so12/acnrso12_web.pdf · vairavan narayanan, krunal patel, stephen price –high grade gliomas:...

ACNRISSN 1473-9348 VOLUME 12 ISSUE 4 SEPTEMBER/OCTOBER 2012

www.acnr.co.uk

ADVANCES IN CLINICAL NEUROSCIENCE & REHABILITATION

NEWS REVIEW > CONFERENCE REPORTS > BOOK REVIEWS > JOURNAL REVIEWS > EVENTS DIARY

In this issue

Martin Turner, Gwenaelle Douaud – Faulty brakes: An inhibitory neuronal deficit in the pathogenesis of motor neurondisease

Lassi A Liikkanen – Involuntary Music Among Normal Population and Clinical Cases

Alys Mikolajczyk, Andrew Bateman – Psychodynamic Counselling after Stroke: A pilot service development project and evaluation

Vairavan Narayanan, Krunal Patel, Stephen Price – High Grade Gliomas: Pathogenesis, Management and Prognosis

ACNRSO12_Layout 1 28/08/2012 23:21

RelapseUnchanged or increased rate,

or ongoing severe relapses

Prescribe GilenyaOnce daily

oral MS therapy

Prior IFN treatment Failed response

to full and adequate

course

+

Now with NICE approval1

An MS treatment that’s oral

Abbreviated Prescribing Information: GILENYA® (fi ngolimod) Important note: Before prescribing, consult Summary of Product Characteristics (SmPC). Presentation: Hard capsule containing 0.5 mg fi ngolimod (as hydrochloride). Indications: Gilenya is indicated as single disease modifying therapy in highly active relapsing remitting multiple sclerosis for the following adult patient groups:- Patients with high disease activity despite treatment with a beta-interferon. These patients may be defi ned as: those who have failed to respond to a full and adequate course (normally at least one year of treatment) of beta-interferon. Patients should have had at least 1 relapse in the previous year while on therapy, and have at least 9 T2-hyperintense lesions in cranial MRI or at least 1 Gadolinium-enhancing lesion. A “non-responder” could also be defi ned as a patient with an unchanged or increased relapse rate or ongoing severe relapses, as compared to the previous year.- Patients with rapidly evolving severe relapsing remitting multiple sclerosis defi ned by 2 or more disabling relapses in one year, and with 1 or more Gadolinium enhancing lesions on brain MRI or a signifi cant increase in T2 lesion load as compared to a previous recent MRI. Dosage: Adults: Treatment should be initiated and supervised by a physician experienced in multiple sclerosis. One 0.5 mg capsule to be taken orally once daily. Patients can switch directly from beta-interferon or glatiramer acetate to Gilenya provided there are no signs of relevant treatment-related abnormalities, e.g. neutropenia. Use with caution in patients aged 65 years and over. No dose adjustments required in patients with mild to severe renal impairment or mild to moderate hepatic impairment. Exercise caution in patients with mild to moderate hepatic impairment. Do not use in patients with severe hepatic impairment (Child-Pugh class C). Use with caution in patients with diabetes mellitus due to an increased risk of macular oedema. Contraindications: Known immunodefi ciency syndrome, patients with increased risk for opportunistic infections, including immunocompromised patients (including those currently receiving immunosuppressive therapies or those immunocompromised by prior therapies), severe active infections, active chronic infections (hepatitis, tuberculosis), known active malignancies, except for patients with cutaneous basal cell carcinoma, severe liver impairment (Child-Pugh class C), hypersensitivity to the active substance or to any of the excipients. Warnings/

Precautions: Bradyarrhythmia: Initiation of treatment results in a transient decrease in heart rate (HR), which may be associated with atrioventricular block. Patients should have an ECG pre-dose, 6 hours post dose and observed for 6 hours with hourly HR and BP. Continuous ECG monitoring is recommended for 6 hours. In the event of bradyarrhythmia-related symptoms, initiate appropriate clinical management and monitor overnight. Also monitor overnight if at 6 hrs: HR <45 bpm, new onset 2nd degree heart block or higher, QTc >500 msec, or 3rd degree heart block at any time. If HR is lowest at 6 hrs monitor for >2 hrs until HR increases. The same precautions apply if Gilenya is discontinued for more than 2 weeks. Do not use Gilenya in patients with Mobitz type II or higher AV block, sick-sinus syndrome, sino-atrial block, symptomatic bradycardia, recurrent syncope, QTc >450 msec signifi cant cardiovascular disease, or severe sleep apnoea unless in consultation with a cardiologist and monitored overnight. Gilenya should not be given to patients taking beta blockers, HR lowering calcium channel blockers or other HR lowering substances (e.g. digoxin, diltiazem, ivabradine) unless in consultation with a cardiologist. Infections: Reduction of the lymphocyte count to 20-30% of baseline values occurs with Gilenya. Perform a complete blood count (CBC) at baseline and periodically during treatment, and in case of signs of infection, stop Gilenya until recovery if absolute lymphocyte count <0.2x109/L is confi rmed. Consider VZV vaccination of patients without a history of chickenpox or VZV antibody negative patients prior to commencing Gilenya. Gilenya may increase the risk of infections. Employ effective diagnostic and therapeutic strategies in patients with symptoms of infection while on Gilenya and for 2 months after discontinuation. Macular oedema: Macular oedema with or without visual symptoms has been reported in patients taking Gilenya. Perform an ophthalmological evaluation 3-4 months after Gilenya initiation. Evaluate the fundus, including the macula in patients reporting visual disturbances. Perform ophthalmological evaluation prior to initiating therapy and periodically thereafter in patients with diabetes mellitus or a history of uveitis. Discontinue Gilenya if a patient develops macular oedema. Liver function: Do not use Gilenya in patients with severe pre-existing hepatic injury (Child-Pugh class C). Delay Gilenya initiation in patients with active viral hepatitis until resolution. Recent transaminase and bilirubin levels should be available before initiation of Gilenya. Monitor liver transaminases at months 1, 3, 6, 9 and 12 and periodically thereafter. Institute more frequent monitoring if transaminases rise above 5 times the ULN, including serum bilirubin and alkaline phosphatase (ALP) measurement. Stop Gilenya treatment with repeated confi rmation

of liver transaminases above 5 times the ULN and only re-commence once liver transaminase values have normalised. Patients with symptoms of hepatic dysfunction should have liver enzymes checked and discontinue Gi an signifi the lymphocyte subset status of a patient treated with Gilenya. Laboratory tests involving the use of circulating m pressure effects: Gilenya can cause a mild increase in blood pressure. Monitor blood pressure regularly during Gilenya treatment. R pulmonary fi expiratory volume (FEV1 No washout is necessary when switching patients from interferon or glatiramer acetate to Gilenya assuming any im Gi cle discontinuation of Gilenya due to possible additive effects on the immune system. I im im e. with a short course of corticosteroids. Vaccination may be less effective during and for up to 2 months after Gilenya treatment. Avoid use of live attenuated vaccines due to infection risk. Due to additive effects on heart rate, Gilenya should not be given to patients receiving beta blockers, or class Ia and III antiarrhythmics, calcium channel blockers, digoxin, anticholinesteratic agents, pilocarpine or other HR lowering substances. Caution is indicated with substances that may inhibit CYP3A4. Co-administration of fi exposure. No interaction has been observed with oral contraceptives when co-administered with fi Fertility, pregnancy and lactation:

Adverse events should also be reported to Novartis (01276) 698370.

R

Code: FIN12-CO70

ACNRSO12_Layout 1 28/08/2012 23:21

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of liver transaminases above 5 times the ULN and only re-commence once liver transaminase values have normalised. Patients with symptoms of hepatic dysfunction should have liver enzymes checked and discontinue Gilenya if signifi cant liver injury is confi rmed. Resume Gilenya only if another cause of liver injury is determined and if the benefi ts of therapy outweigh the risks. Exercise caution with Gilenya use in patients with a history of signifi cant liver disease. Serological testing: Peripheral blood lymphocyte counts cannot be utilised to evaluate the lymphocyte subset status of a patient treated with Gilenya. Laboratory tests involving the use of circulating mononuclear cells require larger blood volumes due to reduction in the number of circulating lymphocytes. Blood pressure effects: Gilenya can cause a mild increase in blood pressure. Monitor blood pressure regularly during Gilenya treatment. Respiratory effects: Use Gilenya with caution in patients with severe respiratory disease, pulmonary fi brosis and chronic obstructive pulmonary disease due to minor reductions in values for forced expiratory volume (FEV1) and diffusion capacity for carbon monoxide (DLCO). Prior immunosuppressant treatment: No washout is necessary when switching patients from interferon or glatiramer acetate to Gilenya assuming any immune effects (e.g. neutropenia) have resolved. Exercise caution when switching patients from natalizumab to Gilenya owing to the long half life of natalizumab and concomitant immune effects. Stopping therapy: Gilenya is cleared from the circulation in 6 weeks. Caution is indicated with the use of immunosuppressants soon after the discontinuation of Gilenya due to possible additive effects on the immune system. Interactions: Anti-neoplastic, immunosuppressive or immune-modulating therapies should not be co-administered due to the risk of additive immune system effects. Exercise caution when switching patients from long-acting therapies with immune effects, e.g. natalizumab or mitoxantrone. No increased rate of infection was seen with concomitant treatment of relapses with a short course of corticosteroids. Vaccination may be less effective during and for up to 2 months after Gilenya treatment. Avoid use of live attenuated vaccines due to infection risk. Due to additive effects on heart rate, Gilenya should not be given to patients receiving beta blockers, or class Ia and III antiarrhythmics, calcium channel blockers, digoxin, anticholinesteratic agents, pilocarpine or other HR lowering substances. Caution is indicated with substances that may inhibit CYP3A4. Co-administration of fi ngolimod with ketoconazole increases fi ngolimod exposure. No interaction has been observed with oral contraceptives when co-administered with fi ngolimod. Fertility, pregnancy and lactation: There is potential for serious risk to the fetus with Gilenya. A negative pregnancy

test is required before initiation of Gilenya. Female patients must use effective contraception during treatment with Gilenya and for 2 months after discontinuation. Discontinue Gilenya if a patient becomes pregnant. Fingolimod is excreted into breast milk. Women receiving Gilenya should not breast feed. Fingolimod is not associated with a risk of reduced fertility. Undesirable effects: Very common ( 1/10); Infl uenza viral infections, headache, cough, diarrhoea, increased alanine transaminase (ALT), back pain. Common ( 1/100 to <1/10); herpes viral infections, bronchitis, sinusitis, gastroenteritis, tinea infections, lymphopenia, leucopenia, depression, dizziness, parasthesia, migraine, blurred vision, eye pain, bradycardia, atrioventricular block, hypertension, dyspnoea, eczema, alopecia, pruritus, asthenia, increased gamma-glutamyl transferase (GGT), increased hepatic enzymes, abnormal liver function test, increased blood triglycerides, decreased weight. Uncommon ( 1/1,000 to <1/100); pneumonia, macular oedema, decreased neutrophil count. Packs and price: Perforated unit dose blister packs containing 7 x 0.5 mg hard capsules: £367.50. Blister packs containing 28 x 0.5 mg hard capsules: £1470. Legal classifi cation: POM. Marketing Authorisation Holder: Novartis Europharm Ltd, Wimblehurst Rd, Horsham, W Sussex, RH12 5AB, UK. Marketing Authorisation Numbers: 7 x 0.5 mg hard capsules: EU/1/11/677/001, 28 x 0.5 mg hard capsules: EU/1/11/677/005. Date of last revision of prescribing information: June 2012. Full Prescribing Information available from: Novartis Pharmaceuticals UK Ltd, Frimley Business Park, Frimley, Surrey, GU16 7SR. Tel: (01276) 692255 Fax: (01276) 692508.

Adverse events should be reported. Reporting forms and information can be found at http://yellowcard.mhra.gov.uk. Adverse events should also be reported to Novartis (01276) 698370.

Reference: 1. National Institute for Health and Clinical Excellence. Final appraisal determination. Available at: http://www.nice.org.uk/nicemedia/live/12170/58500/58500.pdf Accessed on 21/05/2012.

Date of preparation: June 2012 Code: FIN12-CO70

ACNRSO12_Layout 1 28/08/2012 23:21

4 > ACNR > VOLUME 12 NUMBER 4 > SEPTEMBER/OCTOBER 2012

FROM THE ED I TOR . . .

Roger Barker, Co-Editor.

Martin Turner and Gwenaëlle Douard provide us with astimulating account on recent thoughts about MND and howthe loss of inhibitory interneurons may underlie some aspects

of the disease. They discuss all this in the context of some of the knownassociations between MND and athleticism and this review certainlygets you thinking about neurodegenerative conditions in a completelynew way.

The concept of involuntary musical imagery and a spectrum ofmusical symptoms is introduced to us by Lassi Liikkanen from Finland.It appears to be prevalent in that it occurs at least once a week in 90%of Finnish internet users who filled out an online questionnaire(presumably not during the Olympic closing ceremony). This imageryis not just about sticky tunes or unshakeable earworms, but can includepalinacousis: ‘the auditory illusion of persistence of sound impressionsafter cessation, sometimes music’, and musical obsessions.

Stephen Price and colleagues in the article for the Neurosurgicalseries, take us through the diagnosis and treatment of high gradegliomas – tumours that carry with them a dire prognosis. They explainhow better defining molecular markers expressed within tumours hashelped to better predict their behaviour and responsiveness to therapy.This excellent up-to-date account also looks to the future and agentsthat may prove useful in the clinic including a range of targetedtherapies, some of which will hopefully be approved for use both inEurope and the US!

Alys Mikolajczyk and Andrew Bateman in the article for theRehabilitation Section of ACNR discuss some of the more subtle, butclinically relevant, consequences of stroke in terms of emotional andaffective problems. They discuss how common these problems are andhow they can be approached through psychodynamic counselling bytaking us through a study they conducted in 15 patients.

Ray Chaudhuri in a Brittania sponsored article discusses the use ofapomorphine and DuoDopa® in patients with advanced Parkinson’sdisease and how these two therapies match up in terms of helping allaspects of the disorder, not just the motor features of these conditions.

Finally, Suffolk artist Jane Southgate weaves together neuronalstrands in her art that she describes in her short article.

We have a large collection of conference reviews in this issue andour usual journal and book reviews, and as usual we hope you enjoy

this issue of ACNR. l

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

Figure 1: Mode of Action of Botulinum Toxin3

B O O K R E V I E W S

Internet addiction is not universally recognised as aclinical disorder as yet, although it will be included inan appendix of DSM-V. The variety of names used forthe condition – including problematic internet use,pathological internet use, online addiction, andinternet-enabled compulsive behaviour (135) –perhaps reflect its uncertain nosological status. But theproblem is real enough, particularly amongst adoles-cents, such that in countries such as South Koreapublic health treatment and prevention programmesare already in place (223-243). Screening tests such asthe Internet Addiction Test (22-24) are available.

The link to impulse control disorders, and in partic-ular to pathological gambling, is repeatedly made (20,47, 144, 224), since all the core components of addiction(i.e. salience, mood modification, tolerance, withdrawalsymptoms, conflict, relapse) may be encountered. Withits “variable ratio reinforcement schedule” the internethas psychoactive properties (144) which may lead topathological use in predisposed individuals. Someargue, however, that the syndrome arises from behav-ioural patterns rather than the medium per se (249).

Treatment is problematic for many reasons. Affectedi

parents are also involved: 245-266). A 45-day inpatienttreatment facility in the US (214-220, 271) would notseem to be a feasible approach on the global scale.Abstinence, a favoured strategy for other addictions(alcohol, drugs, sex), is not really an option because ofthe ubiquity of the internet and its unavoidable use inboth domestic and occupational settings. In theabsence of controlled trials for any treatment option,prevention (via education) would seem to be the mostattractive management approach at present. Theimportance of assessing for and vigorously treatingother, concurrent, psychiatric disorders (depression,bipolar disorder, substance abuse) is repeatedlyemphasised.

A number of psychosocial models of internet addic-tion are discussed in the book, but there is little in theway of neurobiology: the basal ganglia and dopamineare only mentioned in passing (e.g. 10, 136, 248), andpathological gambling in Parkinson’s disease patientstreated with dopamine agonists not at all. When suchlinks are established, and the neurobiology betterunderstood, it may be that this condition will gravitateaway from the psychiatric to the neurological sphere.W

Internet Addiction. A Handbook and Guide toEvaluation and Treatment

E

The available guidancei

Graphs and algorithms are incorporated

t

l

P I

1916: The pathological anatomy of thelesion in multiple sclerosis

Dawson JD. The Histology of DisseminatedSclerosis. Transactions of the Royal Society ofEdinburgh 1916;50: 517-740.

James Dawson (1870–1927) left the greatestpathological account of multiple sclerosis inthe English language (Dawson 1916). First hesummarises the literature. The issue (then asnow for some contemporary logicians) iswhether the the disease is ‘inflammatory’ or‘developmental’ (degenerative). The primaryvascular, inflammatory, doctrine was espousedby Dejerine,2 Williamson3,4 and Marie,5 whosuggested that infections initiate the changes inblood vessels. Bielschowsky6 considered thatthe vascular process is directed primarily atnerve fibres. Strumpell7 considered that exoge-nous insults act upon an ‘intrinsically weak-

ened’ system; and Bramwell8 also saw multiplesclerosis as primarily a developmental distur-bance. Müller,9 the most articulate teacher fromthe developmental school, proposed that anyparticipation of the blood vessels within thelesion is secondary and his concept of ‘multiplegliosis’ as the essential process rehearses thefinal position taken by Charcot10 and most of hisschool. Redlich11 and Huber12 also saw the insultas a toxin- or microorganism-induced primarydegeneration of the myelin sheath withsecondary inflammation and blood vesselchanges. But, as often is the case, the bestaccount was the first: Rindfleisch13 assignedpriority to the blood vessels, proposing asequence in which a chronic irritative condi-tion of the vessel wall alters the nutrition ofnerve elements, leading to atrophy with meta-morphosis of the connective tissue producingmonster glia (Deiters or Rindfleisch cells).

T

Alastair Compston is Professor of Neurology andHead of the Department ofClinical Neurosciences inCambridge; President of theAssociation of BritishNeurologists (2009-2010); andEditor of Brain (from 2004). He isa foundation Fellow of theAcademy of Medical Sciences,and Foreign Member of theNational Academy of Sciences ofGermany. His research on theclinical science of humandemyelinating disease has beenrecognised by award of the SobekFoundation International ResearchPrize (2002), the Charcot Awardof Multiple Sclerosis InternationalFederation (2007), and the ZülchPrize of the Max-Planck Society(2010).

Alasdair Coles is co-editor of ACNR. He is aUniversity Lecturer inNeuroimmuniology at C

H g g y y, j years of research on multiple sclerosis. Over this time, a picture has emerged of this disease as aninflammatory disorder of the central nervous system, caused by a complex interplay of multiple

genetic susceptibility alleles and unknown environmental triggers. We have tried to illustrate this in ourchoice of landmark papers, at the same time being aware that strong cases could be pressed for otherstudies to be included. It is clear that many lines of scientific attack on the disease have benefited fromincreasingly potent weapons, and in many cases our papers reflect the application of the very latest tech-nology of the day. Finally we note that three of our ‘top ten’ were authored by Ian McDonald (1933-2006),testimony to his extraordinary contribution to understanding multiple sclerosis.1 Here are our first threelandmark papers, which chart the beginnings of understanding of pathology, immunology and treatmentof multiple sclerosis.

REPRINTS AVAILABLE

For more information & quotes, contact: [email protected]

• Peer reviewed • ABPI compliant• Translations available • Multiple country coordination

ACNRSO12_Layout 1 28/08/2012 23:21

ACNR > VOLUME 12 NUMBER 4 > SEPTEMBER/OCTOBER 2012 > 5

ACNRPublished by Whitehouse Publishing, 1 The Lynch, Mere, Wiltshire, BA12 6DQ.Publisher. Rachael HansfordE. [email protected]

ADVERTISING Rachael HansfordT. 01747 860168 M. 07989 470278E. [email protected]

COURSE ADVERTISINGRachael Hansford E. [email protected]

EDITORIALJohn Gustar E. [email protected]

PRINTED BYBuxton Press T. 01298 21 2000

Copyright: All rights reserved; no part of this publication maybe reproduced, stored in a retrieval system or transmitted inany form or by any means, electronic, mechanical, photo-copying, recording or otherwise without either the prior written permission of the publisher or a license permittingrestricted photocopying issued in the UK by the CopyrightLicensing Authority. Disclaimer: The publisher, the authors and editors accept noresponsibility for loss incurred by any person acting orrefraining from action as a result of material in or omittedfrom this magazine. Any new methods and techniquesdescribed involving drug usage should be followed only inconjunction with drug manufacturers' own published litera-ture. This is an independent publication - none of thosecontributing are in any way supported or remunerated by anyof the companies advertising in it, unless otherwise clearlystated. Comments expressed in editorial are those of theauthor(s) and are not necessarily endorsed by the editor,editorial board or publisher. The editor's decision is final andno correspondence will be entered into.

CONTENTSC O N T E N T S

SEPTEMBER/OCTOBER 2012

Cover picture: “In Search of the Big Fish” by AnnaSendelbeck, winner of the Jury Prize in the “The LabThrough Your Eyes” category, FENS student committeecompetition 2012.

ACNRISSN 1473-9348 VOLUME 12 ISSUE 4 SEPTEMBER/OCTOBER 2012

www.acnr.co.uk

ADVANCES IN CLINICAL NEUROSCIENCE & REHABILITATION

NEWS REVIEW > CONFERENCE REPORTS > BOOK REVIEWS > JOURNAL REVIEWS > EVENTS DIARY

In this issue

Martin Turner, Gwenaelle Douaud – Faulty brakes: An inhibitory neuronal deficit in the pathogenesis of motor neurondisease

Lassi A Liikkanen – Involuntary Music Among Normal Population and Clinical Cases

Alys Mikolajczyk, Andrew Bateman – Psychodynamic Counselling after Stroke: A pilot service development project and evaluation

Vairavan Narayanan, Krunal Patel, Stephen Price – High Grade Gliomas: Pathogenesis, Management and Prognosis

04 From the Editor

06 Awards

Review Article10 Faulty brakes: An inhibitory neuronal deficit in the

pathogenesis of motor neuron diseaseMartin Turner, Gwenaelle Douaud

Review Article12 Involuntary Music Among Normal Population and Clinical

CasesLassi A Liikkanen

Sponsored Feature15 The EuroInf survey

Ray Chaudhuri

Rehabilitation Article16 Psychodynamic Counselling after Stroke: A pilot service

development project and evaluationAlys Mikolajczyk, Andrew Bateman

Neurology in Art21 An Artist’s View of the Brain

Jane Southgate

Neurosurgery23 High Grade Gliomas: Pathogenesis, Management and

PrognosisVairavan Narayanan, Krunal Patel, Stephen Price

Regulars22 Book Reviews

29 Conference News

30 Events Diary

37 Journal Reviews

39 News Review

The Q-Sense from Medocfor Quantitative Thermal Sensory Testing (QTST)

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ACNRSO12_Layout 1 28/08/2012 23:22


AWARDS AND APPO INTMENTS

FENS Photography WinnersAnnouncedA Scientific Photography contest with “ScientificPhenomena” and “The Lab Through Your Eyes” categorieswas launched by the FENS students’ committee for thefirst time at the 8th FENS Forum in July. The aim of theinitiative was that young scientists should show science ina new way. The prizes were sponsored by Olympus, Mentey Cerebro magazine and ACNR. Congratulations to thewinners of this first contest and thanks to all the scientistswho sent their photographs.Scientific Phenomena category: winner of the Jury Prize –“Fight and Surrender” by Carmen Agustín Pavón. Vox PopPrize – “Happy Hippos” by Chris Henstridge.The Lab Through Your Eyes category: Jury Prize – “In Searchof the Big Fish” by Anna Sendelbeck (see cover picture ofACNR this issue). Vox Pop - “PhD Title Recipe” by MarcoDavid Brockmann.

You can see all the photographs in an exhibition on the Jumpthe FENS 2012 Facebook page.

Nominations for UKABIFAwards 2012Do you know someone who deserves recognition for theinnovative or inspirational work that they do in the field ofAcquired Brain Injury (ABI)? If you do, then nominate themnow for one of two prestigious United Kingdom AcquiredBrain Injury (UKABIF) Awards. �The UKABIF Award for Innovation is open to individuals ororganisations that make a difference in ABI; innovation by alawyer/law firm, clinician, care provider, social care worker,

educational or voluntary sector provider or registeredcharity. The Stephen McAleese Award for Inspiration is foran individual in the field of ABI. �

To enter simply complete the form that can be found on theUKABIF website: www.ukabif.org.uk. The deadline for entriesis the 19th October 2012.

Naomi Gilbert joins the TNANaomi Gilbert has joined the Trigeminal NeuralgiaAssociation UK as their new CEO. Naomi trained as a nurseat Guy’s Hospital and went on to become a surgical wardsister at St George’s Hospital in Tooting and then a nurseteacher. Following two years monitoring clinical trials at amajor pharmaceutical company, Naomi moved into thevoluntary sector. �

Further information from http://www.tna.org.uk/news.php

New Appointments at ImperialCollege LondonDr Hena Ahmad joins the Neuro-Otology team inSeptember. She is currently working at Charing CrossHospital and will be looking at the use of non-invasivebrain stimulation techniques in understanding the brainmechanisms underlying symptoms in patients withdizziness and eye movement problems.

Dr Ed Roberts has recently joined the Neuro-Otology teamas a post-doctoral researcher looking at the cerebralcortical mechanisms involved in chronic dizziness usingbrain stimulation and magnetic resonance imagingtechniques.

Reference: 1. Trobalt Summary of Product Characteristics. GlaxoSmithKline; 2011.

Trobalt® (Retigabine) Prescribing Information (Please refer to the full Summary of Product Characteristics before prescribing).Presentation ‘Trobalt tablets’ each containing retigabine equivalent to either: purple film coated round tablets containing 50 mg retigabine; green film coated round tablets containing 100 mg retigabine; yellow film coated oblong tablets containing 200 mg retigabine; green film coated oblong tablets containing 300 mg retigabine; purple film coated oblong tablets containing 400 mg retigabine. Indications Adjunctive treatment for partial onset seizures with or without secondary generalisation in adults aged 18 years and above. Dosage and Administration Trobalt must be taken orally in three divided doses each day. The maximum total daily starting dose is 300 mg (100 mg three times daily). Thereafter, the total daily dose is increased by a maximum of 150 mg every week according to individual patient response and tolerability. An effective maintenance dose is expected between 600 mg/day and 1,200 mg/day. Renal impairment: No dose adjustment is required in patients with mild renal impairment. A 50% reduction in the initial and maintenance dose of Trobalt is recommended in patients with moderate or severe renal impairment (creatinine clearance <50 ml/min). The total daily starting dose is 150 mg, and it is recommended that during the titration period the total daily dose is increased by 50 mg every week to a maximum total dose of 600 mg/day. Hepatic impairment: No dose adjustment is required in patients with mild hepatic impairment. A 50% reduction in the initial and maintenance dose of Trobalt is recommended in patients with moderate or severe hepatic impairment (Child-Pugh score ≥7). The total daily starting dose is 150 mg and it is recommended that during the titration period the total daily dose is increased by 50 mg every week to a maximum total dose of 600 mg/day. Elderly (65 years of age and above): A reduction in the initial and maintenance dose of Trobalt is recommended in elderly patients. The total daily starting dose is 150 mg/day and during the titration period the total daily dose should be increased by a maximum of 150 mg every week according to the individual patient response and tolerability. Doses greater than 900 mg/day are not recommended. Contra-indications Hypersensitivity to retigabine or any of its excipients. Special warnings and precautions Urinary retention, dysuria and urinary hesitation were reported in controlled clinical studies with retigabine generally within the first 8 weeks of treatment. Trobalt must be used with caution in patients at risk of urinary retention and it is recommended that patients are advised about the risk of these possible effects. Caution should be taken when Trobalt is prescribed with medicinal products known to increase QT interval and in patients with known prolonged QT interval, congestive cardiac failure, ventricular hypertrophy, hypokalaemia or hypomagnesaemia and in patients initiating treatment who are 65 years of age and above. In these patients it is recommended that an electrocardiogram (ECG) is recorded before initiation of treatment with Trobalt and in those with a corrected QT interval >440 ms at baseline, an ECG should be recorded on reaching the maintenance dose. Psychiatric disorders: Confusional state, psychotic disorders and hallucinations were reported in controlled clinical studies, it is recommended that patients are advised about the risk of these possible effects. Suicide risk: Suicidal ideation and behaviour have been reported in patients treated with anti epileptic agents in several indications. Patients (and caregivers of patients) should be advised to seek medical advice if signs of suicidal ideation or behaviour emerge. Elderly (65 years of age and above): Elderly patients may be at increased risk of central nervous system events, urinary

retention and atrial fibrillation. Retigabine must be used with caution in this population with a reduced initial and maintenance dose recommended. As there is individual variation in response to all antiepileptic drug therapy, it is recommended that prescribers discuss with patients the specific issues of epilepsy and driving. Overdose In the event of overdose it is recommended that the patient is given appropriate supportive therapy as clinically indicated, including ECG monitoring. Further management should be as recommended by the national poisons centre, where available. Fertility, pregnancy and lactaction Trobalt is not recommended during pregnancy and in women of childbearing age not using contraception. It is unknown whether retigabine is excreted in human breast milk. The effect of retigabine on human fertility has not been established. Drug interactions In vitro data indicated a low potential for interaction with other antiepileptic drugs. Pooled analysis from clinical studies showed no clinically significant effect of the inducers (phenytoin, carbamazepine and phenobarbital) on retigabine clearance. Steady-state data from a limited number of patients in smaller studies indicate that phenytoin and carbamazepine could reduce retigabine systemic exposure by 35% and 33% respectively. Trobalt interaction with digoxin at therapeutic doses may increase digoxin serum concentrations. Retigabine may increase the duration of some anaesthetics. Adverse reactions A dose relationship seems to exist between dizziness, somnolence, confusional state, aphasia, coordination abnormal, tremor, balance disorder, memory impairment, gait disturbance, blurred vision and constipation. Metabolism and nutrition disorders; common: weight increase, increased appetite. Psychiatric disorders; common: confusional state, psychotic disorders, hallucinations, disorientation, anxiety. Nervous system disorders; very common: dizziness, somnolence, common: amnesia, aphasia, coordination abnormal, vertigo, paraesthesia, tremor, balance disorders, memory impairment, dysphasia, dysarthria, disturbance in attention, gait disturbance, myoclonus, uncommon: hypokinesia. Eye disorders; common: diplopia, blurred vision. Gastrointestinal disorders; common: nausea, constipation, dyspepsia, dry mouth, uncommon: dysphagia. Hepatobiliary disorders; common: increased liver function tests. Skin and subcutaneous disorders; uncommon: skin rash, hyperhidrosis. Renal and urinary disorders; common: dysuria, urinary hesitation, haematuria, chromaturia, uncommon: urinary retention, nephrolithiasis. General disorders and administrative site conditions; very common: fatigue, common: asthenia, malaise, peripheral oedema. Basic NHS costs Initiation packs of21 x 50 mg tablets and 42 x 100 mg tablets (EU/1/11/681/013) is £24.33. Maintenance packs of 21 and 84 x 50 mg tablets are (EU1/11/681/001) £4.87 and (EU/1/11/681/002) £19.46 respectively. Maintenance packs of 21 and 84 x 100 mg tablets are (EU/1/11/681/004) £9.73 and (EU/1/11/681/005) £38.93 respectively. Maintenance packs of 84 x 200 mg tablets are (EU/1/11/681/007) £77.86. Maintenance packs of 84 x 300 mg tablets are (EU/1/11/681/009) £116.78. Maintenance packs of 84 x 400 mg tablets are (EU/1/11/681/0011) £127.68. Legal category: POM Marketing authorisation holder Glaxo Group Limited. Berkeley Avenue, Greenford, Middlesex, UB6 0NN, United Kingdom. Further information is available from: Customer contact centre, GlaxoSmithKline, Stockley Park West, Uxbridge, Middlesex UB11 1BT. Email: [email protected] Customer Services Freephone 0800 221441. Trobalt® is a registered trademark of the GlaxoSmithKline group of companies. All rights reserved. Prescribing information last revised September 2011 UK/RTG/0151/11

Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported to GlaxoSmithKline on 0800 221 441

Naomi Gilbert

Hena Ahmad

Ed Roberts

ACNRSO12_Layout 1 28/08/2012 23:22

An element of changeA first-in-class potassium channelopener for the adjunctive treatmentof adults with partial epilepsy1

UK/RTG/0051d/12Date of preparation: June 2012 Prescribing information is available on the adjacent page

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Episenta® (sodium valproate)Prescribers should consult the Summary of Product Characteristics before prescribing Episenta®

Sodium valproate available as Episenta® 150 or 300mg Prolonged-release Capsules, Episenta® Sachets containing 500mg or 1000mg Prolonged-release Granules and Episenta® 100mg/ml Solution for Injection. Indication: Epilepsy. Solution for injection: For use in patients normally maintained on oral sodium valproate but temporarily not possible. Oral: For treatment of manic episode in bipolar disorder when lithium is contraindicated or not tolerated. The continuation of treatment after manic episode could be considered in patients who have responded to valproate for acute mania. Dose and Administration: Epilepsy: Oral: Monotherapy: Adults: 600mg daily increasing by 150-300mg at 3-day intervals until controlled; usual dose range 1000mg to 2000mg/day. Max dose 2500mg/day. Children >20kg: 300mg/day increasing until controlled; usual dose range 20-30mg/kg/day. Max dose 35mg/kg/day. Children <20kg: 20mg/kg per day; in severe cases up to 40mg/kg/day. Daily dosage should be given in 1-2 single doses. Contents of the capsule/sachet may be sprinkled or stirred into soft food or drinks (cold or room temperature) and swallowed immediately without chewing or crushing the granules. Changing from sodium valproate enteric coated tablets to Episenta®, keep the same daily dose. Elderly: Care when adjusting dosage. Dosage should be determined by seizure control. Renal insufficiency: May be necessary to decrease dosage. Hepatic insufficiency: see Contraindications, Warnings and Precautions and Undesirable effects. Salicylates should not be used concomitantly. Combined Therapy: Start Episenta® in patients already on anticonvulsants gradually. Target dose reached after about 2 weeks. In combination with barbiturates, barbiturate dose should be reduced, particularly if sedation observed. Solution for injection: Adults: 400-800mg daily increasing by 150-300mg at 3-day intervals until controlled; usual dose range 1000mg to 2000mg/day. Max dose 2500mg/day. Children: 300mg/day increasing until controlled; usual dose range 20-30mg/kg/day. Max dose 40mg/kg/day, only in patients in whom plasma levels can be monitored. Above 40mg/kg/day clinical chemistry and haematology should be monitored. Patients already satisfactorily treated with oral continue at current dosage. The total daily dose divided into 3-4 single slow intravenous injections or given by continuous or repeated infusion. Should not be administered via same line with other drugs. Should be replaced with oral therapy as soon as practicable. Close monitoring of plasma levels required during therapy and when changing to/back from parenteral therapy. Manic episodes: Adults: initial daily dose 750mg or 20mg/kg body weight, rapid dose increase if possible, mean daily dose btw. 1000 and 2000mg. Patients receiving daily doses higher than 45mg/kg/day body weight should be carefully monitored. Contraindications: Active liver disease; History of severe hepatic dysfunction, especially drug related; Porphyria; Hypersensitivity to valproate or excipients. Warnings and Precautions: Monitor for signs of suicidal ideation/behaviour. Discontinue gradually. Patients should be closely monitored for early signs of liver damage. Use with carbapenem not recommended. Risk of severe liver damage, including fatal hepatic failure; children <3 years most at risk especially with multiple anticonvulsants, severe seizure disorders, organic brain disease, diseases associated with mental retardation. Avoid concomitant salicylates in children <3 years. Salicylates should not be used in children <16 years. Measure liver function before treatment and during the first 6 months. Risk of severe or fatal pancreatitis, particularly young children; risk decreases with increasing age. Blood cell count, platelet count, bleeding time and coagulation tests recommended prior starting therapy before surgery, or if spontaneous bruising/bleeding. Caution in patients with systemic lupus erythematosus. Risk of hyperammonaemia in patients with urea cycle enzymatic deficiency. Risk of weight gain. Caution in women of childbearing potential. Interactions: Episenta® on other drugs: may potentiate psychotropics, e.g. antipsychotics, monoamine oxidase inhibitors, antidepressants, benzodiazepines. Increases phenobarbital concentrations which may cause sedation particularly in children. Increases primidone levels exacerbating side effects. Phenytoin total levels decreased, the free form is increased leading to possible overdose symptoms. Toxic effects of carbamazepine may be potentiated. May reduce lamotrigine metabolism and increase its mean half-life. May raise zidovudine concentrations leading to increased toxicity. Anticoagulant effect of warfarin and other coumarin anticoagulants may be increased. Effects of other drugs on Episenta:® Antiepileptics with enzyme inducing effects e.g. phenytoin, phenobarbital, carbamazepine, decrease levels. Combination with felbamate may increase levels. Mefloquine and chloroquine increases metabolism. Levels may be increased with highly protein bound agents e.g. acetylsalicylic acid. Levels may be increased with cimetidine/erythromycin. Decreased levels with carbapenem. Colestyramine may decrease absorption. Rifampicin may decrease levels. Other interactions: No enzyme-inducing effect. Does not reduce efficacy of oestroprogestative agents including oral contraceptive pill. Caution in combination with newer antiepileptics. Coadministration with topiramate has been associated with encephalopathy/hyperammonaemia. Pregnancy and Lactation: Women of childbearing potential should not be started on Episenta® without specialist neurological advice. Women who are taking Episenta® who may become pregnant should receive specialist neurological advice and the benefits should be weighed against risks. Increased incidence of minor and major malformations in children born to mothers treated with valproate. When Episenta® treatment is deemed necessary, precautions to minimize the potential teratogenic risks should be followed. Very rare cases of haemorrhagic syndrome have been reported in neonates. Lactation: Small quantities of valproic acid pass into breast milk (1-10% of the maternal serum level). The safety profile of Episenta® and particularly possible haematological risks must be taken into account. Manic episode additionally: Valproate should not be used in pregnant women or women of childbearing age unless clearly necessary. Effects on ability to drive and use machines: Reaction time may be altered at start of treatment, at higher doses or with combination of other centrally acting drugs. Risk of transient drowsiness especially when taken during anticonvulsant polytherapy, with benzodiazepines or with alcohol. Undesirable effects: Frequently reported side effects include: nausea; gastralgia; diarrhoea; increased liver enzymes; hyperammonaemia without change in liver function; thrombocytopenia; transient hair loss; weight gain (risk factor for the development of a polycystic ovary syndrome, therefore requires careful monitoring). When using Episenta® intravenously, transient nausea or dizziness may occur. The following side effects have also been reported: hepatic dysfunction; severe liver damage including hepatic failure; pancreatitis; sedation; lethargy; stupor with/without hallucinations/convulsions; encephalopathy; coma; reversible extrapyramidal symptoms; reversible dementia with reversible cerebral atrophy; ataxia; fine postural tremor; aggression; hyperactivity; behavioural deterioration; hyponatraemia; hyperammonaemia with clinical presentation of vomiting, ataxia and increase in clouding of consciousness; anaemia; leucopenia; pancytopenia; bone marrow failure, including red cell aplasia; agranulocytosis; reduction in blood fibrinogen and/or increase in prothrombin time; spontaneous bruising/bleeding; rash; toxic epidermal necrolysis; Stevens-Johnson syndrome; erythema multiforme; hirsutism; acne; decrease in bone mineral density, osteopenia, osteoporosis and fractures in long-term therapy; amenorrhoea; irregular periods; gynaecomastia; vasculitis; reversible or irreversible hearing loss; reversible Fanconi’s syndrome; enuresis; angioedema; Drug Rash with Eosinophilia, Systemic Symptoms (DRESS syndrome); allergic reactions (rash to hypersensitivity reaction); non-severe peripheral oedema. Pack sizes and NHS price: Packs of 100, 150mg capsules £7.00 [PL14040/0024]; Packs of 100, 300mg capsules £13.00 [PL14040/0025]; Packs of 100, 500mg sachets £21.00 [PL14040/0026]; Packs of 100, 1000mg sachets £41.00 [PL14040/0027]. Packs of 5, 3ml ampoules 100mg/ml solution for injection £35.00 [PL14040/0028]. Legal category: POM. Marketing Authorisation Holder: Desitin Arzneimittel GmbH Weg beim Jäger 214 D-22335 Hamburg Germany. Prepared in: July 2012. For further information on Episenta® please contact Medical Information on [email protected]

References:1. Episenta® Summary of Product Characteristics 2012.2. Retzow A et al. Arzneim-Forsch/Drug Res 1997;47(II):1347-1350.3. MIMS, July 2012.

Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be

reported to Desitin Pharma Limited on [email protected]

UK/EP/12/0011 Date of preparation: August 2012.

Roger Barker is co-editor of ACNR, and is Honorary Consultant inNeurology at The Cambridge Centre for Brain Repair. His main area ofresearch is into neurodegenerative and movement disorders, in particularparkinson's and Huntington's disease. He is also the university lecturer inNeurology at Cambridge where he continues to develop his clinical researchinto these diseases along with his basic research into brain repair usingneural transplants.

Editorial board and contributors

Professor Riccardo Soffietti, Italy: Chairman of the Neuro-Oncology Service, Dept ofNeuroscience and Oncology, University and S. Giovanni Battista Hospital.

Professor Klaus Berek, Austria: Head of the Neurological Department of the KH Kufstein.

Professor Hermann Stefan, Germany: Professor of Neurology /Epileptology in theDepartment of Neurology, University Erlangen-Nürnberg.

Professor Nils Erik Gilhus, Norway: Professor of Neurology at the University of Bergen andHaukeland University Hospital.

International editorial liaison committee

Peter Whitfield is ACNR’s Neurosurgery Editor. He is a ConsultantNeurosurgeon at the South West Neurosurgery Centre, Plymouth. His clin-ical interests are wide including neurovascular conditions, head injury,stereotactic radiosurgery, image guided tumour surgery and lumbarmicrodiscectomy. He is an examiner for the MRCS and is a member of theSAC in neurosurgery.

Alastair Wilkins is our Case Report Co-ordinator. He is Senior Lecturer inNeurology and Consultant Neurologist, University of Bristol. He trained inNeurology in Cambridge, Norwich and London. His research interests arethe basic science of axon degeneration and developing treatments forprogressive multiple sclerosis.

Rhys Davies is the editor of our Book Review Section. He is a consultantneurologist at the Walton Centre for Neurology and Neurosurgery inLiverpool and at Ysbyty Gwynedd in Bangor, North Wales. He has a clinicaland research interest in cognitive neurology.

Boyd Ghosh is the Editor of our Conference News section. He is currentlya Specialist Registrar in Southampton having completed a PhD in Cambridgein cognitive neuroscience. His special interests are cognition and movementdisorders, with a particular interest in progressive supranuclear palsy.

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.

Alasdair Coles is co-editor of ACNR. He is a University Lecturer inNeuroimmuniology at Cambridge University. He works on experimentalimmunological therapies in multiple sclerosis.

Heather Angus-Leppan is ACNR's ABN representative on the EditorialBoard. She is Head of the Neurology Department at Barnet Hospital andConsultant Neurologist, Honorary Senior Lecturer and Epilepsy Lead at theRoyal Free Hospital, London, UK. She is the Honorary Assistant Secretary ofthe Association of British Neurologists, Honorary Secretary of theNeurosciences Section of the Royal Society of Medicine and current Chairof the Map of Medicine Epilepsy Group, UK.

Mike Zandi is co-editor of ACNR and Specialist Registrar in Neurology atAddenbrooke's Hospital, Cambridge. He trained in Cambridge, Norwich andLondon. He is interested in clinical and experimental neuroimmunology.

ACNRSO12_Layout 1 28/08/2012 23:22

Prescribing information can be found opposite.

At the centre of managing epilepsy – is a treatment your patient should take

Episenta®

Prolonged release sodium valproate

O.D. or B.D.

Tried, tested and cost-effective control

Unique mini-tablet formulation: An innovative way of delivering sodium valproate

Extended release provides once daily evening dosage option

Easy to swallow – can be taken with food or drinks1,2

Lower cost than extended release oral forms of leading sodium valproate3

A decision to use Episenta® in women of childbearing potential should not be taken without specialist neurological advice, and

only if the benefits outweigh the potential risks to the unborn child. See Summary of Product Characteristics for more information.

100374 DES Episenta ACNR (297x210) (+105) AW.indd 2 08/08/2012 14:55


Martin R Turner, MA, MBBS, PhD, FRCP,is a Medical Research CouncilClinician Scientist & MotorNeurone Disease Association LadyEdith Wolfson Fellow within theOxford University NuffieldDepartment of ClinicalNeurosciences. He established theOxford Study for Biomarkers inMND (‘BioMOx’), a large cohort ofpatients who have undergone serialadvanced MRI, eye-tracking, serumand CSF sampling.

Gwenaëlle Douaud,PhD,is a senior post-doctoral scientist atthe Oxford University FMRIBCentre. She works on theintegration of advanced MRImodalities to explore thepathogenesis of Huntington’s andAlzheimer’s disease in addition toMND. Her most recent focus is onmovement disorders and the roleof circuit changes in the basalganglia.

Correspondence to:Dr Martin Turner,Clinical Neurology,West Wing Level 3,John Radcliffe Hospital,Oxford OX3 9DU, UK.Email: [email protected]

IntroductionMotor neuron disease, in its commonest clinical formamyotrophic lateral sclerosis (ALS), is characterisedby the degeneration of upper motor neurons (UMNs)of the corticospinal tract (CST) and lower motorneurons (LMNs) of the brainstem nuclei and spinalcord anterior horns.1 It is recognised to have clinical,pathological and, in cases with an intronic hexanu-cleotide repeat expansion in C9ORF72, geneticoverlap with frontotemporal dementia (FTD).2 Halfof MND patients die within three years of symptomonset, typically via respiratory failure. There is nospecific test for MND, and diagnosis is based on clin-ical features, with an average delay from symptomonset to diagnosis of one year.

To ask “what is the cause of MND?” is to underes-timate the emerging pathogenic complexity. Only5% of cases report a family history. Cytoplasmicinclusions of the ubiquitinated 43 kDa transactive-region DNA-binding protein, TDP-43, superficiallyappear to be the unifying hallmark for the 95% whohave apparently sporadic MND. However, TDP-43inclusions are notably absent in the 20% of familialcases associated with mutations of SOD1, despitebeing clinically indistinguishable from other MNDpatients. Thus, there appear to be multiple discrete‘tributaries’ flowing towards a common ‘waterfall’,beyond which there is a typically rapid, relativelyselective motor neuronal degeneration. In the vastmajority of apparently sporadic cases, MND is likelyto involve multiple genetic influences operating ata low level individually, combined with as yetpoorly-defined environmental factors.

The brain in MNDCase reports of MND with brain involvementbeyond the motor cortex can be found in the early20th Century literature, now recognised as MNDassociated with FTD, largely of the behaviouralvariant. Later post mortem studies confirmed wide-spread cerebral involvement in MND even withoutfrank dementia.3 A spectrum of cognitive dysfunc-tion, predominantly of a dysexecutive nature, anddetectable in at least a third of MND cases withoutfrank FTD, emerged over the following decades,cemented by the finding of the common TDP-43histological signature.4

Aberrant axonal transport is one of several majorthemes in MND pathogenesis,5 in which a LMN‘dying back’ is then presumed to account for theconsistent involvement of the CST, noted even inapparently clinically LMN-only cases. However, theearly occurrence of cognitive impairment in somecases of ALS, and a rare UMN-only variant of MND(primary lateral sclerosis) often associated withsevere atrophy of the motor cortex and strikinglyabsent LMN pathology, support a top-down ‘dyingforward’ process. Combined clinical and postmortem analysis supports a main focus of

pathology at the site of symptom onset, withcontiguous spread through UMN and LMN popula-tions.6 A clear primacy of one over other remainsuncertain, with the increasing sense that thedisease must be understood as a whole ‘system’degeneration that includes the brain at some levelin all cases.

Excitotoxicity and cortical hyperexcitabilityin MNDRaised levels of CSF glutamate, and abnormalitiesof glutamate transport and reuptake in human postmortem tissue as well as animal models of MND,underpin an excitotoxic theme of pathogenesis, inwhich over-stimulation of motor neurons results ineventual calcium-mediated cell death.5 An alterna-tive or contributory mechanism might be a reduc-tion in inhibitory neuronal influences. Cortical andspinal cord interneuronal local circuits are foundintimately associated with both the UMN and LMNpopulations respectively, and a diverse range ofevidence supports a role for their involvement inpathogenesis.7 Paired transcranial magnetic stimu-lation can be used to explore cortical inhibitorycircuits, and studies in MND demonstrated a reduc-tion in the normal inhibitory response seen at shortinterstimulus intervals.8 An adapted threshold-tracking method to assess this reduction in short-interval intracortical inhibition has demonstratedspecificity for MND over mimic disorders.9

Furthermore, this methodology provided pivotalevidence for an increase in cortical hyperex-citability prior to the development of symptoms incarriers of SOD1 mutations.10

Neuroimaging evidence for an ‘interneuronopathy’ in MNDPioneering in vivo cortical studies in MNDemployed activation positron emission tomography(PET), observing an extended area of cortical acti-vation in response to a motor task. It was suggestedthis “boundary shift” might reflect loss of inhibitorylocal circuits.11 Application of the PET ligandflumazenil confirmed widespread cerebral reduc-tions in γ-amino butyric acid (GABA)-A receptorbinding in MND, crucially with relative preservationin those with a consistently more slowly progressivefamilial form of the disease (matched for disabilityand UMN involvement).12

Blood oxygenation level-dependent (BOLD)functional MRI involving a motor task, confirmedthe original activation PET findings (reviewed in[13]). However, it is now possible to analyse thespontaneous fluctuations in BOLD signal that occurat rest (as opposed to during a motor task). This isbeing explored as a potentially sensitive in vivomarker of pathology in several neurodegenerativedisorders. Diffusion tensor imaging (DTI) is anestablished MRI technique that can be used to

Faulty brakes: An inhibitory neuronal deficit in the pathogenesis of motor neuron disease

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define the characteristic structural white matter tract involvement inMND, which consistently involves the CST and corpus callosum,14 but alsoextra-motor frontal lobe pathways. The grey matter projections from thesedamaged white matter tracts were mapped using tractography in order toexplore the resting-state functional changes in relation to an ‘MND-specific’ cortical network.15 Unexpectedly this revealed increased func-tional connectivity within the structurally degenerating cortical network.Furthermore, this network overlapped strikingly with areas previouslynoted to show reduced GABA binding12 (Figure). Whilst a ‘compensatory’explanation cannot be entirely dismissed, it was noteworthy that thosewith faster rates of disease progression showed greater functional connec-tivity, raising the possibility that loss of inhibitory neuronal influencesmight directly contribute to the pathogenic cascade in MND.

Is there a potential MND brain architecture?Osler noted that: “It is much more important to know what sort of patienthas a disease, than what sort of disease a patient has.” Case-control studiesof the strong anecdotal observation of pre-morbid athleticism amongthose developing MND have been inconclusive. The significant increasedoccupational risk of MND associated with professional football and mili-tary service superficially fits with greater athleticism, and a significantlyreduced vascular risk profile has also been noted among MND patientsand relatives.16 Debate continues over exercise as a direct precipitant ofdisease, versus athleticism as an associated phenotype. Developmentalfactors must also be considered, with MND patients noted to have a surro-gate marker for high intrauterine testosterone exposure (also commonamong athletes) in the form of reduced 2D:4D digit ratio.17

With these data in mind, though entirely speculatively, it is conceivablethat athleticism might in part reflect a particular cerebral architecture,which may in turn be a preferred substrate for MND in a minority. Eisenspeculated on the relatively rapid human neocortical development asso-ciated with opposable thumbs and bipedalism as holding potentialimportance for the pathogenesis of MND.18 Distinct patterns of structuraland functional brain network organisation in healthy individuals havealready been linked to the stereotyped patterns of neurodegenerativediseases.19 Aptly summarised: “What wires together, dies together”.20

Hand dominance has been linked to reduced inhibitory influences inthe contralateral hemisphere, and so the finding of significantlyincreased concordance of site of onset and handedness in those withupper limb-onset MND might reflect inhibitory, interneuronal organisa-tion, rather than an activity-driven mechanism.21 In this way, a less inhib-ited, or perhaps more functionally connected motor cortex, with all itsevolutionary advantage in terms of physical performance in youth, mightsomehow be more vulnerable, perhaps more permissive of spread ofpathology, or otherwise define variable rates of progression in MND.

Primary prevention of MND?Speculation aside, it is likely that the development of clinical symptomsin MND represents the late stages of long-standing pathological

processes. Indeed the primary reason for the failure of so many of thecandidate therapies for MND may be their administration in a relativelyintractable phase of pathology. Although a minority of cases, thoseasymptomatic individuals carrying single genetic mutations linked to thedevelopment of MND offer a valuable opportunity to study the earliestchanges. The observation of a similar pattern of metabolic changes in thecervical spinal cord of presymptomatic SOD1 mutation carrierscompared to those with established disease,22 marks a major conceptualshift in where pathology in MND begins, and brings it in line with obser-vations in Alzheimer’s, Parkinson’s and Huntington’s Diseases.

High-field MR spectroscopy can now be used to specifically demon-strate reduced GABA within the motor cortex in MND patients.23 Incombination with other advanced MRI techniques, the refinement of acortical ‘disinhibitory signature’ in presymptomatic cases will be animportant step towards the long-term aspiration of primary prevention.For the larger apparently sporadic and symptomatic group, identifyingsuch a signature has the potential to reduce diagnostic delay, and permitearlier administration of therapy, one strategy for which might beboosting inhibitory interneuronal function. l

R E V I E W A RT I C L E

Left panel: MND grey matter network (in blue) directly associated with the white matterdamage identified using DTI (in red).Middle panel: Within the MND grey matter network, there was an increased functionalconnectivity using resting-state functional MRI - an increased synchronisation of the sponta-neous fluctuations of the BOLD signal between the regions of the brain involved (in yellow).15

Right panel: The regions showing increased functional connectivity have some spatial overlapto the reduced GABA binding found in a previous study using flumazenil PET (in yellow).12

1. Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A, Hardiman O, et al. Amyotrophiclateral sclerosis. Lancet. 2011;377:942-55.

2. Majounie E, Renton AE, Mok K, Dopper EG, Waite A, Rollinson S, et al. Frequency of theC9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis andfrontotemporal dementia: a cross-sectional study. Lancet Neurol. 2012;11:323-30.

3. Smith MC. Nerve fibre degeneration in the brain in amyotrophic lateral sclerosis.JNeurolNeurosurgPsychiatry. 1960;23:269-82.

4. Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, et al.Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral scle-rosis. Science. 2006;314:130-3.

5. Rothstein JD. Current hypotheses for the underlying biology of amyotrophic lateral sclerosis.Ann Neurol. 2009;65 Suppl 1:S3-9.

6. Ravits JM, La Spada AR. ALS motor phenotype heterogeneity, focality, and spread: decon-structing motor neuron degeneration. Neurology. 2009;73:805-11.

7. Turner MR, Kiernan MC. Does interneuronal dysfunction contribute to neurodegeneration inamyotrophic lateral sclerosis? Amyotroph Lateral Scler. 2012;13:245-50.

8. Yokota T, Yoshino A, Inaba A, Saito Y. Double cortical stimulation in amyotrophic lateralsclerosis. JNeurolNeurosurgPsychiatry. 1996;61:596-600.

9. Vucic S, Cheah BC, Yiannikas C, Kiernan MC. Cortical excitability distinguishes ALS frommimic disorders. Clin Neurophysiol. 2011;122:1860-6.

10. Vucic S, Nicholson GA, Kiernan MC. Cortical hyperexcitability may precede the onset offamilial amyotrophic lateral sclerosis. Brain. 2008;131:1540-50.

11. Kew JJ, Leigh PN, Playford ED, Passingham RE, Goldstein LH, Frackowiak RS, et al.Cortical function in amyotrophic lateral sclerosis. A positron emission tomography study.Brain. 1993;116 (Pt 3):655-80.

12. Turner MR, Hammers A, Al-Chalabi A, Shaw CE, Andersen PM, Brooks DJ, et al. Distinctcerebral lesions in sporadic and 'D90A' SOD1 ALS: studies with [11C]flumazenil PET. Brain.2005;128:1323-9.

13. Turner MR, Agosta F, Bede P, Govind V, Lule D, Verstraete E. Neuroimaging inamyotrophic lateral sclerosis. Biomark Med. 2012;6:319-37.

14. Filippini N, Douaud G, Mackay CE, Knight S, Talbot K, Turner MR. Corpus callosuminvolvement is a consistent feature of amyotrophic lateral sclerosis. Neurology.2010;75:1645-52.

15. Douaud G, Filippini N, Knight S, Talbot K, Turner MR. Integration of structural and func-tional magnetic resonance imaging in amyotrophic lateral sclerosis. Brain. 2011;134:3470-9.

16. Turner MR, Wotton C, Talbot K, Goldacre MJ. Cardiovascular fitness as a risk factor foramyotrophic lateral sclerosis: indirect evidence from record linkage study. J NeurolNeurosurg Psychiatry. 2012;83:395-8.

17. Vivekananda U, Manjalay ZR, Ganesalingam J, Simms J, Shaw CE, Leigh PN, et al. Lowindex-to-ring finger length ratio in sporadic ALS supports prenatally defined motor neuronalvulnerability. J Neurol Neurosurg Psychiatry. 2011;82:635-7.

18. Eisen A. Amyotrophic lateral sclerosis-Evolutionary and other perspectives. Muscle Nerve.2009;40:297-304.

19. Seeley WW, Crawford RK, Zhou J, Miller BL, Greicius MD. Neurodegenerative diseasestarget large-scale human brain networks. Neuron. 2009;62:42-52.

20. Bak TH, Chandran S. What wires together dies together: Verbs, actions and neurodegenera-tion in motor neuron disease. Cortex. 2012;48:936-44.

21. Turner MR, Wicks P, Brownstein CA, Massagli MP, Toronjo M, Talbot K, et al.Concordance between site of onset and limb dominance in amyotrophic lateral sclerosis. JNeurol Neurosurg Psychiatry. 2010;82:853-4.

22. Carew JD, Nair G, Andersen PM, Wuu J, Gronka S, Hu X, et al. Presymptomatic spinalcord neurometabolic findings in SOD1-positive people at risk for familial ALS. Neurology.2011;77:1370-5.

23. Foerster BR, Callaghan BC, Petrou M, Edden RA, Chenevert TL, Feldman EL. Decreasedmotor cortex gamma-aminobutyric acid in amyotrophic lateral sclerosis. Neurology.2012;78:1596-600.

REFERENCES

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Dr Lassi A Liikkanen,is a post-doctoral researcher atAalto University, Finland. His workfocuses on psychology of mediaand technology, especially music.He is pioneering the research oninvoluntary musical imagery with asmall group of scholars acrossEurope. His publications haveappeared in journals ofneuroscience and musicpsychology.

Correspondence to:HIITPO Box 15600FI-00076 Aalto University,FinlandTel: +358 50 384 1508Web: http://hiit.fi/lassial

AcknowledgmentThis work was supported by aresearch project grant fromAcademy of Finland. Parts of thisreview were presented at theworld’s first symposium onInvoluntary musical imagery atICMPC-ESCOM 2012 conference,Thessaloniki, Greece in July 2012.The author declares no conflicts ofinterest.

There is a new topic in general psychologycalled involuntary musical imagery (INMI).1,2

It is of great potential interest to practitionersof clinical neuroscience because of its notablesimilarities to clinical involuntary musicphenomena. INMI is defined as a conscious expe-rience of reliving a musical memory without delib-erately attempting to do so. It is also known byother colloquial names such as earworms, stickytunes, or tune in the head phenomenon. In thispaper I review recent empirical findings on thetopic of involuntary music, highlighting how thefindings from INMI research in the normal popula-tion1 may support the diagnosis of involuntarymusic in clinical practice.

It is proposed here that involuntary musicinvolves a continuum of musical imageryphenomena, like the perceptual continuumproposed for hallucinatory perceptions.3 Thesephenomena range from common, “normal” invol-untary music to pathological conditions (seeFigure 1), such as musical obsessions,4 hallucina-tions,5 and palinacousis.6 This review includesinvoluntary phenomena from three disciplines:general psychology (specifically music), clinicalneuroscience and psychodynamic psychology.

Involuntary music in general psychologyThe human capacity to imagine sounds is generallycalled auditory imagery,7 and musical imagerywhen it involves music.8 Involuntary musicalimagery is considered to be a manifestation ofmusical imagery7 with uncontrolled onset ofimagery.9 This review is focused on INMI. As asubjective experience, INMI involves insight that themusic is self-generated and its quality is not veryvivid, in comparison to the perception of stimulus.

The first psychology paper related to INMI cameout in 2004 when Kvavilashvili and Mandler10

reported a series of studies on involuntarysemantic memories. Melodies were found to bethe most frequently recurring memory type whichpeople recall unintentionally. Since this seminalwork, researchers have been interested in thefrequency and duration of involuntary music,1,11

along with the phenomenology,1 triggers,2 anddynamics of INMI.9

There is a high prevalence of INMI in everydaylife. An experience sampling study of musicologymajors11 revealed that the students are deeplyimmersed in both voluntary and involuntary imag-ined music throughout the day. A questionnairestudy of over 11,900 Finnish Internet users foundthat almost 90% of respondents experienced INMIevery week (see Figure 2).1 In another recentstudy, a diary method was used for data collectionover a four week period.12 The INMI episodeslasted 25 minutes in average and happened morethan once a week.

The conscious experience of INMI variesconsiderably between people. For instance,despite the higher likelihood of certain songsbeing reported as INMI, the songs are very idiosyn-cratic overall.9 In the Beaman and Williams12 diarystudy, 74% of INMI reports involved a unique song.The songs can be old, contemporary, or evencompletely novel.1 Experiences of new, self-gener-ated songs are more typical among musically-educated people.1,11 Features of the musical expe-rience have also been examined. In the study ofFinnish internet users,1 an INMI episode was typi-cally contemporary, lyrical, and involved only afraction of a song, presumably the chorus. Thestudy found that the frequency and characteristicsof the experience are influenced by age, genderand musical dispositions. Women reported experi-ences more often as did the younger cohorts. Thefrequency of musical activities correlated posi-tively with the frequency of INMI experiences.

The causes of INMI are pretty much as yetunknown. The hypotheses often involve the func-tion of memory, in terms of enforcing anddecaying activation in semantic memorynetworks.9,10 It is hypothesised that the activation ofmemory through recall, recognition, or cross-modal memory associations can evoke theseexperiences immediately or after a delay. A studyof INMI triggers identified several common cate-gories of triggers.2 Exposure to music, recent andrepeated, was the most prominent category, butcross-modal associations to music, and affectivestates were also repeatedly mentioned by subjects. Further evidence about the role of memory activa-tion comes from the only experimental study of

Involuntary Music AmongNormal Population andClinical Cases

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Melodies were found to be the most frequently recurringmemory type which people recall unintentionally

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INMI published thus far.9 Using a novel induc-tion technique, it was found that the propor-tion of recently processed music among INMIreports increased in response to cueing.Familiarity with music was a necessary butnot a sufficient condition for the emergenceof INMI. The relative freshness of the song wasimportant for its later induction, contempo-rary songs being more powerful cues thanclassic ones. The interpretation was that therepeated activation facilitates later, intentionalor unintentional, imagination of music.

Involuntary music in clinical neuroscienceSeveral conditions in neurology and psychi-atry involve symptoms very much like INMI,but are much more pronounced. For thisreview, I have included the most relevantphenomena with a known cause: peripheralnervous system, brain damage and functionaldiseases.13 Additionally, intoxication andepilepsy are known to sometimes trigger thesesymptoms.5 A rare phenomenon known aspalinacousis has also been documented.6 Itinvolves an auditory illusion of persistence ofsound impressions after the cessation of theauditory stimulation, sometimes music. Thiscondition is related to brain damage and

epilepsy and should not be confused withother types of involuntary music.

Involuntary music is sometimes associatedwith obsessive-compulsive disorder (OCD)and schizophrenia. For OCD, so-called musicalobsessions4,14 in the absence of otherpsychopathological symptoms, can be anadequate criterion for diagnosis when accom-panied by subjective distress and dysfunction.For instance, Zungu-Dirway and colleagues4

described two patients who perceived theinternally created music as intrusive, irritatingand disruptive of other thought. The soledifference in the phenomenology of musicalobsessions to INMI is their noticeable disrup-tiveness.

Hallucinations, including musical ones, aretypical in schizophrenia. Musical hallucina-tions are more common than musical obses-sions, even though they occur in less than0.2% of hospital populations and typicallyinvolve elderly females.5 Among theresearchers studying schizophrenia, there hasbeen a long discussion about musical halluci-nations and pseudo-hallucinations.15 Forinstance, Terao and Ikemura16 disagreed withthe aforementioned musical obsessions diag-nosis.4 They preferred to call the conditionpseudo-hallucinations because the hallucina-

tions (music) were perceived in the subjectivespace and were under limited consciouscontrol.

Reduction or loss of hearing can triggerauditory hallucinations.5,17 This is sometimescalled an auditory Charles Bonnet syndromeor auditory release hallucinations. Thecommon denominator with these oftenelderly people is that their otherwise impover-ished auditory consciousness becomes occu-pied with hallucinatory perceptions, in somecases music. Subjects usually have insight intothe hallucinatory nature of their experiences.These conditions seem to relate to a lack ofexcitation to cortical auditory areas andlimbic regions, as if the intact auditorycortices have become hypersensitive due tosensory deprivation.17 Brain damage or brainstimulation can alter normal musicalprocessing and create involuntary musicexperiences. For instance, a brain stem lesioninduced a temporary hearing loss and accom-panying musical hallucinations in a middle-aged man.18

Involuntary music in psychodynamicpsychologyFreud was known for his indifference tomusic, unlike many of his followers. Forinstance, Reik, a psychotherapist and ascholar, was convinced that involuntarymusical memories had a function in theservice of psychoanalysis.19 He believed thatthe INMI experiences of the analyst and thepatient carried a hidden message about theworkings of psyche, which the analyst couldperceive and benefit from in the clinical work.Another hypothesis on the function of INMIportrays music as a substitute for the presenceof a mothering person, comparing the role ofmusic to the role of dreams in Freud’s theory.This idea finds some support in the trends ofpopular culture. Hannet20 studied the lyricalcontents of 2111 “hit songs” from the first halfof 20th century. Of those, 69% were classifiedas romantic love songs. The domination oflove songs in the sample was interpreted asreflecting the universal need for love andpassion, particularly that the popular lyricsexpress “unconscious infantile attitudes... orpartial attachments to the image ofpreoedipal mother,” according to Hannett.20

Implications for practiceThis review has illustrated involuntary musicphenomena from harmless, common forms totroublesome clinical conditions. I proposedthat there is a continuum3 of phenomena ofinvoluntary music, with a variable degree ofcommonality and severity. It seems that thephenomenology of INMI and music-relatedmental disorders have much in common.INMI presents a case of intact self and realitymonitoring (insight), but inadequate controlof conscious thought. Regarding the latter,there is little evidence to support the sugges-tion that the use of mental coping strategies,12

for instance intentionally replacing an INMI

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Figure 1: Hypothetical space of imagery-based involuntary music phenomena, ranging from normal (lower left) to clinical (upperright). The axes of the space are two perceptual categories: vividness (x-axis) and disturbance (y-axis) of imagery.

Figure 2: Self-reported, retrospectively assessed frequency of INMI experiences in the everyday life of 11,910 Finnish internetusers. Error bars mark 99% confidence interval for the proportion. Modified from (1).

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References

1. Liikkanen LA. Musical activities predispose to involuntary musical imagery. Psychology of Music 2012;40(2):236-56.

2. Williamson VJ, Jilka SR, Fry J, Finkel S, Müllensiefen D & Stewart L. How do "Earworms" Start? Classifying the everydaycircumstances of involuntary musical imagery. Psychology of Music 2012;40(3):259-84.

3. Vogeley K. Hallucinations emerge from an imbalance of self-monitoring and reality modelling. Monist 1999;82(4):626.

4. Zungu-Dirwayi N, Hugo F, van Heerden BB & Stein DJ. Are musical obsessions a temporal lobe phenomenon? Journal OfNeuropsychiatry And Clinical Neurosciences 1999;11(3):398-400.

5. Evers S & Ellger T. The clinical spectrum of musical hallucinations. Journal of the Neurological Sciences 2004;227(1):55-65.

6. Podoll K. Musical palinacousis as an aura symptom. In: Neurology of music, ed. Rose, F.C. 2010; 221-35. London:Imperial College Press.

7. Hubbard TL. Auditory imagery: Empirical findings. Psychol. Bull. 2010;136(2):302-29.

8. Halpern AR & Zatorre RJ. When that tune runs through your head: A pet investigation of auditory imagery for familiarmelodies. Cerebral Cortex 1999;9(7):697-704.

9. Liikkanen LA. Inducing involuntary musical imagery: An experimental study. Musicae Scientiae 2012;16(2):217-34.

10. Kvavilashvili L & Mandler G. Out of one's mind: A study on involuntary semantic memories. Cognitive Psychology2004;48(1):47-94.

11. Bailes F. The prevalence and nature of imagined music in the everyday lives of musical students. Psychology of Music2007;35(4):1-16.

12. Beaman CP & Williams TI. Earworms (‘stuck song syndrome’): Towards a natural history of intrusive thoughts. BritishJournal of Psychology 2010;101(4):637–53.

13. Berrios GE. Musical hallucinations. A historical and clinical study. The British Journal of Psychiatry 1990;156(2):188-94.

14. Hermesh H, Konas S, Shiloh R, Dar R, Marom S, Weizman A & Gross-Isseroff R. Musical hallucinations: Prevalence inpsychotic and nonpsychotic outpatients. Journal Of Clinical Psychiatry 2004;65(2):191-7.

15. van der Zwaard R & Polak M A. Pseudohallucinations: A pseudoconcept? A review of the validity of the concept, related toassociate symptomatology. Comprehensive Psychiatry 2001;42(1):42-50.

16. Terao T & Ikemura N. Musical obsessions or hallucinations? Journal Of Neuropsychiatry And Clinical Neurosciences2000;12(4):518-9.

17. Griffiths TD. Musical hallucinosis in acquired deafness - phenomenology and brain substrate. Brain 2000;123(10):2065-76.

18. Murata S, Naritomi H & Sawada T. Musical auditory hallucinations caused by a brainstem lesion. Neurology1994;44(1):156.

19. Reik T. The haunting melody: Psychoanalytic experiences in life and music, 1953; 380. New York: Farrar, Straus and Young.

20. Hannett F. The haunting lyric - the personal and social significance of american popular songs. Psychoanalytic Quarterly1964;33:226-69.

song with another (musical displacementstrategy), are effective in modulating thefrequency, duration, or disruptiveness of INMI.

An important characteristic of INMI is highinter-individual variability. Even thoughnearly everyone has experienced it, thefrequency and the nature of the experienceis different from person to person.1 It is note-worthy that the majority of people experi-encing INMI several times a day find itcompatible with everyday life.1,12 An inter-esting parallel between INMI1 and musicalhallucinations13 is the female preponder-ance, although this is not characteristic ofmental illness such as schizophrenia ingeneral. For clinical practice, it is important tounderstand that even nearly constant, invol-untary musical imagery may not indicatemental disorder if it does not impedeeveryday life. I believe future work on thetopic is needed to clarify diagnostic criteriafor OCD and schizophrenia to distinguishtheir features from “normal” INMI. Thus far,brain research techniques successfully usedfor imaging voluntary imagery and hallucina-tions have not been able to capture INMI, butwe can hope future efforts will bring insightsfrom the neural level to help diagnose invol-untary music phenomena. l

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Speaking at an interactive webinar, Professor RayChaudhuri discussed the European Infusion(EuroInf) survey, part of the EUROPAR project

endorsed by the EPDA and involving over 14 centresacross Europe. This survey was presented as aposter at the MDS meeting in Dublin and alsopresented as one of the highlights at the Dublincongress earlier this year in June. This ongoing multi-centre observational study across several centres inthe UK and Europe compares the two infusionaltherapies for advanced Parkinson's disease - subcu-taneous apomorphine and intrajejunal levodopa.

The study focuses on motor and non-motor symp-toms and their cumulative effect, namely quality oflife. While not a randomised placebo-controlledstudy, the outcome measures used (UPDRS III and IVfor motor symptoms, NMSS for non-motor symptomsand PDQ-8 for quality of life) reflect good clinicalpractice in a ‘real-life’ population. Aiming ultimately tohave 50 patients in each treatment arm, the study hasalready recruited over 40 patients on levodopa and37 on apomorphine. Because the two groups do notmatch identically, the study looks at the effect size ofthe two interventions and numbers needed to treat.

With regard to inclusion criteria, these reflectexisting clinical practice across Europe for treat-ment with advanced therapies, said ProfessorChaudhuri. Not included are patients who aredemented or have significant cognitive problems,those with a diagnosis other than Parkinson'sdisease or where the Parkinson's diagnosis is uncer-tain, and patients whose response to levodopa isfailing. Patients included in the study are thereforeessentially those considered fit for further therapyin whom deep brain stimulation using the subthal-amic nucleus or globus pallidus internus is notappropriate.

Summarising the observations from the EuroInfsurvey Professor Chaudhuri outlined that infusionsof both apomorphine and levodopa worked well interms of UPDRS-III, but apomorphine had a verystrong effect on motor symptoms, perhaps notsurprisingly since previous studies have shown thatapomorphine can often quite dramatically return apatient who is otherwise ‘off’ and bradykinetic toessentially normal motor function. In addition, thestudy found that apomorphine improved certainnon-motor symptoms, though the effect on dyskine-sias was not quite as good as might have beenexpected, perhaps because apomorphine therapywas given as monotherapy in only a few centres andwas often associated with concomitant use of oraldopaminergic treatment. Levodopa on the otherhand was generally given as monotherapy. However,the effect of apomorphine on the non-motor symp-toms scale, as well as on quality of life, was as strongas in the levodopa arm.

Addressing the availability of infusion treatments

Professor Chaudhuri noted that even in well estab-lished Parkinson's disease treatment centres thenumber of patients receiving these therapies is low.Clearly a significant number of patients suitable forapomorphine or levodopa are not being offeredthese interventions. This may be due to non-avail-ability of the relevant expertise or the supportingservices required, but perhaps also because clini-cians are not familiar with these treatment strategies.By contrast, deep brain stimulation is a well recog-nised therapeutic option with a good evidence basefrom randomised controlled trials. However, toProfessor Chaudhuri’s knowledge, deep brain stimu-lation therapy has yet to be examined holisticallyusing the validated non-motor scale used forapomorphine and levodopa in the EuroInf survey.For patients who cannot undergo deep brain stimu-lation because of their age, or because they havecognitive impairment or depression, infusion withapomorphine or levodopa provides an alternativetherapeutic option.

Looking to the future the aim is therefore to add athird arm to the EuroInf survey to compare amatched group of patients undergoing deep brainstimulation, as well as a fourth comparator armcomprising patients who have not received any ofthese advanced therapies and who instead continueon conventional best medical therapy. Such a cohortexists in the UK, where funding streams are some-what different to other countries in Europe.Professor Chaudhuri stressed that access to treat-ment with apomorphine, levodopa and deep brainstimulation is very variable. A good state-of-the-artParkinson's disease centre should be able toprovide access to all three therapies, based oninformed patient choice. This is not currently thecase. Patients can be influential here. ProfessorChaudhuri noted that, empowered by initiativessuch as expert patient groups, patients arebecoming better educated about Parkinson'sdisease and its potential treatments. In addition, themedia has considerable influence in this area.

Impulse control disorders continue to be a majortopic of discussion in Parkinson's disease. ProfessorChaudhuri outlined that the relationship betweenimpulse control disorders and oral therapy, particu-larly dopamine agonist therapy, remains unclear.However data from his own group suggest that therate of impulse control disorders occurring withlonger-acting dopaminergic therapies, particularlydopamine agonists, is actually low compared to theoverall prevalence. Single infusional therapies (aspossible with apomorphine) appear not to be asso-ciated with a high rate of impulse control disorders.Professor Chaudhuri stressed that this is an anec-dotal observation, however, which needs to besupported by evidence from a controlled study ordata from a large case series like the EuroInf survey.

The EuroInf survey

S P EC IA L F EATURE

Dr Prash Reddy who presented theposter at MDS.

A grant was provided by Britannia Pharmaceuticals Ltd as a contribution towards the production and design costs of thisarticle. Britannia Pharmaceuticals sponsored the Webinar held during the Movement Disorder Society’s 16th InternationalCongress of Parkinson’s Disease and Movement Disorders held 17-21 June 2012.

Prof Ray Chaudhuri, who spoke at thewebinar, is a neurologist with expertisein movement disorders and non-motorissues, particularly in relation toParkinson’s disease. Based at theNational Parkinson Foundation Centreof Excellence at King’s College Hospital,King’s College, London, he works forKing’s Health Partners, which includesLondon’s King’s College Hospital, and StThomas’s and Guy’s Hospitals.

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T he benefit of 1:1 psychodynamic counsellingand couples counselling to people who havesuffered from stroke was investigated in this

pilot service development project. This work aimedto demonstrate the importance of provision ofstroke psychological services in the community andexplore the issues that arose in the course oftherapy provided with individuals and couples seenin the course of a year.

Method: seven individuals and four couples wereseen. Response to therapy was measured using TheDepression, Anxiety and Stress Scales.1

Findings: With this small sample of participants,pre-assessment and post-assessment evaluationshowed positive changes on the DASS. Assessmentsrevealed high severities of stress, anxiety anddepression post-stroke. Important and recurringthemes of grief, loss, attachment, dependency, deathanxiety and fear are shown.

Discussion: This work adds to the well knownneed for increased specialist psychological supportfor those experiencing moderate – severe mooddifficulties following stroke by illustrating the appro-priateness of this specific clinical approach. In addi-tion, the value of long-term support groups wereshown as a lifeline and focus for a person’s week.

IntroductionLong-term disability is experienced by a third ofpeople living in England who have had a stroke. Thisdisability includes psychological difficultiesfollowing a stroke. There are 900,000 people inEngland who have had a stroke, and 300,000 of thesepeople are living with moderate to severe disabili-ties. Stroke is the third largest cause of death.2

Advances in acute care mean that we are seeingimproved survival and reduced morbidity. However,this means that some of the subtler consequences ofstroke are now more apparent in the day to day inter-actions with clinicians. In particular the cognitiveand emotional consequences of stroke are increas-ingly recognised by clinicians and service users whoare seeking help for these problems.

There are a range of long-term difficulties thatfollow stroke that can impact on a person’s mood. Itis well recognised that the consequences of a strokecan be experienced as a massive, traumatic event ina person’s life. It can cause feelings of crisis andsuicide, and dramatic changes to a person’s phys-

ical, emotional and social well-being.3 Followingthe shock of a stroke, a person can feel anxious,stressed and depressed. Patients report statementssuch as “you feel like you want to stay in bed andcan’t face things anymore,” “Tasks that were simpletake so much effort and concentration,” “It is easy tocry and hard to control,” “You can be snappy andnot mean to be,” “You want to avoid people, becauseyou don’t want anyone to see you,” “It feels devas-tating,” “It feels like you’ve lost yourself.”

These are compelling reasons why any therapistwould wish to seek to reconsider the servicesprovided alongside existing services. Typically inthe UK at present it is routine for physiotherapy,speech and language therapy, and occupationaltherapy services to be provided. There has beenrelatively less attention to the psychological needsof patients in commissioning guidelines despite alongstanding recognition of the need to providesuch services.4

Psychodynamic counselling is an approach thatenables a person who is struggling to cope with lifeto have space to explore their feelings, and findways to recover from depression, stress and anxiety.Counselling supports people to move from stages ofcrisis to develop realistic goals and make adjust-ments to their self-concepts.5 This process can beexceptionally challenging and can feel like a fightand a battle to keep going.

Psychodynamic counselling also reflects on pastexperiences that have relevance to difficult recentlife events. For example, a husband being unable toprovide for his family triggered feelings about a pastrelationship that had not been talked about andgrieved for.

There are past studies that look at psychothera-peutic interventions for working with stroke. Forexample, Cunningham’s case study6 describes theuse of personal construct therapy with severeaphasia. Oliveira et al7 discuss in detail psychody-namic work with physically disabled patients. Thereis also plenty of literature looking at psychothera-peutic approaches to pain.8 In addition, Wilson etal’s work on neuropsychological rehabilitationcovers various approaches including social andpersonal identity, systemic family therapy, and narra-tive therapy.9 This pilot service has focused on theuse of another psychotherapeutic approach calledpsychodynamic counselling. Many aspects ofgeneral psychodynamic theory can be useful whenworking with those experiencing strokes. In thisshort introductory review we will highlight a

PsychodynamicCounselling after Stroke:A pilot service developmentproject and evaluation

R E H A B I L I TAT I O N A RT I C L E

Alys Mikolajczykis a Senior Speech and LanguageTherapist based in Ely, working forCambridgeshire CommunityServices NHS Trust. She completedher post-graduate training inpsychodynamic counselling in2006.

Andrew Batemanis a Physiotherapist who did a PhDin Neuropsychology in 1996.Manager at the Oliver ZangwillCentre for NeuropsychologicalRehabilitation since 2002, he hasalso recently taken on clinicalleadership of CCSNeuroRehabilitation services.Research is supported by the NIHRCLAHRC Cambrigeshire andPeterborough.

Correspondence to:Andrew Bateman,Neurorehabilitation Clinical Lead,Oliver Zangwill Centre,Cambridgeshire CommunityServices NHS Trust.

Acknowledgements:• NHS East of England Stroke

Psychology Group• Frances Igbonwoke• Anglia Stroke and Heart

Network for funding this work • Dr Lucy King

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number of themes including grief, loss,mourning, attachment and fear.

A key theme is grief and mourning. After astroke, a person can feel lost. Counselling triesto help a person rediscover parts of his orherself that feel lost. Stroke specific psychody-namic counselling helps a person to talkabout their sense of loss after their stroke andto encourage a person through their rehabili-tation. It also aims to help a person findresilience to cope with the long-term conse-quences of a stroke. An added dimension ofstroke experienced counselling is the provi-sion of information about expected recovery,ability to answer some general medicalconcerns, and to refer on to other profes-sionals such as medicines management.

Understanding unconscious object rela-tions such as the ‘lost object’ is important topsychodynamic counselling. In relation tostroke, the lost object may be a part of theself.10 Leader proposes ‘Grief is our reaction toloss, but mourning is how we process thisgrief.’ (p.26). He describes how we anticipatehearing a loved ones voice on the phone afterthey have died. This could be compared tosomeone thinking back to their pre-stroke selfand seeing themselves back at work or drivingthe car. One hypothesis that underpins thera-peutic interventions is that the more thesememories are processed, feelings begin toimprove. Through therapeutic conversations,the sense of discrepancy from ‘pre-stroke’ selfmay be reduced.9 For some, this can be a longand difficult process after a stroke. The chal-lenge for counselling following a stroke is tosupport a person to rediscover parts of theirself and develop an adjusted self-concept.Many people also have loss in their lives wherethere is mourning still to be done. Counsellinghelps to look at the unconscious processes ofgrief and mourning to support people torecover from depression.10

Following a stroke, a person often feels alack of confidence and insecurity in theirsense of self and especially how they feelabout their body. Blando11 describes theoutcomes of Fortner & Neimeyer’s research(1999, p.90) that found higher death anxiety inolder people with more psychological prob-lems and a reduced sense of self. Feelinganxious about the prospect of death is knownas death anxiety. Awareness of death can be acause of anxiety particularly after middleage.11 Near-death experiences such as sufferinga stroke and the memories of the daysfollowing a stroke can evoke high anxiety.Death anxiety can restrict how someoneengages with life, and this could includerestrictions to their recovery and their abilityto socialise.

Attachment is also important to anypsychotherapeutic approaches. The trauma ofa stroke can affect attachments, for example,there can be increased dependency on part-ners and new strong attachments to healthcare staff. The stroke may amplify previous

attachment patterns such as ‘anxious avoidant’and ‘anxious resistant’ attachment types(Blando, 2011, p.111-p.112). If someone feelsvulnerable, they may feel as insecure as theydid as a child. A stroke can cause a person tofeel frightened. The support of others helpsalleviate these feelings, and enables a personto cope better. There may especially be diffi-culties if a partner has died or a key attach-ment figure is unavailable. In psychodynamicworking, the type of transference and attach-ment type can be closely associated.11

In light of these themes, this project wasconceived following Speech and LanguageTherapist Alys Mikolajczyk’s post-qualificationtraining in Psychodynamic Counselling atCambridge University Continuing Education.Funding from the local Stroke and HeartNetwork to implement this project was soughtand approved because it was recognised thatthere was a lack of service descriptions andevaluation of work in this field locally, despitethe need for psychological support outlined inThe National Stroke Strategy for England (2007).

MethodThis service was initially advertised to the reha-bilitation team to support participants and theirfamilies experiencing low mood since a stroke.As a consequence, referrals mainly came fromthe neurological rehabilitation multidiscipli-nary teams, though all GP practices in thecatchment area were sent a letter and leaflets.People could also self-refer. This service aimedto be flexible by seeing both individuals andcouples, and aimed to be participant-led andflexible to circumstances. Domiciliary andoutpatient sessions were offered.

The number of sessions offered wasdependent on the outcome of the initialassessment and severity of anxiety, stress anddepression that was shown. Initially up totwelve sessions were offered, though as theresults will show this changed as the projectprogressed.

ParticipantsIn total, 15 people have been seen over thetime period of this project, seven people seenindividually and four couples (see Table 1 fordemographics). Due to the high severity ofdepression, anxiety and stress fewer peoplewere seen than anticipated in the originalgrant application. At point of referral, 10 partic-ipants had experienced a stroke in the last twoyears, and one man experienced a stroke fouryears previously. Three participants werereferred after a second stroke. All of thesethree participants reported that they had notreceived any psychological support after theirfirst strokes and did not know that helpexisted.

Seven participants were over 65 years and 8participants were under 65 years. Only oneparticipant had severe speech difficulties, andtwo other participants had mild-moderatespeech and language difficulties.

Outcome Measures: The Depression, Anxiety and Stress Scales1

were used with the majority of participants.‘The Visual Analog Mood Scales’12 were usedwith only one couple. As Table 2 shows, overalloutcome measures are very positive andencouraging. Individualised assessment andinterview also helped to evaluate outcomesfor participants, and for one participant achange questionnaire seemed appropriate.

ResultsAs this project developed, the level of anxietyand depression in this caseload was found tobe moderate to severe. Seven of the peopleseen were experiencing at least one severerating on the DASS (The Depression, Anxiety,Stress Scales). Four participants needed to beconsidered for risk issues due to suicidalideation and one attempted suicide near to thestart of therapy. With two participants, otherservices were involved, specifically psychiatryand a community psychiatric nurse in onecase and the crisis team and mental healthcare coordinator in the other. More detailedcognitive assessment was also completed fortwo participants by a clinical psychologistspecialising in stroke. These complex partici-pants required more time investment andliaison with other professionals. As a conse-quence of the overall severity, only three partic-ipants were offered the originally-planned sixsessions. All other participants were offeredmore sessions due to need, risk and multiplelife issues. As Table 1 shows, in some cases thiswas substantially more (range 6-27 sessions),demonstrating the need for long-term treat-ment for some participants.

One referral was a self-referral from a manand his wife, who were looking for strokerelated counselling due to this man’s severedepression and emotionalism. All other refer-rals were from the multidisciplinary team anda PhD student. Couples were not always seentogether and sometimes only the participantexperiencing the stroke was seen. This wasflexible to daily circumstances. As Table 1shows, this service was mainly domiciliary,though three participants were seen both attheir homes and as outpatients. Dominantconcerns were losses in their lives such as lossof occupation, mobility, income, self-esteem,self-worth and loss of previous overall lifestyle.

It seemed that a psychodynamic approachwas appropriate for most of the people seen.With participants 2, 7 & 11 however (See Tablesabove), the psychodynamic approach was notcentral. Participant 2 required a supportiveclient-centred relationship. She requiredcompanionship and was introduced to asupport group during the duration of oursessions. Participant 7 was one of the laterparticipants in the study and wanted furthersupport to understand his stroke, including thetype of stroke he experienced four years previ-ously. He required factual information abouthis stroke and needed to talk about his difficul-


ACNRSO12_Layout 1 28/08/2012 23:22



ties. This participant also required furtherspeech and language therapy guidance forreading and writing, and work on confidence.Participant 11 (a couple) required a mixture ofsome psychodynamic counselling in the earlysessions but also communication advice andsupport. The couple also benefitted hugelyfrom the long-term support groups they

attended (an aphasia support group in theirlocality). With this couple, their mood deterio-rated when a support group was having breakdue to staffing problems. In this case, it seemedthat long-term conversational support wasmore valuable than counselling as it providedopportunity to get out of their home andsocialise. For all these three participants (2, 7,

11), negative mood could be linked to level ofconversational support available to them.

Level of daily activity was a recurring themefor many participants. Reduced ability toparticipate in daily activities and boredom athome has been a pattern for participants andnegatively reinforced low mood. This hasshown the crucial need for long-term support

Findings: Table 1 – Demographic Table

Couple/Individual Age of person Time Post-Stroke Location Number of sessions Referred by Themes ofwith Stroke and Total Face – the Counselling

Face Hours

1. Individual: Female 81 5 months Home visits 6 Sessions Speech and Isolation and loneliness.Left middle + 1 cancelled session Language Loss of mobility and social circle.Cerebral Artery Therapist

2. Individual: Female 85 7 monthsHaemorrhagic Stroke Home visits 6 sessions PHD Student Loss. Relationship pressures.

3. Individual: Female 64 3 months Home visits 14 sessions (in addition, Physiotherapist Multiples losses. Boredom.Right Posterior some gaps and breaks) Massive impact of visual losses.MCA Infarct

4. Individual: Female 67 6 months Home visits 13 sessions Ward Multiples losses. Grief andRight Haemorrhagic and outpatient Consultant Mourning. Attachment. Fear.Stroke sessions Pain. Rehabilitation support

and advice.

5. Individual: Female 51 2 months post Home visits 10 sessions Occupational Anxiety. Loss. Family issues.2nd Stroke Therapy General stroke support and

advice.

6. Individual: Male 51 7 months Since Home visits 17 sessions Occupational Boredom. Self-image and sense 2nd Stroke Therapy of self. Multiple losses.

Feeling inadequate. Pain.

7. Individual: Male 68 Left Parietal Infarct Outpatient and 6 sessions PHD Student Understanding stroke. Home visits Confidence. Reading and writing.

Loss. Pain.

8. Individual sessions 52 23 months Outpatients 27 sessions Self-referral Acceptance of stroke. Multipleand couple sessions: post stroke sessions and a (plus some breaks/holiday losses (occupation, movement,Husband had stroke few Home visits and 2 sessions cancelled) social, hobbies). Grief and

mourning. Dependency. Fear. Vulnerability. Death Anxiety.

9. Individual and 73 2 months Home visits 13 sessions Occupational Communication difficulties.couple sessions Left basal ganglia Therapy Fear. Frustration. Tiredness.Husband had stroke haemorrhage. Dependency.

10. All couples: 52 1 month post Home visits 9 sessions Speech and Loss. Rehabilitation andHusband had stroke 2nd Stroke Language expectations. Social anxiety and

Therapy confidence.

11. All couples 75 10 months post Home visits 9 sessions Speech and Pervading unpredictable lowHusband had stroke Left MCA Stroke Language mood. Loss. Confidence.

therapy Self-esteem. Attachment.

Findings: Table 2 – Baseline and Outcome Measure Table

Participant Depression, Anxiety and Stress at Initial Assessment Depression, Anxiety and Stress at End of sessions

1 Extremely Severe Moderate Moderate Normal Normal Mild - Normal

2 Refused to complete outcome measure questionnaires

3 Extremely Severe Moderate Severe Moderate Normal Normal

4 Extremely Severe Extremely Severe Extremely Severe Moderate Severe Moderate

5 Extremely Severe Extremely Severe Severe Mild Extremely Severe Moderate

6 Extremely Severe Extremely Severe Extremely Severe Still high. Under Mental Health Teams.

7 Normal Normal Normal Not repeated. Needed factual information about stroke not previously received.

8 Extremely Severe Mild Moderate Severe Normal Mild–moderate

9 Normal Moderate Normal Mid–Normal Normal Mid–NormalEnd–moderate Normal Normal

10 Normal Moderate Moderate–Severe Mid–Normal Mid–Moderate Mid–Mild

11 (VAMS Used) Scored differently to DASS, some improvement seen especially on measures of anger and tension.

ACNRSO12_Layout 1 28/08/2012 23:22



groups and health professionals to supporttransition back to accessible social andpleasure activities if possible, before dischargefrom therapy.

Two of the participants experienced severephysical pain during the course of the sessions.It was clear that this influenced their mood andcould be associated with suicidal thoughts. Painmanagement was shown to be crucial for theseparticipants. For client 6, improvements wereharder to see on the DASS and were unchangingon objective outcomes. This participanthowever began to demonstrate positivechanges, and though he rated ‘I felt I hadnothing to look forward to’ highly (3), he haddescribed looking forward to a trip out and hissocialisation was improving. In addition,suicidal comments stopped during the sessions.

Most participants were able to completethe outcome measures, though help wasrequired by one participant to be clear aboutthe meaning of elements of the rating scale.This help was by writing out the choices of 0-3in a larger font and by giving reminders foreach question. With the Visual Analog MoodScale, the scales were completed together withthe couple and differences were discussed asthe scales were completed. Sometimes thesedifferences were not anticipated, so this was initself useful to the counselling work.

DiscussionImportantly this service development projecthas identified people experiencing moderateto severe stroke associated depression, stressand anxiety. Most of these people werealready on antidepressants and were in needof psychological support after stroke. It seemsto us convincing that there is a need for aservice such as this, especially when some riskof suicide has been shown. More specificallyfor most of these people, support was neededfor their feelings of grief, loss, death anxietyand fear.

With the majority of participants, there weremultiple issues as well as a stroke. In somecases, a person’s stroke brought out otherissues that were repressed and that had notbeen spoken about before. In other cases, thestroke had coincided with other life issues,

such as the loss of parents and businesses, andwith the poor health of a family member. Examples of issues for participants covered inthis counselling work:• Recent loss of a mother and similarities in

medication and mobility to mother.• Forced retirement, loss of job, loss of busi-

ness. • Loss of mobility and some participants

already had losses prior to stroke, such asimpaired vision.

• Other medical challenges such as epilepsy,heart attacks, arthritis.

• Difficult family relationships e.g. step-relationships, fostered children.

• Previously undisclosed abuse. • Losses of siblings at a younger age.• Previous relationship break-ups and

divorce. The trauma of stroke has been central to all thecounselling, but exploration of relevant andrelated issues such as those mentioned abovewere vital for counselling to be beneficial.

Accessible services that doctors and healthprofessionals know about and know how torefer to are crucial for those experiencingstrokes. For three participants that did nothave access to psychological support servicesafter their first strokes, we can questionwhether their assessment outcome measureswould have been better at the start of thispilot. A referral pathway for psychologicalsupport needs to be clear to all GP services, assome participants’ needs after their first strokewere not recognised and there were limitedservices to refer to. Some participants said, “Ididn’t know services existed; I didn’t get anyhelp after my first stroke.”

We argue that commissioning of Stroke-specialist psychological services is needed forlong-term post-stroke. Without this there willremain poor service provision, such as failingto meet The National Stroke Strategy forEngland (2007) guidelines.13

A harder element to articulate in a servicedevelopment project is the observation thatpsychodynamic counselling ‘felt’ appropriateto the counsellor for the majority of partici-pants, especially participants, 3, 5, 6, and 8. Itwas also felt some participants could have

continued to benefit from longer termsessions. One reason was because thedynamic of the sessions seemed appropriatein terms of the application of psychodynamictheory and the rapport, transference and inter-pretation of feelings and emotions thatevolved.

This service evaluation has shown the valueof a stroke experienced counsellor. Forexample some of the counselling was aimedat helping the individuals to understand ‘whatis normal’ after stroke. The counsellingprovided included sharing of expert knowl-edge about stroke and gave support andunderstanding of rehabilitation. Tiredness wasa recurring issue with most of the participantsseen. In particular, partners understandingissues such as tiredness was important. ‘TheStroke and Aphasia Handbook’14 was a muchappreciated resource and reading about theseissues was reassuring for some people.

The DASS was shown to be a good acces-sible outcome measure for these clients as itdirected assessment and understanding of thedegree of stress, anxiety and depression. It isinteresting to note from the results that thecounselling appeared to be more effective atreducing depression than anxiety for partici-pants 4, 5 & 10. With a psychodynamicapproach, depression and stress showedgreater improvements. It is indicated thatfurther sessions may be needed to reduceanxiety.

At the outset of this project, some groupwork with participants was anticipated, suchas a carers’ group. 1:1 work and couplessessions were however shown to be the mostappropriate for this particular group of partici-pants.

This service development project and eval-uation has identified that increased psycho-logical support is needed for people followingstrokes who have moderate-severe depression,stress and/or anxiety. This small evaluationproject demonstrates that increased clinicalpsychology provision and/or provision ofcounsellors/psychotherapists specialising instroke are needed as part of a permanentlyfunded service. This service has shown that 15participants needed – and benefited from –

Participant 4 (from Tables 1-2, female, aged 67) was on antidepressantsand despite this stress, anxiety and depression were rated as extremelysevere initially. There was some risk of self-harm due to low mood andat one point clear suicidal ideation. Losses were multiple, not onlysevere mobility losses due to her stroke, but loss of occupation andgrief for her mother who had recently died.

Sessions were focused on the mourning her mother, alongside herown mourning of previous role. In addition, the counselling wassupportive and client-centred and followed her through her rehabilita-tion when the level of recovery was uncertain.

There was clear reliance on attachment figures with strong depend-ency in the first year post stroke. As the sessions progressed, there was

less dependency. In our final sessions, she stated, “I’m not worried ofsitting alone. Not terrified anymore.”

Outcomes improved from extremely severe to lower levels as shownin Table 2. She was later referred back for a further four sessions due toconcern from another health professional that her levels of depressionhad deteriorated again. She was however maintaining improvementwell. Her level of depression had however been extremely severeinitially and some level of enduring depression was likely. This is inter-esting as it shows different perceptions of depression. Participant 4 feltthat the counselling was very beneficial to her and described it as, “Arelief through a difficult time.” Since these sessions, follow-up appoint-ments have indicated that she has maintained the gains that she made.

Individual case study with more details of this counselling service.

Case Study, illustrating how losses are discussed in therapy.

ACNRSO12_Layout 1 28/08/2012 23:22



psychological support that was previ-ously unavailable. This service devel-opment project and evaluation wascompleted in one day per week for ayear including travel and administra-tion. If services such as this arecontinued, further people havingstrokes could benefit. This will havebenefits for the health and well-beingof those experiencing strokes andtheir families, and positive benefits torehabilitation outcomes.

ConclusionThis service development project andevaluation has identified and filled anunmet need for psychological provi-sion after stroke in this locality. All theparticipants were appreciative of theservice and felt that they benefited. Theresults show that participants’ overallmood improved after receiving thisservice. The DASS was an appropriatemeasure to assess mood and enabledchanges in stress, anxiety and depres-sion to be assessed and evaluated.

Psychodynamic counselling wasshown to be a potentially effectivepsychotherapeutic approach and avaluable extension to the communitymultidisciplinary rehabilitation

approach. This evaluation addsfurther to the literature and evidencebase of the effectiveness ofpsychotherapeutic approaches withstroke. It has also been identified thatthe commissioning of a well-struc-tured psychological support serviceis needed. Anticipated benefits arelikely to include: reduced demand onGPs due to reduced risk, supportingGPs to meet higher ratings on theirquality and outcomes framework andtherefore making cost savings, andthe provision of a high quality servicethat meets the quality markers of TheNational Stroke Strategy (Departmentof Health, 2007).

Helping to support a person to feelbetter about life can only be valuable,and therefore this has been a veryworthwhile project. One participant’spositive feedback through a changequestionnaire made the followingcomments about the counsellingsessions.

“A relief through a difficult time”“I couldn’t have stayed in hospital if Ididn’t have you.”“Not worried if sitting alone. Not terri-fied anymore.”

1. Lovibond SH, Lovibond PF. (2004) DASS: The Depression, Anxiety, StressScales. 2nd ed. School of Psychology, University of New South Wales,Sydney, Australia.

2. National Audit Office (2005) NHS: Department of Health: ReducingBrain Damage: Faster access to better stroke care.

3. Kvigne K, Kirkevold M, Gjengedal E. ‘Fighting back – Struggling tocontinue life and preserve the self following a stroke.’ In: Health Care forWomen International, 2004;25:370-87.

4. Royal College of Physicians (2008) National Clinical Guidelines forStroke. Prepared by the Royal College of Physicians intercollegiatestroke working party. 3rd ed.

5. Banks P. Pearson C. ‘Parallel lives: younger stroke survivors and theirpartners coping with crisis.’ In: Sexual and Relationship Therapy2004;19(4):413-29.

6. Cunningham R. ‘Counselling someone with severe aphasia: an explo-rative case study’ In: Disability and Rehabilitation 1998;20(9):346-54.

7. Oliveira RA, Milliner EK, Page R. ‘Psychotherapy with PhysicallyDisabled Patients.’ In: American Journal of Psychotherapy.2004;58(4):430-41.

8. Hsu MC, Schubiner H. ‘Recovery from Chronic Musculoskeletal Painwith Psychodynamic Consultation and Brief Intervention: A Report ofThree Illustrative Cases.’ In: Pain Medicine. 2010;11:977-80.

9. Wilson BA, Gracey F, Evans JJ, Bateman A. (2009) NeuropsychologicalRehabilitation: Theory, Models, Therapy and Outcome. CambridgeUniversity Press, UK.

10. Leader, D. (2009) The New Black: Mourning, Melancholia andDepression. London, England, Penguin Books.

11. Blando, John (2011) Counseling Older Adults, East Sussex, Routledge,Taylor & Francis Group.

12. Stern, R. (1997) Visual Analog Mood Scale –VAMS. PsychologicalAssessment Resources, Inc. USA.

13. National Stroke Strategy for England (2007) NHS: Department ofHealth

14. Parr, S. (2004) The Stroke and Aphasia Handbook. London. Connect.

REFERENCES

Monday 26th November 2012University of Warwick Conference Centre, Coventry, CV4 7AL

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ACNRSO12_Layout 1 29/08/2012 16:28


T here is always a biological element in mywork, usually human but not exclusively,however lately I have been fascinated by the

brain. This interest arose after the death of a familymember from a brain tumour. As an artist, themajority of my work involves life cycles and has attimes addressed pregnancy, the lifecycle and nestingof birds, reclamation and recycling, decay and newlife within the natural world. I wasn’t looking foranswers, reasons or even explanations linked withthis event. It merely highlighted to me what anamazing and fascinating organ the brain is. Initially Iconcentrated on the theoretical concepts, I amenthralled by how we can be ourselves, have ourown individual personality and yet everything weare, do and think has been explained by some asmerely a process in the brain, how can this be all weare? How can electro-chemical reactions within ourbrains make me an artist and you a neurologist? Andwhere does the spirit of each of us come from, andreside, within that amazing network of firingsynapses? Well, these questions I still can’t answerand they still fill me with awe. I have, however, beenlearning more about the physical construction ofthe brain and, as a sculptor who frequently workswith textiles, this grasping at an understanding of thefabrication of the brain holds another area foramazement.

In order to explore my thoughts and findings Ibegan making papercuts of the outer appearance ofthe brain, that beautiful folded and pleated, almostquilted surface. I followed this with a papercut of anartistic interpretation of neurons. Neurons, it seemsto me, really are the thread of our thoughts. Theirdelicate spidery dendrites and axons have a trulytextile, woven quality to them. For this very reason Icrocheted a neuron, but this wasn’t delicate enoughand I felt it lacked the fantastically fragile appear-ance of the real thing. This led me into an experi-ment of embroidering neurones onto dissolvablefabric so that I could make a neuron lace. I washappier with the results but currently I am trying tofind a way of making them more three-dimensionalas the flat lace doesn’t do justice to the the neuralnetworks and interconnections. I have embroidereda side view of the brain and upper brainstem, andmade a quilted version although I intend to work onthis quilting effect much more as my first attemptdoesn’t embody the sumptuous depths of thecrenellations that I want to capture. I have justfinished knitting myself a brain. I took my knitting inmy bag with me wherever I was going for the last fewweeks so I could work on it whenever I had a fewminutes. It was fantastic fun to see people’s reactionsas they often stopped me to ask what it was I wasknitting. I am trying to design a way to make a veryloose 3-D weaving based on images of thought path-ways and digitally recoloured photographs ofneuron interconnections especially the gorgeous

‘Brainbow Mouse’ images by Jean Livet, Joshua RSanes and Jeff Lichtman but it is proving to be ratherdemanding. Having recently visited the WellcomeTrust to see ‘Brains: The Mind as Matter’ exhibition Iwas captivated by the fantastic drawings of SantiagoRamon y Cajal. I am hoping to create a body of workthat will be exhibited together in order to inspireother peoples’ interest and exploration into thisfascinating organ. Particularly, I hope to encapsulatea sense of its visual beauty in physical construction,externally and internally, not just its vast, assortedand amazing functions. l

An Artist’s View of theBrain

NEUROLOGY IN ART

Jane Southgategained her BA at Chelsea School offine art and has worked as aprofessional artist from her studioin Suffolk for the last 17 years. Sheregularly exhibits, undertakescommissions and runs workshopsfor a variety of different groups.Her work is generally three-dimensional and often contains atextile element.

Correspondence to:Jane Southgate, 1 Bridges Cottages,Darmsden, Ipswich,Suffolk,IP6 8RA UK.Email: [email protected]

Knitted brain

Neuron lace

ACNRSO12_Layout 1 28/08/2012 23:22


B O O K R E V I E W S

From a nurse’s perspective, I would recommend thisbooklet as a handy reference guide to neurologicalaspects of nursing care. It is of a convenient size, to fit intouniform pockets. Its spiral binding and waterproofed cardmake it hard wearing and practical for use on a dailybasis within the workplace.

The Pocket Reference will be ideal for nurses workingin general hospital, general practice or communitysettings who encounter patients with neurologicaldiseases (either as the patient’s primary diagnosis, or as aco-existing condition). Student nurses will find it a greatintroduction to Neuroscience Nursing, as would moreexperienced nurses moving into Neurology andNeurosurgery work for the first time.

The booklet provides an easy guide to neurosciencepractice, divided into three sections. Section 1 gives anintroduction to the nervous system including diagrams

and definitions of the central and peripheral nervoussystems, the motor and sensory pathways. Section 2 is avery comprehensive guide to neurological assessmentsexplaining how to do and how to document. Section 3introduces common neurological disorders bydescribing the conditions, explaining signs and symp-toms, outlining possible investigations and possible treat-ment. Importantly, within this section, there are referencesto appropriate NICE guidelines and tips on where to gofor more information.

The format is clear, logical and easy to read. Its brevitymeans that it will be most useful as a reference forgeneral nurses and nurses new to the, often complicated,field of Neuroscience. However, the guide’s referencingand bibliographies mean that it would also be a usefulacquisition for more experienced nurses and other prac-titioners. l

Clinical Pocket Reference: Neurosciences

Authors: Juliet Bostwick andDeborah SladePublished by: Clinical PocketReference, OxfordPrice: £9.99 ISBN: 978 0 9543065 7 1

Reviewed by: Kerry Mutch, RGN, BSc(Hons) MSc, Specialist Nurse(Neuromyelitis Optica), WaltonCentre Foundation Trust, Liverpool.

This book boasts a stellar authorship from the world ofneuro-oncology with chapters written by many of thecurrent leading lights in the field from around the world.Part I contains an overview of basic principles includingpathogenesis and epidemiology of CNS Tumours and thebasic principles of therapy including surgery,chemotherapy, radiotherapy, symptom management andthe role of clinical trials. Each chapter is succinct andvery readable. There are extensive references for thoselooking for more detail. Volume II promises a more

detailed exploration of specific tumour types and neuro-logical complications of systemic cancer.

Although most likely to appeal to those with a specialinterest in neuro-oncology, the sections on neuro-imagingand principles of therapy are of wider appeal.

There are few, comprehensive and up-to-date works inthe area of neuro-oncology and this book goes a longway towards filling that gap and I would highly recom-mend it. l

Neuro-oncology Part 1 Handbook of Clinical Neurology (Volume 104)

This book provides a comprehensive review of multiplesclerosis (MS) and, pretty much, everything related to it. Itcovers historical aspects, basic science, clinical practice,psychosocial issues, and provides a glimpse into thefuture of MS research. All the chapters are easy to digestand benefit from experience and expertise of an impres-sive list of contributors.

The primer begins with a fascinating review of thehistory of MS. We are taken through an evolutionary narra-tive from initial misconceptions to Charcot’s illuminatingaccount. The numerous and, in many cases, agonisinglypainful treatments of the past are described, with chrono-logical progression to treatments more familiar in modernday practice. There are nostalgic moments too: ‘beef steakstwice daily with London porter beer’ offered to Augustusd’Este in the early 19th century sounds more appealing,albeit (slightly) less efficacious, than weekly injections ofAvonex!

A concise overview is provided on MS Genetics, high-lighting current understanding of genetic and epidemio-logical factors, bringing together knowledge attained fromyears of linkage and association studies and the explosionof information from genome-wide association studies.The ever controversial topics of viral aetiology and

vitamin D are also explored.The initial part of the Neuropathology section may have

been ‘common knowledge’, but covered aspects ofdemyelination, remyelination, and axonal loss of interestto me as a trainee. I was pleased to see that the section ondiagnosis was not just a review of the Revised McdonaldCriteria, or a lesson in lesion-counting. Specific chapterswere also included on supportive paraclinical tests(imaging, CSF, and evoked potentials) and their utility.Given the date of publication, the most recent (2010) revi-sions to the criteria were not included.

A large section of the book is devoted to the clinicalmanifestations of MS. Challenging clinical scenarios suchas cognitive impairment, fatigue, pain, sexual dysfunction,and reproductive issues are covered in informative chap-ters. We are taken on a whistle stop tour of paediatricmultiple sclerosis in a level of detail ‘just right’ for neurol-ogists in adult practice. The review of immune therapiesvery neatly summarises relevant trials.

Exactly as it says on the cover, ‘Primer on MultipleSclerosis’ provides a second-to-none reference for traineesintending to work in the field of MS Neurology or forgeneral neurologists with a significant MS workload,which probably covers most of us.l

Primer on Multiple Sclerosis (OUP)

Editors: Wolfgang Grisold andRiccardo Soffietti Published by: Elsevier Price: £162.65 ISBN: 978-0444521385

Reviewed by:Simon Kerrigan, NeurologyRegistrar, Edinburgh Centre forNeuro-oncology, WesternGeneral Hospital, Edinburgh.

Editors: Barbara S Geisser Published by: Oxford UniversityPress Price: £45.00 ISBN: 978-0195369281

Reviewed by:Saif Huda,Clinical Research Fellow,Nuffield Department of ClinicalNeurosciences,John Radcliffe Hospital Oxford.

ACNRSO12_Layout 1 28/08/2012 23:22

Save 15%: retail £9.99 ACNR readers’ price £8.50 P&P free

NEUROSCIENCE NURSING FEATURE

his new handbook provides practical support for the nursecaring for patients with neurological conditions. Trainees

will find this an essential learning and reference tool, while trainers and mentors will find the book invaluable as atraining aid. Neuroscience nurses will find this a useful update on key topics.

To order the complete book with special offer for readers of ACNR, go to www.clinicalpocketreference.comand at check-out enter Offer Code ACNR1213

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ACNR are publishing selectedcontent from Clinical PocketReference: Neurosciences over thenext few issues... neurosciencenurses will find this a useful aidememoire. Keeping a copy on theward will be ideal for reference and teaching.

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Reviewer’s comments:

From a nurse’s perspective, I recommend this booklet as ahandy reference guide toneurological aspects of nursingcare.... The format is clear,logical and easy to read.

...It will be most useful as areference for general nurses andnurses new to Neuroscience.However, the referencing andbibliographies mean that it wouldalso be a useful acquisition formore experienced nurses andother practitioners.

ACNR

T

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IntroductionThe term high grade glioma(HGG), is usuallyused to describe WHO grade III and IV tumours.The incidence of these tumours is approximately5/100,000 person years in Europe and NorthAmerica.1 Of these, glioblastomas account for 60to 70%, anaplastic astrocytomas for 10 to 15%,anaplastic oligodendrogliomas and anaplasticoligoastrocytomas for about 10%, whileanaplastic ependymoma and anaplastic gangli-oglioma make up the rest.

There has been a recent increase in incidenceof HGGs in the Western world, particularly in theelderly population. This probably reflects the easyavailability of vastly improved diagnosticimaging.2 The median age of onset is 45 for GradeIII and 60 for Grade IV tumours.3 There is a 40%greater incidence among males.4

In the majority of cases, no causative factors canbe attributed. However, exposure to ionising radia-tion, such as from treatment of previous cancer isan established risk factor.5 Many other factors havebeen studied including head injury, foods with N-nitrose compounds, electromagnetic fields,smoking and most recently usage of cellularphones, all of which have not been shown to berisk factors in the development of HGG.6-8

Approximately 5% of patients with HGG have afamily history of gliomas.9 Some of these arefamilial and associated with genetic syndromessuch as neurofibromatosis types 1 & 2, Li-Fraumeni syndrome and Turcot’s syndrome.Recent studies have also shown links betweenDNA repair genes and tumour aggressiveness.10-12

PresentationMost patients with HGG present with signs andsymptoms of raised ICP from mass effect, oedemaor haemorrhage. These frequently manifest asheadaches, nausea & vomiting, reduced visualacuity, diplopia, drowsiness and confusion.13

Other presentations include focal neurologicaldeficits, symptoms which are dependent on thelocation of the tumour such as aphasia, limbweakness, altered sensorium and neurocognitivedefects including disinhibition and personalitychanges.14 Approximately 50% of grade III and25% of Grade IV tumours present with seizurescompared to 80% of low grade gliomas.

ImagingThe initial imaging modality is usually a contrastenhanced Computed Tomography (CT).However, Magnetic Resonance Imaging (MRI) ismore sensitive than CT and is now the imagingmodality of choice for all patients with braintumours – especially if considered for surgery.

HGG typically appear as irregular, ill-definedmasses with associated vasogenic oedema onboth CT and MR. Enhancement typically isaround the rim of the mass with a central area ofnon-enhancing tissue. Enhancement per se,cannot be taken as a diagnostic feature asbetween 30-50% of anaplastic tumours fail toenhance on CT,15 and 16% fail to enhance onMRI.16 In addition, 20% of low grade gliomas (typi-cally oligodendrogliomas) enhance on CT15 and35% enhance on MRI16 (see Figure 1).

Identification of tumour margins is notpossible with conventional imaging. Both postmortem and biopsy studies have shown tumour

High Grade Gliomas:Pathogenesis, Managementand Prognosis

N E U R O S U R G E RY A RT I C L E

Vairavan Narayanandid his basic Neurosurgical trainingin Malaysia and completed histraining in Addenbrooke’s Hospital,Cambridge in 2011. He is currently ajunior consultant neurosurgeon inUniversity Malaya, Malaysia. Hisclinical interest lies in neuro-oncology and skull base surgery.

Krunal Patelgraduated from the University ofCambridge & University CollegeLondon Medical Schools in 2006.He is currently working as aSpecialist Registrar in Neurosurgeryat Addenbrooke’s Hospital inCambridge.

Stephen Price is a NIHR Clinician Scientist at theUniversity of Cambridge and anHonorary ConsultantNeurosurgeon at Addenbrooke’sHospital, Cambridge. His interest isin surgical neuro-oncology and hisresearch interest involves usingimaging based methods to betterunderstand the heterogeneity ofglioma pathology in individualpatients.

Correspondence to:Mr. Stephen J Price PhDFRCS(Neuro.Surg),Neurosurgery Division,Department of ClinicalNeurosciences,Box 167,Addenbrooke’s Hospital,Cambridge CB2 0QQ,Tel. +44 (0)1223 274295Fax. +44 (0)1223 216926Email: [email protected] Figure 1: Imaging of a glioblastoma. (a) An unenhanced CT and

contrast enhanced CT (b) show the lesion and the oedema. Thelatter is better identified on the FLAIR imaging (c). Contrastenhanced T1-weighted imaging shows a small focus ofenhancement separate from the main body of the tumour thatwas not identified by other methods.

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extends beyond the margin on CT,17-20 contrast-enhanced T1-weighted MRI20-21 and T2-weighted MR.20-23 These techniques cannotdetermine the margin or the invasiveness ofthese tumours. Advanced imaging methodshave been developed for assessment of thesetumours. These are being used in clinical prac-tice and are summarised elsewhere.24

Post-operative MRI is the only method ofobjectively assessing the extent of resection.Studies have shown it identifies more cases ofincomplete resection compared to the judge-ment of the surgeon.25 Imaging within 72 hoursavoids the post-operative changes that occurlater.

HistologyHigh grade gliomas arise from supporting glialcells in the brain. The predominant cell typedetermines the pathological classification.Tumours are graded according to the WorldHealth Organisation (WHO) grading system(Grade I to IV).26 HGGs comprise of WHOgrade III and IV tumours. Multiple subtypeshave been identified which may alterresponse to treatment and prognosis. Theseinclude subtype III which comprisesanaplastic astrocytoma, oligoastrocytoma,anaplastic oligoastrocytoma as well assubtype IV which includes glioblastoma,glioblastoma with oligodendrocyte compo-nent and gliosarcoma.27

Grade III tumours are diffusely infiltratingastrocytomas with focal or dispersedanaplasia and a marked proliferative potentialwith increased cellularity, distinct nuclearatypia and high mitotic activity while Grade IVtumours show cellular polymorphism, nuclearatypia, brisk mitotic activity, vascular throm-bosis, microvascular proliferation and necrosis(see Figure 2).

Grading is determined by the most malig-nant part of tumour, which makes it essentialfor adequate sampling to determine theproper grade, especially in biopsy procedures.

Molecular markers and their significanceOne of the biggest advances in high gradeglioma management has come in the form ofmolecular markers. Three particular markershave been well studied over the past fewyears.

1. MGMT Methylation Status The MGMT gene encodes O-6-methylguanine-DNA methyltransferase enzyme – a DNA repairenzyme that removes alkyl groups from the O-6 position of guanine, an important site of DNAalkylation. MGMT methylation status has beenused to prognosticate response to alkylatingchemotherapeutic agents like Temozolomide.In the methylated form, it is non-functional(i.e. the enzyme is not produced) thus limitingDNA repair, cf. Figure 3). Two recent retrospec-tive studies by Hegi et al28 and Stupp et al29

analysed this particular molecular marker andfound the methylation phenomenon presentin up to 45% of cases of GBM. Further, in thepresence of methylation, median survival forradiotherapy with Temozolomide was signifi-cantly longer than radiotherapy alone (21.7months, 95% CI 17.4-30.4 vs 15.3 months, 95%CI 13.0-20.9; P=0.007). In comparison, thedifference in survival in the unmethylatedgroup was insignificant (11.8 months, 95% CI9.7-14.1 vs. 12.7 months, 95% CI 11.6-14.4). Asthe methylated group with radiotherapy alonehas better survival than either unmethylatedgroups, it suggests MGMT methylation func-tions as a prognostic marker rather than apredictive marker. A prospective analysis byWeller et al shows an improvement in bothprogression free survival (7.5 months vs 6.3months) and overall survival (18.9 months vs11.1 months).30 MGMT methylation statusassessment is not without its problems –

multiple sites for mutation have been identi-fied making this marker difficult to assess. Inaddition, the results are semi-quantitative withno clear cut off to define positive or negativestatus, resulting in non-standard interpretationof test results.

2. IDH-1 Mutation The IDH-1 gene encodes the enzyme isocitratedehydrogenase (IDH-1) gene that convertsisocitrate to α-ketoglutarate within the Krebscycle. This stage generates NADPH thatappears to be important in dealing with cyto-toxic oxidative stresses. Mutation of this generesults in an alternative metabolism of isoci-trate to 2-hydroxyglutarate. Mutations cause a10 fold increase in the production of 2-hydrox-yglutarate.31 Accumulation of 2-hydroxyglu-tarate also leads to the breakdown of HIF-1α, afactor important for generating a malignantcell phenotype.

Mutation of IDH-1 gene was found in 12% ofGBM patients and seems to confer a bettermedian survival, (3.7 years vs 1.1years).32

Weller et al reconfirmed this via the GermanGlioma Network study which found IDH-1mutations in 16/286 patients (5.6%). They alsofound an improvement in both progressionfree survival (16.2 months vs 6.5 months) andoverall survival (30.2 months vs 11.2months).30 As with the MGMT mutation, IDH-1mutation is prognostic rather than predictive.33

Virtually all mutations (96%) are a point muta-tion involving arginine 132. This allows animmunohistochemistry test on paraffinembedded tissue.

3. Chromosome 1p19q Loss inOligodendroglial Tumours One of the commonest chromosomal abnor-malities seen in oligodendrogliomas is theconcurrent loss of part or all of the short armof chromosome 1 (1p) and the long arm ofchromosome 19 (19q). Cairncross et alshowed loss of 1p19q in 50-70% of anaplasticoligodendrogliomas.34 This mutation had animproved survival with chemotherapy andwas originally thought to be predictive ofchemosensitivity. Results from a trial of radio-therapy vs chemoradiotherapy showed theradiotherapy only arm with 1p19q loss didbetter than the chemoradiotherapy armwithout loss of 1p19q suggesting again theprognostic nature of these molecularmarkers.35

PathogenesisGlioblastomas develop either as primarytumours or arise from pre existing low gradegliomas (Table 1). These primary andsecondary GBMs constitute separate anddistinct disease entities. They affect differentepidemiological groups and carry differentprognoses.

Primary gliomas usually are of a de novomanifestation involving older patients with ashorter clinical history. On the other hand,secondary gliomas are usually part of a malig-nant progression from low grade to high grade


Figure 3: Methylation of MGMT inhibits repair of DNAdamaged by both radiotherapy and chemotherapy drugs.

Figure 2: Histology of a glioblastoma. (a) shows the microvascular proliferation and (b) shows evidence of tumour necrosis –the presence of either of these factors in an astrocytic tumour is sufficient to make a diagnosis of glioblastoma. (Picture cour-tesy of Dr Kieren Allinson, Addenbrooke’s Hospital, Cambridge).

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involving younger patients with a variableinterval between 1 to 10 years.

Large numbers of genetic abnormalities havebeen found in gliomas. These genetic abnormal-ities increase as the grade of glioma increases.Most of these abnormalities affect entry into cellcycle or inhibit apoptosis via multiple pathways,which is discussed in depth elsewhere.36

Recent data from the Cancer GenomeProject suggests genetic abnormalities canclassify GBM’s into four categories37:• CLASSICAL – amplification of EGFR• MESENCHYMAL – NF1 deletion• PRONEURAL – mutations of PDGFR-A and

IDH-1• NEURAL – expressed neuronal markersThe proneural group showed improvedsurvival, but interestingly showed no survivaladvantage with chemoradiotherapy vs. radio-therapy alone. Further work is underway tounderstand the significance of this classifica-tion for individual patients.

ManagementHGGs are best managed using a multi-discipli-nary team (MDT) approach. Options formanagement span the spectrum from conser-vative treatment, to surgery and adjuvanttherapy. The main thrust of management is diag-nosis and prolongation of progression freesurvival.

Dexamethasone is vitally important incontrolling cerebral oedema associated withtumours. The response to steroids can beextremely rapid. Failure to improve withsteroids suggests radical surgical resectionmay cause a worsening neurological deficit.38

The role of steroids, their complications anddosing in neuro-oncology has been recentlyreviewed elsewhere.39

Conservative management is a valid optionin patients with a poor prognosis as identifiedby age and poor performance status. In thissituation good palliative and supportive care isimportant.

SurgerySurgery ranges from diagnostic biopsy to

debulking to gross total resection.

1. Tumour BiopsyBiopsies are minimally invasive, well toleratedand suitable for lesions of any site or size.Biopsy is usually considered when the risks ofresection outweigh the benefit.40 It is bestutilised in cases where initial diagnosis mayinfluence subsequent management. However,it has its pitfalls in the form of sampling errorespecially in small or heterogeneous samples.To reduce the risk of non-diagnostic biopsies,image-guidance is routinely used to guidebiopsies.

2. Tumour ResectionDebulking surgery is beneficial in reducingthe tumour load and thus the side effects ofraised intracranial pressure and providing amore representative histological sample.Whether it provides an improvement insurvival is controversial. The Cochrane reviewof the literature has highlighted the lack of

quality studies in this area.41 Retrospectivestudies have suggested that gross total resec-tion as defined by post operative MRI findingsof more than 98% tumour resection, has shownbetter quality of life and progression freesurvival.42 The median survival, according toone study, improved from 8 months forsubtotal resection to 13 months after grosstotal resection (GTR).43 This was reconfirmedby Pichlmeier et al whose RPA analysisrevealed survival benefit was greatest inpatients with higher RPA scores (i.e moresevere baseline disease based on age, perform-ance status, neurology and mental status). Themedian survival for GTR vs incomplete resec-tion was 17.7 vs 12.9 months for RPA IV and13.7 vs 10.4 months for RPA V.44 The problemwith GTR remains balancing maximal resec-tion against potential neurological deficits.

5-ALA is a new surgical adjuvant used toidentify glioma tissue under blue light (seeFigure 4). 5-ALA is taken up and is convertedin the normal heme biosynthesis pathway. Intumours there is a deficiency of theferrochelatase enzyme that leads to the accu-mulation of the fluorophore protoporphyrin IXthat fluoresces under blue light. The use of 5-ALA enables more complete resections ofcontrast enhancing tumour, leading toimproved progression free survival in patientswith malignant glioma. Stummer et al showeda 29% increase in complete resections rates inthe 5-ALA group as opposed to the white lightgroup. The 5-ALA group also had a higher 6-month progression free survival than the whitelight group (41% vs 21.1%).45

Another adjuvant to surgery has been localtherapy with BCNU loaded wafers. Thesewafers provide a method of local delivery ofhigh concentration chemotherapeutic agentbypassing the blood brain barrier. The use ofthese agents remain controversial though, asquestions have been raised about their effi-cacy as well as side effects including CNS andwound infection rates as high as 28%.46,47

However, there is substantial evidence for theuse of BCNU wafers in adjuvant treatment. Aretrospective review on BCNU wafer implanta-


Table 1: Differences between Primary and Secondary GBM’s

PRIMARY (de novo) SECONDARY

Definition No clinical or pathological evidence of pre-existing lesion Malignant progression from lower grade tumour

Age Typically older (mean 55 years) Typically younger < 45yrs

Genetics Early EGFR overexpression Early p53 mutation and PDGF overexpression. V early IDH-1 mutation

Clinical Probably worse outcome Better survival (esp. if IDH-1 mutation)

Figure 4: An intra-operative image of a resection of aglioblastoma under white light (upper panel) and blue light(bottom panel) after administration of 5-ALA. With bluelight the tumour can be seen as pink fluorescence in anarea that looked relatively normal with white light.

MGMT methylation and mutation of the IDH-1 gene are both prognostic factorsassociated with better progression free survival and long term outcome

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tion in combination with TMZ and radio-therapy in newly diagnosed GBM revealed amedian survival of 20.7 months with a twoyear median survival of 36%.48

RadiotherapyRadiotherapy has been the mainstay of adju-vant therapy for high grade gliomas sincemultiple studies from the 1970s showed asurvival benefit.49 However, attempts toimprove on the initial benefits by increasingdosage of radiation has failed to have anysuccess. Unfortunately the therapeuticwindow for radiotherapy to the brain is narrowand there is an increased incidence of radia-tion necrosis with increased radiation dose.Part of the reason for this is the inability ofconventional imaging to identify infiltratingtumour. As a result radiotherapy planningoutlines the obvious tumour as the GrossTumour Volume (GTV). A 2.5cm margin isthen applied to form the Clinical TargetVolume (CTV). A 0.5cm margin is added toaccount for set up errors and patient move-ment to form the Planning Target Volume(PTV). In other words, a 3cm margin is appliedaround the tumour that will contain normalbrain. To reduce the risk of radiation necrosisthe dose is therefore limited (see Figure 5).

Although various radiotherapy regimeshave been proposed, traditionally two areused in HGG:1. Radical radiotherapy: gives 60 Gy dose

over 30 daily fractions. 2. Short Course/Palliative Radiotherapy:

gives 30 Gy over two weeks in six fractions.As there is little planning patients can starttreatment very quickly and it is well toler-ated. It is useful where patients are acutelydeteriorating.

Cytotoxic ChemotherapyPCV was the standard adjuvant chemothera-peutic regime in use until the advent ofTemozolomide. PCV is nitrosurea basedchemotherapy providing a small survivalbenefit; a 5% increase in two year survivalrates.50 The treatment involves a 10 day oralcourse of procarbazine, a single oral dose ofCCNU and a single intravenous infusion ofvincristine given in six weekly cycles.

The introduction of Temozolomide hasprovided some improvement in survival. It isgiven orally over five consecutive days within a28 day cycle. Leucopenia and thrombocy-topenia are commonly associated side effectsof this treatment. The combination of radicalradiotherapy and daily, concomitantTemozolomide followed by six cycles of adju-vant Temozolomide has significantly alteredthe prognosis of GBM. Stupp et al. in a multi-centre trial showed that at a median follow upof 28 months, the median survival was 14.6months in radiotherapy plus TMZ group ascompared to 12.1 months with radiotherapyalone. The two year survival rate was 26.5% vs10.4% while a five year review of the same

population has revealed 9.8% survival at fiveyears in the TMZ group compared to 1.9% inthe radiotherapy group.29 This represents asignificant advance over previous survivalstatistics in high grade glioma. The MGMTstatus was found to be the single most impor-tant predictive factor for a favourableoutcome.

It is now well recognised that MR appear-ances immediately after chemoradiotherapycan show apparent progression of disease–22% of patients in the study reported by Stuppet al did not receive the adjuvantchemotherapy phase due to presumed tumourprogression. Subsequent imaging shows thatthese changes either stabilise or improve. Thispseudoprogression is more commonly seen inpatients with methylated MGMT and is thoughtto represent a good prognostic sign of responseto therapy (see Figure 6).

Treatment at Tumour ProgressionDespite the best management, virtually allpatients with HGG will develop recurrence oftumour at some point. Salvage therapies maybe considered depending on the patient’s clin-ical condition. These may include: 1. Surgery: Re-operation is associated with

higher morbidity and mortality than for theoriginal operation. However, it is an optionin patients with a long progression freesurvival who have tumour that is maxi-mally resectable. Insertion of carmustinewafers at this stage has been shown toimprove survival.51

2. Radiotherapy: There has been somesuggestion that the toxicity of re-irradiationhas been overestimated. Re-irradiation is


Table 2 Recursive partitioning analysis (RPA) of GBM survival based on Karnofsky performance status (KPS), the age of the patient, and treatment53

RPA class Definition Historical Median Survival Time Historical 1-Year Survival

III Age < 50, KPS ≥ 90 17.1 months 70%

IV Age < 50, KPS < 90Age > 50, KPS ≥ 70, surgical removal with good neurologic function 11.2 months 46%

V + VI Age ≥ 50, KPS ≥ 70, surgical removal with poor neurologic functionAge ≥ 50, KPS ≥ 70, no surgical removal 7.5 months 28%Age ≥ 50, KPS < 70

Figure 5: An example of radiotherapy treatment volumes.The enhancing tumour is outlined as the gross tumourvolume (GTV). A 2.5cm margin is then applied to accountfor the infiltrating margin and is referred to as the clinicaltarget volume (CTV). A further 0.5 cm margin for set uperror is then applied, the patient target volume (PTV). Theareas outside the GTV will include normal brain at risk ofradiation injury. (Picture courtesy of Dr Neil Burnet,Addenbrooke’s Hospital, Cambridge).

Figure 6: An example of pseudoprogression in a patient with a glioblastoma being treated with concomitant Temozolomide andradiotherapy. Before starting the adjuvant phase the tumour appears to have enlarged in size. This is not true progression butpseudoprogression as continuation of adjuvant Temozolomide shows excellent response after two more cycles.

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an increasingly used option with precisefractionated radiotherapy being theoptimal technique. There has also beensome suggestion that for accurate, focalradiotherapy to a recurrent tumour, radio-surgery may be considered. On average,time to secondary progression is in therange of several months.

3. Cytotoxic Chemotherapy:Conventional chemotherapy regimensalso improve time to secondary progres-sion; however the efficacy is only modestand treatment related toxicities likemyelo-suppression occur very frequently.52

Recent Phase III Trials have failed to showthat Temozolomide has a survival advan-tage over PCV regimes.

PrognosisDespite advances in management, a diagnosisof HGG still carries a dismal prognosis. Themedian survival without any treatment is lessthan six months, but with treatment, thisincreases up to 18 months. Increasing age,poor initial neurology, poor general conditionas evidenced by Karnofsky Performance score

(KPS) and absence of MGMT methylationhave all been associated with poor survival.53

[Table 2: RPA of GBM survival based on KPS,the age of the patient, and treatment]

Patients who undergo surgery and chemora-diotherapy have shown better long term bene-fits. Why certain groups of patients survivelonger than others is still unknown. Death isusually due to cerebral oedema and raisedintracranial pressure.

The futureTargeted molecular therapies are an excitingprospect currently at various stages ofresearch and development. These are drugsthat target the oncogenic pathways in gliomaseither by interacting with receptors oraffecting a downstream target. Clinical trials ofdrugs blocking the epidermal growth factorreceptor (EGFR), platelet-derived growthfactor receptor (PDGFR), phosphatidylinositol3-kinase (PI3K) and related pathways and theSRC related pathways have so far been disap-pointing. It is clear that monotherapy will havelittle effect and trials combining treatmentsare now underway as summarised by Wick et

al.54 The reason for this poor response isthought to be the fact that multiple receptortyrosine kinases are activated in the develop-ment of a glioma, so blocking one receptor haslittle effect on the overall pathway.55

Combinations of targeted therapies are likelyto be the way forward.

One targeted therapy of particular interestblocks the vascular endothelial growth factorpathway involved in tumour angiogenesis. Alarge non-randomised phase 2 study ofBevacizumab at recurrence showed a highresponse rate (progression free survival at sixmonths 46%; overall survival at six months77%).56 This trial paved the way for FDAapproval. But the non-randomised nature ofthe study and non-standard endpoints hasmade the European Medicines Agency(EMEA) reject its use in Europe. One of theproblems with studies using anti-angiogenicagents is the marked decrease in enhance-ment due to closure of the blood-brain barrier.This so called pseudoresponse does notpredict the response to these agents, andsubsequent progression can occur with noapparent contrast enhancement.57 l


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43. McGirt MJ, Chaichana KL, Gathinji M.Independent association of extent of resection withsurvival in patients with malignant brain astrocy-toma. J Neurosurg 2009Jan; 110(1):156-62.

44. Pichlmeier U, Bink A, Schackert G et al. Resectionand survival in glioblastoma multiforme: AnRTOG recursive partitioning analysis of ALA studypatients. Neuro-Oncology 2008;10:1025–34.

45. Stummer W, Pichlmeier, Meinel T. Fluorescence-guided surgery with 5-aminolevulinic acid forresection of malignant glioma: a randomisedcontrolled multicentrer phase III trial. LancetOncol 2006;7:392-401.

46. Engelhard HH. The role of interstitial BCNUchemotherapy in the treatment of malignantglioma. Surg Neurol 2000;53:458-64.

47. McGovern PC, Lautenbach E, Brennan PJ et al.Risk factors for postcraniotomy surgical site infec-tion after 1,3-bis (2-chloroethyl)-1-nitrosurea(Gliadel) wafer placement. Clin Infect Dis 2003;36:759-65.

48. McGirt MJ, Than KD, Weingart JD et al. Gliadel(BCNU) wafer plus concomitant Temozolomidetherapy after primary resection of glioblastomamultiforme. J Neurosurg 2009;110:583-8.

49. Walker MD, Alexander E, Hunt WE et al.Evaluation of BCNU and/or radiotherapy in thetreatment of anaplastic gliomas. A cooperativeclinical trial. J Neurosurg 1978;49:333–43.

50. Stewart LA. Chemotherapy in adult high-gradeglioma: a systematic review and meta-analysis ofindividual patient data from 12 randomised trials.Lancet 2002;359:1011-18.

51. Brem H, Piantadosi S, Burger PC et al. Placebo-controlled trial of safety and efficacy of intraoper-ative controlled delivery by biodegradable poly-mers of chemotherapy for recurrent gliomas. ThePolymer-brain Tumor Treatment Group. Lancet 1995;345(8956):1008-12.

52. Niyazi M, Siefert A, Schwarz SB. Therapeuticoptions for recurrent malignant gliomaRadiotherapy and Oncology 2011;98:1-14.

53. Shaw E, Seiferheld W, Scott C, Coughlin C,Leibel S, Curran W, Mehta M. Reexamining theradiation therapy oncology group (RTOG) recur-sive partitioning analysis (RPA) for glioblastomamultiforme (GBM) patients. International Journalof Radiation Oncology Biology Physics2003;57(2):S135-6.

54. Wick W, Weller M, Weiler M, Batchelor T, YungAWK, Platten M. Pathway inhibition: emergingmolecular targets for treating glioblastoma.Neuro-oncol 2011;13(6):566-79.

55. Stommel JM, Kimmelman AC, Ying H et al.Coactivation of receptor tyrosine kinases affectsthe response of tumour cells to targeted therapies.Science 2007;318(5848):287-90.

56. Vredenburgh JJ, Desjardins A, Herndon JE et al.Bevacizumab plus irinotecan in recurrent glioblas-toma multiforme. J Clin Oncol2007;25(30):4722-9.

57. Norden AD, Young GS, Setayesh K et al.Bevacizumab for recurrent malignant gliomas: effi-cacy, toxicity, and patterns of recurrence.Neurology 2008;70(10):779-87.

C O N F E R E N C E R E P O RT S

The Eighth Congress on Mental Dysfunctions and other Non-Motor Features in Parkinson’s Disease Conference details: 3-6 May, 2012, Berlin, Germany. Reviewed by: Professor Amos D Korczyn, Tel Aviv University.

Remarkable success in treating the keymotor problems of Parkinson's disease(PD) has been achieved over the past

fifty years, with drugs, mainly levodopa andlater dopamine agonists, as well as with surgicalapproaches, particularly deep brain stimula-tion. However all these therapies, important asthey are, provide only symptomatic relief andnone affects the progression of the underlyingpathology.

As therapy of motor features improved, moreattention has been paid to other manifestationsof the disease. Although James Parkinsonclaimed that "the senses are unaffected", in factmost PD patients manifest early cognitivechanges and most progress to full blowndementia in later stages of the disease.Autonomic changes are also common andaffect quality of life of the patients. Thesefrequently start with constipation but othersystems become affected as well. Orthostatichypotension may

interfere with standing and walking. Sleepchanges pose problems for the patient,bedfellow and physician. Many people developREM-sleep behaviour disorders years before theappearance of motor manifestations, which areexpressed as vivid dreams, frequently fright-ening. Unlike normal dreams, in which theperson is unable to move, in PD the motorsystem is not inhibited and the patient mayenact the dream, sometimes with violent move-ments which may hit the spouse. Some patientscomplain of insomnia. Affective changes, partic-ularly depression, are also common in PD.These are not only a reaction to the motor prob-lems. In fact these, like the autonomic manifes-tations, can appear years before the tremor,rigidity or bradykinesia first show. The sensorysystem is also affected in PD. Patients maydevelop pain, visual changes, and particularlyanosmia fairly early on. In addition to thesechanges, which are part of the underlyingdisease process, there are many iatrogenic non-motor problems which PD patients develop.Most intriguing is the newly described impulsecontrol disorder and the associated dopaminedysregulation syndrome.

Many of these topics are not covered suffi-ciently in international meetings, where indus-trial support leads the organisers to focus onissues which are of interest to the sponsors.

Therefore there was a growing need forspecialised congresses. The first in this seriestook place in Jerusalem, Israel in 1994. In thepast few years, as interest grew and attendanceincreased with it, the congresses became moreregular, increasing to biannually and now annu-ally.

The eighth congress in Berlin attractedabout 800 participants, including neurologists,psychiatrists, geriatricians and basic scientists.The faculty included eminent scholars fromaround the world who participated in plenarytalks, symposia and discussions. There werealso hundreds of free communications andposters, where young clinicians and scientistswere able to face the distinguished leaders inthe field.

There was extensive discussion of new devel-opments in the field, the understanding of nonmotor aspects not only of PD but also of othermovement disorders such as Huntington'sdisease, Gilles de la Tourette syndrome andmany others. Psychological and biologicalmarkers of cognitive decline in PD werepresented, and the Pathogenesis of them delib-erated at length. l

The full program of the Congress can beseen at www.kenes.com/MDPD, where

details can also be found of the 9thMDPD Congress, which will be held in

Seoul April 18-21, 2013.

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2012September16th Congress of the European Federation ofNeurological Societies8-11 September, 2012; Stockholm, SwedenT. +41 22 908 04 88, E. [email protected]/efns2012

Cognitive Behavioural Approaches to PhysicalRehabilitation: Intermediate level18 Sept, 2012; Derby, UKT. 01332 254679, E. [email protected]

Neurological Upper Limb for OccupationalTherapists19 Sept, & 10 Oct, 2012 Derby, UKT. 01332 254679, E. [email protected]

Imperatives in Regional Anaesthesia: Current hot topics and future developmentsWorkshop sessions and lectures24th and 25th September, 2012; The Royal College of Anaesthetists, London, UKAnna Mawe, Event Coordinator, T. 0114 2259057/36, E. [email protected]

Multiple Sclerosis: MS Trust Study Day onPostural Management25th September 2012; Leeds U.K. (Advanced Level)E. [email protected]/professionals/

11th Annual Brain Injury Legal SeminarA Changing Legal Landscape - the View fromAcquired Brain Injury26 September, 2012; Birmingham, UKwww.biswg.co.uk for the full programme andbooking formContact Chloe Hayward [email protected], T. 07501 483989.

Squeezing the best out of stroke care27 September, 2012; London, UKConference DepartmentT. 020 3075 1436/1300/1252, E. [email protected]

OctoberThe Intoxication of Power: From neurosciences tohubris in healthcare and public life9 October, 2012; London, UKRuth Cloves, Senior Events Co-ordinator, Psychiatry Section, Royal Society of Medicine. [email protected]; T. 44 (0)20 7290 2985 www.rsm.ac.uk/psychiatry

Complex Epilepsy ConferenceIn collaboration with Matthew’s Friends12 October, 2012; Solihull, UKT. 01342 832243 ext 296, E. [email protected]

Sleep and Sleep Disorders from a Neurological Perspective24th Oct, 2012; Royal College of Physicians of EdinburghE. [email protected]

Practical Skills in Managing Fatigue25th Oct, 2012; Bedford Lodge Hotel, NewmarketE. [email protected]

NovemberPutting epilepsy first – supporting individualswith epilepsy in primary care2 November, 2012: London UKE. [email protected]/epilepsyfirst

Managing Cognitive Impairment7th November, 2012; Bedford Lodge Hotel, NewmarketE. [email protected]

Assessment and Treatment of the Thorax inNeurology14th November, 2012; Derby, UKT. 01332 254679E. [email protected]

8th Essential Neuro MRI Study DayOne day course in how to interperet MRI Brain &Spine17 November, 2012; Liverpool, UKLimited places. Kath Tyler, T. 07799 723 925, E. [email protected]

Delivering Community Rehabilitation – Learningfrom Experience28th November 2012; Hippodrome, BirminghamE. [email protected]

MS Trust Specialist Health Professionals Master Class: Sexuality in MS29th November, 2102; LondonE. [email protected]/professionals/

December

UK Stroke Forum4-6 December, 2012; Harrogate, UKT. 01527 903913 E. [email protected]

2nd Annual Regulatory Cells in Autoimmunityevent: Analysing and moderating function6 December, 2012; London, UKT. 07507 799380E. [email protected]/autoimmune2012

2013

FebruaryBiomarkers for Brain Disorders: Challenges and Opportunities3-5 February, 2013; Cambridge, UKhttps://registration.hinxton.wellcome.ac.uk/display_info.asp?id=303E. Lucy Criddle,[email protected]

Basic Applied Neurophysiology13th February, 2013; Derby, UKT. 01332 254679E. [email protected]

MayMS Frontiers: Bringing the research community together to beat MS9-10 May, 2013; London, UKT. 020 8438 0941E. [email protected]/frontiers

JuneNew Avenues for Brain Repair: Programming andReprogramming the Central Nervous SystemJune 10-11, 2013; Cambridge, USE. [email protected]

To list your event in this diary, email brief details to Anna Phelps at [email protected] by 6th October, 2012

E V E N T S D I A RY

Natural History and Gut Microbiota. Forward Players in the Multiple Sclerosis fieldNovember 29 and 30, December 1, 2012, Marbella, Spain

18th European Charcot Foundation LectureProf. G. Ebers ‘Lessons learned from the Natural History studies aimed atimproving Therapeutic Trial Methodology and Designing MSPrevention Trials’.

Sessions on:• The risk of MS has changed• Natural History of Disease Evolution• Long term prognoses: Lessons for Treatment and

Prevention• Gut Immunology and Multiple Sclerosis • Gut Immunology and Treatment consequences in MS

NB: Young Investigators Awards

For detailed information and registration visit our website www.charcot-ms.eu

EUROPEAN CHARCOT FOUNDATION UNIVERSITY CLASSES IX

EUROPEAN CHARCOT FOUNDATION SYMPOSIUM 2012

Focused on Clinical Forms of Multiple SclerosisA teaching courseNovember 28, 2012, Marbella, Spain

Programme:Session 18.00 MS in adults. MS in children – J. Haas

Early MS-RIS and CIS – J. De KeyserCase presentations

10.00 Discussion

Session 210.30 Relapsing-Remitting MS. Transitional forms. Decrease of annual

relapse rate – A. ScalfariSecondary Progressive MS – B. BrochetCase presentations

12.30 Discussion

Session 314.00 Primary Progressive MS – K. Selmaj

MS or not MS: on diseases closely related to MS-neuromyelitis optica – J. Palace• PML • Post vaccinal encephalitis • ADEM Case presentations

16.00 Discussion

Session 4 16.30 Pathology of MS – T. Kulhmann

MRI-Charles Guttmann’s laptop images – M. TintoréCognitive-Behavioural Changes – I-K. PennerCase presentation

18.00 Discussion

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CONFERENCE RE PORTS

T he ABN were welcomed to Brighton forfour days of glorious sunshine and a stimu-lating mix of teaching, scientific break-

throughs and case study conundrums. This yearthe ABN conference was brought right up to datewith a conference app for smart phones and adedicated twitter feed.

The conference opened on Monday the 28thwith the medical student road show in parallelwith the Specialist Registrar teaching session.The Registrar session, attended by over 70trainees, kicked off with small group teaching onprescribing in epilepsy. There were then seminarson ‘Neurology on the ITU’ from Lionel Ginsberg,‘How to interpret the EMG’ from David Allen and‘Dementia’ from Jonathan Schott. The day wasrounded off with Jeremy Isaacs describing howto get (and keep!) a first consultant job andTrevor Pickersgill showing how to negotiate a jobplan once you have got it.

The main conference opened the followingday and started with a teaching session onepilepsy, with Mark Manford reminding us of theimportance of taking a good history, TejalMitchell exploring the use (and misuse) of theEEG and John Duncan describing advances inimaging technology allowing refined diagnosisand more targeted epilepsy surgery. Parallelsessions on improving neurology services andneuromuscular platform presentations camenext. Michael Pearson gave the perspective of aRespiratory Physician on improving outcomesfor patients by using national audit data to driveservice change.

The 18th Gordon Holmes Lecture was deliv-ered by John Leigh from Cleveland, Ohiodescribing the neuronal control of eye move-ments and their use as research tools. The after-noon teaching session covered head injury, anarea often neglected by neurologists. We learntabout the acute management of head injury andthe on going efforts to improve this, using clinicaltrials, from Maxwell Damian, the surgical optionsfrom neurosurgeon Peter Hutchinson and thelong term consequences of head injury fromRichard Greenwood. This was followed byparallel platform sessions on neurodegenerationand multiple sclerosis. The NeurolympicChallenge drew the day to a close. Quiz MasterPhillip Smith pitted the regions against eachother with the team comprising Scotland andNorthern Ireland reigning supreme. The trainees’dinner was held at Al Duomo restaurant.

Wednesday started early with a stimulatingbreakfast with neuro-ophthalmology expertsfollowed by a teaching session on degenerationand regeneration of the nervous system. Parallelplatform sessions followed on epilepsy and cere-brovascular disease. A highlight was thediscovery by Lilleker and Mohanraj of anti-VGKCcomplex antibodies in a small proportion ofpatients with unexplained refractory epilepsy,

who became seizure free followingimmunomodulatory treatment. Walking tours ofthe posters followed lunch. Then the ABNMedallist, Mark Wiles, told us about learningneurology and that pyramidal pattern weaknessdoes not exist. The day was rounded off with amovement disorders video session with manyexcellent videos including a case from ChrisAllen of paroxysmal exercise-induced dystoniasecondary to demyelination. The ABN Galadinner at the Corn Exchange, Brighton Domewas well attended and was a great opportunityto unwind and digest the conference’s offeringsso far.

The final day of the conference started withthe ACNR sponsored case presentation competi-tion where we were reminded that commondiseases may present in atypical ways and some-times, rare diseases can present like they aresupposed to. Hugh Adler won the case presenta-tion prize for his description of a patient withOphelia syndrome associated with anti-mGluR5antibodies. The plenary lecture from IainMcGilchrist looked at how the two hemisphereswork in very different ways resulting in a kind ofpower struggle in our interaction with the world.

Brighton has a high incidence and prevalenceof HIV and so it was fitting that the morningteaching session looked at this now manageableinfection. Hadi Manji explained the effect of HIVon the brain, and, in particular, premature cogni-tive decline. Nick Davies categorised the immunereconstitution syndrome and Martin Fisherdescribed his 30 years experience of dealingwith the epidemic in Brighton. We werereminded of the importance of offering HIVtesting to all patients with neurological symp-toms, as this is now an infection that can becontrolled. The final teaching session of theconference was an overview of antibody-medi-ated neurology, an area where our knowledge israpidly expanding and our understanding of theclinical phenotypes of each antibody and howto treat them deepening.

The clinicopathological conference was acomplex case with many a red herring, butexpertly discussed by Peter Enevoldsen. Theaudience was able to participate via twitter ortext, but none clinched the final diagnosis ofprimary angiitis of the central nervous system.

An excellent conference attended by over 550neurologists, trainees and medical students fromacross the UK and beyond. The level of posterand platform presentations was high and therewere excellent opportunities to meet andsocialise with old colleagues, in the glorioussouth coast sunshine. The Charles Symondsprizes for best platform presentation was won byMichaela Simoni and for best poster by TimShakespeare. As mentioned before, Hugh Adlerwon the case presentation prize. I am certainlylooking forward to Glasgow 2013! l

ABN National MeetingConference details: 28-31 May, 2012, The Brighton Centre, Brighton, UK. Reviewed by: Seán J Slaght.

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CONFERENCE RE PORTS

British Society of Rehabilitation Medicine ConferenceConference details: 14-15 June, 2012; Southampton, UK. Reviewed by: Dr John Burn, Rehabilitation Consultant, Poole General Hospital.

PREVIEW The Fifth Practical Cognition CourseCourse details: 1-2 November, 2012, Newcastle upon Tyne, UK.

T he Major Trauma Centre (MTC) initiativehas thrust rehabilitation into the limelightand it was the focus of this year’s meeting.

The identification of patients who needspecialist services will be a particular responsi-bility of Rehabilitation Medicine (RM) special-ists. Presentations from both Manchester andLondon described a cultural change wherebyRM specialists were forming an integral part ofacute trauma teams and moving patientsquickly on to appropriate rehabilitation facili-ties. To do this well services need to be availableon the acute site and RM physicians need toacquire new skills, particularly in muscu-loskeletal conditions. There was extensivediscussion on the requirements for‘Rehabilitation Prescription’. Well organisedMTCs are securing this not only for patientswith an Injury Severity Score (ISS) of > 15 butalso for > 8 (three fractured ribs) thus securingmore ‘best practice tariffs’. These monies willhave to be invested in enhanced services forthis not just to be a paper exercise.

The conference brought unfamiliarspecialisms to the BSRM. Mr Michael Fox fromStanmore described surgical approaches tobrachial plexus injury and Dr Chris Lowe fromPoole Hospital described continuing problemsafter Critical Care. Survival is reduced for 15years after ARDS and this is determined princi-pally by weakness. This affects almost 50% of

patients and, although not completely under-stood, is detectable as a reduced 6 minutewalking distance for at least 5 years afterwards.There are recommendations for early mobilisa-tion but little supporting evidence as yet.

Public awareness of rehabilitation has beenenhanced by the work amongst veterans atHeadley Court. Prof Greenberg, visitingprofessor of psychiatry, gave a robust defence ofthe psychological management of Britishservice personnel. Despite, or maybe becauseof, fewer mental health personnel, the rate ofPTSD is significantly less than in the US armyand, although peaking at 6% at 4 years, appearsto decrease subsequently. The incidence ofPTSD is less for the majority of combatants whodescribe their leadership as good or very goodor who have fewer stresses at home. Early (lessthan 4 year) army discharges or reservists aremore at risk. There is no significant increase insuicide or imprisonment but rates of alcohol

abuse are frighteningly high: up to 25%.Spiritual care was introduced into a BSRM

meeting by Dr Collicut, both a neuropsycholo-gist and an Anglican priest. She distinguishedreligion from spirituality by describing threeaxes of Transcendence, Meaning and TheSacred. Traumatised patients face keen ques-tions of meaning (why me?) but often becauseof cognitive and physical problems are less ablespiritually to address them. Spiritual help cannotbe left to faith practitioners but crosses profes-sional boundaries. She suggested focusing onShalom (wholeness/peace) through supportingdignity and identity, conveying hope, andexpressing solidarity and loving kindness.

The conference finished with a symposiumon the definitions and management of minorbrain injury. We were encouraged to movebeyond the dualisms of ‘is it structural oremotional?’, and address the combined prob-lems of patients using a number of treatmentsthat can be practised in the clinic.

In all, a broad and satisfying conference thatdemonstrated to visitors and members alike theincreasing range of the specialty. The nextconference, from 7th – 9th November 2012,willbe hosted by colleagues in Belfast and willinclude presentations on teleneurology, assis-tive technology, transcranial magnetic stimula-tion and the transitional rehabilitation of chil-dren with cerebral palsy. l

T his very successful course is for consult-ants and trainees in neurology, psychiatry,neuropsychology and rehabilitation medi-

cine who want to develop their practicalexpertise in cognitive assessment and relatethis to clinically relevant neuroscience. Therewill be a practical introductory session tocognitive assessment followed by four sessionsof case presentations discussing the assess-ment, diagnosis and management of commoncognitive syndromes. The course begins andends with the patient. Case presentations willfeature video material illustrating disorders thatclinicians may encounter in daily practice.Each session will also include a talk from aninvited expert, who will provide a framework forunderstanding the clinically relevant neuro-science. The case presentations and talks arehighly interactive and lively discussion isencouraged.

This year’s programme will cover memory,sleep and cognition, hallucinations and motorfunction and cognition. Our highly acclaimed

speakers include Kirsty Anderson (Newcastle),David Burn (Newcastle), Tom Kelly(Newcastle), Andrew Larner (Liverpool),Sinéad Mullally (UCL) and Peter Woodruff(Sheffield). The course is organised by neurolo-

gists Tim Griffiths (Newcastle) and Chris Butler(Oxford), sponsored by the Guarantors of Brainand will be accredited for CME points.

The course will be held in the Beehiveconference centre on the main campus ofNewcastle University within the city. The regis-tration fee includes a superb dinner on the firstevening at the Quayside in Newcastle.

The Practical Cognition course has receivedhighly enthusiastic feedback in previous years.Participants have enjoyed the practicalapproach to an area of clinical work that isextremely important but often neglected in post-graduate education. Here are links to reviews oflast year’s course by a trainee psychiatrist [http://careers.bmj.com/careers/advice/view-article.html?id=20006682] and consultantneurologist [http://www.acnr.co.uk/contents11-6.htm].

Bookings can be made online (www.practi-calcognition.com) or by telephoning LauraPereira on 0191 222 8320. Places are limited andshould be reserved early. l

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C O N F E R E N C E R E P O RT S

The 10th European Congress of NeuropathologyConference details: 6-9 June, 2012, Edinburgh, Scotland. Reviewed by: Dr Valerie Critcher, Specialist Registrar in Neuropathology at the Royal Hallamshire Hospital,Sheffield, UK.

An invitation from the European Confederation ofNeuropathological Societies (Euro-CNS) and the BritishNeuropathological Society drew almost 400 participants from

across the globe to the Edinburgh International Conference Centre forthis Neuropathology Congress. The meeting was preceded by the Euro-CNS training course on Leukoencephalopathies.

Plenary LecturesThe programme included plenary lectures by eight distinguishedspeakers working at the forefront of neuroscience research and its appli-cation to improvements in diagnosis and treatment. In his talk on themolecular pathology of CNS tumours, Professor David Louis focused ondevelopments in this rapidly expanding field that have been translatedinto valuable diagnostic and prognostic tools. An example was the use ofMGMT promoter methylation to help distinguish glioblastoma recurrencefrom pseudoprogression during temozolomide therapy. Professor JohnHardy discussed how advances in sequencing and DNA chip technologyare being used to identify different types of genetic risk for neurodegen-erative diseases, thereby increasing understanding of the aetiologies.Professor Richard Gilbertson described his laboratory’s cross-speciesgenomics approach to the subgrouping of CNS tumours. This is helpingto explain why tumours of similar histopathological appearance mayshow very different biological behaviours. For example, ependymomasarising in the forebrain, hindbrain and spinal cord have distinct molecularprofiles, reflecting their different stem cell type origins. Professor WilliamBrown illustrated his techniques of creating three dimensional views ofvascular networks to investigate the vascular changes in deep whitematter in ageing, neurodegeneration and dementia. The increasingcomplexity and diversity of prion diseases were discussed by ProfessorPierluigi Gambetti. He talked about the identification and characterisa-tion of novel forms such as variably protease-sensitive prionopathy whichis suggested to represent a sporadic form of Gerstmann-Sträussler-Scheinker disease. Professor Ingmar Blümcke described how the surveyof over 5,000 surgical epilepsy specimens collected at the EuropeanEpilepsy Brain Bank has enabled correlation between histopathology,preoperative imaging and clinical response to surgery, which in turn isleading to more specifically tailored resection strategies. Developmentsin understanding the pathogenesis of lysosomal diseases were explainedby Professor Steven Walkley. He showed that the complex role of lyso-somes within a major metabolic regulatory network indicates that braindysfunction in lysosomal diseases is not simply the consequence ofabnormal storage of non-degraded materials. In the final lecture to theCongress, Professor Robin Franklin described the work in his laboratoryon the biology of remyelination. The findings show that declining effi-ciency of remyelination with age is largely due to failure of stem celldifferentiation. Evidence that the innate immune response has a key rolein remyelination led to an interesting discussion on the effects of anti-inflammatory therapy in multiple sclerosis.

Seminars and WorkshopsA total of 10 symposia and 7 workshops provided platforms to discussaspects of research and diagnostic practice related to a wide range ofneurological/neurosurgical disorders. There were sessions dedicated toregenerative neuroscience and to brain inflammation. A personal high-light was the lecture by Professor Arie Perry in which he presented a verypractical approach to the subtyping of glioblastomas, with emphasis onthe clinical relevance of making the distinctions.

PostersOver two hundred posters, grouped into ten themes, were displayed in theexhibition hall throughout the Congress, giving ample opportunity for

viewing. The standard was high and twenty-six poster presenters wereinvited to give oral presentations within the above symposia and work-shops. In addition, there were two plenary poster discussions. For these,eight discussants were asked to reflect on what they had found of interestamong the posters. I enjoyed the different approaches taken by the eightindividuals to present their choices and seeing which strategies had mostsuccess in promoting audience participation in the ensuing discussions.

Social EventsThe large exhibition hall provided a place to encounter old friends andmake new acquaintances. On day two the delegates were treated to anexclusive evening reception in Edinburgh Castle. This included a chanceto view Scotland’s Crown Jewels and experience the stirring sounds of apipe band through the mist over Crown Square. The Gala Dinner was heldin the newly refurbished National Museum of Scotland, surrounded bythe eclectic Window on the World exhibition in the Grand Gallery.Entertainment was provided by the excellent Kilter Ceilidh Band and Iobserved that many eminent neuropathologists are also adept at Strip theWillow and other traditional dances performed that night.

ConclusionsThe scientific programme was scheduled so that in general sessions witha bias towards clinical diagnostics ran alongside those with a more dedi-cated research content. This allowed delegates to select the topics mostrelevant to their areas of interest and there was truly ‘something foreveryone’ throughout the Congress. Inevitably clashes occurred and sowe hopped between the auditoria to catch the anticipated highlights fromeach symposium and workshop. Some of the sessions suffered from lessthan strict timekeeping, thus limiting the opportunities for discussion andone of the plenary poster sessions had to be cut short. In the welcomeaddresses there had been references to the inclement weather and to therecent outbreak of Legionnaires’ disease in Edinburgh. Nonetheless I amsure that most delegates remained within the Conference Centre eachday not because of these external factors but as a consequence of suchan informative and enjoyable meeting. l

The Abstracts of the 10th European Congress of Neuropathologyare published in: Clinical Neuropathology. 2012;31(4):232-5.

Details of future Euro-CNS events, including the neuropathologytraining courses, can be found at: www.euro-cns.org

A friendly encounter between congress participants in the exhibition hall.

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CONFERENCE RE PORTS

Epilepsy Nurses Association (ESNA) conference 2012Conference details: 13-14 May 2012, Nottingham. Reviewed by: Phil Tittensor, Lead Epilepsy Nurse, Department of Neurology, Stafford Hospital, UK.

2012 marked the 20th anniversary of the formation of ESNA. In that time theorganisation has expanded from an initial handful of pioneering epilepsynurses to the two hundred and forty or so that make up its current comple-ment. ESNA is now recognised both nationally and internationally as theleading voice of epilepsy nursing in the UK. Its views influence health carepolicymakers and the organisation has been at the forefront of efforts toestablish the necessity of an epilepsy specialist nurse as part of a compre-hensive multidisciplinary service.

ESNA holds a biennial scientific conference which this year was hostedby the well appointed Nottingham Belfry hotel. Delegates were treated to anoutstanding series of platform presentations from both medical andnursing leaders in the field. Generous sponsorship from a number of phar-maceutical companies, most notably Eisai and GlaxoSmithKline made theconference affordable for delegates without the need to compromise onvenue or content.

The Sunday afternoon sessions began with Prof Matthew Walker and DrSunny Philip delivering a generalised epilepsies symposium. Prof Walkertook delegates candidly through the proposed new International LeagueAgainst Epilepsy (ILAE) epilepsy classifications while Dr Philip looked atsyndromic classification and the thorny issue of when to withdraw medica-tion. A further paediatric specific session was held on day two when DrRobert Robinson gave delegates an overview of catastrophicencephalopathies.

There followed a neuro-oncology symposium presented by Dr DougMcCorry and Prof Garth Cruickshank. Prof Cruickshank presented work inprogress to examine whether Valproate might be a useful tool in modifyingtumour progression as well as treating resultant seizures.

Much of the first afternoon was given over to nurse led care innovation.Malissa Pierri presented her work which examined different healthcaremodels in the UK, America and Australia. Nurses in all three countries wereat the forefront of patient care, streamlining the patient experience from firstseizure through to diagnosis and treatment. Service delivery varied enor-mously between the models but the crucial role of the epilepsy specialistnurse was evident across all three. Each country's nurses were clearlyworking at an advanced level and Malissa's talk dovetailed nicely into apresentation on what is arguably the greatest step forward in epilepsyspecialist nursing since its inception. Doctors in particular, with their rigiddevelopment programme find it very difficult to work out the level at whichan individual nurse is working as the majority have very similar titles(usually a play on the phrase 'epilepsy specialist nurse'). Yvonne Leavypresented a framework of adult epilepsy nursing competencies which forthe first time sets out what can be expected of a nurse working at novice,competent or expert level. Competencies for paediatric epilepsy nurseshave been around for a few years but conference heard that they are in theprocess of being updated. Brand-new competencies for epilepsy nursesworking in the field of learning disability are also being developed and arescheduled for launch later this year.

At this point, conference indulged itself in a little nostalgia. Carina Macand Lorraine Reynolds were both epilepsy specialist nurses in the early1990s (incidentally both are still practising although Carina has a manage-rial role these days) and are founder members of ESNA. They took dele-gates on a light-hearted look back at the organisation over the last 20 yearswith plenty of photographs illustrating the ageing process and questionablefashion sense!

The evening began with a drinks reception followed by an excellent galadinner punctuated by awards ceremonies for the best poster in conferenceand the 'achievement in epilepsy' (ACE) awards. The biggest cheer of thenight was reserved for Ena Bingham, epilepsy specialist nurse from Belfastwho has recently received an MBE for services to epilepsy and who wasmade an honorary life member of ESNA.

Day two opened with a transient loss of consciousness symposium. The

diagnosis of epilepsy can be extremely tricky and the differentials betweenit, non epileptic seizures, vasovagal syncope and cardiac causes of loss ofconsciousness were covered by Dr Richard Grunewald and Dr SanjivPetkar. The theme of nonepileptic seizures was to be taken up later in theday by Catherine Crow with a fascinating overview of conversationalanalysis which examines how patients with different diagnoses describetheir seizure episodes.

Their presentations were followed by an examination of the treatment ofseizures in the accident and emergency department. Prof Tony Marson gavedelegates an overview of the recent national audit of seizures managementin hospital (NASH) while Vicky Myson presented an audit of an innovativenurse led first seizure service operating in Cardiff.

Nurses are always keen to learn about approaches that improve seizurecontrol. In common with many conferences, a session was given over to'rational poly-therapy'. This title can be a poisoned chalice for speakers butdelegates pretty much universally praised Prof Mike Kerr for his rather uniquestance with an emphasis on demonstrating to patients both the knowledge ofthe practitioner and the theory behind combining antiepileptic drugs withdifferent modes of action. The message was not so much innovative treatmentbut rather innovative presentation.

The day concluded in somewhat unusual style for an epilepsy confer-ence. Mr Doug Feeny is a barrister specialising in medicolegal cases. Heused two hypothetical case scenarios involving people who have epilepsybut also lack capacity to illustrate current legislation and considerationsthat all practitioners need to be aware of when planning the treatment andmanagement of people with epilepsy.

The ESNA conference 2012 represented a celebration of epilepsy nursingin the UK. Twenty years ago the handful of original epilepsy specialist nursesmay never have really believed that there would now be an epilepsy nursesorganisation with a membership of over 260 and a national voice in deci-sions relating to epilepsy care, or that both NICE and SIGN guidelines wouldidentify epilepsy specialist nurses as integral to high quality care provision.That the organisation can now hold a conference of such quality is tributein itself to the drive and determination of epilepsy nurses. It must also berecognised that this development process has received incredible supportfrom our medical colleagues as evidenced by the faculty list from thisexcellent meeting. By working together, we can make the next twenty yearseven more successful to the benefit of all people with epilepsy. l

Ena Bingham (left) showing her MBE to delegates and receiving her honorarymembership from the ESNA Chair Mel Goodwin.

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CONFERENCE RE PORTS

Neuroradiology and Functional Neuroanatomy: Correlating Anatomical, Brain Imaging and Clinical StudiesConference details: 16-19 April, 2012, London, UK. Reviewed by: Dr Sathiji Nageshwaran (Foundation Trainee, North Central Thames Foundation School), Dr ImranNoorani (Foundation Trainee, Southampton University Hospital Trust).

For the 12th year running the Neuroradiology andFunctional Neuroanatomy course was held at TheHospital for Neurology and Neurosurgery in Queen

Square, arguably the home of British neurology. All atten-dees were hoping to gain a better grasp on the complexdisciplines of neuroanatomy and neuroimaging. We werenot disappointed.

Why attend and who is it for?We decided to attend the course as we are applying forneurosurgery and neurology specialty training posts andthis course is ideal for building on our knowledge andunderstanding the anatomy and imaging of the nervoussystem, essential for our practice. There were a number ofother neurosurgery, neurology and neuroradiologytrainees in the audience, ranging from very junior to moresenior level. The majority of attendees, however, wereneuroscience researchers including PhD students andpost-doctoral researchers.

Course PreparationA basic understanding of neuroanatomy was essential andcan make the course far more accessible. There was frequentreference to Nieuwenhuy’s The Human Central NervousSystem with its excellent illustrations but a simple text suchas Crossman & Neary Neuroanatomy: An Illustrated ColourText covers many of the introductory topics.

Course Organisation and StructureThe course was organised by Professor Thomas Naidich(Neuroradiology Mount Sinai, New York), ProfessorChristopher Yeo (Behavioural Neuroscience, UCL) andProfessor Tarek Yousry (Lysholm Department ofNeuroradiology, Queen Square). The course was held over 4days and consisted of a mixture of interactive lectures andpractical sessions. Lectures covered a host of topics frombasic neuroanatomy, the evolution and development of thenervous system, cellular and chemical structure of various brainregions and talks on MRI, fMRI and tractography.

Lecture HighlightsFollowing the welcome address, day one began with Professor Naidichdiscussing the surface anatomy of the brain on MRI. The interactivelecture had all those in the auditorium chanting key landmarks of gyriand sulci throughout, which made for enjoyable and surprisingly effectivelearning. When reviewing brain MRI in a clinical setting it is often difficultto orientate oneself to the depth of the slice and the specific area of thebrain affected by a lesion (for example many can identify the pre- andpost-central gyrus on lateral sagittal views but this is difficult on midlinesagittal sections). Through highlighting several reference points, whichexhibit minimal variation between patients/subjects, and their relation to

key areas such as the motor strip, we were able to systemati-cally work through and orientate ourselves to key brainregions in different MRI planes.

We then considered imaging of normal and abnormalbrain development and the embryological development ofthe cerebral hemispheres (Professor Griffiths, Sheffield). Thiscovered the fundamentals of brain development anddiscussed the pathophysiology and nomenclature ofabnormal hemisphere development. Professor Valvanis(Zurich) talked about the evolution of the brain and lessonsthat came from neuroimaging.

The anatomy of movement, vision, sleep and balancewere covered in different sessions by experts in each fieldacross the 4 days. All assumed basic background knowledgeand then built upon this, finally covering controversial andfrontier aspects in each field.

Imaging – Hands-On PACSOne of the highlights of the course was the ‘Hands on PACS’sessions, where we were able to discuss clinical cases, prac-tice using the PACS systems with specialist advice and testour ability to report MRI studies. In these sessions, cases werecompiled with presenting symptoms and questions posed,asking us to localise the lesion (and confirm this on MRI),describe the lesion and attempt to make a diagnosis. Amixture of pathologies were presented, ranging fromtumours and stroke to neuromigrational abnormalities.

Dissection - Hands-On AnatomyThe two ‘Hands-on Anatomy’ sessions were held at nearby

University College London. Professor Yeo and Professor Naidichled the anatomy demonstration. In these sessions specimens were

studied working from the surface anatomy towards deep struc-tures discussed in lectures earlier that day, such as the basalganglia. This helped orientate and bring to life the morning’steaching sessions. Following this we were able to handle

prepared brains in small groups to further familiarise ourselveswith the anatomy. Several senior faculty members were available to

provide individualised teaching and answer questions. These sessionswere incredibly useful: allowing students to reinforce earlier lessons andvisualise the 3 dimensional concepts. We were however not able to under-take our own dissection.

ConclusionsThe course was very well organised, the lecturers and demonstrators werehighly enthusiastic, and the content certainly helped us on our waytowards a better understanding of neuroanatomy and neuroradiology.Moreover, the neuroscience lectures broadened our knowledge of currenthot topics in research. With the themes varying each year, it wouldcertainly be worthwhile to attend the course in order to keep one’s knowl-edge up-to-date. l

Prof Thomas Naidich

Prof Christopher Yeo

Prof Tarek Yousry

11th Annual Clinical Trials in CNS conference5th and 6th of November, 2012.The Copthorne Tara Hotel, London Kensington, UK.Tel: +44 (0)20 7827 6000 www.smi-online.co.uk • [email protected]

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CONFERENCE RE PORTS

7th World Congress for Neurorehabilitation 2012Conference details: 16-19 May, 2012, Melbourne, Australia Reviewed by: Louise Blakeborough, on behalf of the World Federation for Neurorehabilitation.

T he WCNR attracted neurorehabilitationclinicians and therapists from 55 coun-tries. More than 1800 health professionals

attended the meeting in Melbourne’s award-winning Congress Centre, where there were 650submitted abstracts, and over 300 posters.

The Congress was held in conjunction with the35th Annual Brain Impairment Congress for theAustralian Society for the Study of BrainImpairment (ASSBI) and the 20th AnnualScientific Meeting of the Australasian Faculty ofRehabilitation Medicine, The Royal College ofAustralasian Physicians (RACP). The Congressincluded 12 half-day workshops, ‘Meet theProfessor’, breakfast sessions and a scientificprogramme covering international research,discovery and innovation in all the major areas ofneurorehabilitation including traumatic braininjury, multiple sclerosis, stroke, spasticity manage-ment and neuro-oncology. In addition there were17 World Federation for NeuroRehabilitation(WFNR) Special Interest Group Meetings takingplace concurrently.

In the Opening ceremony, Professor JohnOlver, Convenor and Chairman of the OrganisingCommittee and WFNR Regional Vice-Presidentfor Australia, New Zealand and Oceaniawelcomed delegates. The meeting officiallyopened with The 2nd Michael Barnes Lecture,established in recognition of the visionary lead-ership and dedication of the founding Presidentand delivered by Professor Randolph Nudo,Director of the Landon Centre on Aging andProfessor in the Department of Molecular andIntegrative Physiology at the Kansas UniversityMedical Centre, USA. Neuroplasticity occurs ona variety of levels, ranging from cellular changesdue to learning, to large-scale changes involvedin cortical remapping in response to injury. Itprovides the scientific basis for the treatment ofacquired brain injury with goal-directed thera-peutic programmes in the context of rehabilita-tion. The adult brain is not ‘hard-wired’ withfixed neuronal circuits. Cortical and subcorticalrewiring of neuronal circuits occurs in responseto training and injury; this active, experience-dependent re-organisation of the synapticnetworks of the brain involves multiple inter-related structures including the cerebral cortex.Individual connections within the brain areconstantly being removed or recreated, largelydependent upon how they are used. If there aretwo nearby neurons that often produce animpulse simultaneously, their cortical maps maybecome one. Professor Nudo encapsulated thisconcept by saying “Neurons that fire together,wire together". He outlined animal studiesshowing that if a tiny stroke is produced byblocking the blood flow to a small part of amonkey’s motor cortex, the part of the body thatused to move in response to electrical stimula-tion of that area of cortex moves when nearby

areas of the brain are stimulated. Understandingthis interaction between the damaged andundamaged areas provides a basis for bettertreatment plans in stroke patients. Functionalimaging studies have shown that the brain canchange its responses in human stroke patients inways similar to that found in monkeys. This hasalso been shown by experiments using transcra-nial magnetic stimulation of the human cortex.“The challenge is to translate these results to theclinic” concluded Professor Nudo.

Current neuroprosthetic applicationsinclude Deep Brain Stimulation in Parkinson’sDisease, the Cochlear Implant, Bionic Eye andepidural stimulation post-stroke. ProfessorNudo is currently collaborating with engineersto develop micro-implantable devices forrepairing neural circuits after stroke and trau-matic brain injury.

Against the exciting developments in neuro-plasticity and neuroprosthetic tools, there arefrustrations due to the limits imposed by thebiology of the brain, and the difficulty in doinghuman experiments that demonstrate the bene-fits of therapy. It has proved difficult forresearchers carrying out rehabilitation trials todetermine how much an improvement is due toa particular therapy, how much is placebo andhow much is the ‘normal’ spontaneous partialrecovery that follows stroke or brain injury.Professor Bruce Dobkin, Professor of Neurologyand Director of the Neurologic RehabilitationProgram at the University of California, LosAngeles, USA highlighted the shortcomings ofneurorehabilitation clinical trials. He illustratedhis talk by looking at randomised control trialsof body weight-supported treadmill trainingand robotic-assisted step training which did notproduce better outcomes than a comparabledose of progressive over-ground training orexercise in disabled persons with stroke, spinalcord injury, multiple sclerosis, Parkinson’sdisease and cerebral palsy. Professor Dobkinsuggested that the shortcomings require betterstrategies to assess the conceptual basis, designand outcome measurements for future trials ofpharmacological, cortical stimulation, neuralrepair and other experimental neurorehabilita-tion interventions.

Professor Robert Teasell, Chair-Chief of theDepartment of Physical Medicine andRehabilitation, University of Western Ontario,Canada pointed out that despite all theevidence available, clinical care for strokepatients is not generally delivered in accor-dance with established guidelines and this maynegate the benefits of specialised, organised,interdisciplinary care. Stroke is increasing - it’sa disease of older people – this was the recur-ring message throughout the Congress andProfessor Teasell emphasised “the demographiccrunch that is coming”. The three key princi-ples for stroke rehabilitation are a) organisedstroke care, b) the earlier the better and c)intensity of therapy. Evidence is growing thatrehabilitation has a significant impact on func-tional outcomes following stroke with improve-ments in discharge disposition and communityreintegration. If the rehabilitation team adhereto guidelines the outcomes are better. “You candiscover all you want but if you don’t transfer itto the patient then it doesn’t matter” saidProfessor Teasell, “the simple existence ofresearch evidence doesn’t automatically resultin alterations in policy or clinical decisions”.

Professor Michael Barnes presented the EarlyCareer Development Awards in recognition ofthe most outstanding oral and poster presenta-tions by a delegate. The Awards, totallingAU$6000, were donated by the MelbourneConvention and Visitors Bureau. The recipients ofthe Poster Awards were Louisa Ng (Australia) andCorina Schuster (Switzerland). The recipients ofthe Oral Presentation Awards were Camila Fiore(Australia) and Mayowa Owolabi (Nigeria).

The meeting closed with a presentation byProfessor Anthony Burkitt on the developmentof the Retinal Implant for the Sight Impaired.The ‘Bionic Eye’ works by using electricalcurrents to stimulate nerves at the back of theeye. This Australian technology is targeted attwo forms of vision loss; retinosa pigmentosaand age-related macular degeneration.

Commenting at the closing ceremonyProfessors Barnes and Clarke said: “The WFNRneeds to position itself to address the chal-lenges of acute to community rehabilitation sowe can do the best possible rehabilitation forour patients. We should strengthen our teachinginitiatives and awareness raising is key amongstpoliticians and the public”. “In 15 years we havecome a long way and we need to keep movingforwards. The WFNR’s 32 National Societiescover half the world’s population but there’s 400million people who are not getting any rehabil-itation at all and we need to address thisthrough education and training. There is reason-able evidence to suggest that low tech aids canprovide some rehabilitation to the masses andwe should work on the concept that somethingis better than nothing”. l

Tracey Mole and Professor Michael Barnes WFNR.

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miRNA and ASO –The initial approachto treating geneticdiseases in a new wayOne of the holy grails of treating geneticdisorders of the CNS is to target theabnormal gene itself and by so doingeffect a cure without having to worryabout off target effects. There have beentwo recent papers which are worth high-lighting in this regard – one using amicroRNA approach, the other an anti-sense oligonucleotide (ASO) strategyand both involving autosomal dominanttrinucleotide repeat disorders.

In the first paper by Miyazaki et al inNature Medicine (with a wonderfullyclear News and Views commentary on itby Christopher Pearson), they concen-trated on spinal bulbar muscular atrophy(SBMA) which is a slowly progressivelower motor neuron disorder of men. Thedisease is characterised by a CAG expan-sion in the androgen receptor, whichthen causes motor neuronal cell dysfunc-tion and death through translocation ofthe mutant receptor within the cell. Thishas in the past led to attempts to blocktranslocation using anti-androgen agents,although as a clinical therapy this createsobvious problems. In this new paper theauthors looked at a transgenic model ofthis condition and found that oneendogenous microRNAs in particular(the imaginatively named miRNA-196a)was upregulated and that by overex-pressing it they could slow down thedisease process. This they did using anAAV delivery system that selectivelytargeted the motoneurons. They thenshowed that miR-196a mediated itseffects on the mutant receptor through aprotein that is involved with mRNAprocessing (CELF2). This beautiful workshows how miRNAs are coming of agenot only in terms of how they regulatenetworks of intracellular processes buthow they can be recruited for treatingdisease.

In the second study the disease underattack is Huntington’s disease, which has itsCAG repeat in exon 1 of the huntingtin(htt) gene. This gene product causes exten-sive cell loss in the CNS but typically notuntil patients are in their 40s, althoughexactly when the disease process beginsrelative to clinical expression remains asubject of great interest (see TRACK-HDand PREDICT-HD studies). Obviouslybeing able to switch off the mutant gene(mthtt) whilst leaving the normal htt to doits job has proven difficult, as has gettingthe silencing agent for the mutant htt in allcells for long period of times. This last pointin particular has vexed the field but arecent paper by Kordasiewicz et al in

Neuron (again accompanied by a lovelyPreview by Lu and Yang) suggests that thismight not be necessary as they showedthat transiently knocking down mthttcould have long lasting benefits in animalmodels of disease. This implies that stop-ping the production of mthtt even if onlyfor a short time may allow the cell torecover, regroup and fight another day, andthus whilst repeated injections of ASOsmay be required, the frequency of admin-istration may be less than once thought.

These papers highlight once more theskill of researchers to get to the heart ofdisease, and their ingenuity in how to dothis. Obviously the challenge still remainsas to how one can translate such findingsinto a much larger, longer living humanpatient – but slowly we are movingtowards therapies that seek to trulyswitch off disease causing genes andtheir products. – Roger Barker, Cambridge Centre for BrainRepair.

Pearson CE. Co-opting endogenousmicroRNAs for therapy. NATURE MEDICINE 2012;18:1011-2.

Miyazaki Y, Adachi H, Katsuno M et al. Viral delivery of miR-196a ameliorates the SBMA phenotype via the silencing ofCELF2. NATURE MEDICINE 2012;18:1136-1141.

X-H Lu & X.W Yang. “Huntingtin Holiday”:progress toward an antisense therapy forHuntington’s disease. NEURON 2012;74:964-6.

Kordasiewicz HB, Stanek LM, Wancewicz EVet al. Sustained Therapeutic Reversal ofHuntington's Disease by TransientRepression of Huntingtin Synthesis.NEURON 2012;74:1031-44.

Intramuscular midazolam for statusepilepticusLarge studies of status epilepticus whichchange practice are hard to come bybut this is one such. The study comparedthe outcome of treatment of statusepilepticus with IM midazolam and IVlorazepam, which has been the goldstandard since 1998. This massive effortincluded 3114 paramedics and 79 hospi-tals. Children estimated to be over 13Kgand adults were included and weretreated if convulsive seizures had beencontinuing for over five minutes. Patientswere excluded with major trauma, hypo-glycaemia, cardiac arrest or HR<40.Essentially the question is does speed ofaccess with an IM injection of mida-zolam 10mg in adults, using an auto-injector make up for speed of distribu-tion of IV access of IV lorazepam 4mg(smaller doses were given to littlepeople) given also that it is a differentdrug being administered. The short

A mutation for protectionagainst Alzheimer’s diseaseThe perceived importance of amyloid in the patho-genesis of Alzheimer’s disease has fluctuated in thelast 30 years. Deposition of amyloid is a pathologicalhallmark of the disease and suggests a central role forthe protein in the disease. The association of Down’ssyndrome, trisomy 21, with Alzheimer’s made theAmyloid Precursor Protein (APP) gene on chromo-some 21 an obvious candidate gene for autosomaldominant Alzheimer’s disease. Initial genetic linkagestudies excluded APP as the site of the causativemutation. The subsequent realisation that Alzheimer’sdisease might be caused by more than one gene byJohn Hardy’s group led to a re-examination of linkageresults and the discovery that APP mutations cancause autosomal dominant Alzheimer’s disease. Over20 further pathological mutations in the APP genehave been described, however, APP mutations provedcomparatively rare. Other genes, Presenilin 1 andAPOE, stole much of the limelight. In Alzheimer’sdisease drug development, there was a clear rationaleto developing treatments that influenced amyloidmetabolism or deposition. These treatments havebeen developed and shown initial promise but, so far,have disappointed.

This paper is another step in the Alzheimer/amyloid story. Jonsson and colleagues utilised wholegenome data from over 1500 Icelanders to look forsequence changes in the APP gene. They identified acoding mutation (A673T) which confers protectionagainst Alzheimer’s disease in their cohort and showthat this mutation reduces the production ofamyloidogenic peptides in vitro. Their controls wereelderly (over 85 years of age) and had passed acognitive assessment. Jonsson and colleagues foundthat the A673T mutation was also rarer in patientswith less specific “cognitive decline”. The results lookrobust and there seems little reason to suppose thatthey will not apply to a wider population thanIceland, but this remains to be shown. 0.6% of thecontrol Icelandic population carry the mutation sothe effect is significant although the protective allelemay be rarer in other populations. This discovery willalso encourage therapeutic approaches aimed ataltering APP metabolism.

It is not surprising that these results apply also topatients with cognitive decline not diagnosed withAD. It highlights the spectrum that exists between the“normal” decline in memory with age, amnestic MildCognitive Impairment and Alzheimer’s disease. Theresult supports the theory that very mild Alzheimer’spathology may be responsible for minor cognitiveproblems as people age. This observation highlightsthe question that already troubles Alzheimer special-ists: of when a minor cognitive problem becomes adisease. – Dr Jeremy Brown, Addenbrooke’s Hospital and QueenElizabeth Hospital, King’s Lynn.

Jonsson et al. A mutation in APP protects againstAlzheimer's disease and age-related cognitive decline.Nature: 488, 96–99. Date published: (02 August 2012)

Editor’s Choice

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J O U R N A L R E V I E W S

answer to the question is yes, which means thatwe should be looking to change practice foremergency management to IM midazolam.

The primary outcome of the study was termi-nation of seizures before arrival in the emer-gency department without the need for the para-medics to provide rescue therapy. The keysecondary outcome was time from opening thebox containing treatment to the termination ofseizures. 448 patients were assigned to IM mida-zolam of whom 443 received the drug. 445 wereassigned to IV lorazepam of whom 297 receivedthe drug. Of the remainder, seizures stoppedanyway in 95, before the drug was given and in 42IV access could not be achieved. In the intentionto treat analysis, treatment failure occurred in26.6% of midazolam patients and 36.6% oflorazepam patients. Per protocol figures were25.1% and 35.7% respectively. Midazolam alsofared better on all secondary measures, exceptslightly longer hospital stays. Seizure recurrencewithin 12 hours was similar and only around 10%in both groups and hypotension was also similar.Although the time from giving the injection tocessation of seizures was slightly longer withmidazolam, this was more than relative speed ofIM access compared with IV access forlorazepam. The authors cautiously state that IMmidazolam is non-inferior to IV lorazepam. Withthese data one might go further. – Mark Manford, Addenbrooke’s and BedfordHospitals.Silbergleit R, Durkalski V, Lowenstien D et al.Intramuscular versus intravenous therapy for pre-hospital status epilepticus.NEJM 2012;366:591-600.

A View to a Kill: Oligodendrocytes in ALSIt is the glia that are to blame, again. Recent reve-lations that astrocytes can trigger neuronaldegeneration in amyotrophic lateral sclerosis(ALS) came as a surprise. Now, it seems thatastrocytes are not alone in serving as a primarycause in neurodegeneration. Oligodendrocytes,normally providing insulation and nutritionalsupport for axons, have currently come into thespotlight. Their primary involvement in multiplesclerosis has been long evident, leading toaxonopathy and cortical neuronal loss followingthe disruption of the myelin sheath. However,their relatively normal initial appearance inneurodenerative disease has perhaps maskedtheir significance in pathogenesis. A new paperpublished by Jeffery Rothstein’s group reports amechanism by which oligodendrocytes maycontribute to early neurodegeneration in ALSpatients, but somewhat unexpectedly, withoutthe loss of myelin.

Youngjin Lee and colleagues have demon-strated that monocarboxylate transporter 1(MCT1) is specifically enriched in oligodendro-cytes in the mouse brain and spinal cord,providing potential energy support to neurons inthe form of lactate. In vitro, the inhibition ofMCT1 in oligodendocytes, either by antisense or

by pharmacological methods, leads to selec-tive motoneuron death in organotypic spinalcord slice cultures. This highlights the possi-bility that the inhibition of lactate transport byoligodendrocytes to neurones could be solelyresponsible for a neurotoxic effect. Indeed, thereplacement of lactate in the culture mediumreversed neurotoxicity. Similar results werenoted also in vivo when MCT1 expression wasdownregulated by a specific small hairpinRNA (shRNA) packaged by a lentivirus.

Could the failure of providing lactate byoligodendrocytes play a primary role in toxi-city in neurodegenerative diseases? Theelegant series of experiments, in which MCT1downregulation was induced selectively inoligodendrocytes, have provided proof of theirdirect involvement. The similar features ofaxon pathology seen in the mouse ALS model(SOD1 transgenic mice) and in mice affectedby a single MCT1 allele deletion lent furthersupport to such a notion. Thus it did not comeas a surprise to learn that the motor cortex ofhuman ALS patients show more than a 50%decline in MCT1 expression, similar to thatseen in the spinal cords of the SOD1 trans-genic mice.

This corroborating evidence may addanother layer to the complexity of ALS patho-genesis, shifting the view to another potentialkiller cell in neurodegenerative disease.Perhaps there is more than meets the eye, andone may speculate that protective approachesdesigned to directly target neurones may notbe sufficient. – Andras Lakatos, Cambridge Centre for BrainRepair and Addenbrooke’s Hospital, Cambridge. Youngjin Lee et al.Oligodendroglia metabolically support axons andcontribute to neurodegeneration. NATURE, Published online on 11 July 2012.

Infection and autoimmunity – an overlap in the brain?NMDA-receptor antibody related encephalitisis now a well-recognised, clinically distinctivecondition often seen in younger individualswith a good response to immunotherapies.Patients frequently develop fever andheadache prior to, or during, their illness.Importantly, the antibodies are of the IgG class.

Pruss et al retrospectively show antibodiesof IgG, IgA and IgM classes which are directedagainst the NMDA receptor in 13 of 44 (30%)patients with proven HSV encephalitis(HSVE). The diagnosis of HSVE appears robustin that patients had the typical symptoma-tology, CSF HSV PCR positivity plus apronounced lymphocytosis, and classicaltemporal lobe changes on imaging.

Although the timing of available serum andCSF samples was understandably rather patchyand variable, it was apparent that some patientshad NMDAR-Igs as early as four days after theirdiagnosis of HSV. By contrast, in other patients,

NMDAR-Igs only appeared many weeks ormonths after the HSV symptom onset. Thismay suggest that in some cases, and slightlysurprisingly, the antibodies are present inHSVE very early in the illness. In others, theantibodies may be part of a secondaryimmune response to the HSV-induced celllysis.

However, the serum-CSF compartmentali-sation of the antibodies, time-course of theirappearance and the NMDA classes wereoften difficult to predict or pathophysiologi-cally model. For example, one patient onlyhad serum NMDAR-IgM ten days into theirillness, these persisted and were accompa-nied by serum NMDAR-IgA after around oneyear but serum NMDAR-IgG or CSF NMDAR-IgG/A/M were never detected. Another casehad serum and CSF NMDAR-IgA two weeksinto their illness, the serum NMDAR-IgApersisted for an additional fortnight, and ataround one year CSF showed no NMDAR-IgG/A/M and only serum NMDAR-IgM waspresent.

These data provide one potentialrationale for the use of steroids in HSVE.They also suggest that infectious andautoimmune encephalitis may coexist.Although headache, fever and cognitivedeficits do overlap, there are marked differ-ences between many clinical and paraclin-ical features of HSVE and ‘typical’ NMDAR-IgG antibody encephalitis. While the pres-ence of these antibodies in the setting ofHSVE is intriguing, their role remainsunclear. Nevertheless, these antibodiesshould certainly be measured in a prospec-tively collected series of HSVE.Reproducible findings may mean that in thefuture steroids are routinely added toacyclovir in the setting of HSVE.– Sarosh Irani, Neurosciences Building,University of California, San Francisco.Prüss H, Finke C, Höltje M, et al. NMDA receptor antibodies in herpes simplexencephalitis. ANNALS OF NEUROLOGY. Accepted manuscriptonline: 16 JUL 2012, DOI: 10.1002/ana.23689.

Panel of reviewersDr Jeremy Brown, Addenbrooke’s Hospital and Queen Elizabeth Hospital, King’s Lynn.

Roger Barker, Cambridge Centre for Brain Repair.

Mark Manford, Addenbrooke’s and Bedford Hospitals.

Andras Lakatos, Cambridge Centre for Brain Repair andAddenbrooke’s Hospital, Cambridge.

Sarosh Irani, Neurosciences Building, University ofCalifornia, San Francisco.

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NEWS REV I EW

Stuart introduces new high capacity shaking incubator for cell culture applications

Brain tumour tissue is difficult for researchers toaccess. Bureaucracy has led to banks beingestablished which are closed to researchers; a reviewof just three centres that returned data on currentarchive holdings (dating back to 1970) revealed thatthe potential of a networked approach is clear to see– in excess of 50,000 surgical cases. Just sitting there.

Brainstrust is working alongside key clinicians tochange this. The Charity is looking to build a UK widenetwork of brain tumour tissue banks, that willsupport a diverse range of brain tumour researchprojects.

The immediate objective is to link existing archivesof brain tumour tissue in one virtual network. Phase 2will support existing brain tumour tissue banks sothat the surgical collection of brain tumour tissue hasfull consent and clinical data attached. Hospitalsachieving this will then be able to link into thenational network.

This project will provide the interface that isneeded between researchers and brain tumour tissue,giving easy access to the right tissue, in sufficientlylarge numbers and of high quality.

To find out more, visit www.brainstrust.org.uk, or call01983 292405.

Shimadzu UK launches liquid chromatographymass spectrometer (LCMS)

New brochure forFujifilm’s Console Advance

Fujifilm is a pioneer in diagnostic imagingand information systems for healthcarefacilities, with a range of constantlyevolving clinically proven products andtechnologies designed to assist medicaland veterinary professionals performmore efficiently and effectively. Thecompany have recently providedsubstantial support to Tiggywinkles - theworld’s busiest wildlife hospital who treatover 10,000 animal casualties, free ofcharge, every year. The hospital receivesno government funding relying entirelyon charitable donation to continue itswork.

Tim Moran, Operations Manager forTiggywinkles Wildlife Hospital said,“Thanks to substantial support from Fujifilm we wereable to invest in the Company’s state-of–the-art CR

X-ray processing system which willallow us to diagnose casualtiesmore efficiently. The equipmentarrived just in time to help duringthe busy spring and summer monthswhen thousands of sick and injuredanimals are brought to our busyAylesbury facilities.”

Mark van Rossum for Fujifilm,presented Tiggywinkles with theirFujifilm PRIMA CR system saying,“Fujifilm are pleased to be able tosupport the world renowned workthat the animal hospital does bymaking this latest imagingtechnology available to them. As aresult their patients will be

diagnosed and treated much faster, increasing thehospital’s capacity.”

Fujifilm supports the world’s busiest WildlifeHospital

Shimadzu UK has launched ahigh-end liquid chromatographymass spectrometer – the LCMS-8080 – which delivers best-in-class sensitivity, high quality dataand fast cycle times. Anextension of its Ultra Fast MassSpectrometry (UFMS) range, thenew model’s high speedcapabilities increase productivityin the laboratory by deliveringaccurate measurements, firsttime.

Ideal for users requiringinformation rich analyses, theLCMS-8080 can be used across a wide range ofapplications including food safety testing, drugs ofabuse screening as well as in clinical, environmentaland ADME laboratories. The instrument delivers high

quality and accurate data over longperiods of use.

The Coaxial Hot Gas Desolvationsource is fundamental in deliveringthe LCMS-8080’s enhancedsensitivity as it focuses the ionplume and improves ionisationefficiency. This is enhanced by HotSource Induced Desolvation whichremoves solvent noise, followed byhigh performance pumping and amulti-orthogonal inlet. The LCMS-8080’s class-leading sensitivityallows accurate quantitation of lowlevel analytes.

For more information T.01908 552209,[email protected]

Fujifilm has published an eight-page, full colourbrochure on their next generation Console Advance.

The brochure details the benefits of Fujifilm’sConsole Advance and includes information on all thenew enhanced features, which make it an idealoption to integrate FDR and FCR Systems.

It is packed with features to streamline workflowand assist users to save time, including a newgradation design monitor and intuitive arrangementof operation buttons, helping users check andconfirm information quickly and accurately, andadvanced functions such as ROI image adjustmentand auto-trimming.

The brochure also details additional optionalfunctions including image stitching and preciseenlargement, helping users get the best imagepossible first time.

The Console Advance automatically recognisesthe region of interest and applies the optimumimage processing parameters to deliver reproducible,high quality images every time.

With connectivity to a range of other equipmentvia the hospital network, and being fully compatiblewith DICOM part 14, Fujifilm’s Console Advance isthe heart of an FDR/FCR System.

For a copy of the brochure, telephone Fujifilm on +44 (0)1234 326780.

Brain Tumour TissueBanking – a newapproach

Stuart, the benchtop scienceequipment specialist, hasunveiled a new addition to thecompany’s SI Series ofincubators. The new SI600 withbuilt-in orbital shaker has acapacity of 115 litres – morethan double that of the existingSI500 – and can accommodateup to six 2 litre Erlenmeyerflasks. Both of these benchtopsystems are equipped with Biocote antimicrobialprotection and are ideal for use in cell culture,especially suspension culture applications, with thelarger SI600 supporting growing demands for largerscale production.

The SI600 incubator is designed for reliable,convenient operation. Like the SI500 it includes aunique retractable platform for effortless loading

and unloading. Under normaluse the platform is locked inplace but can be drawnforward from the chamberto give easy to access tosamples at the back.

Microprocessor controldelivers long-termtemperature stability, withforced air circulationensuring uniformity

throughout the incubator. Separate control oftemperature and shaker speed guards againstaccidental temperature adjustment, while USBenabled communication allows long term trackingof the incubator temperature.

For more information see www.stuart-equipment.com

ACNRSO12_Layout 1 28/08/2012 23:22

As effective as high-dose IFN-beta at reducing relapses, with less fl u-like symptoms1,2

Copaxone. Helping RRMS patients maintain a working life

Standing up toRRMS every day

(glatiramer acetate)

COPAXONE® (glatiramer acetate) PRE-FILLED SYRINGE PRESCRIBING INFORMATIONPresentation – Glatiramer acetate 20mg solution for injection in 1ml Pre-filled Syringe. Indication – Treatment of patients who have experienced a well-defined first clinical episode and are determined to be at high risk of developing clinically definite multiple sclerosis (MS). Reduction of frequency of relapses in relapsing-remitting MS in ambulatory patients. In clinical trials this was characterised by at least two attacks of neurological dysfunction over the preceding two-year period. Dosage and administration – 20mg of glatiramer acetate (one pre-filled syringe) administered sub-cutaneously once daily. Children (12 - 18 years) No specific studies. Limited published data suggest the safety profile of 20mg administered sub-cutaneously once daily is similar to that seen in adults. Children (<12 years) Not recommended. Elderly No specific data. Impaired renal function No specific studies. Monitor renal function during treatment and consider possibility of deposition of immune complexes. Contra-indications – Known allergy to glatiramer acetate or mannitol (excipient). Pregnancy. Special warnings and precautions – Sub-cutaneous use only. Initiation to be supervised by neurologist or experienced physician. Supervise first self-injection and for 30 minutes after. One or more of vasodilatation, chest pain, dyspnoea, palpitations or tachycardia may occur within minutes after injection. These generally resolve spontaneously after a short time. If severe, treat symptomatically. Caution in patients with pre-existing cardiac disorders and review such patients

regularly. Rarely convulsions and/or anaphylactic or allergic reactions. Rarely, hypersensitivity (bronchospasm, anaphylaxis or urticaria). If severe, treat appropriately and discontinue Copaxone. Interactions – No formal evaluation. Increased incidence of injection-site reactions with concurrent corticosteroids. Theoretical potential to affect distribution of protein-bound drugs, therefore concomitant use of these should be monitored. Pregnancy and lactation – Not to be used in pregnancy. Consider contraceptive cover. No data on excretion in human milk. Undesirable effects – Local injection site reactions (erythema, pain, mass, pruritus, oedema, inflammation, hypersensitivity, injection site atrophy). An immediate post-injection reaction (one or more of vasodilation, chest pain, dyspnoea, palpitation, tachycardia) may occur within minutes, reported at least once by 31% of patients receiving Copaxone compared to 13% of patients receiving placebo. Other undesirable effects more than 2% (>2/100) higher incidence in the Copaxone treatment group than in the placebo group: Nausea, anxiety, rash, back pain, chills, face oedema, vomiting, skin disorder, lymphadenopathy, tremor, eye disorder, vaginal candidiasis, weight increased. Rarely: Anaphylactoid reactions. Please refer to the SPC for a full list of adverse effects. Overdose – Monitor, treat symptomatically. Pharmaceutical Precautions – Store Copaxone in refrigerator (2ºC to 8ºC). If the pre-filled syringes cannot be stored in a refrigerator, they can be stored at room temperature (15ºC to 25ºC) once for up to one month. Do not freeze. Legal Category – POM. Package Quantity and Basic NHS Cost – 28 pre-filled syringes of Copaxone: £513.95.

Product Licence Number – 10921/0023 Further Information – Further medical information available on request from Teva Pharmaceuticals Limited, The Gate House, Gatehouse Way, Aylesbury, Bucks, HP19 8DB. Date of Preparation – February 2012.

References1. Mikol DD et al. Lancet Neurology 2008; 7:903-914.2. O’Connor P et al. Lancet Neurology 2009; 8:889-897.

C0212-806 February 2012

Adverse events should be reported.Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events

should also be reported to Teva Pharmaceuticals Ltd on telephone number: 01296 719768.

COP-11-17269 Copaxone Ad_ACNR_AW3.indd 1 01/05/2012 17:59

so12/acnrso12_web.pdf · vairavan narayanan, krunal patel, stephen price –high grade gliomas:...

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