, Schyns P, Damasio AR.A mechanism for impaired fear recognition after amygdala damage.NATURE2005;433(7021):68-72.

NEURODEGENERATION: antibiotics are the answerUnlocking the full potential of existing pharmaceutical agents, given theenormous expense of developing new compounds, seems an ever moreattractive proposition. Such endeavors encompass drugs for which years ofinvestment and favourable initial safety studies ended with disappointingefficacy trials, as well as drugs listed in current formularies perhaps withunsuspected virtues. This paper describes a series of experiments wherebybeta-lactam antibiotics show promise in the context of glutamate excitotox-ity, a pathogenetic mechanism implicated in several neurological diseases,including motor neuron disease. The foundation of the study was a screen ofover 1000 currently licensed drugs that involved immunoblotting GLT1 (thereceptor responsible for glutamate reuptake) on rat spinal cord slices exposedto one of the myriad drugs. Beta-lactam agents as a group were found toincrease expression of GLT1 and this led to further experiments focusingspecifically on ceftriaxone. In doses similar to those achieved during treat-ment of infectious diseases, ceftriaxone activated the human GLT1 promoterin cell culture and, in vivo, induced long-lasting increases in rat brain GLT1expression. Neuroprotective properties were shown both in cultured neuronsand in neural tissue preparations. Crucially, administration of ceftriaxone ina mouse model of motor neuron disease delayed the onset of clinical signsand prolonged survival. The initiative of Rothstein and colleagues is espe-cially welcome given the various factors that conspire to limit pharmaceuti-cal investment in neurodegenerative diseases generally. It is to be hoped thattheir specific findings will be substantiated by further work. – RDRothstein JD, Patel S, Regan MR, Haenggeli C, Huang YH, Bergles DE, JinL, Dykes Hoberg M, Vidensky S, Chung DS, Toan SV, Bruijn LI, Su ZZ,Gupta P, Fisher PB.Beta-lactam antibiotics offer neuroprotection by increasing glutamatetransporter expression.NATURE2005;433(7021):73-7.

DEMENTIA: Painkillers kill neurons

Traditional pain medication has been associated with protection fromAlzheimer’s disease. However, a recent study by Kukar and colleagues, pub-lished in Nature Medicine, suggests that non-steroidal anti-inflammatorydrugs (NSAIDs) may in fact be detrimental to Alzheimer’s disease. Severallines of evidence have indicated that NSAIDs would be useful in treatingAlzheimer’s disease. First, epidemiological studies suggest that long-termNSAID therapy reduces the risk of developing Alzheimer’s disease. Second,inflammatory processes are activated in Alzheimer’s disease. Third, Kukarhas previously shown that NSAIDs are able to lower Aβ42 production. Aβ42is a neurotoxic peptide that readily aggregates into fibrils and deposits asplaques in Alzheimer’s disease brain. It is believed to be the initiating mole-cule in the pathogenesis of Alzheimer’s disease. The initial aim of this cell-based screen was to identify NSAID-like compounds that reduced Aβ42 pro-duction but had little effect on the COX enzymes. COX enzymes are the tar-gets of NSAIDs, which convert arachidonic acid to prostaglandin H2 in thefirst step of prostanoid production. There are two classes, COX-1, which isconstitutively expressed and COX-2, which is expressed only during inflam-mation and is responsible for the production of pro-inflammatoryprostanoids. Due to its constitutive expression, inhibitors of the COX-1enzyme are associated with detrimental side-effects. The results of Kukar’sscreen of hundreds of NSAIDS and their analogues were both surprising anddisappointing. Just a single compound was identified that lowered Aβ42 pro-duction and lacked COX activity. Numerous compounds, principally theCOX-2 selective NSAIDs, were found to promote Aβ42 production in vitroand in vivo. Three-day oral treatment of mice with the COX-2 inhibitor, cele-coxib, raised Aβ42 production 2-fold. Alzheimer’s disease-causing mutationsin presenilin-1 and presenilin-2 and in amyloid precursor protein (APP) onlyincrease Aβ42 production by 30-100%. Despite the curious associationbetween COX-2 selectivity of NSAIDs and propensity for Aβ42-raising, theeffect was independent of COX-2 binding. Like the Aβ42-lowering NSAIDs,these compounds were shown to target the γ-secretase complex, whichcleaves APP to generate Aβ42. It is proposed that these compounds alter APPcleavage via allosteric modulation of the enzyme complex. The authors arewary of extrapolating their findings to humans because the concentrations ofthe Aβ42-raising compounds in vitro were higher than those found inhumans. The concentrations in mice were more similar to those found inhumans but pharmacokinetic differences between the species must be takeninto account. The main implication of the study is that exogenous com-

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significant improvement on the currently available disease modifying ther-apies for multiple sclerosis, which offer at best a third reduction in relapserate.

However, in early March 2005, Biogen stopped distributing natalizumab.A fatal case of PML was diagnosed in a patient treated with the drug in com-bination with interferon-beta-1a. The pathology of this case has now beenpublished. After three years of seemingly characteristic (if oligoclonal bandnegative) multiple sclerosis, and two years’ treatment with interferon-beta-1a, she was entered into the SENTINEL study. Thirty months later she haddeveloped new neurology, including a “decreased fund of information”(how ever did that nonsense get past the editors?) Three months later shewas dead, after a clinical typical course for PML. For some reason, a MRIscan done seven months before the first PML symptoms was “not available”and the report was insufficiently clear to tell if there were pre-symptomaticPML lesions. The pathology of her case is scary: nearly every tissue sectionfrom both cerebral hemispheres had either macroscopic or microscopicPML lesions!

The second multiple sclerosis patient is the most instructive. He devel-oped the first symptoms of PML 25 months after starting natalizumab. But,actually, a MRI scan the preceding month showed an odd lesion that - in ret-rospect - was the first sign of PML. The reason this is important is that thereis a hint in this report that PML may not have the awful prognosis we allassume. The patient continued to deteriorate for three months after natal-izumab was stopped. However, after that point, JC virus was no longerdetectable in his blood. And his MRI lesions became enhancing, suggestingan inflammatory response (similar to the “immune reconstitution syn-drome” seen in HIV patients with PML). This is not always a good thing:patients can deteriorate during this phase of the illness. However it doesmean the blood-brain-barrier is breached and this can allow access to thebrain for cytarabine. This is the only drug which kills JC virus in vitro,unlike cidofovir which is sometimes used in this condition. At all events, thispatient received cytarabine and his condition improved somewhat. Heremains very disabled... but he is alive and has survived PML which is nomean feat.

News of these two cases came to the attention of a Belgian group, who hadlooked after a man with Crohn’s disease who had taken part in a trial ofnatalizumab for inflammatory bowel disease. 16 months after starting natal-izumab, he presented to hospital with confusion and several large non-enhancing white matter lesions on a MRI scan. He deteriorated and died. Atthe time, he was thought to have an astrocytoma. But, when his pathologywas re-examined, it was more compatible with PML. Furthermore, hisserum contained measured JC virus DNA from 12 months onwards aftertreatment. An important point is that PML had not appeared at any timeduring his previous treatment with azathioprine or infliximab.

So what have we learnt about PML, the demyelinating central nervoussystem infection by the “JC virus”? 50-80% of the population are seroposi-tive for JC. It is believed that the virus itself remains latent in the kidneysand the lymphoid organs. We associate its reactivation normally with dev-astating immune damage, particularly HIV infection. We now know thatthis need not be the case: natalizumab has - until all of this - seemed arather benign drug, certainly no less toxic than azathioprine or infliximab.It seems that we are all poised to get PML.. and only prevented from it bythe quiet continuous trafficking of T lymphocytes through the brain. As theNEJM editorial puts it: “bad things may happen when rescuers are turnedback at the gates”.

And is this the end of natalizumab treatment of multiple sclerosis? Thedata, such as we have, suggests that it may be more efficacious than the cur-rent licensed drugs. First we need to know the risk of PML after natalizum-ab. Biogen are currently re-examining and imaging all 3000 pts who havereceived natalizumab for any condition. Then we need to ask if that risk isworth the benefit? Difficult decisions. - AJCVan Assche G, Van Ranst M, Sciot R, Dubois B, Vermeire S, Noman M,Verbeeck J, Geboes K, Robberecht W, Rutgeerts P.Progressive Multifocal Leukoencephalopathy after Natalizumab Therapy forCrohn’s Disease.NEW ENGLAND JOURNAL OF MEDICINE2005;Jun 9; [Epub ahead of print].Kleinschmidt-Demasters BK, Tyler KL.Progressive Multifocal Leukoencephalopathy Complicating Treatment withNatalizumab and Interferon Beta-1a for Multiple Sclerosis.NEW ENGLAND JOURNAL OF MEDICINE2005;Jun 9; [Epub ahead of print].Langer-Gould A, Atlas SW, Bollen AW, Pelletier D.

pounds or even alterations of endogenous isoprenoids could increase Aβ42production and in this way represent a novel risk factor for Alzheimer’s dis-ease development. Greater understanding of the mode of action of these γ-secretase modulators may aid in the design of new inhibitors of Aβ42 pro-duction and improve Alzheimer’s disease therapy. It still remains unclear if thebeneficial effects of NSAIDs on inflammation in Alzheimer’s disease outweighthe harmful effects. - LMS & SJTKukar T, Murphy MP, Eriksen JL, Sagi SA, Weggen S, Smith TE, Ladd T,Khan MA, Kache R, Beard J, Dodson M, Merit S, Ozols VV, Anastasiadis, DasP, Fauq A, Koo EH, Golde TE.Diverse compounds mimic Alzheimer disease-causing mutations by aug-menting Aβ42 production.NATURE MEDICINE2005;11(5):545-50.

PAIN: rTMS can provide long lasting relief fromneuropathic painElectrical stimulation of motor cortex using surgically implanted electrodesprovides pain relief for some but not all people with medication resistant neu-rogenic pain. The implantation surgery is expensive and there has been noway of determining which patients could benefit from the treatment. Recentlya non-invasive method of cortical stimulation using rapid rate TranscranialMagnetic stimulation (rTMS) has been shown to provide transient pain reliefin some patients suffering from neurogenic pain. Now a paper in JNNPreports that a course of rTMS over five days can result in prolonged and sig-nificant pain relief. This raises the possibility that response to treatment withrTMS could be a useful and inexpensive predictor of the effectiveness of directmotor cortex stimulation. In a randomised controlled trial of 48 patientsKhedr et al compared rTMS treatment with sham rTMS. Twenty-four of thepatients had trigeminal neuralgia and 24 had post stroke pain mostly affect-ing face upper limb and trunk. Fourteen patients with each diagnosis weretreated with 10 minutes of real TMS over the hand area of motor cortex (20Hz, 10 x 10s trains with stimulator intensity at 80% of motor threshold). Thestimulation was given every day for five consecutive days. The control groupreceived sham stimulation of the same duration. Pain was assessed with theLeeds Assessment of Neuropathic Symptoms and Signs and by VisualAnalogue Scale. Compared with the sham treated group, the group treatedwith real rTMS showed a statistically significant and clinically meaningfulreduction in pain. The effect appeared to be cumulative over the first four daysand lasted at least until the final assessment at two weeks after the last treat-ment session. Distributions of rating scores among the patients showed thatnot all patients with either diagnosis responded to the real rTMS. In additionto the promise of rTMS as a predictor of which patients might benefit fromimplanted electrodes, the results of this study show that stimulating over thehand area of motor cortex can reduce pain in the face as well as the upperlimb; presumably because of spread of the effects to adjacent cortical repre-sentations. Since it is easy to determine the stimulation intensity needed fromthe motor threshold of small hand muscles, this means that in future patientson the waiting list for motor cortex implanted electrodes and those who donot want to undergo surgery could be offered courses of rTMS in the clinic. -AJTKhedr EM, Kotb H, Kamel NF, Ahmed MA, Sadek R, Rothwell JC.Long lasting antalgic effects of daily sessions of repetitive transcranial mag-netic stimulation in central and peripheral neuropathic pain.JOURNAL NEUROLOGY, NEUROSURGERY & PSYCHIATRY2005;76:833-8.

MULTIPLE SCLEROSIS: Bad things may happen whenrescuers are turned back at the gates

So, at last, we have some published data on the much-discussed complica-tion of progressive multifocal leucoencephalopathy (PML) with the newdrug, natalizumab (Antegren or Tysabri). Amazingly, and surely wrongly,this drug was licensed as a treatment for relapsing remitting MS on the basisof an interim analysis of two phase III trials, which have yet to be published:AFFIRM (natalizumab alone) and SENTINEL (natalizumab in combinationwith interferon-beta-1a). Natalizumab is a monoclonal antibody that bindsto the α4-integrins on lymphocytes and prevents their entry to gut andbrain. Press releases from the manufacturers of natalizumab, Biogen, hadclaimed that, in the recent two-year results from the AFFIRM trial, natal-izumab reduced relapse rate by 67% and reduced progression of disabilityby 42% compared to placebo over two years. These results represent a very

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Journal ReviewsJournal Reviews


Progressive Multifocal Leukoencephalopathy in a Patient Treated withNatalizumab.NEW ENGLAND JOURNAL OF MEDICINE2005;Jun 9; [Epub ahead of print].

EPILEPSY: Neuropsychiatric porphyria in patients withrefractory epilepsy: report of three cases“Would I have thought of it?” is the question that I always ask myself when Isee reports like this. The first patient was a twenty year-old woman whodeveloped tonic clonic seizures at the age of 12. She then developed recurrentbouts of abdominal pain and vomiting – phew, a smart handle I could prob-ably spot! Epilepsy deteriorated with drop attacks and she developed dis-turbed sleep, weight loss and constipation and was found to have elevatedurinary δ-aminolaevulinic acid and a metabolic defect in the hydroxymethyl-bilane synthase gene. She was treated with haem arginate and antiepilepticdrugs were changed to gabapentin and clonazepam on which she has oneseizure per year. The second patient was 40 with a 3 year history of refracto-ry epilepsy and hyponatraemia around 119 mmol/L (I didn’t know that). Shehad an episode of limb shaking during an EEG thought to be non-epileptic(oh dear, I’m in trouble!). She suffered with recurrent low back and leftinguinal pain and constipation (no, I still wouldn’t have got it). She had noc-turia with dark, foul smelling urine and paraesthesiae in both hands and men-tioned that she was sensitive to sunlight with occasional rashes (at last, per-haps the penny would have dropped, but I guess these were sought rather thanvolunteered). Urinary δ-aminolaevulinic acid was raised along with total fae-cal porphobilinogens and a mutation of protoporphyrinogen oxidase oxidasewas found confirming a diagnosis of variegate porphyria. Phenytoin waschanged to lamotrigine and seizures reduced to 2 per year, along withimprovements in her biochemistry. The third case was a 27 year-old womanwith an 18 year history of refractory epilepsy. She had had 3 tonic-clonicseizures at the onset but subsequent attacks were of shooting of pins and nee-dles through her body, sometimes with shaking or weakness of the right sidefor a few seconds without loss of consciousness (this is looking tricky!).Telemetry showed epileptiform discharges during the attacks (that’s better).She then developed tonic falls thought to be non-epileptic (Oh no, notagain!). A wide variety of AED’s was tried and finally she was started on top-iramate with her carbamazepine. Four months later she was found collapsedon the ground and required intensive care. Standard investigations yielded nocause but her EEG showed a metabolic encephalopathy and then urine wasnoted to be dark (Bingo, but too late!). She had elevated urinary δ-aminolae-vulinic acid and faecal protoporphyrin with a mutation in the protopor-phyrinogen synthase gene. She was treated with haem arginate and medica-tion was changed to gabapentin plus clobabzam and then her seizuresdeclined but she was left with a severe spastic quadriparesis, and dysarthriawith preserved cognition. So, the important lessons are that refractory epilep-sy can be the presentation and other features may only emerge years later.Seizures can be odd and may be mistaken for non-epileptic attacks. Severeconstipation and hyponatraemia as well as abdominal pain should ring alarmbells and the colour of the urine needs to be asked for. How much porphyriaare we missing? I confess I have never diagnosed a case. - MRAMWinkler AS, Peters TJ and Elwes RDC.Neuropsychiatric porphyria in patients with refractory epilepsy: report ofthree cases.JNNP 2005;76:380-3.

EPILEPSY: Removal of epileptogenic sequences fromvideo material. The role of colour565 children had a fit whilst watching Pokémon on Japanese TV in one show-ing in the 1990’s. Personally, having endured my son watching Pokémonvideos and swapping Pokémon cards, I can understand this as a valid criticalresponse. However, the Japanese medical community felt it was pathologicaland worthy of investigation. The authors of this paper assessed whether spe-cific components of the broadcast could be modified to alter the EEGresponse to transmission rather than my favoured but less scientific approachof chucking a brick at the telly. (Fuddy-duddies of the world unite!) In thistransmission, a particular property of colour modulation, especially flickertransitions between red and blue were critical in generating seizures, a prop-erty termed chromatosensitivity. The authors took 25 patients with clear pho-tosensitive epilepsy and measured the range of frequencies of flash to whichthey were photosensitive. The most epileptogenic sequence was embedded in12 seconds of cartoon. Different colours were altered separately to reduce thecolour modulation, with as little effect on the cartoon content as possible.

Because the sequence was digitised at 25Hz, only a flicker frequency of 12.5Hzwas assessed in the experiments. The cartoon was then played back on 50Hzand 100Hz televisions. and the maximal epileptogenic properties of thesequence, involving alternating red-blue flicker were suppressed. Twenty-three patients were sensitive to the Pokémon video and one of the others wascolour-blind (deuteranope). One man taking valproate was not sensitive tostandard flashes did show EEG changes to Pokémon. The responses of the 23patients sensitive to the original cartoon were compared to the responses tothe modified cartoon. The number of grade 4 photoparoxysmal responses(the worst grade) was 56% on the 50Hz TV and 41% on the 100Hz TV, reduc-ing to 17% on the 50Hz and 4% on the 100Hz TV. A 100Hz TV may reducethe epileptogenic properties of mains flicker but will not protect against theepileptogenic effects of the most potent colour switching components of acartoon. Cartoonists may need to take the colour composition into accountin planning their cartoons but nothing works better than a brick. – MMParra J, Kalitzin SN, Stroink H, Dekker E, de Wit C, Lopes da Silva FH.Removal of epileptogenic sequences from video material. The role of colour.NEUROLOGY 2005;64:787-91.

EPILEPSY: Neuropsychological effects of exposure toanticonvulsant medication in uteroThe authors contacted 547 women attending epilepsy clinics, of whom 219agreed to participate in the study and 163 women had 256 children betweenthe ages of 6 and 16. Of these, 249 underwent neuropsychometric assessment.Factors associated with a lower IQ were maternal IQ, exposure to valproateand more than 5 maternal seizures during pregnancy. Valproate was the onlydrug to show differences compared to children of women not exposed toAED. Verbal IQ of the 41 children born to mothers taking valproate was84(77-89) compared to 94(90-99) for the 52 children born to women takingcarbamazepine. Of valproate children 22% had VIQ<69 compared to 4-6%in the other groups. Polytherapy had no effect in this study, unless it includ-ed valproate, which differs from other studies. The results add to the authors’previous findings in a younger cohort also with a selective verbal IQ deficitattributable to valproate - making this trend increasingly worrying to those ofus who regularly find that valproate is the only drug that works for somewomen. Apparently testosterone has selective effects on right and left hemi-sphere development; enhancing right and inhibiting the left. Valproate-induced rises in testosterone levels could in theory cause differential develop-mental effects through this mechanism. - MRAMVinten J, Adnab N, Kini U, Gorry J, Gregg J, Baker GA for the Liverpool andManchester Neurodevelopment Study Group.Neuropsychological effects of exposure to anticonvulsant medication inutero.NEUROLOGY 2005;64:949-54.

EPILEPSY: More tea vicar?Ginseng contains a variety of ginsenosides, in the leaves, stems and roots. Theproportion of the different types varies between plants; American ginseng(Panax quiquefolius) has a lower Rg1/Rb1 ratio than Asian ginseng (Panaxginseng). Rg1 is said to have excitatory properties and Rb1 inhibitory proper-ties so in theory American ginseng is more likely to have antiepileptic effects.A variety of concentrated ginsenosides, with differing concentrations of keycomponents such as an extract of Rb1, were given to rats before havingseizures induced by pilocarpine, kainic acid or pentylenetetrazole (PTZ). TheRb1 extract was given in different doses. The latency to seizure onset was pro-longed and seizure duration shortened in PTZ preparations by Rb1 in a dose-dependent manner. Mortality of the animals was reduced from around 30%to zero at higher doses of Rb1 and other ginsenosides also had a beneficialeffect. Dose dependent changes were also seen with Rb1 in kainate prepara-tions. In the pilocarpine animals Rb preparations improved various parame-ters. There was a dramatic reduction in heat-shock protein expression intreated animals, a measure of brain stress. Mortality was increased by unse-lected extracts of roots or leaves from American ginseng, when compared withcontrol untreated animals. These have a lower proportion of Rb ginsenoside.So when the vicar comes to tea, find out what sort of epilepsy he has beforeyou offer the ginseng. - MRAMXiao-Yuan Lian, Zhi-Zhen Zhang and Janet L Stringer.Anticonvulsant activity of ginseng in seizures induced by chemical convul-sants.EPILEPSIA 2005;46:15-22.

Journal Reviews


Market Researchers make Increasing use of Brain ImagingAlthough it is now more than thirty years since EEG wasfirst used to evaluate viewer responses to television com-mercials1 and a decade since the introduction of fMRI, itis only in the past eighteen months or so that one hasstarted to hear the unmistakeable rumble of anapproaching band wagon! The name of that bandwagonis Neuromarketing.

Hailed by some leading market researchers as the mostimportant advance in their industry for a century it hasalso been dismissed by sceptical neuroscientists as verg-ing on a pseudo-scientific scam. A recent editorial inNature Neuroscience, for example, suggested that manycognitive scientists who had watched colleagues in mole-cular science grow rich were now ‘jumping on the com-mercial bandwagon,’ adding that, “According to this view,neuromarketing is little more than a new fad, exploitedby scientists and marketing consultants to blind corpo-rate clients with science.” *

That interest in Neuromarketing is growing rapidly isbeyond doubt. A recent edition of the trade publicationAdmap (May 2005) gave over almost an entire issue tothe subject, the Market Research Society’s conference ear-lier in the year devoted a substantial section to the topicwhile the ESOMAR Congress, a world association ofresearch professionals, due to be held in Cannes thisSeptember, is presenting several key-note papers on thesubject. It has been reported that eight new fMRI facili-ties, intended for Neuromarketing rather than medicalpurposes, have opened over the past twelve months in theUnited States.

While the first use of fMRI as a marketing tool wasreported by Gerry Zaltman of Harvard towards the endof the 1990’s2 the term ‘Neuromarketing’ was only coinedby Professor Ale Smidts in 2002 and it was not until 2004that the first ever Neuromarketing conference was held atBaylor College of Medicine in Houston.

Of the three brain-imaging techniques currently usedin Neuromarketing - fMRI (Functional magnetic reso-

nance imaging), QEEG (Quantitative electroencephalog-raphy) and MEG (magnetoencephalography) - it is fMRIwhich has captured the greatest interest among marketresearchers and enjoyed the widest publicity in the gener-al and marketing trade press.

The piece of research most frequently cited in this con-text concerns the use of fMRI to investigate the impact ofbrand perception on consumer taste preferences conduct-ed at the above mentioned Baylor College of Medicine. Inthis study researchers repeated the famous Pepsi/Coca-Cola blind taste test challenge while scanning the brains ofvolunteers. When ignorant of which beverage they weresampling, the subjects favoured Pepsi with their scansrevealing activation of the ventromedial prefrontal cortex(a reward centre). When aware of which brand they tast-ed, however, the scans revealed activity in the hippocam-pus, midbrain and dorsolateral prefrontal cortex - areasassociated with memory, emotions and emotional infor-mation processing. This led the researchers to concludethat a preference for Coke is more influenced by the brandimage than by the taste itself.3

Other studies have used brain-imaging to evaluatevideo clips and TV advertisements, study decision makingamong shoppers and even to investigate the likely impactof political advertising during the recent presidential elec-tion. An unpublished study at the University of California,Los Angeles, for example reported differences in the neur-al responses of Democrats and Republicans to commer-cials depicting the 9/11 terrorist attacks.

MEG has also been used for Neuromarketing purpos-es, albeit to a far lesser extent. In one study, it was used tomeasure decision making among consumers in a ‘virtual’supermarket. The authors reported that the right parietalcortex became active only when faced with a preferredbrand and concluded that this region was involved inmaking conscious decisions about shopping choices, and,perhaps, for “more important life choices too.”4

When it comes to QEEG, we must declare an interestsince we are both directors of Neuroco, a newly formedcompany specialising in the application of this technolo-gy for commercial purposes. Among the numerous pro-jects for which we have used QEEG over the past twelvemonths were; analysing the responses of viewers to tele-vision commercials and other forms of advertising,exploring the effects of looking at happy or sad facialexpressions, exploring the mental states of motorists dri-

David Lewis, BSc(Hons) D.Philhas been working in the field ofQEEG since the late 80’s, follow-ing an interest which began whenhe was in the Department ofExperimental Psychology at theUniversity of Sussex. He is cur-rently research and developmentdirector of Neuroco, a recentlyestablished Neuromarketing re-search consultancy. He is co-author (with Darren Bridger) ofThe Soul of the New Consumer:Authenticity – What We Buy andWhy in the New Economy.

Darren Bridger BSc(Hon) is asso-ciate director of Neuromarketingat Neuroco.

Special Feature

Subject wearing electro-cap behind the wheel of her car during a study of brain activity and driver stress.

* Brain Scam? NatureNeuroscience Vol.7. No. 7. July2004, page 683.

Subject wired and carrying a Track-it ambulatory EEG in Lakesideshopping centre, Essex.

Copyright QBO Bell Pottinger

Copyright Steven Matthews

ving against a deadline and examining how people reactto an unexpected ‘freebie’.

We believe that QEEG rather than fMRI or MEG ismost likely to emerge as the technology of choice inNeuromarketing, since it is simpler and less expensive touse and enables recordings to be made in a wide range ofnatural environments.

Although spatial resolution is poor, it is capable of pro-ducing a continuous record of ongoing neuronal activity.Furthermore it is backed by more than 2,500 researchpapers published in peer reviewed journals going backmore than two decades.5,6,7,8

Clearly there are many pitfalls awaiting those who failfully to appreciate the inevitable limitations of all brainimaging technologies when used for market research ratherthan medical diagnosis. Tempted by unscrupulous ‘special-ists’ who dangle before them the tantalising prospect ofbeing able to ‘read’ the mind of consumers, even cynicaladvertising and marketing executives may be persuaded topart with large sums of money to little or no great purpose.This seems especially likely to happen where fMRI is usedsince, in our experience, non-professionals tend to be over-ly impressed by the images it produces and all too likely toconfuse correlation with causation.

In our view QEEG, when used in conjunction with otherqualitative research methods, can provide insights into con-sumer choices which would not otherwise come to light. Insome instances it may be that these cannot be articulated,no matter how skilled the interviewer or how co-operativethe subject, because they operate below the level of con-scious awareness. In other cases the very act of acquiringinformation may interfere with the cognitions researchersare attempting to measure. This happens when, for exam-ple, people are instructed to move a so called ‘interest’ leverto indicate which parts of the screen has caught their atten-

tion while watching TV commercials.The use of brain-imaging will never enable marketing

professionals to discover that Holy Grail of marketresearch, a ‘buy button’ - some mythical region of thebrain which need only be stimulated to compel con-sumers to purchase a product whether or not they actu-ally want to do so! It will never be found because, ofcourse, it does not exist!

More realistically, we believe, Neuromarketing offersthe prospect of gaining a better understanding of how thebrain responds in a wide variety of everyday situations. Inaddition to proving of great commercial value suchresearch offers the possibility of increasing our knowl-edge of brain function among a non-clinical populationas it extends powerful medical technologies into a newand challenging area of research.

References1. Krugman HE. Brain wave measures of media involvement. Journal of

Advertising Research, 1971;11:3-10.2. Addison T. More science: more sense or nonsense? Ad-Map, May, Issue

2005;461:24.3. McClure SM et al. Neural Correlates of Behavioral Preference for

Culturally Familiar Drinks. Neuron 2004;44(2):379–87.4. Brautigam S et al. Magnetoencephalographic signals identify stages in

real life decision processes. Neural Plasticity 2001;8:241-53.5. Rothschild M et al. EEG activity and the processing of television com-

mercials. Communication Research 1986;13(2):182-220.6. Rothschild M and Hyun YJ. Predicting memory for components of TV

commercials from EEG. Journal of consumer research1990;16(4):472-8.

7. Smith ME and Gevins A. Attention and brain activity while watchingtelevision: components of viewer engagement. Media Psychology2004;Vol6:285-305.

8. Coan JA and Allen JJB. Frontal EEG asymmetry as a moderator andmediator of emotion. Biological Psychology 2004;67:7-49.

Special Feature

Azilect 1mg (rasagiline) has beenlaunched in the UK by Teva and Lundbeckfor use as monotherapy in earlyParkinson’s disease (PD) and as adjunc-tive therapy in moderate to advanced dis-ease. British and German doctors are thefirst in Europe to be able to prescribeAzilect, a potent, second-generation, high-ly selective, reversible inhibitor ofmonoamine oxidase-B (MAO-B).

In patients with early PD, Azilect alonesignificantly improves the cardinal symp-toms of tremor and bradykinesia, anddemonstrated significant quality of lifebenefits when compared to placebo.

Results from a 26-week, randomised,double-blind multi-centre EarlyMonotherapy for Parkinson’s diseaseOutpatients (TEMPO) study, involving 404patients, showed that patients takingAzilect maintained their baseline totalUnified Parkinson Disease Rating Scale(UPDRS) score, while patients takingplacebo experienced a 4.2 UPDRS declinein score. Furthermore, patients takingAzilect in the TEMPO study benefitedfrom a 2.91 point PD-QUALIF(Parkinson’s Disease QUAlity of LIFe)score advantage over patients takingplacebo.

When used as adjunctive therapy forpatients with moderate to severe PD, whoare optimised on levodopa and other PDtreatments such as dopamine agonistsand entacapone, Azilect provides signifi-cant additional therapeutic benefits byreducing ‘off ’ and increasing ‘on’ timewith most of the ‘on’ time without trouble-some dyskinesias.

In another 26-week, randomised, dou-ble-blind placebo-controlled trial, involv-ing 472 patients with more advanced dis-ease, Azilect decreased ‘off ’ time signifi-cantly: by 1.85 hours daily in patientstreated with Azilect 1mg and by 1.41hours in patients taking a daily 0.5mgdose. Patients enrolled in the PRESTOstudy (Parkinson’s Rasagiline: Efficacy &Safety in the Treatment of Off) were

already optimised on levodopa and otherconcomitant anti-parkinsonian medica-tions, but were nevertheless experiencingat least 2.5 hours of daily ‘off ’ time.

The second of the adjunct studies,LARGO, compared Azilect 1mg and thecatechol-O-methyl transferase (COMT)inhibitor entacapone (200 mg with everylevodopa dose) with placebo. The resultsdemonstrated that once-daily Azilect 1mgis as effective as multi-dose entacapone inreducing total daily ‘off ’ time. The 687-outpatient LARGO (Lasting effect inAdjunct therapy with Rasagiline GivenOnce daily) study showed that Azilect andentacapone reduced mean ‘off ’ time by1.18 and 1.2 hours respectively com-pared with placebo.

Additional benefits of Azilect include itsonce-daily dosing, lack of titration and tol-erability in patients of all ages. In particu-lar, Azilect is associated with a low inci-dence of side-effects such as hallucina-tions, oedema, somnolence and orthostat-ic hypotension that often limit treatmentwith agents such as dopamine agonists.

For more information, contact TevaPharmaceuticals Medical Information on 01296 719768 or use ACNR’s readerenquiry service.

News Review: Once daily treatment for Parkinson’s disease


News Review

The world’s firstSomatom®Sensation 40 com-puted tomography(CT) scanner wasrecently installed atthe radiology depart-ment of AlamanceRegional MedicalCentre (ARMC), U.S. Siemens z-Sharp™technology is said to deliver, in the clini-cal routine, unprecedented image qualityand the industry’s highest isotropic reso-lution of below 0.4 millimetre voxel sizefor the 40 slices per rotation.

The proprietary z-Sharp technologyutilises an accurately and rapidly deflect-

ed electron beam cre-ating two alternatingand overlapping X-rayprojections reachingeach detector elementthat doubles scaninformation without acorresponding increasein dose. The result is a

substantially enhanced spatial resolutionand image quality, establishing z-Sharptechnology as a new benchmark fordiagnostic excellence, as proven by the250 installations of the SOMATOMSensation 64 systems.

For more information Tel: 01344396317.

Somatom Sensation 40 reports initial results

Carl Zeiss is bringing a novel microscopesystem to the marketplace that will pro-vide researchers with a fascinating newinsight into imaging living organisms.The company has signed a licensing dealwith EMBLEM Technology TransferGmbH, the commercial entity of theEuropean Molecular Biology Laboratory(EMBL) to commercialise a new technolo-gy called SPIM (Selective PlaneIllumination Microscopy).

SPIM produces detailed three-dimen-sional films of the inner workings of livingorganisms by eliminating a traditionalmicroscopy problem – vertical resolutionalong the lightpath. In SPIM, the speci-men is passed through a thin sheet oflight originating from the side of the

instrument and images captured layer-by-layer. The specimen may be rotated andviewed along different planes, eliminatingthe fuzzy and unwanted light that hasprevented scientists from looking deepinto tissues.

SPIM allows specimens to be imagedwithin a liquid-filled chamber. Thismeans that specimens can be kept aliveand enables researchers to track changesduring developmental processes, such asorgan formation in zebrafish or othermodel organisms. The imaging process isvery rapid and post-processing softwareassembles one or more stacks of imagesinto a high-resolution movie file.

For more information Tel: 01707871233.

A Sideways Look at Life

Bilaney Consultants arebased in the UK andGermany and supplyquality pre-clinicalresearch equipmentand software to life sci-entists and biomedical researchers in Europe.Coulbourn Instruments: Habitest modular animal behav-iour test systems and Graphic State control and dataacquisition software. Animal Startle, Tru Scan PhotoBeam Activity Monitoring, Modular systems forPsychophysiology and Human Startle.Actimetrics: Video based behaviour acquisition/analysissystems - FreezeFrame, WaterMaze, LimeLight, and BigBrother. ClockLab circadian biology acquisition/analysissystem.Plastics One: Pre-clinical research components.Standard and custom made cannula and electrode sys-tems.Kopf Instruments: Stereotaxic systems and Pipettepullers.ISI ResearchSoft Bibliographic Software: EndNote,Reference Manager and ProCite.

For more information, contact Bilaney ConsultantsLtd, St Julians, Sevenoaks, TN15 0RX. Tel: 01732 450002, Email: [email protected],www.bilaney.com

Instrumentation & equipment forlife sciences research

New initiatives for better access to life-savingthrombolysis

Abcam’s neuroscience anti-body range includes over1500 reagents covering:neuronal markers, neurode-generation, neurotransmis-sion, growth & development,sensory pathways and more.

Online neuroscienceresourcesAbcam’s Neuroscience‘abwire’ (www.abcam.com/neuroscience) has beendeveloped to help customers browse the entire antibodyrange. The ‘abwire’ is regularly updated with new neuro-science protocols, exclusive articles, conference informa-tion and improved data. You are also invited to exploreAbcam’s Neuroscience antibody locator to track downthe synaptic, neuronal or neuronal environment productson offer.

Recent focus – new IHC data for key antibodiesAbcam’s Neuroscience team have been hard at worktesting many of their best selling neuronal marker anti-bodies in IHC. These reagents are now known to workwell in a wide range of applications. For new images,revised working dilutions and the recommended proto-cols for many neuronal marker products go to the‘abwire’ (www.abcam.com/neuroscience) for the IHCGalleries.

For more information contact Dr Rhian Hayward,Abcam Ltd, 332 Cambridge Science Park, CambridgeCB4 0FW, Tel: 01223 472030, Email: [email protected]

Neuroscience antibodies fromAbcam

At the recent EuropeanStroke Congress, strokespecialists were intro-duced to new initiativessuch as telemedicine andthe ACT NOW ‘StrokeLysis Box’ which areallowing an increasingnumber of acute strokevictims to receive life-sav-ing thrombolysis treat-ment.

Only 30% of patients with acuteischaemic stroke arrive at hospital withinthe first three hours. However, studieshave shown that thrombolysis with aclot-busting drug (rtPA - alteplase),administered within three hours of theonset of symptoms of ischaemic stroke,significantly improves clinical outcome atthree months.

Telemedicine involves an expert strokephysician in a specialist stroke centre,

linked to non-specialistcentres in a telemedicinenetwork. The expert physi-cian can support the car-ing physician in diagnos-ing a stroke and assessingacute stroke victims fortreatment. Remote patientinterviewing, data trans-mission and videoconfer-encing are available 24hours a day to all hospi-

tals in the telemedicine network.The ‘Stroke Lysis Box’ helps in another

way. It enables hospital emergencydepartments to provide rapid clot-bustingtreatment to appropriate acute stroke vic-tims and is extending the availability ofthrombolytic treatment to trained physi-cians in a wider range of hospitals thanstroke centres.

For more information contact the ACTNOW secretariat on 020 7309 1029.


News Review

The atypical antipsychotic,Abilify® (aripiprazole) is effi-cacious and well tolerated inthe treatment of schizophre-nia, according to new guide-lines on best practice pre-scribing.

The guidelines, publishedin the International Journalof Clinical Practice, weredrawn up by a number ofleading UK psychiatrists.Lead author Dr Mike Travisfrom the Institute of Psychiatry in London said, “Abilifywas launched in the UK last June. These guidelines pro-vide practical guidance on how to optimise outcomes inpatients using Abilify and recommend its use in clinicalpractice, particularly as a choice for patients for whompotential side effects such as weight gain may be barri-ers to long-term treatment and for patients or clinicianswho are dissatisfied with current treatment.”

Abilify is the first available antipsychotic of a new gen-eration. It is effective in long-term treatment of both posi-tive, negative and cognitive symptoms of schizophrenia.

The new guidelines, drawn up by the SchizophreniaInnovation Working Group, provide a summary of theefficacy and tolerability of Abilify as seen in clinical trialsand a naturalistic study.

For more information contact Bristol Myers SquibbPharmaceuticals on 020 8754 3519.

Consensus statement backs theuse of Abilify in treatingschizophrenia

Nikon havelaunched threenew illuminationoptions for theTE2000 invertedmicroscope.TIRF2, W-TIRFand PA-GFPattachments cre-ate scope toundertake an even wider range of research level fluores-cence applications - including the unique SurfaceReflection Interface Contrast (SRIC) to study the surfacecondition of a specimen.

Unifying the TIRF and epi-fluorescence systems in asingle layer, TIRF2 provides more flexibility for combina-tion with other equipment such as optical tweezers.TIRF2 widens the range of application bases for theTE2000 from simple epi-fluorescence to intricate obser-vation of living cells at the molecular level. Single molec-ular activity in contact with the surface of the coverglasscan easily be captured.

Researchers using W-TIRF can achieve high perfor-mance epi-fluorescence using the TIRF illumination tech-nique more affordably than ever. Utilising mercury, xenon,metal halide or high intensity halogen, illumination costscan be kept to a minimum without compromising quality,thanks to the superior quality of Nikon’s optics.

For more information Email: [email protected]

Seeing living cells in a whole newlight

Neurological Disorders inFamous Artists: Frontiers ofNeurology and Neuroscience,Vol. 19 has been published byKarger.

The study of how a neurolog-ical disorder can change theartistic activity and behaviourof creative people is a largelyunexplored field. This publica-tion looks closer at famouspainters, writers, composers and philoso-phers of the 18th to the 20th centurieswho suffered from neurological diseasessuch as stroke, epilepsy, brain traumaand dementia. The diseases of VanGogh, Ravel, Poe, Kant, Haydn and manymore are diagnosed in retrospect and

treatment options according tomodern medical technologiesare discussed.

Presenting fascinatinginsights into the relationshipbetween brain disease and cre-ativity in famous minds, thispublication is highly recom-mended to neurologists, psy-chiatrists, physicians as well asto everybody interested in art,

music and literature. Editors: J. Bogousslavsky; F. Boller;

ISBN 3-8055-7914-4, CHF 109.50/EUR78/USD 99.75

For more information Email: [email protected] or seewww.karger.com

Fascinating insights into the relationship betweenbrain disease and creativity

Flexible dosing with Lyrica® is effective in relievingchronic peripheral neuropathic pain

NeuroSwing is the newpositioning and move-ment system for dynam-ic magnetic resonance(MR) imaging examina-tions of the cervicalspine. The system wasdeveloped by HightechElectronic GmbH incooperation withSiemens MedicalSolutions. The continu-ously variable, smoothmovements of the NeuroSwing enables,for the first time, dynamic MR acquisi-tions of the cervical spine to be per-formed in anteflexion, retroflexion, lateralflexion and rotation, either separately orin combination.

Approximately 30% of all MR examina-tions are neurological and orthopaedicacquisitions of the cervical spine.Acquisitions of the cervical spine inmotion and functional examinations were

difficult to perform.Study results haveshown that 50% of alllesions can only be dis-played correctly indynamic examinations,during motion or inmultiple, varied posi-tions. One of every tenstatic examinationsproduces no results.

NeuroSwing pro-vides the ability to

perform dynamic imaging of the cervicalspine in daily routine diagnostics. Allcervical spine movements relevant tothe examination can be realised with asingle device, without retrofitting orrepositioning the patient. As a result,lesions or functional limitations near thecervical spine can be detected quicklyand easily.

For more information, visitwww.siemens.co.uk/medical

First dynamic examinations of the cervical spine

Tailoring of Lyrica® dosage to suit patients’ individual needs may help to achieve anoptimal efficacy/tolerability balance. Flexible dosing with Lyrica® (pregabalin) is aseffective as fixed dosing in reducing the pain experienced by patients with painful dia-betic peripheral neuropathy (PDN) and post-herpetic neuralgia (PHN), according toresearch published in Pain.

Results from the patients’ pain scores demonstrated that the mixed group of PDNand PHN patients responded well to both fixed and flexible dosing regimens.Approximately 50% of patients experienced a ≥50% pain score reduction on eithertreatment regimen, a clinically significant improvement, compared with 24% of theplacebo group. The study also demonstrated that both the fixed and flexible dose regi-mens were significantly superior to placebo in improving sleep-interference.

Dr Barbara Hoggart, a Consultant in Pain Management at the Heart of England NHSFoundation Trust, commented, “As demonstrated by this study, not all patients need highdoses of pregabalin to achieve meaningful improvement in their pain. With tailored, flexi-ble dosing the incidence of adverse events and discontinuation of therapy may decrease.”

For more information contact Pfizer Ltd on Tel: 01737 331264.

AriceptSignificantly

ImprovesBehaviouralSymptoms1-3Compared to untreated AD patients

Dr. Alois Alzheimer

®

Continuing Commitment To Alzheimer’s

Before Him,The Disease Didn’t Have A Name

donepezil hydrochloride

Before Aricept,It Didn’t Have A Realistic Treatment

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 conduction

conditions. 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, <1/10): common cold, anorexia, hallucinations,agitation, aggressive behaviour, syncope, dizziness, insomnia, diarrhoea,vomiting, nausea, abdominal disturbance, rash, pruritis, musclecramps, urinary incontinence, headache, fatigue, pain, accident.

Uncommon effects (>1/1,000, <1/100): seizure, bradycardia, gastrointestinalhaemorrhage, gastric & duodenal ulcers, minor increases in serumcreatine kinase. Rare (>1/10,000, <1/1,000): extrapyramidal symptoms,sino-atrial block, atrioventricular block, liver dysfunction includinghepatitis. Presentation and basic NHS cost: Blister packed in strips of14. ARICEPT 5 mg; white, film coated tablets marked 5 and Aricept, packsof 28 £68.32. ARICEPT 10 mg; yellow, film coated tablets marked 10and Aricept, packs of 28 £95.76. Marketing authorisation numbers:ARICEPT 5 mg; PL 10555/0006. ARICEPT 10 mg; PL 10555/0007.Marketing authorisation holder: Eisai Ltd. Further Informationfrom/Marketed by: Eisai Ltd, Hammersmith International Centre,3 Shortlands, London, W6 8EE and Pfizer Limited, Walton Oaks, DorkingRoad, Tadworth, Surrey KT20 7NS. Legal category: POMDate of preparation: January 2002.References: 1. Gauthier S, Feldman H, Hecker J, et al. Curr Med ResOpin 2002; 18 (6): 347-354. 2. Holmes C, Wilkinson D, Dean C, et al.Neurology 2004; 63: 214-219. 3. Cummings JL, Donohue JA, Brooks RL.Am J Geriatr Psychiatry 2000; 8:2: 134-140.

A735-ARI572-09-04

®donepezil hydrochloride

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