Volume 1 Issue 5 November/December 2001
Advances in Clinical Neuroscience & Rehabilitation
journal reviews • events • management topic • industry news • rehabilitation topic
Review Articles: How to assess reports of clinical results
Ethical barriers in research into diseases of the human brain
Neuropsychiatry of Huntington’s disease
Rehabilitation Article: The practicalities of treadmill training for
non-ambulant hemiplegic patients
Management Topic: Management of refractory epilepsy
THE TRUTH BEHIND THE MASK
Neuroimaging has proved to be both sensitive and
highly effective in detecting dopaminergic dysfunction in Parkinsonian Syndromes. It can help establish
the truth of the disorder when clinical features are
incomplete or contradictory.
Now the truth is out. Nycomed Amersham are proud
to announce the first and only approved nuclear
imaging product in Europe to help differentiate
Essential Tremor from Parkinsonian Syndromes
related to idiopathic Parkinson’s disease, Multiple
System Atrophy and Progressive Supranuclear Palsy.
The images are easy to read and available the same
day. DaTSCAN™ gives you clear diagnostic pictures
that provide accurate visual differentiation of
Parkinsonian Syndromes from Essential Tremor.
Currently, diagnostic methods rely on the use of
clinical criteria, with formal confirmation only possible
at post mortem. DaTSCAN can reduce the time
required to reach a diagnosis.With 97.5% sensitivity†,
you can be more confident than ever that your
diagnosis is correct and that the medication you
prescribe will have the desired effect.
DaTSCAN – another major step forward in the
partnership of success between Neurology, Geriatrics,
Nuclear Medicine and Nycomed Amersham.
Further information from: Zilla Moore,
Abbreviated Prescribing Information
Presentation: Vials containing 185 MBq ioflupane (123I) at reference time.
Uses: Detecting loss of functional dopaminergic neuron terminals in the striatum of
patients with clinically uncertain Parkinsonian Syndromes in order to help
differentiate Essential Tremor from Parkinsonian Syndromes related to idiopathic
Parkinson’s Disease (PD), Multiple System Atrophy (MSA), Progressive
Supranuclear Palsy (PSP). DaTSCAN is unable to discriminate between PD, MSA
Dosage and Administration: DaTSCAN is a 5% (v/v) ethanolic solution for
intravenous injection and should be used without dilution. Clinical efficiency has
been demonstrated across the range of 111-185 MBq; do not use outside this range.
Appropriate thyroid blocking treatment must be given prior to and post injection of
DaTSCAN. SPECT imaging should take place 3-6 hours after injection of DaTSCAN.
DaTSCAN is not recommended for use in children or adolescents. For use in
patients referred by physicians experienced in the management of movement
disorders. See SPC.
Contraindications: Pregnancy and in patients with hypersensitivity to iodide or
any of the excipients.
Precautions: Radiopharmaceuticals should only be used by qualified personnel
with appropriate government authorisation and should be prepared using aseptic
and radiological precautions. DaTSCAN is not recommended in moderate to severe
renal or hepatic impairment.
Interactions: Consider current medication. Medicines that bind to the dopamine
transporter may interfere with diagnosis; these include amphetamine, benzotropine,
buproprion, cocaine, mazindol, methylphenidate, phentermine and sertraline. Drugs
shown during clinical trials not to interfere with DaTSCAN imaging include
amantadine, benzhexol, budipine, levodopa, metoprolol, primidone, propranolol and
selegiline. Dopamine agonists and antagonists acting on the postsynaptic dopamine
receptors are not expected to interfere with DaTSCAN imaging and can therefore
be continued if desired.
Pregnancy and Lactation: Contraindicated in pregnancy. Information should be
sought about pregnancy from women of child bearing potential. A woman who has
missed her period should be assumed to be pregnant. If administration to a breast
feeding woman is necessary, substitute formula feeding for breast feeding.
Side Effects: No serious adverse effects have been reported. Common side effects
include headache, vertigo and increased appetite. Exposure to ionising radiation is
linked with cancer induction and a potential for hereditary defects and must be
kept as low as reasonably achievable.
Dosimetry: Effective dose from 185 MBq is 4.35 mSv.
Overdose: Encourage frequent micturition and defaecation.
Legal category: Subject to medical prescription (POM). Consult full SPC before
prescribing. Further information available on request.
Marketing Authorisation number: EU/1/00/135/001
Basic NHS price: £420
Date of Preparation: July 2000
Nycomed Amersham plc., Amersham Place, Little Chalfont,
Buckinghamshire, England HP7 9NA. www.na-imaging.com
† Benamer H et al. Accurate differentiation of Parkinsonism and Essential Tremor using visual
assessment of 123I-FP-CIT SPECT imaging: the 123I-FP-CIT Study Group. Movement Disorders
his issue has an emphasis on clinical trials.
Peter Rothwell, director of the Oxford
Stroke prevention Research Unit, critically
assesses how to interpret clinical trial results.This is
especially helpful as big trials are often so influential
in governing clinical practice, and to the uninitiated
it is often difficult to know how to interpret large
clinical trials and meta-analyses. It is therefore useful to have the
view of an expert, so that we can all critically review what is being
claimed in the publication of trial results.
This article is followed by a personal view from Professor
Charles Warlow on the new data protection legislation and where
it will lead and what it will mean for epidemiological research.This
article is a transcript of the talk he delivered to the British
Association science festival in September, and plots a course
through his medical history and removed organs to the heart of
the problem with data protection and clinical research. This is an
issue that all of us should have an opinion on, as it will impact on
anyone doing clinical research by restricting access to medical
information. This will be felt most in epidemiological studies,
where knowing incident and prevalent cases forms the backbone
of much research and without which the work is ultimately built
on shifting sand.As Professor Warlow points out, protecting infor-
mation on patients is clearly essential but the way in which this
has been implemented seems to have been poorly thought out,
especially given the excellent record of confidentiality that exists
in medical research.
Following on from our article in the last ACNR on cognition in
Huntington's disease, we have an article from the same authors on
the neuropsychiatric problems of this disorder. We also have our
regular articles. Mark Manford takes us through status epilepticus
and Alasdair Coles treats us to the painful topic of the spinothalamic tracts.We have a number of conference reports including the
annual Neuroscience for Clinicians meeting held in Cambridge
and organised by Professor Alastair Compston, and the neuroimmunology conference held in the heartland of this journal,
Edinburgh. We also have a summary of the recent ABN held in
Durham. Finally we also have our regular review of the journals.
So there it is for another issue, if you have any ideas or thoughts
on how to improve the journal (if that is possible!) or would like
to suggest an article and author then do let us know. Finally many
of you will be pleased to know Alasdair Coles has agreed (or been
forced) to join me as Co-editor of ACNR.
Roger Barker, Editor
How to assess reports of
Ethical barriers in research
into diseases of the human
brain Charles Warlow
The practicalities of treadmill
training for non-ambulant
Catherine Kendrick & Stephen Kirker
Neuropsychiatry of Huntington’s
Niall Pender & John Mellers
Management of refractory
epilepsy Mark Manford
Int. Society of Neuroimmunology
Neuroscience for Clinicians
events 24 journal reviews 29 book review 35 news review 37
ACNR is published by Whitehouse Publishing,
7 Alderbank Terrace, Edinburgh EH11 1SX.
Tel. 0131 477 2335/0777 969 7677, Fax. 0131 313 1110,
E-Mail. [email protected]
Publisher: Rachael Hansford
Design & Production: Barbara Newton
Printed by: Stephens & George Magazines, Tel. 01685 388888.
ANCR • VOLUME 1 NUMBER 5 NOVEMBER/DECEMBER 2001
Copyright: All rights reserved; no part of this publication may be reproduced, stored in a retrieval
system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise without either the prior written permission of the publisher or a license permitting restricted photocopying issued in the UK by the Copyright Licensing Authority.
Disclaimer: The publisher, the authors and editors accept no responsibility for loss incurred by
any person acting or refraining from action as a result of material in or omitted from this magazine. Any new methods and techniques described involving drug usage should be followed only
in conjunction with drug manufacturers' own published literature.
This is an independent publication - none of those contributing are in any way supported or remunerated by any of the companies advertising in it, unless otherwise clearly stated.
Comments expressed in editorial are those of the author(s) and are not necessarily endorsed by
the editor, editorial board or publisher. The editor's decision is final and no correspondence will
be entered into.
Control is a reflection of dose
Move up to 10mg at 6 months
With ReQuip, stepping up the dose steps up the control.
In a landmark 5 year study1 recently published in
The New England Journal of Medicine, the full benefit
of ReQuip was achieved in the upper dose range.
At 6 months the average dose was over 10mg/day.2
Dosage should be titrated against efficacy and tolerability.
TO START WITH AND STAY WITH
REQUIP ropinirole Prescribing Information
Presentation ‘Requip’ Tablets, PL 10592/0085, 0087-0089, each containing
ropinirole hydrochloride equivalent to either 0.25, 1, 2 or 5 mg ropinirole. 0.25
mg tablets – 210 tablets starting pack, £43.12, 1 mg tablets – 84 tablets, £46.20,
2 mg tablets – 84 tablets, £92.40, 5 mg tablets – 84 tablets, £184.80.
Indications Treatment of idiopathic Parkinson’s disease. May be used alone
(without L-dopa) or in addition to L-dopa to control “on-off” fluctuations and
permit a reduction in the L-dopa dose. Dosage Adults: Three times a day, with
meals. Titrate dose against efficacy and tolerability. Initial dose for 1st week
should be 0.25 mg t.i.d., 2nd week 0.5 mg t.i.d., 3rd week 0.75 mg t.i.d., 4th
week 1 mg t.i.d. After initial titration, dose may be increased in gradual weekly increments until acceptable therapeutic response established. Do not
exceed 24 mg/day. Concurrent L-dopa dose may be reduced gradually by
around 20%.When switching from another dopamine agonist follow manufacturer’s guidance on discontinuation. Discontinue ropinirole by reducing doses
over one week. Renal or hepatic impairment: No change needed in mild to moderate renal impairment. Not studied in severe renal or hepatic impairment –
administration not recommended. Elderly: Titrate dose in normal manner.
Children: Parkinson’s disease does not occur in children – do not give to children. Contra-indications Hypersensitivity to ropinirole, pregnancy, lactation
and women of child-bearing potential unless using adequate contraception.
Precautions Caution advised in patients with severe cardiovascular disease
and when co-administering with anti-hypertensive and anti-arrhythmic agents.
Patients with major psychotic disorders should be treated with dopamine agonists only if potential benefits outweigh the risks. Patients should avoid driving
or other potentially dangerous activities, since rarely, sudden onset of sleep
has been reported during daily activities. Caution advised when taking other
sedating medication or alcohol in combination with ropinirole. If sudden onset
of sleep occurs in patients, consider dose reduction or drug withdrawal. Drug
interactions Neuroleptics and other centrally active dopamine antagonists
may diminish effectiveness of ropinirole – avoid concomitant use. No dosage
adjustment needed when co-administering with L-dopa or domperidone. No
interaction seen with other Parkinson’s disease drugs but take care when
adding ropinirole to treatment regimen. Should not be given with other
dopamine agonists. In a study with concurrent digoxin, no interaction seen
which would require dosage adjustment. Metabolised by cytochrome P450
enzyme CYP1A2 therefore potential for interaction with substrates or
inhibitors of this enzyme – ropinirole dose may need adjustment when these
drugs are introduced or withdrawn. Increased plasma levels of ropinirole have
been observed with high oestrogen doses – in patients on hormone replacement therapy (HRT) ropinirole treatment may be initiated in normal manner,
however, if HRT is stopped or introduced during ropinirole treatment, dosage
adjustment may be required. No information on interaction with alcohol – as
with other centrally active medications, caution patients against taking ropinirole with alcohol. Pregnancy and lactation Do not use during pregnancy –
based on results of animal studies. There have been no studies of ropinirole
in human pregnancy. Do not use in nursing mothers as lactation may be inhibited. Adverse reactions In early therapy: nausea, somnolence, leg oedema,
abdominal pain, vomiting and syncope. In adjunct therapy: dyskinesia, nausea,
hallucinations and confusion. Incidence of postural hypotension (commonly
associated with dopamine agonists), not markedly different from placebo,
however, decreases in systolic blood pressure have been noted; symptomatic
hypotension and bradycardia, occasionally severe, may occur. As with another
dopamine agonist, extreme somnolence/ and/or sudden onset of sleep have
(see Precautions and Effects on ability to drive and use machines).
Effects on ability to drive and use machines Patients must be informed
not to drive and to avoid other potentially dangerous activities, since rarely,
cases of sudden onset of sleep have been reported. If this event occurs, consider dose reduction or drug withdrawal. Overdosage No incidences reported. Symptoms of overdose likely to be related to dopaminergic activity. Legal
category POM. 8.11.99 ‘Requip’ and the SB logo are registered trade marks.
References: 1. Rascol O et al. N Engl J Med 2000; 342(20); 1484-1491. 2. Data
on file (Study 056 Report Synopsis) SmithKline Beecham 2000.
Further information is available on request from:
Welwyn Garden City, Hertfordshire AL7 1EY
© 2000 SmithKline Beecham Pharmaceuticals
Editorial Board and
Roger Barker is co-editor in chief of Advances in
Clinical Neuroscience & Rehabilitation (ACNR), and
is Honorary Consultant in Neurology at The
Cambridge Centre for Brain Repair. He trained in
neurology at Cambridge and at the National
Hospital in London. His main area of research is into
neurodegenerative and movement disorders, in particular parkinson's and Huntington's disease. He is also the university lecturer in Neurology at Cambridge where he continues to
develop his clinical research into these diseases along with his
basic research into brain repair using neural transplants.
Alasdair Coles is co-editor of ACNR and contributes our Anatomy Primer. He is a Wellcome
Advanced Fellow working on experimental
immunological therapies in multiple sclerosis, based
at the Dunn School of Pathology in Oxford and
Department of Neurology in Cambridge.
Stephen Kirker is the editor of the Rehabilitation
section of ACNR and Consultant in Rehabilitation
Medicine in Addenbrooke's NHS Trust, Cambridge.
He graduated from Trinity College, Dublin in 1985
and trained in neurology in Dublin, London and
Edinburgh before moving to rehabilitation in
Cambridge and Norwich. His main research has
been into postural responses after stroke. His particular interests
are in prosthetics, orthotics, gait training and neurorehabilitation.
David J Burn is the editor of our conference
news section and Consultant and Senior Lecturer
in Neurology at the Regional Neurosciences
Centre, Newcastle upon Tyne. He qualified from
Oxford University and Newcastle upon Tyne
Medical School in 1985. His MD was in the functional imaging of parkinsonism. He runs Movement
Disorders clinics in Newcastle upon Tyne and Sunderland.
Research interests include progressive supranuclear palsy and
dementia with Lewy bodies. He is also involved in several drugs
studies for Parkinson's Disease.
Andrew Larner is the editor of our Book Review
Section. He is a Consultant Neurologist at the
Walton Centre for Neurology and Neurosurgery in
Liverpool, with a particular interest in dementia and
cognitive disorders. He is also an Honorary
Apothecaries' Lecturer in the History of Medicine
at the University of Liverpool.
Mark Manford contributes our Epilepsy
Management Feature. He has been Consultant at
Addenbrooke's Hospital, Cambridge and at Bedford
Hospital for 3 years. He was an undergraduate at
University College London and trained in
Neurology in London at The National Hospital for
Neurology and Neurosurgery, Charing Cross
Hospital and at Southampton. His special interest is epilepsy and
he is closely involved with undergraduate training in neurology. He
has co-authored an undergraduate textbook of neurology and is
currently working on a guide to epilepsy.
Niall Pender is a member of the editorial board.
He is a Neuropsychologist and Clinical Leader of
the Neuro-behavioural Rehabilitation Unit at the
Royal Hospital for Neuro-disability, London. He is
also Neuropsychologist to the Huntington’s
Disease Unit at the Royal Hospital. In addition he is
an Honorary Lecturer in Psychology at the
Institute of Psychiatry, King’s College. Following degrees in
Psychology and Neuropsychology he completed his training in
Clinical Psychology at the Institute of Psychiatry. His research
interests include cognition in Huntington’s disease, behaviour
management in brain injury rehabilitation, memory, and visual
impairments after brain injury.
How to assess reports of clinical results
n recent years there has been a substantial
increase in the number of randomised controlled
trials (RCT) of treatments in neurology. This is a
brief review of some of the questions to ask when
assessing a report of an RCT. More detailed reviews
are available elsewhere1,2.
Were the treatment groups balanced?
Details of the important clinical characteristics of
the patients should be reported by treatment
group. If a prognostic variable is particularly important, a relatively minor (and not necessarily statistically significant) imbalance between the treatment
groups may have a major effect on the trial result.
Was it randomised?
Randomisation (an experimental approach) has two
How were patients selected, and what were the
main advantages over a non-randomised compariexclusion criteria?
son (an observational approach). First, it ensures
The inclusion and exclusion criteria of a trial define
that clinicians do not know which treatment the
the type of patient to whom the results can be
Dr Peter M Rothwell
patient will receive, and cannot select certain types
extrapolated. Criteria can be much more exclusive
PhD MD MRCP
of patients for one particular treatment. Second, it
than they seem. For example, the exclusion criteria
Peter Rothwell is an MRC
Senior Clinical Fellow and
tends to result in an equal balance of baseline risk
of a recent trial of thrombolytic therapy for acute
Consultant Neurologist at
across the treatment groups.The importance of ranischaemic stroke were so specific that only 0.4% of
the Radcliffe Infirmary,
domisation is not that no worthwhile observations
a typical population of stroke patients would have
Oxford. He is Director of
the Stroke Prevention
can be made without it, but that major biases can
been eligible5. Even when the limit on time from
Research Unit, funded by the
occur in non-randomised comparisons. This is illusstroke onset was ignored this only rose to 4%. In
MRC and The Stroke
trated by a recent non-randomised comparison of
another acute stroke trial, one centre screened 192
Association. Research interests include risk factors for
the effect of aspirin dose on the operative risk of
patients over a two-year period, and found only one
ischaemic stroke, and the
carotid endarterectomy (table 1, see facing page)
patient who could be randomised6. This is an
biology and management of
which showed a clinically and statistically significant
extreme example, but trial entry rates of 10-20%
lower operative risk in patients on high dose aspirin
are very common. Ideally, all trials should report the
(1300 mg) vs low dose aspirin (325mg or less)3. A
proportion of potentially eligible patients that were
subsequent RCT4, performed to confirm this observation,
actually entered into the trial.
showed that high-dose aspirin was, in fact, harmful (table 1). It is
It is also important to check whether or not there are spelikely that the non-randomised comparison had been biased by
cific groups of patients to whom the results cannot be extrapounmeasured differences between the patients in low-dose and
lated. For example, trials of antiplatelet drugs often exclude
high-dose aspirin groups.
patients with any history of upper gastrointestinal symptoms, no
matter how mild or how long ago, in order to reduce the sideHow was randomisation performed?
effects and risks of treatment. However, the results are then
It is important that the method of randomisation is actually ranonly applicable to about 50% of the patient population.
dom.Treatment allocation according to day of the week, date of
Was the trial sufficiently powered?
birth, date of admission, or alternate cases, is not random. The
Sample sizes in RCTs in neurology may need to be large, either
investigator will often know what treatment the patient will get
because treatment effects are relatively small, or because the
if they enter the trial and so these methods are open to bias.
progression of disease is slow (table 2, see facing page).The risk
Randomisation must be based on tables of random numbers or
of getting the wrong result when a trial has an inadequate samcomputer generated random allocation. It is also important that
ple size is illustrated in figure 1. In this trial, there was considerrandomisation is secure.
Central telephone randomisation is preferable to other methFigure 1.
ods, such as sealed envelopes containing the treatment
Was it a pragmatic trial or an explanatory trial?
Whether the results of a trial can be applied in routine clinical
practice depends on the type of trial. Explanatory (phase II) trials measure the effectiveness of treatment, whereas pragmatic
(phase III) trials measure the usefulness of treatment. A treatment may be effective, but may not be useful because it is too
poorly tolerated, too expensive, or too complex to administer.
Explanatory trials are often small, include only a tightly defined
group of patients, and frequently have non-clinical (surrogate)
measures of outcome. Pragmatic trials seek to measure the usefulness of treatments in situations which, as far as possible, mimic
normal clinical practice.
Can I apply the results to my clinical practice?
The results of an RCT may not be directly applicable to clinical
practice. For example, a trial of carotid surgery might be confined
to a small number of highly experienced surgeons with very low
complication rates, or a trial of anticoagulation to prevent stroke
might insist on much more frequent testing of the INR than is
possible in clinical practice. In both cases, the risks of treatment
are likely to be greater in everyday clinical practice.
Figure 1: The evolution of the estimate of treatment effect in the UKTIA-Aspirin
Trial (high-dose aspirin vs low-dose aspirin vs placebo in patients with TIA or minor
stroke).The treatment effect calculated at each point is based on the outcomes at
final follow-up for patients randomised to that point. The dashed lines represent
the level at which the apparent treatment effect approached statistical significance
at the P=0.05 level.
ANCR • VOLUME 1 NUMBER 5 NOVEMBER/DECEMBER 2001
TOPAMAX® Abbreviated Prescribing
Please read Summary of Product
Characteristics before prescribing.
Presentation: Tablets: 25, 50, 100, 200 mg
topiramate. Sprinkle Capsules: 15, 25, 50 mg
topiramate. Uses: Adjunctive therapy of
seizures: partial, Lennox Gastaut Syndrome
and primary generalised tonic-clonic. Dosage
and Administration: Oral administration (not
to be chewed). Over 16 years: Usually 200-400
mg/day (two divided doses; maximum 800
mg/day). Initiate at 25 mg daily with weekly
increments of 25 mg. Renal disease may
require a dose modification. Children 2 to 16:
Approx. 5 - 9 mg/kg/day (two divided doses).
Initiate at 25 mg nightly with weekly increments
of 1 - 3 mg/kg.
Sprinkle Capsules should be taken whole or
sprinkled on a small amount (teaspoon) of soft
food and swallowed immediately. Contra-indications: Hypersensitivity to any component.
Precautions and Warnings: May cause sedation; so caution if driving or operating machinery. Contraception recommended for women
of childbearing potential (oral contraceptives
should contain at least 50 µg oestrogen).Side
Effects: Abdominal pain, ataxia, anorexia,
CNS side effects, diplopia, fatigue, nausea,
nystagmus, weight decrease, agitation, personality disorder, insomnia, increased saliva,
hyperkinesia depression, apathy, leucopenia,
psychotic symptoms (such as hallucinations),
venous thrombo-embolic events, nephrolithiasis. Pharmaceutical Precautions:
Tablets: Store in a dry place at or below 25°C.
Sprinkle Capsules: Store below 25°C.
Legal Category: POM
Package Quantities and Prices:
Bottles of 60 tablets. 25 mg (PL0242/0301) =
£22.02, 50 mg (PL0242/0302) = £36.17;
100 mg (PL0242/0303) = £64.80; 200 mg
(PL0242/0304) = £125.83. Containers of 60
capsules. 15 mg (PL0242/0348) = £16.88, 25
mg (PL0242/0349) = £25.32, 50 mg
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Product licence holder: JANSSEN-CILAG
LIMITED, SAUNDERTON, HIGH WYCOMBE,
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Date of text revision: August 2000
Date of preparation: July 2001
Because life without seizures is so much better.
F I R S T
C H O I C E
A D D - O N
T H E R A P Y
F O R
M O S T
S E I Z U R E
T Y P E S
Table 1. The relationship between aspirin dose and the risk of stroke and death within 30 days of
carotid endarterectomy in a non-randomised comparison within the NASCET trial3, and in a subsequent randomised controlled trial4.
Operative risk of stroke and death
Table 2. Effect of sample size on the reliability of the result of a trial of a hypothetical neurological treatment which is assumed to reduce the risk of
a poor outcome by 20%, from 10% to 8%.
Trial Power (%)
Comments on Trial Size
Not really adequate
* probability of failing to achieve p<0.01 significance if true relative risk reduction is 20%.
able variability in the apparent effect of treatment until several
hundred patients had been randomised. If the trial had been
small, misleading trends in treatment effect could easily have been
statistically significant, and apparently clinically important,
increase in bone density. However, further follow-up revealed a
30% increase in vertebral fractures and a three-fold increase in
non-vertebral fractures in the sodium flouride group.
Was the trial stopped early?
Was outcome assessment blind?
A trial may need to be stopped early if a treatment has serious
adverse effects, or if there is clear benefit. However, as is seen in
figure 1 the chance fluctuations during the early stages of a trial
can easily reach statistical significance at the p=0.05 level. If the
stopping rule is based on a p-value of 0.05, it is quite possible that
the trial will be stopped early, and the wrong conclusions drawn.
Stopping rules should be based on significance levels of p<0.01 or
less, and the evolving results should be assessed on only a limited number of pre-specified occasions.
There are two main reasons for blinding the trial clinicians.
Firstly, so that the use of non-trial treatments and interventions
is not influenced by a knowledge of whether or not the patients
received the trial treatment. Secondly, so that clinicians are not
biased in their assessment of clinical outcomes.The potential for
bias depends on the subjectivity of the trial outcome. Biased
assessment of neurological impairment and disability was clearly
demonstrated in a multiple sclerosis trial in which blind and nonblind outcome assessment produced very different results9.Trials
with blind assessment should also report whether or not blinding was effective. Non-blind trials should report data on non-trial
treatments given to patients during follow-up to ensure that
these were not biased.
Was follow-up sufficient?
It important that the trial follow-up is sufficient to provide data
on the usefulness of a treatment over a clinically relevant time
period. For example, RCTs of new anticonvulsant drugs often
have only a few weeks follow-up. This is insufficient to judge
whether or not the treatment is clinically useful.
Was a surrogate outcome used?
Surrogate outcomes (e.g. infarct size on CT brain scan in an acute
stroke trial, or MRI activity in multiple sclerosis) are often used
to assess the effects of treatments.They can be useful in explanatory trials because they may be more sensitive to the effects of
the treatment than clinical outcomes, and they are readily
assessed blind to treatment allocation. However, they do not
measure clinical effectiveness, and may sometimes be highly misleading. For example, a trial of three different antiarrhythmic
drugs vs placebo after acute myocardial infarction assessed the
frequency of ventricular extrasystoles on 24 hour ambulatory
ECG monitoring7. All three drugs produced a substantial reduction in the frequency of extrasystoles, but the trial was subsequently stopped because of a major excess of deaths in the treatment group (33 vs 9, p=0.0003). Similarly, reduced bone density,
which is known to be a useful marker for risk of fractures, was
used as a surrogate outcome in a trial of sodium flouride in
women with osteoporosis8. Sodium flouride produced a highly
Were serious complications of treatment included in the
Some treatments have serious complications which should be
included in the primary outcome, rather than relegated to a
table of “side-effects” e.g. life-threatening gastrointestinal bleeding in trials of antiplatelet agents and anticoagulants.
Was the main analysis an intention-to-treat analysis?
The primary analysis in any RCT should be an intention-to-treat
analysis i.e. patients remain in the treatment group to which they
were originally randomised, irrespective of the treatment they
eventually received.The alternative, an efficacy analysis (an analysis which is confined to patients who complied with the randomised treatment), is prone to bias.This was illustrated by the
Coronary Drug Project10, an RCT comparing several different
lipid-lowering regimens with placebo following myocardial infarction. By intention-to-treat analysis, the five year mortality in the
clofibrate group was 20.0% versus 20.9% in the placebo group.
However, when patients who complied with treatment in the
clofibrate group were compared with non-compliers the results
seemed to suggest that there was a treatment effect: five year
ANCR • VOLUME 1 NUMBER 5 NOVEMBER/DECEMBER 2001
mortality was 15.0% in the compliers versus 24.6% in the noncompliers. Perhaps clofibrate was beneficial. However, the same
analysis in patients in the placebo group showed exactly the same
trend: 15.1% mortality in compliers versus 28.2% mortality in
non-compliers.The apparent effect of clofibrate in the treatment
group was simply a bias due to the fact that patients who do not
comply with treatment tend to have a worse prognosis.
Were any patients excluded from the main analysis?
It is common in reports of RCTs to find that a certain number
of the patients who were randomised are excluded from the final
analysis. A common reason for exclusion is that following randomisation it was found that a number of patients did not actually fit the eligibility criteria; so called protocol violators.
However, the interpretation of what is a protocol violation can
be rather subjective, and since the decision will often be made
towards the end of the trial, and may not be blind to outcome, it
is open to abuse. For example, 71 of 1629 patients randomised in
a trial of an antiplatelet agent following myocardial infarction
were excluded from the final analysis, apparently because they did
not meet the eligibility criteria11. It subsequently transpired that
there was a large excess of deaths in the exclusions from the
treatment group compared with the placebo group12. Exclusion of
these patients led to a bias which had contributed to the statistically significant apparent benefit in the treatment group. A second trial failed to confirm any benefit.
How many patients were lost to follow-up?
Another important potential cause of bias in the analysis of trial
results is loss of patients to follow-up. Just as patients who comply with treatment are different from patients who do not,
patients who are lost to follow-up are usually different from
those who remain in the trial. For example, it may not be possible to contact patients because they are either incapacitated in
some way, or even dead. It is therefore very difficult to interpret
the results of a trial with significant loss to follow-up.
Friedman LM, Furburg C, DeMets DL (1996). Fundamentals of clinical
trials, 3rd ed. St Louis, MS: Moseby.
2. Collins R, Peto R, Gray R, Parish S (1996). Large scale randomised evidence: trials and overviews. In: Weatherall D, Ledingham JGG, Warrell
DA, eds. Oxford Textbook of Medicine. Oxford; Oxford University
3. North American Symptomatic Carotid Endarterectomy Trialists’
Collaborative Group (1998). The final results of the NASCET trial. N
Engl J Med; 339: 1415-25
4. Taylor DW, Barnett HJM, Haynes RB et al (1999). Low dose and high
dose acetylsalicylic acid for patients undergoing carotid endarterectomy: a
randomised controlled trial. Lancet; 353: 2179-84.
5. Jorgensen HS, Nakayama H, Kammersgaard LP et al (1999). Predicted
impact of intravenous thrombolysis on prognosis of general population of
stroke patients: simulation model. BMJ 1999; 319: 288-89.
6. LaRue LJ.Alter M,Traven ND et al. (1988) Acute stroke therapy trials:
problems in patient accrual. Stroke; 19: 950-954.
7. The Cardiac Arrhythmia Suppression Trial (CAST) Investigators.
Preliminary report: effect of encainide and flecainide on mortality in a randomised trial of arrhythmia suppression after myocardial infarction. N
Engl J Med 1989; 321: 406-412.
8. Riggs BL, Hodgson SF, O’Fallon WM et al (1990). Effect of flouride
treatment on fracture rate in postmenopausal women with osteoporosis.
N Engl J Med 1990; 322: 802-9.
9. Noseworthy JH, Ebers GC,Vandervoort MK, Farquhar RE,Yetisir E,
Roberts R. (1994) The impact of blinding on the results of a randomized, placebo-controlled multiple sclerosis clinical trial. Neurology;44:1620.
10. Coronary Drug Project Research Group (1980). Influence of adherence to treatment and response to cholesterol on mortality in the
Coronary Drug Project. N Engl J Med; 303: 1038-41.
11. Anturane Reinfarction Trial Research Group (1980). Sulfinpyrazone in
the prevention of sudden death after myocardial infarction. N Engl J Med;
12. Temple R, Pledger GW (1980). The FDA’s critique of the Anturane
Reinfarction Trial. N Engl J Med; 303:1488-92.
Peter Rothwell, Department of Clinical Neurology, Radcliffe
Infirmary,Woodstock Road, Oxford OX2 6HE.
Tel: 01865 224237, Fax: 01865 790493
E-Mail: [email protected]
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ANCR • VOLUME 1 NUMBER 5 NOVEMBER/DECEMBER 2001
Ethical barriers to research into
diseases of the human brain
This article by Professor Charles Warlow is a transcript of a lecture he gave at the British Association Science
Festival this September in Glasgow. We have decided to include it in its entirety because of its importance to
research in this country, especially epidemiological studies. The implementation of the new Data Protection Act
has important consequences to all those involved with clinical research and whilst the article represents the personal views of Professor Warlow, it nevertheless highlights a number of issues that are relevant to all practising
neurologists and associated specialists. - RB
to the centrally held death certificates. Have there
been more deaths due to CJD in those with, compared to those without prions? But this research
can no longer be done. Retained organs have been
cleared out, maybe including my old appendix,
because we the patients were not asked for our
permission to have our organs retained - a scandal we are told.The real scandal is that I have not
been asked if my potentially useful appendix can
be destroyed. In truth, I don’t much care what
happens to my discarded organs, but I do care
about the witch hunt against pathologists who
have material which may lead to us all being
Warlow is Professor of
healthier if it can be exploited by bone fide medMedical Neurology in the
University of Edinburgh,
having previously been in
But, irrespective of the retained organs hooha,
this research cannot now be done because we
Infirmary, Oxford. He
patients had not been asked our consent for our
leads a large research
medical records - personal data - to be used for
team into clinical aspects
some future, and at the time, impossible-to-specof
ify medical research. The 1998 Data Protection
management, as well as
having more general
Act has done in that sort of opportunity.
neuroAlthough the Act does not apply to dead people,
epidemiology and clinical
the researchers do not know who is dead and
trials. He was, for instance,
one of the main forces
who isn’t when they examine the medical records
behind the MRC European
from 35 years ago. So, this research avenue is
Carotid Surgery Trial
blocked by the current obsession with patient
whose final results were
confidentiality.What if there were prions in some
reported in the Lancet in
1998. He is the principal
appendices? What if those patients with prions
author of one of the major
had given blood which we could find out, and
stroke textbooks (Stroke:
might give blood again? And what if that blood
a practical guide to
management. See our
causes CJD which we could also find out if we
book review on page 35).
looked at the medical records of the blood recipCharles
The appendix story
ients, albeit without their consent - consent to be
currently President of the
In 1966 I developed appendicitis and the offending
scared witless that they might develop an incurAssociation of British
vestigial organ was removed and put into a pot of forable disease? I would sue for causing anxiety if
malin. As you know, partly thanks to recent media
anyone told me that I might develop an incurable
coverage, pathologists tend to keep removed organs, they might
disease which no one could prevent. Far better the researchers
be useful in the future, one can’t tell at the time. But, even long
find out without bothering me. But no, I have to be told or the
before the Alder Hey business of retained body parts of dead
research has to be done another way, or we give up on blood
children which led to a wholesale clearing out of retained organs
transfusion from UK donors at enormous cost and inconveall over the country, it was not that easy to keep things in pots.
nience to us all - perhaps unnecessarily.Today, the ethical imperThey took up too much space. But some places managed, and
ative enshrined in personal data protection ignores the other
just suppose my appendix, and others, is still there in Cambridge
side of the coin, responsibility to society and the greater good.
where I left it. And further suppose that today researchers into
The most eminent epidemiologist in the UK, Richard Doll, who
variant Creutzfeldt-Jakob Disease (CJD) want to find out, in
discovered the link between smoking and lung cancer, and his
their search for the origins of what may become a public health
longstanding colleague Richard Peto, put this point rather well.
disaster of unimaginable proportions, whether the infectious
“The right to medical care should generally continue to include
particles called prions - the presumed cause - were actually
the responsibility to allow the information gained in its course
around long before the Bovine Spongiform Encephalopathy
to be used for others who develop a similar disease, or are at
(BSE) epidemic in cattle in the 1980s. Maybe variant CJD is nothrisk of developing it”.
ing to do with BSE, maybe British beef is OK after all, maybe variIn fact the Data Protection Act is probably not all that restricant CJD was there all along and we could prove that by finding
tive, but it has been interpreted as being so, albeit with different
the offending prions in the appendix long before there were any
consequences. In England, legislation was rushed through
brain symptoms.The quickest and easiest way would be to look
Parliament just before the last general election. Section 60 of
in retained appendices like mine, and to link the patient names
the Health and Social Care Act 2001 allows the Secretary of
must confess three conflicts of interest. Firstly, I am
a doctor. We doctors are under attack as never
before, by the media, by politicians, by patients and
their organisations, and by ethicists.We are said to be
incompetent, paternalistic, unable to adapt to new
information and new ways of working, and some are
even murderers. So I feel undervalued, threatened
and vaguely anxious. I am defensive. Maybe I should
retire a bit early. Secondly, I do research, not with
molecules, test tubes or rats, but with people who
are usually but not always patients. But we
researchers are mistrusted, we exploit our patients,
we recruit them into research projects for our own
financial and academic gain without telling them. We
cheat, we lie, we are fraudulent. Again, I feel threatened and definitely anxious. I am more defensive.
Maybe I should give up research and do commercial
practice instead.And thirdly, I have been a patient. My
health was certainly threatened and sometimes I felt
more than just anxious.Very likely I will be a patient
again. So rather than being defensive, about being a
patient as well as a doctor and researcher, I will
exploit my third conflict of interest and tell you how
medical research is obstructed by people who,
although not representing patients, believe they have
our patients’ best interests at heart. But the ethical
barriers these people construct to protect my privacy and rights are wrecking the research that will help
me, and thousands of patients like me. I will tell you
four stories about me the patient, the first three true,
the last imaginary.
ANCR • VOLUME 1 NUMBER 5 NOVEMBER/DECEMBER 2001
State to sanction the use of patient data in the public interest
but the bureaucracy and expense required for researchers to
gain permission will be enormous - the red tape will kill off the
research before it even starts. No mechanism to do this seems
to be in place. Research using medical records will shudder to
a halt. In Scotland, the Confidentiality and Security Advisory
Group for Scotland (CSAGS) means to recommend to
Ministers that “unless data is acceptably anonymised, informed
consent must be obtained before processing”. This will wreck
medical research. Actually, although the Data Protection Act
states that any use of personal identifiable data relating to the
“physical or mental health or condition” of a living individual
requires their informed consent, it adds an or - or that the “processing is necessary for medical purposes”, and this does
include research. However, the Act has been interpreted very
differently by different bodies who offer conflicting guidance some insist that consent must be obtained for every research
use of personal data unless they are anonymised. But this is
often impractical, expensive, or plain impossible. If patients are
to be followed up, one needs to know who they are! One has
got to look at the records for things like past exposure to medications, for example the oral contraceptive in a study of leg
vein thrombosis in air travellers. The most important guidance
for doctors comes from the General Medical Council (GMC)
but even here there is confusion.The GMC do sanction the use
of medical records where “you are satisfied that it is not practicable” to obtain consent and it is in the public interest to do
so, but patients still have a right to object. Not only would the
research be jeopardised if a lot of patients objected, but the
door seems open to litigation against bone fide medical
The broken leg story
Second story. In 1993 I broke my leg, conveniently for the ambulance not up the mountain but - ridiculously - at the bottom, in
the car park. It was straightened out and an alloy pin put down
the middle of my tibia, where it still is. It is not at all clear
whether that pin should come out.This would require a few days
in hospital, an anaesthetic, possibly bone infection, and certainly
some time hobbling around afterwards. Best avoided,
unless...unless what? Who knows, but might that alloy gradually
degrade, might some particles get into my brain, might that cause
me to get unsteady on my feet, is my own increasing but still minimal unsteadiness due to natural ageing or that old metal pin?
Should all such pins come out forthwith from thousands of limbs
around the world? Seems a reasonable question to me, the
patient. So a researcher might want to contact me and others
like me to ask about my balance and compare our answers with
those whose pins have been removed. To do so, the researcher
would need to get my name from the Stirling Royal Infirmary and
that would require the permission of my surgeon. But he is
retired now, possibly gone to Saudi Arabia to earn lots of money
for all I know, possibly dead. First obstacle. But even with the surgeon’s permission, the researcher cannot look at my medical
records without my permission too which at the time I was not
asked.The Data Protection Act seems to require it now according to many authorities, including the CSAGS in Scotland. Second
obstacle. So the researcher needs to find me, and I have moved
twice since 1993. Third obstacle - check. Even trickier, the hospital refuse to give the researcher my name without my permission. Final obstacle - check mate, end of research, we don’t know
what to do about the pins, and I the patient lose out because
some busybody is protecting my privacy which, for medical
research, I would be happy to give up.Who asked my opinion as
a patient? Nobody.
ANCR • VOLUME 1 NUMBER 5 NOVEMBER/DECEMBER 2001
The colon cancer story
Third story. In 1995 my cancerous colon was removed. Suppose
some researchers had been looking at the genes in my personal
bit of cancer (assuming the pathology department retained my
colon, which might not happen now given the witch hunt).They
would like to know (and so would I) if a particular gene abnormality is associated with a high risk of a secondary growth in my
brain.To do that, they need to follow up hundreds of people like
me to find out.They could do so rather easily in Scotland where
you can track the same person from each hospital in-patient
episode to their eventual death certificate. It would be easy to
track me and my fellow cancer patients until we had a brain secondary, and then compare our genetic abnormalities with the
other colon cancer patients who did OK. Impossible now, without my permission. None of my personal details can be released,
not even my name. Even if the researchers could get my name
from the records system, find me years later, and ask for my consent I might be already dead, I might be difficult to find, I might
be in the midst of a recurrence and not too keen to fill in a questionnaire, I might be chronically anxious and so terrified of any
recurrence that any reminder would make me suicidal, I might
have emigrated because I felt so well, or I might be on a cruise
enjoying the last days of my life.There are all sorts of reasons for
the researcher not to be able to find all us colon cancer patients,
and to find out how we are, without using hospital information
systems. But maybe the researcher has a go but he will never find
us all so long after surgery. However, say he discovers that a gene
abnormality seems to be associated with brain secondaries. But
this could be complete nonsense if more of those without than
with the gene abnormality were actually very well and couldn’t
be followed up because we had moved cheerily away. Or, the
other way round, the researcher finds no association although
there really is one, because more of those with than without the
genetic abnormality are away on that terminal cruise and cannot
be traced. Conclusions based on data from incomplete follow up
of patients to relate some baseline factor to their eventual outcome are likely to be biased.We have no idea which way any bias
goes, and how big it is, and so our conclusions are unreliable,
possibly dangerously wrong. How irresponsible can you get? But
tough, patient rights stop these lines of research. Responsibilities
are for someone else to worry about. But I the patient am
incensed that research cannot be done on my disease using my
records, even without my consent. In the future, at every point
they encounter the health care system, it is likely that patients
will be asked if their records can be used for research.The systems to do this are far from up and running, to work they will
have to be enormously expensive taking resources away from
the clinical service.What happens if a patient changes their mind,
how are refusers to be reliably identified as they pass through
the health system (a black spot on their forehead)? And another
thing, as a cancer patient, I am incensed that all the UK Cancer
Registries may have to close down such is the obsession with
My objections, as a patient and as a researcher
These three stories illustrate how medical research is obstructed by the current demand that to look at patient records always
requires the patient’s consent, either at the time when the
records were made or later, and moreover - in some instances the patient’s explicit consent for a specific research project, not
blanket consent for any research. Consent is compulsory in the
Scottish CSAGS document. There is no waiver. How ridiculous
can you get? Why can’t my records be used by any bone fide
researcher who is interested enough in my disease to help me,
or at least others with my disease? Who do I the patient com-
plain to about this nonsense? Of course if the privilege of looknumerous research ethics committees up and down the land,
ing at patient records had been frequently abused, there would
and it has been funded by the Stroke Association, the main charbe cause for alarm. But it hasn’t. How many of you know of any
ity in the field. But, all these well meaning people trying to do
case where confidential patient records have been given to a
their best for me and other stroke patients are obstructed by
third party by a researcher? Last October, a British Medical
those who say that to protect my rights as an incapacitated
Journal editorial asked the very same question, and no one has
adult I must have the research explained to me, including the
come up with an example. Of course, research should be carerisks, and that I must consent to being in the trial. But the stroke
fully designed, thought about by researchers and their peers, and
has rendered me unconscious and - to add to the dilemma - let
passed by a research ethics committee. But it is totally impractime tell you that the new treatment is unlikely to work unless it
cal to ask every patient at every medical contact for their peris given within three hours of stroke onset, the sooner the very
mission for their records to be used for research - maybe - at
much better. My stroke started two hours ago. What is the
some later date. Even if it was practical, and here we are on
researcher supposed to do? Ask my partner for her approval?
more dangerous ground, why should some patients opt out of
She may be dead.Ask my brother? He could be in Australia.Ask
research on just their records which would be in the public
my children? On holiday. Anyway, the assent of someone for
interest? We are not talking about the use of personal data to
research on me is not, in English law, regarded as my consent,
track our buying habits in Tescos, nor where we last used our
although this has never been challenged. So far, research ethics
mobile phone, we are talking about our health. Of course
committees have taken a pragmatic view and randomised trials
patients have rights, but rights come with responsibilities, and we
involving assent are quite common. In Scotland, however, the
all have responsibility to the society that looks after us
new ‘Adults with incapacity (Scotland) Act 2000’ when we are sick. We benefit from the fruits of
designed to protect the rights of incapacitated
medical research when they apply to us peradults - will stop randomised trials in emersonally. Do these “you are not looking at my
gency situations. Because, in Section 51
notes” patients understand what they
we are told that “before any research
These three stories
are doing by denying access to their
involving an adult is undertaken conmedical records for bone fide well
must be obtained from the
illustrate how medical research is sent
constituted medical research in
adult’s proxy or next of kin”. But,
everyone’s best interest? What
all this could easily take far too
obstructed by the current demand
right have those opting out to
much time - “time is brain” is
that to look at patient records always the current slogan and I will
obstruct the public interest for
their own selfish ends? If they
run out of both. So no
requires the patient’s consent, either at have
had received a bottle of blood
trial can be done, and we will
contaminated by CJD, and if
never know if the new treatthe time when the records were made
there turned out to be a way of
ment works or not. As a
preventing infection because all
potential stroke patient, I am
or later, and moreover - in some
those appendices had given us a
incensed but the Act is the law
instances - the patient’s explicit consent now, at least in Scotland. I wonclue, should the opters out benefit from this information? Is it
der what other stroke patients
for a specific research project, not
OK if the results of research based
have to say? Have they been conon the records of the other people
I doubt it.
blanket consent for any research... sulted?
who do consent are then applied to
Perhaps the new treatment could
the benefit of the objectors? Not in my
be tried just on those able to consent
How ridiculous can you
book. Perhaps the objectors would like
to enter the trial? Yes, but they would
several bottles of blood?
have mild strokes and it may be that for
them the hazards of the treatment are greater
The stroke story
than the benefits because they may recover withNow I am going to imagine that one day, like my mother, I
out the treatment, unlike the unconscious patient at
have a stroke and am rushed to hospital where a stroke team is
death’s door. Could the research be done on rats? No, they are
waiting to give me the best possible care. They are doing
different to humans. Could the research be done in countries
research too, and are testing a treatment which may - just may with a laxer attitude to patient protection? Of course not, it
reverse my stroke and restore me to normal. But there are risks,
would be outrageous to do research elsewhere just because it
it may - just may - kill me.They need to know, and so do future
is unacceptable here. It has to be done here and now in sudstroke patients, whether the benefits are worth the risks. The
denly incapacitated patients. It is the same problem for patients
only way to find out reliably is by randomly allocating hundreds
who drop unconscious in the street with a cardiac arrest, or
of patients like me to either the new treatment as well as the
who have a severe head injury.Are they to be denied new treatcurrent best care, or to the current best care alone and seeing
ments because the research to test new treatments is impossihow we get on. Half the patients get the new treatment with its
ble because of the ethical and legal obstructions? Whose side
benefits and its risks, whatever they both are and whatever the
are the obstructionists on? What right have they to deny my
balance between them turns out to be. The other half get the
right to have treatments tested on me for the benefit of others
current best care and lose out on any benefits of the new treatwith my disease, and the rights of those future patients too?
ment if there really are any, but also avoid the risks.This is a ranA possible solution
domised controlled trial. Remember at this stage no one knows
So what can we do about unconscious patients, or others unable
what the balance of risk and benefit is for me in particular with
to give their own consent to enter a randomised trial in an
my stroke, and nor for stroke patients in general. But, after the
emergency situation? Waiver of consent is really the only solutrial, we will all know whether future patients like me are, on
tion, at least unless assent can be obtained very quickly from a
average, benefited or harmed by the new treatment and clinical
close relative and is regarded as sufficient, as it now is in
practice can be altered appropriately.
Scotland. This waiver of consent - and wherever possible
The researchers have consulted far and wide with other
deferred consent at a later more reflective time - now happens
researchers and doctors, the research has been approved by
ANCR • VOLUME 1 NUMBER 5 NOVEMBER/DECEMBER 2001
in the USA but only if the trial has been carefully vetted by peers
In this current climate of suspicion of doctors and our research,
and a research ethics committee, and has been disclosed to and
and of litigation and recrimination which leads to defensive and
approved by the community, and the results eventually made
so bad, risky and expensive medicine, we must be open and we
public. Earlier this year the New England Journal of Medicine
must explain.We must defend our position to all comers. It may
published a trial showing that cooling down acute head injured
not seem very professional to grapple with the media, most docpatients did not work. In the words of the editorialist “This study
tors hate it. If ethicists and others dominate the airwaves it is
would never have been completed without the provision that
because we doctors are not prepared to get in there and debate
waived the requirement to obtain consent for the enrolment of
the issues. Of course all this wastes doctor and researcher time.
38% of the patients,” and he later remarked “The period during
This is not what we are paid to do, it is our evening and weekwhich an intervention is likely to be effective is short, and by the
end work not the daytime work of the journalist and ethicist.
time consent is obtained by traditional means the treatment may
One of our research fellows has wasted weeks wading through
be futile”. So where does that leave testing emergency treatthe ethical swamps trying to get an innocuous research project
ments in acute stroke, head injured and cardiac arrest patients in
agreed, funded and done in Scotland. Just getting ethics commitScotland? I fear nowhere, the research will stop. I am told it is
tee approval required literally more than an arm and a leg - you
don’t believe me? The overwhelming red tape required nearly
I believe that as well as waiver of consent for emergency
6000 sheets of A4 paper and that weighed 27kg! Understanding
treatment trials we should involve patients much more explicitthe 1998 Data Protection Act has been a nightmare and I don’t
ly in agreeing that the trial should be done in the first place and
think we do yet. Certainly others have not succeeded
helping in its design. For stroke we should and could - and
because gathering together, reading and trying to
indeed have - talked with stroke patients and with
make sense of all the guidance from august
older people who are the type of person who
bodies based on the Act reveals inconsismay have a stroke. I value these people’s
tency and confusion. Another colleague
views more than any number of ethiHow many of you
has wasted weeks trying to explain to
cists, lawyers, politicians and media
civil servants and politicians that
commentators.Those of us involved
know of any case where confithe Adults with Incapacity
with research must try again and
dential patient records have been
(Scotland) Act will stop all ranagain to explain what we are
domised trials in acute stroke,
doing, why, and how it really is for
given to a third party by a
head injury and cardiac arrest.
the greater good. Let the objecTrying to repair the damage
tors come and talk with real
to medical research - and to
patients and ask them what they
the health of patients like me think, not to some university or
Last October, a British Medical
by those who have the best
Fleet Street crony. Let them try
Journal editorial asked the very
interests of us patients at heart,
getting full frontal informed conbut who simply have not thought
sent from a sick patient frightened
same question, and no one has
through the consequences of their
out of their mind that they are
actions, has been and still is a huge
about to die and who is barely comcome up with an
waste of time. It is dispiriting for us
petent to understand anything very
doctors and researchers. We should be
much - waiver of consent is surely the
doing medicine and research or at least
kinder and more appropriate option if no
fighting other more important battles - medical
proxy is instantly available. Mind you, the ethicist
fraud, bribery dressed up as marketing, and the overwould demand that we first get the patient’s consent to
influence of pharmaceutical companies on medical research. But
be approached by anyone other than the doctor!
those are other stories. In the meantime we are kept far too
We researchers do not benefit anyone by backing off, throwbusy dealing with the ethical barriers which obstruct bone fide
ing away usefully retained organs, ignoring the public health gold
- and ethical - medical research. We doctors, we researchers
mine in patient medical records, and abandoning randomised
and we patients have grounds for complaint.
controlled trials in unconscious patients.
ABN Spring Scientific Meeting
3-5 April, 2002
University of Oxford
For further information contact:
Susan Tann, Association of British Neurologists
Ormond House, 27 Boswell Street, London WC1N 3JZ.
Tel. 020 7405 4060, Fax. 020 7405 4070, E-Mail. [email protected]
ANCR • VOLUME 1 NUMBER 5 NOVEMBER/DECEMBER 2001
What do these movement
disorders have in common?
They all respond to Xenazine 25
Although the diagnosis of a hyperkinetic movement disorder can be devastating, help is at hand in the form
of Xenazine™ 25, an established agent with proven efficacy in the suppression of involuntary movements.1-5
Xenazine™ 25’s benefits include excellent, sustained response and good tolerability.1 What's more, Xenazine™ 25
has an indication for patients with tardive dyskinesia.1,4,5 So consider Xenazine™ 25 for your patients –
it could well prove to be the right move.
XENAZINE™ 25 ABBREVIATED PRESCRIBING INFORMATION: Please refer to
Summary of Product Characteristics before prescribing Xenazine™ 25. Each tablet contains 25mg tetrabenazine. USES: Movement disorders associated with organic central
nervous system conditions, e.g. Huntington’s chorea, hemiballismus, and senile
chorea. Moderate to severe tardive dyskinesia, which is disabling and/or socially
embarrassing, and persistent despite withdrawal, switching or reduction of the dose of
antipsychotic medication, or where withdrawal of the medication is not a realistic
option. DOSAGE: Organic Movement disorders: Dosage and administration are variable and only a guide is given. An initial starting dose of 25mg three times a day is recommended. This can be increased by 25mg a day every three or four days until 200mg
a day is being given or the limit of tolerance, as dictated by unwanted effects, is reached,
whichever is the lower dose. If there is no improvement at the maximum dose in seven
days, it is unlikely that Xenazine™ 25 will be of benefit to the patient. Tardive Dyskinesia:
An initial starting dose of 12.5mg a day is recommended, subsequently titrated to
response. Again medication should be discontinued if there is no clear benefit or side
effects cannot be tolerated. Children & Elderly: No specific dosage recommendations
are made for the administration of Xenazine™ 25 to children or the elderly. CONTRAINDICATIONS, WARNINGS, ETC. Contra-indications: Xenazine™ 25 blocks the
action of reserpine. Precautions: Xenazine™ 25 may cause drowsiness and could interfere with activities requiring mental alertness. Patients should be advised not to drive
or operate machinery until their individual susceptibility is known. For use in tardive
dyskinesia the condition should be persistent despite withdrawal, reduction in dose or
alteration of antipsychotic medication, or where withdrawal of the medication is not a
realistic option. Pregnancy and Lactation: There is inadequate evidence of safety of the
drug in human pregnancy and no evidence from animal work. Xenazine™ 25 should
be avoided in breast-feeding mothers. Interactions: Levodopa should be administered
with caution in the presence of Xenazine™ 25. Side effects: Side effects are usually
mild with little hypotensive action and few digestive disorders. The main unwanted
effect reported to date has been drowsiness, which occurs with higher doses. If depression occurs, it can be controlled by reducing the dose or by giving antidepressant treatments. Xenazine™ 25 should not be given immediately after a course of any of the
monoamine oxidase inhibitors as such treatment may lead to a state of restlessness,
disorientation and confusion. A parkinsonian-like syndrome has been reported on rare
occasions, usually in doses above 200mg per day, but this disappears on reducing the
dose. Neuroleptic malignant syndrome (NMS) has been reported rarely. This may
occur soon after initiation of therapy, following an increase in dosage or after prolonged
treatment. The clinical features usually include hyperthermia and severe extrapyramidal
If NMS is suspected Xenazine™ 25 should be withdrawn and appropriate supportive
therapy instituted, treatment with dantrolene and bromocriptine may be effective.
Overdosage: Signs and symptoms of overdosage may include drowsiness, sweating,
hypotension and hypothermia. Treatment is symptomatic. PHARMACEUTICAL PRECAUTIONS: Store below 30ºC LEGAL CATEGORY POM PRESENTATION, PACK
SIZE, PRODUCT LICENCE NUMBER & BASIC NHS COST: Round yellowish buff
tablets, printed with CL25 containing 25mg of tetrabenazine in packs of 112. PL
14576/0005 £100.00 FURTHER INFORMATION IS AVAILABLE FROM THE PRODUCT LICENCE HOLDER: Lifehealth Limited, 23 Winkfield Rd, Windsor, Berkshire, SL4
4BA. Date of preparation: July 2000. © Cambridge Laboratories.
References: 1. Jankovic J, Beach J. Neurology 1997;48:358-362. 2. McLellan DL et al.
Lancet 1974;1:104-107. 3. Shoulson I and Goldblatt D. Neurology 1981;31:79. 4. Ondo
WG, Hanna PA, Jankovic J. Am J Psychiatry 1999;156:1279-1281. 5. Watson MWB,
Skelton D, Jamali F. Can J Psychiatry 1988;33:11-13.
Deltic House, Kingfisher Way, Silverlink Business Park, Wallsend, Tyne and Wear NE28 9NX. Tel: 0191 296 9300 Fax: 0191 296 9368
ANCR • VOLUME 1 NUMBER 5 NOVEMBER/DECEMBER 2001
Neuropsychiatry of Huntington's disease
motional and behavioural changes are often the
earliest clinical manifestation of Huntington's
disease (HD) and may precede more obvious signs
of dementia and movement disorder by several
years. Up to 40% of patients with HD are likely to
be misdiagnosed initially as having a primary psychiatric disorder1. Neuropsychiatric problems have a
profound impact on quality of life for the individual
with HD and are probably the most distressing
aspect of the disease for families and care providers.
An understanding of these problems and an
informed approach to their management is therefore critical for anyone involved in the care of
patients and families affected by this devastating disorder.
Dr John D C Mellers is a
consultant psychiatrist in the
Neuropsychiatry Unit at the
Maudsley Hospital and at the
Royal Hospital for Neurodisability, London.
ness5,6,7. Hypomania (and mania) are seen in
between 5 and 10%8. Anxiety disorders are common but their prevalence has not been systematically studied. As with personality changes, depressive episodes may occur before other signs of the
disease are present, leading some to stress biological aetiological factors. However, as with other neuropsychiatric problems in HD (and indeed in other
neurological conditions), a multifactorial aetiology
must be considered. Living with the risk of developing HD and witnessing parents or siblings develop the disorder obviously represents a significant
predisposing stressor for depression even when the
individual themselves is asymptomatic.The development of more obvious clinical symptoms and the
individual's growing realisation that they are affected often coincides with the stresses of early adult
life, including marriage, the responsibilities of a family and establishing a career. The indirect social consequences of the disease, such as marital breakdown, unemployment, and estrangement from family and social supports, contribute further as precipitating and maintaining factors for emotional
problems in HD.
The early emotional, behavioural and cognitive
changes in HD are best understood as a frontal disconnection syndrome.Although pathological abnormalities are relatively confined to the basal ganglia,
in particular to the corpus striatum in the early
stages of the disease, cell loss in these areas is associated with disruption of cortical pathways. A wave
of cell loss begins within the caudate, starting
antero-medially and spreading ventro-laterally.Thus
The risk of suicide is greatly increased in HD and up
the first cortical areas affected are frontal and perNiall Pender is a Neuroto 6% of patients with the disorder will take their
sonality changes are the conspicuous clinical feapsychologist and Clinical
Leader of the Neuroown lives, at least a 4 fold increased risk compared
ture. The earliest change is often emotional with
with the general population. Suicide rate is
irritability and a reduced tolerance of frustration.
Unit at the Royal Hospital
increased not just in those with the disease but also
While triggers for outbursts of anger often remain
London. He is also
in family members regardless of their risk status9.
easily identified the episodes become increasingly
Neuropsychologist to the
Others have found that the single most predictive
explosive and disproportionate. They also become
Huntington’s Disease Unit
factor against suicide was having children10. Factors
more difficult to defuse and carers learn that it is
at the Royal Hospital. In
associated with an increased risk were being
better to walk away from an argument than try to
addition he is an Honorary
Lecturer in Psychology at
unmarried, living alone, having a family history of
resolve it. Irritability and emotional lability are often
the Institute of Psychiatry,
suicide and having no contact with others suffering
accompanied by impulsivity and disinhibition - the
King’s College. Following
from HD.These findings emphasise the tremendous
so-called pseudopsychopathic syndrome of frontal
degrees in Psychology and
Neuro-psychology he comimportance of social supports for patients with the
lobe impairment, associated with impairment in the
pleted his training in
orbitomedial prefrontal cortex2. This may co-exist
Clinical Psychology at the
with the contrasting pseudodepressive state of apaInstitute of Psychiatry. His
thy and self-neglect (thought to be more closely
research interests include
cognition in Huntington’s
Psychotic disorders resembling schizophrenia
associated with dorsolateral prefrontal dysfuncdisease, behaviour manageoccur in between 3 and 12% of patients11. Psychotic
tion). Irritability and apathy are more common in
ment in brain injury rehabilstates with prominent persecutory delusions but
HD compared with Alzheimer's disease, each sympitation, memory, and visual
impairments after brain
relatively little in the way of hallucinations or other
tom occurring in 60 and 50% of HD patients
psychotic symptoms, referred to in the earlier literrespectively3. Similar figures were obtained more
recently using the Neuropsychiatric Inventory4. As
ature as atypical psychosis, may be more common
the disease progresses, intellectual impairment
than schizophrenia-like states but prevalence is difdominates the clinical picture. Mental slowness, perseveration
ficult to establish. In the more advanced stages of the disease a
and impairments of judgement, reasoning and planning concomprehensive assessment of mental state is often very difficult
tribute to behavioural problems.The patient's mental and behavand it may not be possible to elucidate clearly the nature of
ioural repertoire becomes increasingly narrow. Agitation and
abnormal experiences or beliefs. In some cases psychosis can
aggression in the latter stages of the disease often arise in the
only be inferred by observations of behaviour.
context of fixed preoccupations that are not amenable to explaManagement
nation or reassurance. Patients sometimes appear to become
Cognitive impairment and communication difficulties may make
stuck in a perseverative loop in which they dwell endlessly on a
psychiatric assessment difficult in HD12. Patients may deny they
particular worrying issue leading to a vicious circle of mounting
are ill. Sometimes this reflects loss of insight as part of a psydistress driven by seemingly inescapable, repetitive negative cogchotic illness, but more often it is better understood as a form
of intense self-deception, perhaps facilitated by subtle cognitive
impairments and temperamental changes. An informant history
Estimates of the prevalence of affective disorder in HD vary
is very important, especially if there is any suggestion of risk. On
widely depending on the patient sample studied and the diagoccasions detention and treatment under the Mental Health Act
nostic criteria used. Up to 40% of patients will suffer a significant
(MHA) may be required. Unfortunately in clinical practice there
episode of depression at some stage in the course of their illis still a reluctance to use the MHA in patients with HD because
ANCR • VOLUME 1 NUMBER 5 NOVEMBER/DECEMBER 2001
the illness is seen as neurological rather than psychiatric or
because it is untreatable. When patients with HD develop psychosis there is seldom a debate. But even when behavioural
problems arise as a direct result of the dementing process, in the
absence of any secondary psychiatric disorder, there should be
no doubt that the patient does indeed suffer from a mental disorder within the meaning of the MHA and that compulsory
assessment and or treatment may be indicated if there are compelling reasons in the interests of the patients health or safety or
for the safety of others. In this context it is important to recognise that nursing care may be regarded as treatment within the
meaning of the MHA.
Treatment starts with explanation and many families are
greatly helped simply through a medical understanding of the
changes in behaviour and personality they see. Contact with
specialist services is ideal but their availability is highly variable
from one region to another. Unfortunately the existence of
such services depends more on the interests of local consultants than on any strategic service planning. Patients with HD
pose the familiar challenge of patient groups affected by joint
mental and physical problems in that psychiatric services lack
the resources to deal with physical disability and services for
the physically disabled complain of an inability to effectively
engage mental health services. In this country the Huntington's
Disease Association plays an invaluable role in providing information both to affected families and to professionals who have
not encountered the disorder before. They are also able to
advise on referral to specialist services at all stages of the illness.
Neuropsychiatric pharmacological treatment in HD has
recently been reviewed13. The empirical evidence for individual
treatments is scant and the literature consists mainly of case
reports and small case series. In general, the indications for
treating psychiatric syndromes are as they would be in the
absence of HD, the choice of drug being dictated by side-effect
profile, in particular by the likelihood of exacerbating physical
symptoms of the disorder.
Antidepressants are effective and the modern generation
of compounds are better tolerated than tricyclics. The
anticholinergic effects of the latter are particularly problematic as they may exacerbate cognitive impairment.
However, some of the less selective modern compounds,
for example sertraline and venlafaxine in higher doses,
have a prominent dopaminergic action and may result in
an unacceptable exacerbation of involuntary movements.
ECT is effective and well tolerated in severe depression.
Conventional antipsychotic agents are effective in the
treatment of psychosis but carry the theoretical risk of
exacerbating involuntary movements in the longer term
through tardive dyskinesia. For this reason atypical agents
are probably the treatment of first choice in psychosis.The
appetite stimulation and weight gain associated with olanzapine that is usually regarded as an adverse effect may be
beneficial in patients with HD.
Treatment of aggression must focus on the underlying
causes: antipsychotics are indicated where aggression arises in the context of psychosis, antidepressants where the
patient is depressed.Where aggression occurs in the context of dementia and organic personality change there is a
largely anecdotal literature describing the use of betablockers, SSRI antidepressants, anti-epileptic drugs, lithium,
neuroleptics and benzodiazepines. It is doubtful whether
any of these drugs have an effect on aggression over and
above a general sedative action.The exceptions to this are
beta-blockers and SSRI's, neither of which are sedative, but
the evidence of their efficacy is sparse and in both cases
there are reports of paradoxical exacerbations of agitation.
In a similar manner there are little data available on psychological treatments for challenging behaviour. In the early phases
psychological management techniques such as Cognitive
Behavioural Therapy can be useful in enabling the individual to
cope with the condition. However, as the patient's cognition
deteriorates, their thinking becomes more rigid and perseverative and insight diminishes the use of such techniques becomes
limited. Behavioural techniques such as differential reinforcement within the context of a planned behavioural treatment
regime may also be helpful. Furthermore, emergency response
strategies as such as antecedent control and stimulus change
can enable the safe management of challenging behaviour using
Patients with HD present with many complex and challenging
behaviours that require careful and balanced management. Such
treatment must be applied with knowledge of the progression of
the condition and an awareness of the associated impairments.
One must balance the necessary treatment of one set of difficulties with the possible exacerbation of others. Impairments in
communication, cognition and movement increase the difficulty
of diagnosing and treating such difficulties. However, the appropriate and timely treatment of neuropsychiatric conditions can
improve the daily functioning in patients with an apparently deteriorating condition.
Niall Pender is supported by a grant from the Neuro-disability
1. Dewhurst, K. Oliver, J. E; McKnight, A. L. (1970) Socio-psychiatric consequences of Huntington's disease. British Journal of Psychiatry, Vol.
116 (532), 255-258.
2. Lishman, W.A. (1997). Organic Psychiatry. 3rd edition. Blackwell
Scientific Publications. Oxford: UK.
3. Burns, A., Folstein, S., Brandt, J., Folstein, M., (1990). Clinical assessment of irritability, aggression, and apathy in Huntington and Alzheimer
disease. Journal of Nervous & Mental Disease,Vol 178(1), 20-26.
4. Paulsen, J.S., Ready, R.E., Hamilton, J.M., et al., (2001). Neuropsychiatric
aspects of Huntington's disease. Journal of Neurology, Neurosurgery
and Psychiatry, 71, 310-314.
5. Shiwach R. (1994). Psychopathology in Huntington's disease patients.
Acta Psychiatrica Scandinavica, 90(4), 241-6.
6. Folstein, S. E., Leigh, R. J., Parhad, I. M., Folstein, M. F. (1986). The diagnosis of Huntington's disease. Neurology,Vol 36(10),1279-1283.
7. Troster,A.I. (1999). Movement and demyelinatng disorders. In P.J.Snyder
and P.D. Nussbaum (eds). Clinical Neuropsychology: A pocket handbook for assessment. American Psychological Association.
8. Mendez MF. (1994). Huntington's disease: update and review of neuropsychiatric aspects. International Journal of Psychiatry in Medicine,
9. Di Maio L. Squitieri F. Napolitano G. et al., (1993). Suicide risk in
Huntington's disease. Journal of Medical Genetics, 30(4), 293-5
10. Lipe H. Schultz A. Bird TD. (1993). Risk factors for suicide in
Huntington's disease: a retrospective case controlled study. American
Journal of Medical Genetics, 48(4), 231-3.
11. Morris, M., Scourfield, J. (1996). Psychiatric aspects of Huntington's disease. In P.S. Harper (ed.). Huntington's Disease. 2nd edn.
W.B.Saunders Co. UK: London
12. Purdon, S.E., Chase, T. Mohr E. (1996). Huntington's Disease. In J.G.
Beaumont, P.K. Kenealy, M.J.C. Rogers (Eds). The Blackwell
Dictionary of Neuropsychology. Blackwell Publishers: UK.
13. Leroi I. M. M. (1998). Treatment of the psychiatric manifestations of
Huntington's disease: a review of the literature. Canadian Journal of
Psychiatry, 43(9), 933-40.
14. Donnellan, A.M., LaVigna G., Negri-Shoultz, N., Fassbender, L.L.
(1988). Progress without punishment. Teachers College Press: NY
ANCR • VOLUME 1 NUMBER 5 NOVEMBER/DECEMBER 2001
Management of Rational epilepsy
bout two thirds of patients with epilepsy will respond to first
line treatment. For the remainder there are three considerations:
● Is the diagnosis correct? Misdiagnosis is common - 20%
of refractory patients. The diagnosis needs to be fully reevaluated. Non-epileptic seizures either alone or in association with epilepsy need to be considered. If necessary a
referral should be made for video-EEG-telemetry
● What is the epilepsy syndrome? This determines choice
● If the epilepsy is focal, might there be a surgical target?
When first-line treatment fails:
Try an alternative first-line drug, determined by the epilepsy syndrome (table 1). Figure 1 shows a scheme to consider medication in focal epilepsy, which forms the greatest
proportion of refractory epilepsy.A good method of changing medication is by crossover, with simultaneous introduction of the new drug and withdrawal of the old drug. This
avoids unnecessary polypharmacy and reduces the risk of
adverse effects with the new drug, which are likely to be
greater if it is added in to an existing AED at high doses.An
alternative method is to add the
new AED and then if it is successful,
withdraw the old one. This allows
one to establish whether it is the
new AED alone or the combination
that is of value, but is more likely to
end in polytherapy.
When monotherapy options have
been exhausted, AED can be added
that are licensed only for add-on. If
these are successful, then again
withdrawal to monotherapy can be
attempted in the understanding
that this is an unlicensed indication.
before and after making the change, may be appropriate.
● Adding an enzyme-inducing drug may reduce the efficacy of existing medication, leading to worsening of seizures.
Anticipatory increases in existing AED may be appropriate.
● Pharmacodynamic interactions may cause adverse
effects without any major change in blood levels. Many AED
may cause sedative or cognitive adverse effects that can be
reduced by a small reduction of concomitant medication
during initial dose titration.
● Lamotrigine titration rates and maintenance doses are
heavily dependent on concomitant therapy. In monotherapy
its half-life is around 20 hours and therapeutic doses are
usually 150-400mg daily.With concomitant valproate its
half-life is around 60 hours and therapeutic doses are usually 100-300mg per day.With concomitant enzyme-inducing
drugs, its half-life is around 10-15 hours and therapeutic
doses are usually 300-800mg per day.
● Informing the patient enhances compliance. Without
prior warning they reasonably blame the new medication
for any problem and stop it rather than modifying previous
Rational polytherapy is an attempt to
predict which AED combinations are
likely to be more helpful and which
should be avoided. There are too many
potential combinations to get the information from clinical trials.
● The most logical combinations of
drugs are those used to treat different seizure types in idiopathic generalised epilepsies (table 1).
● Combinations of enzymeinducing drugs often leads to
erratic blood levels and it may be
difficult to achieve satisfactory levels of both drugs e.g carbamazepine
● Combining drugs with similar
mechanisms of action may be
expected to give additive adverse
effects with little therapeutic benefit eg. gaba-ergic AED gabapentin
and tiagabine may increase sedation
and weight gain.
● Adding an enzyme-inhibiting
drug such as valproate may inhibit
the metabolism of other drugs
(especially lamotrigine), rendering
them toxic. Anticipatory changes in
drug dosages and AED blood levels
ANCR • VOLUME 1 NUMBER 5 NOVEMBER/DECEMBER 2001
Selecting patients for epilepsy
● Epilepsy is generally considered
refractory after failure of 2-3
AED (figure 3). The earlier
appropriate patients are treated
surgically, the more likely the psychosocial consequences of the
epilepsy will be reversible. One
should aim for surgical treatment
within 2-3 years of diagnosis
● The principles of selection of
patients for resective epilepsy
1. The epilepsy must come from a
single brain region.
2. Resection of that region must not
result in unacceptable neurological deficit.
3. The patient must be psychiatrically able to tolerate the investigation for surgery, surgery itself
and the lifestyle changes imposed
by a sudden transition to seizurefreedom.
● The presence of a relevant neuroimaging abnormality is the
most important prognostic factor
for epilepsy surgery but highly
specialised neuroimaging may be
needed to identify it.
● Mesial temporal sclerosis is
the commonest surgically treatable cause of epilepsy but needs
special MRI analysis used in
epilepsy centres to find it. Clues
to the presence of mesial temporal sclerosis include: childhood
onset epilepsy; focal temporal
lobe seizure pattern; a history of
severe febrile convulsions and
focal temporal EEG changes.
● Other treatable causes include
foreign tissue lesions and
developmental abnormalities which usually require specialised neuroimaging.
Table 1. Rational drug combination
1. Pharmacokinetic interaction
2. Illogical combination
3. Additive adverse effects likely
* Despite this being an apparently illogical combination, one study has shown benefit from this combination
ANCR • VOLUME 1 NUMBER 5 NOVEMBER/DECEMBER 2001
F O R P A R T I A L S E I Z U R E S I N A D U LT S
• Highly effective: up to 4 out of 10
refractory patients had ≥50% partial
• Excellent tolerability, discontinuation
rates not significantly different from
ADD-ON THERAPY STARTS WITH
• No known drug/drug interactions6
• Therapeutic starting dose (500mg bd)
KEPPRA® Prescribing Information:
Presentation: Keppra 250 mg, 500 mg and 1,000 mg film-coated tablets containing
250 mg, 500 mg and 1,000 mg levetiracetam respectively. Uses: Adjunctive therapy in the
treatment of partial onset seizures with or without secondary generalisation in patients with
epilepsy. Dosage and administration: Adults and adolescents older than 16 years: The initial therapeutic dose is 500 mg twice daily which can be started on the first day of treatment.
Depending upon clinical response and tolerance the dose can be increased up to 1,500 mg
twice daily. Dose changes can be made in 500 mg twice daily increments or decrements
every two to four weeks. Elderly: Adjustment of the dose is recommended in elderly patients
with compromised renal function. Children (under 16 years): Not recommended. Patients
with renal impairment: Adjust dose according to creatinine clearance as advised in SPC.
Patients with hepatic impairment: No dose adjustment with mild to moderate hepatic impairment. In patients with severe hepatic impairment and creatinine clearance
<70 ml/min a 50% reduction of the daily maintenance dose is recommended.
Contraindications: Hypersensitivity to levetiracetam, other pyrrolidone derivatives or excipients. Warnings and special precautions for use: If discontinuing treatment reduce dose
gradually as advised in SPC. Interactions: Keppra did not affect serum concentrations of
phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin or primidone. Drugs excreted by active tubular secretion could reduce the renal clearance of the
metabolite. Levetiracetam 1,000 mg daily did not affect the pharmacokinetics of oral contraceptives (ethinyl-estradiol and levonorgestrel) or levels of luteinizing hormone or progesterone. Levetiracetam 2,000 mg daily did not affect the pharmacokinetics of digoxin and
warfarin and prothrombin times were not modified. Pregnancy and lactation: Should not
be used during pregnancy unless clearly necessary. Breast-feeding not recommended.
Driving, etc: Caution recommended when performing skilled tasks, e.g. driving vehicles or
operating machinery. Undesirable effects: The most commonly reported undesirable
effects are somnolence, asthenia and dizziness. In the pooled safety analysis there was no
S I M P L I F Y I N G
clear dose-response relationship but incidence and severity of the central nervous system
related undesirable effects decreased over time. Incidence of undesirable effects considered
to be at least possibly related in controlled clinical studies: Very common (>10%): asthenia
and somnolence. Common (between 1%–10%): accidental injury, headache, anorexia, diarrhoea, dyspepsia, nausea, amnesia, ataxia, convulsion, depression, dizziness, emotional
lability, hostility, insomnia, nervousness, tremor, vertigo, rash and diplopia.
Legal category: POM. Marketing Authorisation numbers: 250 mg x 60 tablets:
EU/1/00/146/004. 500 mg x 60 tablets: EU/1/00/146/010. 1,000 mg x 60 tablets:
EU/1/00/146/024. Basic NHS cost: 250 mg x 60 tablets: £27.00. 500 mg x 60 tablets:
£49.50. 1,000 mg x 60 tablets: £94.50.
Further information is available from: UCB Pharma Ltd., 3 George Street, Watford, Herts
WD18 0UH. Tel: 01923 – 211811 or e-mail [email protected]
Date of Preparation: October 2001.
1. Shorvon S et al. Pooled efficacy and safety data of levetiracetam (LEV) used as adjunctive
therapy in patients with partial onset seizures. Epilepsia 1999;40,S7:76,abstract B.01.
2. Cereghino J et al. Levetiracetam for partial seizures. Results of a double-blind, randomized
clinical trial. Neurology 2000;55:236-242.
3. Ben-Menachem E et al. Efficacy and tolerability of levetiracetam 3,000 mg in patients with
refractory partial seizures: a multicenter, double-blind, responder-selected study evaluating
monotherapy. Epilepsia 2000;41,10, 1276-1283.
4. Shorvon S et al. Multicenter, double-blind, randomized, placebo-controlled trial of levetiracetam as add-on therapy in patients with refractory partial seizures. Epilepsia 2000;41,9,1179
5. Data on file, UCB Pharma Ltd.
6. Patsalos P. Pharmacokinetic profile of levetiracetam: towards ideal characteristics.
Pharmacol Ther 2000;85(2):77-85.
© 2001, UCB Pharma Ltd.
S E I Z U R E
C O N T R O L
The Basics. Pain is a perception and not a sensation.The same stimulus can elicit different levels of pain depending on context. To some
extent this modulation of sensation is reflected in the anatomy of the
pathways that subserve noxious sensation.They relay onto neurons in
the dorsal horn that cross the spinal cord at the same level of entry
and ascend in the contralateral “anterolateral system” to terminate in
the reticular formation, mesencephalon, hypothalamus and thalamus.
(The term “spinothalamic tract” should strictly only be used for the
latter pathway, but tends to be used for all). At the level of the spinal
cord there are several mechanism to modulate the firing of this
anterolateral system. Study of a surgical treatment for pain, anterior
cordotomy, reveals subtleties of the pain pathways.
Afferent Pain Fibres. Myelinated A∂, and unmyelinated, fibres
carry impulses from noxious stimuli. Because they are smaller
than primary somatic afferents, their conduction velocity is
lower. They enter the spinal cord at their appropriate somatic
level (in Lissauer’s tract), but then send dorsal root collaterals up
and down several segments in the dorsal horn before synapsing
onto second order neurones using the following neurotransmitters glutamate, substance P and calcitonin gene related peptide.
Dorsal Horn Laminae
Myelinated A∂, and unmyelinated, dorsal ganglion cells project
mainly to Rexed’s laminae I and V of the dorsal horn, but with
minor contributions to laminae II,VI-VIII.
In the cat, there are some lamina I cells with small receptive
fields that specifically respond to either noxious or thermal stimuli.The thermoreceptive cells project to the dorsomedial part of
ventroposterior medical thalamic nucleus, whereas nociceptive
cells project to the ventro-posterolateral nucleus. These pathways may provide the sensory-discriminative aspects of pain.
However other lamina I cells are less modality specific and project to sites outside the thalamus. For instance, in the cat, three
times as many lamina I neurons project to periaqueductal grey
than to thalamus.
Laminae IV-VI neurones have larger receptive fields and respond
to both noxious and innocuous stimuli. Laminae VII-IX cells have
still larger (often bilateral) fields and respond to a wide variety
of stimuli.These neurones project to the reticular formation and
intralaminar nuclei of the thalamus, perhaps subserving the emotional-affective component of pain.
Crossing of the ALS. Fibres of the ALS move anteriorally from
their origin in the dorsal horn to cross in front of the anterior
commisure and lie in the anterolateral white matter tracts.
Projections of the ALS:
● Reticular formation (from which relay neurones ascend to the
thalamus) as spinoreticular fibres.
● Periaqueductal grey, which relay down to the nucleus raphe,
magnus, and from there back down to laminae I, II and V of the
dorsal horn in the raphespinal tract.
● Thalamus, in the intralmainar nuclei,VPL and parts of the posterior thalamus.
ANCR • VOLUME 1 NUMBER 5 NOVEMBER/DECEMBER 2001
Somato-topography of the anterolateral system.
Most textbooks say that, as new fibres join the anterolateral system as it ascends the cord, so fibres from the
lumbar cord are pushed dorsally. Recent reports in
monkeys however indicate that spinothalamic neurons
from lumbar cord ascend in increasingly ventral position
as new fibres enter dorsally.
A few weeks ago, Patrick Wall died at the age of
76. He studied medicine at Oxford, but worked
throughout his life in the USA. With Ron
Melzack he pioneered pain research, at all levels. In 1965 they published their famous “spinal
gate control theory”.
The anterolateral system
A∂ fibre dorsal
Wall’s T cell
Melzack & Wall’s Gate Control Theory (1965)
Melzack and Wall proposed that there was modulation of pain
impulses at the level of the spinal cord. Specifically they proposed there were “T-cells” that received excitatory input from
unmyelinated and A∂ fibres (transmitting noxious stimuli) and
inhibitory input from large afferent fibres (carrying impulses
from discriminative senses) as well as descending raphespinal
tracts.The output of this summation of influences on the T cells
was transmitted caudally to be appreciated as pain. A prediction
of this model is that if noxious stimuli are accompanied by other
cutaneous sensations, the perception of pain will be reduced.
This is the basis for the automatic rubbing a painful area, and also
for the introduction of transcutaneous electric nerve stimulation
(TENS) which has an established role in pain control. The gate
control theory has been enormously fruitful but remains a theory. Many of its components remain unproven.
Spinal inhibitory pathways acting
on the anterolateral system
Sensory loss following anterior cordotomy
Much useful information on the pain pathways has been gained
from careful observation of the effects of anterior cordotomy
(especially by PW Nathan).This operation is designed to relieve
intractable pain by severing the anterolateral system.
Minor spinal pain pathways
Some patients do not experience complete pain relief after anterior cordotomy.This can be explained by the presence of minor
pain pathways, not normally regarded as prominent in man
although they are in smaller animals. First, A∂ collaterals ascend
the cord in the dorsal columns in the post-synaptic dorsal
column system. Second, in the dorsolateral region of the lateral
funiculus there is an ascending Spino cervico-thalamic tract.
Typically there is a level of complete loss of pain and temperature sensation. However, just above this there is an area of
reduced noxious and temperature sensation.This is explained by
the fact that A∂ fibres have collaterals that supply the dorsal
horns immediately above and below their spinal segment. So, in
the case of a T10 anterior cordotomy, the T9 spinothalamic complex has lost the input of T9 callaterals that descend to lower
spinal levels before crossing and the T10/11 complex receives
fibres that ascended to T9 in the dorsal horn before crossing.
Anterior cordotomy at level T10
W Nathan, Smith & Deacon.The crossing of the spinothalamic tract.
Brain (2001), 124, 793-803
Melzak & Wall. (1965) Pain mechanisms: a new theory. Science 150: 9719
ANCR • VOLUME 1 NUMBER 5 NOVEMBER/DECEMBER 2001
The practicalities of treadmill gait training
for non-ambulant hemiplegic patients
Techniques and equipment
ait training with partial body weight support for
Most cheaper treadmills are designed for fast
brain and spinal cord lesions was first described
by Sherrington in 19101, when he studied the reflexwalking and running, and may overheat, stall or
es of cats. He noted that they could learn to walk in
burn out when used with high loads at slow
a rather automatic fashion, but their balance did not
speeds e.g. 0.8 kph. Our Powerjog worked reliably,
recover: “the performance of mere stepping movebut the side rails got in the therapists way and prements as exhibited by the decapitate preparation is
vented sideways access to the treadmill. Ideally
amplified in the decerebrate preparation into the
they would be removable. The overhead support
performance of actual walking and running - impermust be able to catch the patient if they fall and
fect it is true, especially in regard to equilibrium, the
take all their weight, and secondly be able to proregulation of which is almost entirely wanting, but
vide controlled lift without impeding normal pelvic
nevertheless amounting to a certain measure of
movement. We used nylon loops designed for
Physioeffective locomotion.” Practical physiotherapy mancatching falling climbers and a set of wall mounted
therapist in the Lewin
uals of gait training with body weight support were
Winchester weights and pulleys suspended from a
published in the 1950s2, but this technique went out
ceiling mounted hoist. Ceiling and wall mounted
Unit, Addenbrooke’s NHS
of fashion until scientific papers describing physiologsupports do not impede side access to the patient,
Trust, Cambridge. She
conducts Stroke Association
ical experiments and controlled trials, initially in
which is a problem with some commercially availfunded
spinal cord injured and subsequently hemiplegic
able floor standing systems, but do make it impractreadmill training.
humans were published3,5 in the last 10 years, and
tical to move the support to another part of the
summarised by Dobkin6.
gym.A home made system should be called a “supEdgerton7 emphasised that the effect of training
port” and not a “hoist”, as hospital insurers and
was limited to the specific task: spinal cats trained to
medical engineering departments have very strinstep can step, but not stand: those trained to stand
gent criteria for hoists which it would be very
can stand, but not step. Human comparisons of musexpensive to meet. Descriptions and recommencle activity have shown a similar distinction: relativedation for treadmill training equipment have been
ly normal patterns of activity during gait in hemipublished13,14.
Several types of harness are commercially availparetic muscles despite loss of response to a perable: they support body weight through broad
turbation of standing balance8,9.This suggests that to
get better at walking, patients should practice walkpadded straps around the proximal thighs when
Stephen Kirker is the ediing, and they may find it easier to activate the affectstanding erect, unlike unmodified parachute or
tor of the Rehabilitation
ed muscles in this task than in static balancing.
climbing harnesses which force the subject to
section of ACNR and
Consultant in Rehabilitation
Conventionally, and from practical necessity, hemiadopt a more seated posture. Ideally it would be
Medicine in Addenbrooke's
plegic patients have been taught to stand and keep
possible to put these on while still sitting in the
NHS Trust, Cambridge. He
their balance before they begin stepping, but body
wheelchair, and then hoist the patient up onto the
graduated from Trinity
weight support allows patients who cannot stand,
treadmill, but this was rarely possible and the therCollege, Dublin in 1985 and
trained in neurology in
balance or walk unaided to practice stepping moveapists had to provide all assistance.
ments. The continuous movement of the treadmill
In general, the physiotherapists facilitate weight
Edinburgh before moving to
encourages more automatic stepping, and reduces
transference, foot placement and hip extension on
rehabilitation in Cambridge
and Norwich. His main
the need for patients to actively and consciously inithe treadmill in the same way as they would if the
research has been into postiate each step from a standing start.
patient was walking on the ground. One therapist
Patterns of muscle activation and movement in
was positioned behind the patient with their
stroke. His particular interpatients walking on the ground and on the treadmill
hands on the pelvis, and the other sat or kneeled
ests are in prosthetics,
orthotics, gait training and
are generally similar, with treadmill gait tending to be
on the ground and lifted, dorsiflexed and placed
more symmetrical10,11. The use of hand rails and
the hemiplegic foot as necessary. This was very
degree of body weight support has a large impact on
hard work and the height of the treadmill and
amplitude of muscle activation and energy expenditure.
position of the hand rails made access difficult. All therapists
Our experience of treadmill training is based on studies funddeveloped back pain, and the duration of training sessions for
ed by the Stroke Association into gait training of hemiplegic
non-ambulant patients was usually limited by the endurance of
patients who either could not walk independently, or who could
the foot therapist rather than the patient. Some patients preonly walk short distances.We sought to reproduce Hesse’s draferred to have their hemiplegic hand strapped to the handrail in
matic 1995 study4, in which the majority of 9 non-ambulant
front of them, but they were discouraged from taking weight
patients, whose walking ability had been static during the prethrough their arms on side rails, as this interfered with their gait
ceding 3 weeks with regular physiotherapy, learnt to walk indepattern. Some patients continued to use ankle foot orthoses to
pendently after 25 treadmill sessions. The mean interval after
overcome low tone foot drop.
stroke in that study was 17 weeks, but it was 17 months in our
While ground ambulant stroke patients may benefit from
group, and we did not see functional benefit which would justiwalking on a treadmill with little physical assistance, treadmill
fy the therapeutic input12. Muscle tone did not increase. We felt
training of non ambulant patients is labour intensive, and carries
the results reflected the different intervals since stroke onset,
a significant risk of back and shoulder pain among therapists.The
and recommended that treadmill training of patients who
duration of each treatment session may be limited by the therrequire hands on help to walk on the ground would be most
apists exhaustion, while the patient may be prepared to continappropriate during the initial period of intensive rehabilitation.
ue.To overcome these two problems Hesse et al have developed
Our subsequent very encouraging experience with more acute
a free standing gait trainer15 which moves the patient’s feet and
pelvis and provides body weight support.This allows one therapatients has confirmed this view.
ANCR • VOLUME 1 NUMBER 5 NOVEMBER/DECEMBER 2001
pist to supervise in place of two doing physically demanding and
repetitive work and, if shown to have similar functional benefit
as treadmill training, would overcome this useful technique’s
Neurol Neurosurg Psychiatry 2000; 68:458-464.
10. Nilsson L, Carlsson J, Danielsson A, Fugl-Meyer F, Hellstrom K,
Kristensen L, Sjolund B, Sunnerhagen KS, Grimby G. Waking training
of patients with hemiparesis at an early stage after stroke: a comparison
of walking training on a treadmill with body weight support and walking
training on the ground. Clin Rehab 2001; 15: 515-527.
11. Hesse S, Konrad M, Uhlenbrock D. Treadmill walking with partial body
weight support versus floor walking in hemiparetic subjects. Arch Phys
Med Rehabil 1999 80:421-7
12. Jenner J, McGlashan K, Kendrick K, Holt R, Kirker S. Treadmill training with partial body weight support for poorly or non-ambulant chronic
stroke patients. Stroke Association Annual grant holders meeting
13. Norman K, Peppin A, Ladouceur M, Barbeau H. A treadmill apparatus
and harness support for evaluation and rehabilitation of gait. Arch Phys
Med Rehab 1995;76;772-78.
14. Wilson MS, Qureshy H, Protas EJ, Holmes SA, Krouskop TA,
Sherwood AM. Equipment specifications for supported treadmill ambulation training. J Rehabil Res Dev 2000; 37:415-22
15. Hesse S, Uhlenbrock D, Sarkodie-Gyan T. Gait pattern of severely disabled hemiparetic subjects on a new controlled gait trainer as compared
to assisted treadmill walking with partial body weight support. Clinical
Rehabilitation 1999; 13: 401-10.
A patient using the Gait Trainer.
Sherrington CS. Flexion reflex of the limb, crossed extension reflex and
reflex stepping in standing, J. Physiol. 1910; 40, 28-121
Hollis M and Roper MHS: Suspension therapy 1958
Hesse S, Bertelt C, Schaffrin A, Malezic M, Mauritz KH. Restoration of
gait in non ambulatory hemiparetic patients by treadmill training with
partial body-weight support. Arch Phys Med Rehabil. 1994;75:1087-93
Hesse S, Bertelt C, Jahnke MT, Schaffrin A, Baake P, Malezic M,
Mauritz KH. Treadmill training with partial body weight support compared with physiotherapy in non ambulatory hemiparetic patients. Stroke
1995; 26: 976-81
Visintin M, Barbeau H, Korner-Bitensky N, Mayo NE. A new approach
to retrain gait in stroke patients through body weight support and treadmill stimulation. Stroke 1998; 29:1122-8.
Dobkin BH. An overview of treadmill locomotor training with partial body
weight support: a neurophysiologically sound approach whose time has
come for randomised trials. Neurorehab and Neural Repair 1999;13:
Edgerton VR, Roy RR, Hodgson JA, Prober RJ, De Guzman CP, De
Leon R, 1992, Potential of adult mammalian lumbosacral spinal cord to
execute and acquire improved locomotion in the absence of supraspinal
input. J. Neurotrauma, 9 (Suppl.1), S119-128
Brunt D,Vander Linden DW, Behrman AL. The relation between limb
loading and control parameters of gait initiation in persons with stroke,
Arch Phys Med Rehab 1995; 76: 627-34
Kirker SGB, Simpson DS, Jenner JR,Wing AM. Stepping before standing: hip muscle function in stepping and standing balance after stroke. J
ANCR • VOLUME 1 NUMBER 5 NOVEMBER/DECEMBER 2001
Box 185, Physiotherapy Department, Addenbrooke’s Hospital, Hills
Road, Cambridge CB2 2QQ. E-Mail: [email protected]
If you would like your event listed in the next issue, send details to: Rachael Hansford on
Fax: 0131 3131110 or E-Mail: [email protected] by December 7th, 2001.
Alzheimer’s Society (UK)
5-8 November, 2001; London, UK
Tel. 020 7306 0606,
Fax. 020 7306 0808,
E. [email protected]
and the Child
7 November, 2001; London, UK
Tel. 01691 650290,
Fax. 01691 670302,
E. [email protected]
Society Autumn Meeting
8 November, 2001; London, UK
Tel. 0161 275 3401
MS 2001- The Way Ahead, MS
Research Trust Fifth Annual
11-13 November, 2001,
Tel. 020 8772 1551,
Fax. 020 8772 1552,
E. [email protected]
Rehab & Care
14-15 November, 2001;
Tel. 020 7874 0200
UKABIF Annual Conference
30 November, 2001; London, UK
Tel. 020 8780 4569,
E. [email protected]
12th Course in Otology &
4-7 December, 2001;Toulouse,
France Secretariat ORL.
Tel. 0033 5 61772401,
Fax. 0033 5 61493644,
E. [email protected]
Brain Awareness Week 2002
12-17 March, 2002; UK
Elaine Snell,Tel. 020 7738 0424,
E. [email protected]
6th Congress of the
European Society for Clinical
14-18 May, 2002; Budapest,
Tel. 0036 1 311 6687, Fax. 0036 1
383 7918, E. [email protected]
7th European Congress of
14-17 July, 2002; Helskinki, Finland
Tel. + 3 58 9 56 07-5 00,
Fax. + 3 58 9 56 07-50 20, E.
4th European Federation of
Autonomic Societies Meeting
16-18 May, 2002; Athens, Greece
Tel. 0030 1 3634 944, Fax. 0030 1
3631 690. E. [email protected]
8th International Conference
on Alzheimer’s Disease and
20-25 July, 2002; Stockholm,
Tel. 001 312 335 5813, Fax. 001
312 335 5781, www.alx.org/internationalconference
7th Meeting of the European
Society of Neurosonology
and Cerebral Hemodynamics
26-28 May, 2002; Bern,
Tel. 0041 41 767 34 49,
Fax. 0041 41 767 34 00,
E. [email protected]
3rd World Congress in
3-6 April, 2002;Venice, Italy
Aristea,Tel. 0039 06 844 98364,
Fax. 0039 06 844 98332, E. [email protected]
13th European Congress of
Physical Medicine &
28-31 May, 2002; Brighton, UK
Melanie Ramsdell, Concorde
Services.Tel. 020 8743 3106,
Symposium on ALS/MND
18-20 November, 2001; Oakland,
Karen Walker, MND Assocation.
Tel. 01604 250505,
Fax. 01604 638289, E. Symposium
International League Against
Epilepsy Annual Scientific
3-6 April, 2002, Exeter, UK
Conference 2000,Tel. 01691
650290, Fax. 01691 670302,
E. [email protected]
33rd Scandinavian Neurology
29 May-1 June, 2002; Reykjavik,
Tel. 00354 585 3900, Fax. 00354
585 3901, E. [email protected], www.congress.is
National Society of Epilepsy
Advanced Lecture Series
22 November, 2001; London, UK
NSE.Tel. 01494 601300,
Fax. 01494 871977.
54th Annual Meeting of the
American Academy of
13-20 April, 2002; Denver, USA
Tel. 001 651 695 1940,
Fax. 001 651 695 2791
11th European Stroke
29 May-1 June, 2002; Geneva,
Tel. 0041 22 33 99 624,
Fax. 0041 22 33 99 621,
E. [email protected]
Royal Hosptal for
Neurodisability Open Day
22 November, 2001; London, UK.
Chloe Hayward,Tel. 020 8780
4561, E. [email protected]
Ageing of the Brain Dementia
23-24 November, 2001; Florence,
Tel. 00390 55 43 68 455,
E. [email protected]
BSRM Autumn 2001 Meeting
26-27 November, 2001;
Sandy Weatherhead, BSRM,
Tel/Fax. 01992 638865,
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The Changing Brain
29 November, 2001; Milan, Italy
55th Annual Meeting of the
American Epilepsy Society
30 November - 5 December,
2001; Philadelphia, USA
Maria Rivera,Tel. 001 860 586
7505, Fax. 001 860 586 7550
5th European Parkinson’s
21-24 April, 2002; Jerusalem, Israel
Tel. 01273 686889, Fax. 01273
570082, E. [email protected]
Society Spring Meeting
24-25 April, 2002; London, UK
Tel. 0161 275 3401
1st Mediterranean Congress
26-28 April, 2002; Limassol,
Tel. 00357 5 749919,
Fax. 00357 5 749744,
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XIV International NeuroOphthalmology Society
5-8 May, 2002; Buenos Aires,
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International Association of
Section. 6th European
Congress of Clinical
June 2002; Moscow, Russia
Prof L B Lazebnik, E.
6th European Headache
17-22 June, 2002; Istanbul,Turkey
Flap Tourism & Organisation,
Tel. 0090 312 4420700,
E. [email protected]
10th International Congress
of Neuromuscular Diseases
7-12 July, 2002;Vancouver, Canada
Tel. 001 604 681 5226,
Fax. 001 604 681 2503,
E. [email protected]
18-24 August, 2002; Paris, France
Tel. 0033 3 83851456, Fax. 0033 3
838 51391, E. l.picard:chu-nancy.fr
5th International Congress of
31 August-4 September, 2002;
Tel. 01454 619347, E.
9th International Child
Neurology Congress & 7th
Asian and Oceanian
Congress of Child Neurology
20-25 September, 2002; Beijing,
Fax. 0086 10 66176450,
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5th European Congress on
6-10 October, 2002; Madrid, Spain
2nd Latin America
Committee for Treatment &
Research in MS (LACTRIMS)
9-12 October, 2002; Monterrey,
E. [email protected]
European Federation of
26-30 October, 2002;Vienna,
EFNS,Tel. 0043 1 880 00270,
Fax. 0043 1 888 925581,
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Parkinson’s Disease &
10-14 November, 2002; Florida,
US.Tel. 001 414 276 2145, Fax.
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Residential Meeting of the
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15-16 November, 2002;
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ANCR • VOLUME 1 NUMBER 5 NOVEMBER/DECEMBER 2001
Association of British Neurologists Meeting
12th-14th September 2001, Durham
he timing of the World Congress of Neurology event in
London, coupled with the immense effort involved in its
organisation, meant that this was a rather unusual year for the
Association of British Neurologists (ABN). Instead of the normal
twice-yearly gatherings, the ABN meeting in Durham was the
only one to be based on ‘home soil’ in 2001. Professor Charles
Warlow presided over the meeting, which, to the relief of the
local organisers, headed by Dr Niall Cartlidge, was very well
attended.The conference dinner was held in Durham Castle.
The theme of the Scientific Symposium, held on the first
afternoon, was Parkinson's disease. This mixed scientific
advances with practical advice.The session clashed with the traditional ABN golf match, held at Brancepeth, and won by Dr
Timothy Walls. There was some consolation to those whose
consciences took them to the auditorium rather than the first
tee to hear the heavens open mid-way through the afternoon!
After a brief but interesting session on Dementia and
Psychiatry on the Thursday morning, there followed a new
departure for the ABN, an Interactive Educational Symposium.
This feature was coordinated by Dr Geraint Fuller and was
undoubtedly extremely popular, judging by feedback forms. The
interactive component meant that the audience could respond
to various clinical scenarios with key-pads. An audiovisual team
that were on top of their game collated the answers immediately and this information, relayed back to the audience, formed
the basis of ensuing debate and discussion. An acute onset
headache (could it be a sub-arachnoid haemorrhage?), blackouts
(fit or faint), episode of optic neuritis (do you tell the patient
they may develop multiple sclerosis?) provided the clinical material for the session, in which Richard Davenport, Phil Smith,
Jacky Palace and Charles Warlow made notable contributions.
(Geraint might have an alternative career in "The Weakest
Thursday afternoon and Friday were then mainly devoted to
the more traditional presentation format, with sessions on
Stroke and Parkinson's disease, Epilepsy, Tumours and Migraine
and Muscle and Mitochondria. Many devotees of demyelinating
disease had travelled to Dublin for the competing ECTRIMS
meeting, hence the lack of a session on this topic.There was the
usual eclectic mixture of leading edge scientific work and clini-
Durham Castle, venue of the conference dinner.
cal observations presented by the ABN speakers. Space for the
discussion of the five best posters is also an essential feature of
the ABN, in recognition of the wide range of topics covered by
the posters, their scientific content and the effort involved in
their production, which is clearly considerable in the majority of
Finally, mention must be made of the clinicopathological conference (CPC), organised by Paul Reading, with Ralph Gregory
as the discussant. It is rumoured that both went for a "bonding"
game of golf prior to the CPC and that the final diagnosis was
never discussed! To the independent observer, it seemed that it
was ‘honours even’, in that Ralph performed extremely well
under pressure (he had been heard to say beforehand "It's so
easy, I don't know how I'll be able to spin it out"!), while Paul,
with a satisfied smile, saw Ralph come only close to the final
diagnosis of Actinomycosis! Peter Goulding came up with the
correct answer from the floor to win the CPC audience prize.
As one of the local organising team, it is a little difficult to be
objective as to how the meeting in Durham was perceived by
others. Overall, however, we tried to provide something for
everyone, with a blend of old and new ideas, crammed in to two
and a half days. There just never seemed to be enough time to
catch up on all the news with colleagues from around the
17th Congress of the European Committee for
Treatment and Research in Multiple Sclerosis (ECTRIMS)
12 -15 September 2001, Dublin , Ireland
lthough heavily overshadowed by the tragic events unfolding
in the United States this conference still managed to provide
an interesting forum for the analysis of current immuno-modulating therapies, potential new therapies including non-drug
related rehabilitation techniques, unusual presentations and new
insights into the pathogenesis of MS.
Several sessions were dedicated to analysing the use of interferons and glatiramer acetate. The general consensus was that
these immuno-modulating agents do have an effect on the number of clinical relapses and on MRI show a decrease in T2 lesion
load throughout the relatively short trials to date. However
their effect on the most disabling progressive phase of the disease is disappointing. Of four large but again relatively short trials the EUSPMS, SPECTRIMS, NASPMS and IMPACT, only the
European study showed a beneficial effect on delaying disability
as measured by deterioration of one point on the widely
accepted Expanded Disability Status Score (EDSS).
ANCR • VOLUME 1 NUMBER 5 NOVEMBER/DECEMBER 2001
Amongst the most intriguing presentations were talks by Prof
Kappos (Basel, Switzerland) on the evidence for a significant
effect on disability by disease modifying drugs. He challenged
the sensitivity of the EDSS as a scale for efficacy and quality of
life whilst also presented compelling data from several trials
demonstrating decreases in relapses, delay in onset of clinically
definite MS if treated early and MRI lesion load.
Prof George Ebers (Oxford, UK) then discussed the weakness in efficacy data from published randomised clinical trials in
MS. He emphasised the difference between effectiveness and
efficacy, outlining that for a drug to be effective it should achieve
what it was intended to do. For MS this would be an impact on
the long-term natural history measured as an effect on hard
outcome measurements and that "surrogate markers need not
apply".To follow on from this Prof Ebers presented unpublished
retrospective data, also presented in two posters from London,
Ontario by Prof GPA Rice and Dr S Karlik on patients who had
Courses and Conferences
National Society for Epilepsy
Professionals caring for people with Neurological conditions
Study by distance-learning with
Leeds Metropolitan University
The National Society for Epilepsy offers a wide range of
training events to suit your organisation. Each programme is
tailored to the needs of the organisation:
● Half or full day courses on any aspect of epilepsy, including
classification and management of seizures and an introduction to topics as agreed with organisation
● One day courses on the administration of rectal medication
in accordance with the Joint Epilepsy Council guidelines
● Specialist courses to train the trainers in administration of
● Specialised visits to the Chalfont Centre
● Conferences, short courses and lectures for professional
groups of doctors, nurses and care workers (where
appropriate CPD accredited)
● Industry sector focused conferences, seminars courses and
For a discussion on your requirements, please contact the
email: [email protected]
Professional Diplomas in:
● Dementia Care
● Epilepsy Care
● Headache and Migraine
● Multiple Sclerosis Care
● Neurological Care
● Parkinson’s Disease Care
● Stroke Care
All of the courses are intended to enhance professional practice and form an
important component of a continuing professional development portfolio.
They are suitable for qualified professionals including nurses, occupational
therapists, health visitors, physiotherapists, speech therapists and social
The Professional Diploma is a Leeds Metropolitan University award which
carries 45 CATS credits at Level 3 (Final Year Undergraduate).
Specially written course reader
Course textbooks and tapes
Journal articles and other materials
One day workshops
University staff support
The cost of each course is £615
For further information please contact Janet Buckingham or
Dr. Steve Mera
Tel: (0113) 283 5918 or fax (0113) 283 3124 or
E-mail: [email protected]
BNA CHRISTMAS SYMPOSIUM 2001
FROM BENCH TO BEDSIDE:
ADVANCES IN CLINICAL NEUROSCIENCE
A special afternoon symposium and evening discussion to explore
recent developments in this important field
WEDNESDAY 12TH DECEMBER, 2001
2.00pm - 7.00pm
AV Hill Lecture Theatre, Department of Physiology,
University College, London, Gower Street, WC1
Chaired by Nancy Rothwell and Raj Kalaria
John Sinden (ReNeuron Ltd) ‘What are the prospects for neural stem cell therapy in the CNS?’
Moira Brown (Glasgow) ‘Killer to cure? Herpes simplex virus in brain cancer therapy’
Jackie Hunter (GlaxoSmithKline) ‘Prevention, protection or promotion of repair - a perspective
of stroke therapies of the future”
Tipu Aziz (Oxford) ‘Surgical management of movement disorders’
Steve McMahon (London) ‘New treatments for pain: real, realisable or ridiculous’
Frank Walsh (GlaxoSmithKline) ‘Inhibitory molecules and their role in neuronal regeneration’
The BNA Awards for ‘Public Service’ and ‘Outstanding Contribution to Neuroscience’ will
also be presented during the afternoon. There will be a panel discussion in the evening,
followed by a ‘seasonal’ reception for everyone in the South Cloisters, UCL
Tickets are FREE to BNA members (£25 for non-members) but must be obtained in
advance from the BNA Conference Office. Email: [email protected] Tel: 0151 794
5449. Please state your BNA membership number (if known).
ANCR • VOLUME 1 NUMBER 5 NOVEMBER/DECEMBER 2001
been on Betaseron for a mean duration of 12 years. Although
this study includes only 15 patients, Prof Ebers stressed that it
was the first study to address the crucial question of effectiveness of interferon and that further studies were crucial. Only
MRI data was presented, the patients on long-term Betaseron
had a dramatic reduction in T2 lesion burden but absolutely no
change in the degree of brain atrophy (probably a better indicator of overall disability). I eagerly await the results of the
changes in the EDSS in these patients versus controls.
Newer treatments such as Mitoxantrone were also discussed. Mitoxantrone now has FDA approval in MS for patients
with increasing disability in SPMS or to decrease the relapse frequency in RR or SPMS. Although limited studies are available in
the effectiveness of mitoxantrone it is still widely used in
Europe. Unfortunately it can only be given short-term with a
lifetime accumulative dose of 140mgm2. Several posters demonstrated its relative safety and proposed effectiveness although I
was struck by the lack of controls used in these studies.
Results presented from a questionnaire on immunosuppressive treatment in MS was most striking for its low response rate
(27%). France had the highest number of MS patients having
been treated with immunosuppresants (32.5%), with Scandinavia
having the lowest levels (1.8%).The UK was towards the lower
range with 4.2% of MS patients receiving immunosuppressive
therapy. The most common drug to be used worldwide was
Azathioprine followed variably by Cyclophosphamide,
Mitoxantrone and Methotrexate.There was a call for the establishment
Immunosuppressive Therapy (ICIT) to create an order on
usage, and to organise clinical trials for these therapies.
A whole session was dedicated to bone marrow transplantation in MS. New control trials are beginning to study the effectiveness of bone marrow transplantations in severe MS.
Previous experience presented from Greece and the Czech
Republic indicated high mortality rates of between 2 and 5%
that raised the issue of the ethics behind such studies. Overall
MS patients who had received transplants had been in the EDSS
range of 6 to 8 and post transplant the majority had not further
significantly deteriorated. However neither had they improved.
Other sessions concentrated on rehabilitation and pathogenesis in MS. In brief, rehabilitation methods developed in stroke
patients such as stimulation or inhibition therapies may provide
relief for MS sufferers. Accumulating evidence demonstrates
both remyelination and remodelling occurs in MS indicating that
the adult CNS retains a certain degree of plasticity. My impression from these sessions was that MS contains several components, an early auto-immune phase precipitated by various
genetic or environmental aetiologies followed by a slow, uncharacterised neurodegenerative process with neuronal loss and
axonal damage. This would explain why immunomodulating
drugs may be effective in the early phase of MS but do not have
an impact on the long-term prognosis. It appears essential that
further long-term data on the effectiveness of the immunomodulators in MS is provided to ensure firstly the cost effectiveness
and secondly to establish whether by partially inhibiting the
immune phase they are not having long-term deleterious
Dr David A Cottrell,
Newcastle upon Tyne.
International Society of Neuroimmunology Sixth
3-7 September, 2001, Edinburgh, Scotland
he International Society of Neuroimmunology meets for an
international conference every three years.The fact that this
is only its sixth meeting betrays the novelty of the discipline of
neuroimmunology. But, as this conference revealed, it is expanding aggressively, straying far outside the traditional immunological domains of myasthenia gravis and multiple sclerosis into
degenerative diseases, epilepsy and movement disorders. For
instance, among the many presentations of unpublished work,
were two nice preliminary studies from Gavin Giovannoni's
(London, UK) group showing the presence of anti-basal ganglia
antibodies in 50/72 children with Tourette's syndrome and 19/20
patients with acute Sydenham's chorea (and none in appropriate
controls). Showing that such antibodies are pathogenic is the
next step and has never been more elegantly done than by Jack
Griffin's peripheral nerve group at Johns Hopkins, studying the
acute axonal motor form of Guillain-Barre, which is associated
with antibodies against the GD1a ganglioside. They implanted
hybridomas secreting anti-GD1a antibodies into normal mice
and found this causes Wallerian degeneration and some demyelination, without T cell infiltration. Another elegant study on the
pathogenesis of autoantibodies came from Robert Darnell,
(Rockefeller University, New York) on POMA (Paraneoplastic
Opsoclonus, Myoclonus,Ataxia syndrome) that is seen in association with gynaecological or small cell cancer. Antibodies from
patients with this syndrome bind to a novel family of proteins
called Nova, which are RNA binding proteins. Disruption of
Nova1 causes failure of alternative splicing of glycine inhibitory
molecules. So Nova-1 knock out mice show loss of inhibition of
motor neurons with symptoms similar to those seen in the
patients. Less secure is the pathogenic role of anti-glutamate 3
receptors in Rasmussen's encephalitis. Levite (Weizmann
Institute) has always proposed that these antibodies are patho-
ANCR • VOLUME 1 NUMBER 5 NOVEMBER/DECEMBER 2001
genic, for which she presented some tissue culture evidence. But
a group in Milan showed that such antibodies were found in 4/11
Rasmussen's patients with and 27/76 patients with nonRasmussen's epilepsy.
A major theme of this conference was the importance of
activated macrophages in some diseases. In particular, and this is
a relatively new concept, such primed macrophages have been
shown to cause damage without being part of a classical inflammatory lesion. For instance, Hugh Perry (Southampton) has
studied a model of prion protein scrapie disease in mice. Here
activated macrophages, but rarely lymphocytes, are found in the
brain. If these animals are exposed to LPS (mimicking a Gram
negative infection), these primed macrophages secrete excessive IL-1 and the animals have increased "sickness behaviour".
This may perhaps explain why the behaviour of patients with
degenerative diseases (in which one also finds primed
macrophages) deteriorates so much with intercurrent infections. J Mcarthur (Johns Hopkins) presented a hypothesis for
the pathogenesis of HIV dementia, based on the established
finding of activated monocytes (macrophages) in the peripheral
circulation. He suggested that these activated macrophages
crossed the blood-brain-barrier by diapedesis (that is by without BBB disruption) and there release inflammatory mediators,
which cause astrocytosis and neuronal death by apoptosis. But
they must also cause some reversible reduction in neuronal
function, as early HIV dementia may be partially reversed by
highly active retroviral therapy.
There was a refreshing friendliness and candour about this
meeting. For instance, Cedric Raine (Albert Einstein, New York),
President of the International Society of Neuroimmunology,
cheerfully took Hugh Perry to task about the use of the word
"inflammation" to describe immune responses consisting only of
© Bruno Vinent
activated macrophages in the absence of the lymphocytes and
neutrophils of the classic inflammatory response. The importance of this dispute is that physicians need to be educated that
not all that is described as "inflammatory" will respond to conventional immunosuppressants. There was polite tolerance of
idiosyncratic views, such as those of A Ebringer, from King's
College, who believes that spongiform encephalopathies are not
due to prion protein deposition but to acinetobacter infections
(associated also with multiple sclerosis, he claims).
Cedric Raine (left) outgoing President of the International Society and Angela
Vincent (right) who takes over the reins.
Adriano Aguzzi's (Zurich) group has done outstanding work
on the spongiform encephalopathies.At this meeting he reported that prion protein enters the body via the 'M' cells of the
intestinal epithelium. His group has shown that prion protein
infectivity is crucially dependent on the presence of B cells in
the periphery and the accumulation of prion proteins in the follicular dendritic cells of the lymphoid organs. Over-expression
of prion protein leads to an anti-B cell autoimmune response.
Aguzzi hypothesised that prion protein may enter and infect the
sympathetic nerves innervating these lymphoid organs and travel from there to the brain.As evidence his team have found that
sympathectomised mice have delayed infection.
This was Cedric Raine's last function as President of the
International Society of Neuroimmunology. He hands over the
reins to Angela Vincent (Oxford), part of the UK team (John
Greenwood, Sandra Amor, John Fazakerly, David Baker) who
organised this conference. The dynamic and exciting range of
talks at this meeting was a tribute to them both.
Alasdair Coles, Cambridge
Neuroscience for Clinicians 11 - The Scientific Basis of
September 3-5 2001, Cambridge, UK
he 11th Neuroscience for Clinicians meeting again allowed
neurologists in both clinical and academic posts to gain an
overview and insight into the latest developments in modern
neuroscience. The meeting was held in the beautiful surroundings of Jesus College, Cambridge, and attracted a wealth of
expert speakers, from both scientific and clinical backgrounds.
No less than nine professors spoke on their subjects of interest
over the three days.
The course was structured, incorporating development of the
nervous system, cell biology, mechanisms of neuronal signalling,
neural systems, cognition and neurodegeneration.We were also
reminded of the work of our predecessors in a wonderfully
entertaining history of neuroscience presented by Professor
Professor Copp from the Institute of Child Health opened
the meeting with an overview of the clinical disorders which
may result from aberrant neural tube development, closure or
neuronal migration. He went on to describe the role of folate in
prevention of spina bifida and also a folate-resistant form of
spina bifida, which may be ameliorated by manipulation of inositol and protein kinase C pathways.
Professor Parnavelas reviewed the migration of cortical pyramidal neurons and interneurons, followed by Dr Sarah Guthrie
discussing the range of axon guidance molecules involved in
chemo-attraction and repulsion of the neuronal growth cone. In
particular she presented her work on hepatocyte growth factor
and its role as a chemo-attractant factor within the developing
Olfactory Ensheathing Cells (OECs) are the only PNS cells
that can survive within the CNS, and as such are a source of
interest in the repair of damaged CNS neurons, in particular following demyelination. Dr Susan Barnett described the factors
and media which are required to allow proliferation and differentiation of these OECs into either Schwann cell-like or
Astrocyte-like cell lines.
Professor O’Keefe from University College London brought
techniques of cognitive science into the 21st century with the
description of virtual mazes based on computer games. Patients
with specific memory deficits were asked to explore this virtual world and were then tested on their recall of the features
within the maze. These experiments have shown the impor-
tance of the right hippocampus in “allocentric spatial memory”
ie the relationship of objects to each other, and the inferior
parietal cortex in “egocentric memory” ie the relationship of
objects to oneself.
The highlight of the meeting must be the presentation by the
Nobel prize winner Sir John Walker. He presented the discovery of the rotatory mechanism by which the enzyme “ATP synthase” functions in order to generate ATP. The accompanying
figure (below right) demonstrates the F1 subunit of ATP synthase in which there is rotation of the y-subunit relative to the
a,ß ring, driven by a flux of H+ down a proton gradient.
Dr Michael Hastings discussed the role of the genes ‘per’ and
‘cry’ responsible for the control of the circadian rhythmicity, in
particular their differential expression in response to light. He
discussed possible concerns relating to junior doctors who undergo
frequent changes in working
hours, and how disruption of circadian rhythms may affect performance.
In the field of neurodegeneration, Dr Tolkovsky described the
importance of the mechanism of
neuronal injury, which dictates
whether damage can be reversed
by the use of caspase inhibitors.
Professor Bates from King’s
College described the use of transgenic mice in Huntington’s disease, and the possible reversibility of both pathology and functional deficit that can be obtained
by manipulation of the abnormal gene.
Overall, this meeting yet again reinforced the importance of
basic science in the understanding of the brain and eventually
treatment of neurological disease, and was made special by the
high calibre of the invited speakers.As always Jesus College provided a delightful venue for the Annual NFC Dinner, and we are
grateful to Professor Compston who again organised this splendid occasion, and to the Guarantors of Brain who provided
sponsorship for the event.
Tom Foltynie and Meena Jain, Cambridge
ANCR • VOLUME 1 NUMBER 5 NOVEMBER/DECEMBER 2001
Deep Brain Stimulation in Parkinson’s Disease
With the realisation of the universal benefit of levodopa
the use of surgery in the treatment of PD was relegated
to the extreme periphery of PD management. However
despite the overwhelming benefit of levodopa and
dopamine agonists in the management of early stage
PD, a need for good treatment later in the disease to
relieve some of the complications of treatment and
symptoms due to the progression of the disease is
required. Surgical treatment has therefore been reconsidered in patients with advanced PD. But this reconsideration occurs with far greater understanding of the
circuitry involved in developing the symptoms in PD
and technical advances in stereotactic neurosurgery
and implantable electrically active devices. Currently
surgical intervention involves either surgical destruction
or electrical stimulation, which is less destructive and
partially reversible on stopping stimulation. Two sites
for surgical manipulation have emerged as being reasonably safe and beneficial in preliminary studies, the
globus pallidus pars interna (GPI) and the subthalamic
nucleus (STN), whilst thalamotomy has fallen by the
wayside because of comparative lack of global benefit.
Thalamotomy has beneficial effect in treating tremor
but none of the other features of PD.
This multi centre study involving most of the significant centres and figures involved in PD research
assessed the benefit of bilateral stimulation of either the
STN (n=96) or the GPI (n=38) in patients with
advanced PD (UPDRS between 40 and 70), in a
prospective, limited double blind crossover study.
Because the design did not involve randomisation
direct comparisons between these two groups was not
possible. Not all of the assessments were strictly blinded and crossover does not mean that electrodes were
exchanged between the STN and GPI but rather that
the stimulators were turned on and off in different
sequences at times of assessment which occurred preoperatively, at 3 months and at 6 months. For STN
stimulation at 3 months the median motor score
improved 49% (p<0.001) and time in the on state at six
months improved from 27% to 74% (p<0.001). For the
stimulation in the GPI motor score improved 37% and
time spent in the on improved from 28% to 64%
(p<0.001for both comparisons). Furthermore significant improvement in activities of daily living, tremor,
dyskinesia were recorded for both techniques and
rigidity and bradykinesia in the STN technique.
Overall intracranial haemorrhage occurred in 7
patients and infected leads in 2 patients. The overall
significant benefit of bilateral stimulation of the STN
and GPI should translate into increased use of these
techniques (with a suggestion of better effect in STN
stimulation) but the underlying mode of action still
needs to be defined. -TH
Deep brain stimulation of the subthalamic nucleus or
the pars interna of the globus pallidus in Parkinson’s
The Deep Brain Stimulation for Parkinson’s Disease
Panel of Reviewers
Roger Barker, Honorary Consultant in Neurology,
Cambridge Centre of Brain Repair
Alasdair Coles, Wellcome Advanced Fellow, Dunn School of
Pathology, Oxford and Dept of Neurology, Cambridge
Tom Foltynie, Neurology Research Registrar, Cambridge
Tarek Gaber, Specialist Registrar in Rehabilitation, Lewin
Rehabilitation Unit, Cambridge
Richard Hardie, Consultant Neurologist and Director of
Neurorehabilitation, St George's & Atkinson Morley's
Tim Harrower, Wellcome Clinical Research Fellow and
Honorary Neurology Clinical Fellow, Addenbrooke’s Hospital
Andrew Larner, Consultant Neurologist, Walton Centre for
Neurology & Neurosurgery, Liverpool
Simon J G Lewis, Honorary Clinical Research Fellow,
Cambridge Centre for Brain Repair
Mark Manford, Consultant Neurologist, Addenbrooke's
Hospital, Cambridge, and Bedford Hospital
Peter Martin, Consultant Neurologist, Addenbrooke's
Brian McNamara, SpR in Clinical Neurophysiology,
Addenbrooke's Hospital, Cambridge
Jane Mickelborough, Research Fellow, University of Salford
Fiona Ritchie, Speech & Language Therapist, Oliver
Zangwill Neurorehabilitation Unit, Ely
John Thorpe, Addenbrooke's Hospital, Cambridge, and
Ailie Turton, Research Fellow, Burden Neurological Institute,
For more information on joining our panel of reviewers,
E-Mail [email protected] or Tel. Rachael Hansford
on 0131 477 2335.
ANCR • VOLUME 1 NUMBER 5 NOVEMBER/DECEMBER 2001
Would you like to join
our panel of reviewers?
We are looking for reviewers to scan the
following journals on a regular basis and
provide short summaries and comment
on interesting papers from:
European Journal of Neurology
Journal of Neurology
If you have access to any of the above
journals and would like to get involved,
please contact Rachael Hansford on
Tel. 0131 477 2335,
Fax. 0131 313 1110,
E-Mail. [email protected],
stating which journal you would prefer.
HIV and motor neuron disease
In 1985, a NEJM report first speculated on an association
between HIV infection and a disorder that resembled amyotrophic lateral sclerosis (ALS). This paper is the fullest
description yet of this syndrome and makes a strong case
for a real association. It is based upon a huge personal
series of HIV neurology cases. Antoine Moulignier, from a
Tropical Diseases unit in Paris, has seen 1700 patients with
neurological syndromes due to HIV from 1987 to 2000.
Six of these had an ALS like syndrome. All were very comprehensively investigated for alternative causes (to the
extent of bone marrow aspirates for occult lymphoma, for
instance). All patients had low CD4+ counts (86/ml on
average) and a detectable serum HIV load. In three
patients the CSF viral load was measured and was high. 5
patients presented with involvement of only one limb, but
there was progression to other sites shortly thereafter.
Physical and neurophysiological examination was entirely
typical for ALS, satisfying El Escorial criteria. However the
patients were younger (mean age 34) and had more
rapidly progressive syndromes than wild-type ALS. The
direct association with HIV infection is best illustrated by
the response to anti-retroviral treatment: two patients
improved and two others returned to normal, but subsequently the ALS symptoms re-emerged as CD4+ counts
began to drop again. The pathogenesis of this syndrome is
obscure; the authors have excluded a known opportunistic
infection and HIV is not found in motor neurons.
In the same issue of Neurology there is a case report from
New York of a 32 year HIV positive old woman with an
ALS syndrome that resolved completely on antiretroviral
treatment and remained well four years later. -AJC
Moulignier A, Moulonguet A, Pialoux G, Rozenbaum W.
Reversible ALS-like disorder in HIV infection.
2001 Sep 25;57(6):995-1001
MacGowan DJ, Scelsa SN, Waldron M.
An ALS-like syndrome with new HIV infection and complete response to antiretroviral therapy.
2001 Sep 25;57(6):1094-7
Five year sequelae of infant meningitis
Meningitis in childhood has its highest incidence during the
first year of life and much is known about its immediate
mortality and morbidity. However, there is a paucity of reliable data from large prospective studies on the longer-term
outcomes of this infection.
In this study, Bedford et al have conducted a detailed
analysis of the sequelae occurring in a cohort of children
aged 5 years who suffered meningitis during the first year
of life. They identified children who were diagnosed with
meningitis in infancy from a prospective national study carried out in England and Wales between 1985 and 1987.
In addition they identified a cohort of matched controls and
targeted general practitioners and parents with detailed
questionnaires about the children’s health and development.
In total 1584 children who had suffered meningitis in
infancy and 1391 controls were included in this research.
The results showed that meningitis in infancy has serious
consequences. Of those cases surviving the acute attack,
2% died before the age of 5 years. In those children surviving to 5 years there was a 10-fold increase in the risk of
severe or moderate disability compared to the control
group. This was reflected in the significantly higher frequency of neuromotor disabilities, seizure disorders, hearing problems, ocular or visual problems, speech or language problems, behavioural problems and the increased
need for non-mainstream schooling. Furthermore, neuromotor and seizure disorders were significantly higher in
those children diagnosed as having meningitis during the
neonatal period compared to those diagnosed after the
first month of life. Disability also seemed to relate to the
causative organism, with Streptococcus pneumoniae having worse outcomes compared to Haemophilus influenzae
and Neisseria meningitides infection.
This study confirms the severity of this disease and its
longer-term sequelae, raises clinical awareness and should
assist in prognosis in such cases. It is also important to note
that since these cases were identified, clinical management
has probably changed with third generation
cephalosporins now forming the mainstay of acute treatment, as opposed to the previous regimes, which would
have seen a much greater use of penicillin and chloramphenicol. Thus a future study may serve to illustrate effectiveness of treatment in this relatively common condition. SL
Meningitis in infancy in England and Wales: follow up at
Bedoford H, de Louvois J, Halket S, Peckham C, Hurley R,
BRITISH MEDICAL JOURNAL
Probably pathological protofibrils
Put simplistically, there are two conflicting theories as to the
pathogenesis of Alzheimer’s disease: the accumulation of
amyloid ß-peptide into amyloid deposits or the presence of
excessive tau. The former has gained considerable support
from the finding that some mutations in the amyloid precursor protein (APP) cause rare familial forms of
Alzheimer’s. APP is a large molecule, which is cleaved by
three enzymes (a,ß,y-secretase) to give the smaller amyloid
ß-peptide, which is normally 40 amino acids long. The
presenilin mutations disrupt APP processing close to the ysecretase site and cause overproduction of an elongated
form of amyloid ß-peptide, called Aß42. These peptides
form fibrils and accumulate into the senile plaques characteristic of Alzheimer’s. An intermediate form of fibril formation is known as protofibrils; they may themselves cause
neuronal death. Similar protofibrils are formed by a-synuclein in early onset familial Parkinson’s disease.
Curiously, mutations within that part of the APP gene
encoding for the amyloid ß-peptide itself (such as the Dutch
mutation) tend to give cerebral amyloid angiopathy rather
than Alzheimer’s disease. However a Swedish group has
described, for the first time, such a mutation that does
cause familial Alzheimer’s without the features of amyloid
angiopathy. They have nicknamed it the Arctic mutation
(because it is found in kindreds in northern Sweden). At
first glance, the biology of the Arctic mutation seems to
buck the trend. Patients with this mutation have reduced
levels of Aß42 in their serum. So how do they develop
Aß42 amyloid plaques? It turns out, from this elegant
study, that the mutation accelerates the rate at which Aß42
forms protofibrils and hence excessive Aß42 deposition.
ANCR • VOLUME 1 NUMBER 5 NOVEMBER/DECEMBER 2001
There are drugs that can reduce protofibril formation.
Would they help the Arctic patients? Much more critically,
have the authors discovered a general mechanism of
Alzheimer’s and Parkinson’s disease toxicity -and therefore
a therapeutic target? -AJC
Nilsberth C, Westlind-Danielsson A, Eckman CB, Condron
MM, Axelman K, Forsell C, Stenh C, Luthman J, Teplow
DB, Younkin SG, Naslund J, Lannfelt L.
The ‘Arctic’ APP mutation (E693G) causes Alzheimer’s
disease by enhanced Abeta protofibril formation
A clinical trial of coenzyme Q10 and remacemide in
Huntington’s disease (HD) is an inherited disorder in which
the expression of mutant huntingtin leads to selective neuronal loss, especially in the striatum. As a result patients
present typically in middle-age with a combination of
abnormalities including a movement disorder, cognitive
decline and psychiatric problems. At the present time treatments are symptomatic and there are no therapies that are
known to affect the natural history of this condition,
although several possible candidate treatments are emerging from laboratory based work using transgenic mouse
models of HD. The Huntington Study Group (HSG) in the
US involves 43 centres and over 200 personnel and by
recruiting large cohorts of patients aims to address questions of disease progression, presentation and therapy.
This recent publication is the result of a trial in which 247
patients with early HD were recruited and randomised to
receive either coenzyme Q10, remacemide hydrochloride,
both or neither. The patients were then followed over a 30month period with regular assessments to see whether
these agents slowed the natural progression of the disease.
Both drugs were selected following small pilot studies and
based on the rationale that they should, relatively nonselectively, protect cells from stressful insults. At the conclusion of the study both drugs were well tolerated but neither
had significantly altered the decline in disease, using the
total functional capacity (TFC) measure of the UHDRS.
However there was a trend to a slowing of TFC with coenzyme Q10 therapy. Whilst this was modest and not significant, it did suggest that this drug in combination with others may be capable of significantly slowing this condition,
and is the first study to show any such effect. Thus this study
will not alter our practice in HD, but does herald a new era
in the approaches to treating this fatal condition.
A randomized, placebo-controlled trial of coenzyme Q10
and remacemide in Huntington’s disease.
The Huntington study Group
TRANSCRANIAL MAGNETIC STIMULATION
As good as a kick in the head?
There has been an explosion in the use of transcranial
magnetic stimulation to investigate cognitive function. The
technique is roughly the same in most of these studies, you
ask the subject to perform a particular task, you attempt to
ANCR • VOLUME 1 NUMBER 5 NOVEMBER/DECEMBER 2001
turn off the bit of brain that you are interested in by applying TMS and you see how well the subject performs at that
task. Obviously these sorts of study complement neuroimaging techniques neatly, area X lights up during a task,
so inhibiting area X with TMS ought to impair performance. The study by Mull and Seyal is fairly typical of the
genre. They were directed to the role of the frontal cortex
in working memory by results of PET, fMRI and spatial EEG
studies. The patients were asked to perform a simple working memory task, a single pulse was then applied to the
frontal region during the task, the authors found that the
number of errors increased when TMS was applied to the
left frontal area but not when the TMS was applied on the
right. Unfortunately this paper is riddled with methodological errors, for instance control experiments were performed in the absence of TMS. Anybody who has had TMS
will tell you that the noise and muscle twitch induced by
TMS is enough to induce errors in any task. This type of
experiment should be properly controlled with some form
of ‘sham’ TMS. Similar errors taint much of the TMS literature; some of the results should be taken with a very large
pinch of salt. However with more rigorously controlled
studies TMS will be a useful tool for investigating cognitive
function and a nifty foil to neuroimaging techniques.
Mull BR, Seyal M.
Transcranial Magnetic Stimulation of Left Pre-frontal
Cortex Impairs Working Memory
2001: 112 1672-1675
Hot Heads After Acute Brain Injury
In experimental models of ischaemic brain damage, cooling the brain improves outcome. Slowing down cerebral
metabolism is presumed to be neuroprotective, and there is
also evidence in acute stroke and traumatic brain injury
(TBI) patients that hyperthermia correlates with poorer outcome. Avoiding fever is therefore generally advocated and
accepted as a good thing, but direct clinical evidence of
interventional efficacy is conflicting, perhaps because standard core body temperature has been measured. Rossi
and colleagues from a Neurosciences ITU in Milan have
studied differences between actual intracerebral (ICT) and
core temperature (Tc) using very accurate thermistors
mounted on intraventricular and Swan-Ganz catheters
respectively. They correlated these with intracranial pressure (ICP) in a group of 20 patients mostly with either
severe TBI or aneurysmal subarachnoid haemorrhage.
They found not only that fever was extremely frequent but
also that ICT was nearly always significantly higher than
Tc. ICT was also more closely correlated with increases in
ICP, and there was some evidence using intra-jugular oxygen saturation monitoring that this was less related to
changes in cerebral metabolism than in cerebral blood
flow itself. It remains to be tested whether avoiding rises in
ICT will improve outcome, but perhaps keeping a cool
head really is good for you, after all. - RJH
Brain temperature, body core temperature, and intracranial pressure in acute cerebral damage.
S Rossi, E Roncati Zanier, I Mauri, A Columba, N
JOURNAL OF NEUROLOGY, NEUROSURGERY &
One Lump or Two?
As every medical student knows, diabetes mellitus is one of
the more common causes of neuropathy so a fasting or
random blood glucose level is essential to the investigation
of any neuropathy. There is also a group of patients who
do not have frank diabetes mellitus but are labelled with
what is known as impaired glucose tolerance. The precise
definition of these entities tends to get diabetologists very
hot under the collar. My layman’s understanding of
impaired glucose tolerance is that it includes patients with
a normal blood glucose but an impaired response to a glucose load. So has this got anything to do with neuropathy?
There are two studies in September’s Muscle and Nerve
that suggest that perhaps it does. The first (Singleton et al.)
was a retrospective study that examined the records of 121
patients with idiopathic polyneuropathy, 25% of these
patients fulfilled the definition of impaired glucose tolerance. Interestingly these patients tended to have a painful
sensory neuropathy. A second similar study (Novella et al.)
looked sequentially at patients who presented to a neuromuscular clinic with idiopathic polyneuropathy, 50% of
these patients had some form of impaired glucose tolerance, 27% met the criteria for impaired glucose tolerance.
Again these patients tended to have a painful sensory neuropathy. These studies leave plenty of unanswered questions, for instance how common is neuropathy in impaired
glucose tolerance? However there is a fairly simple take
home message, if there are no obvious causes of neuropathy it is worth doing an oral glucose tolerance test, after all
it is an inexpensive and non-invasive test. -BMcN
Singleton JR, Smith G, Bromberg MB. Painful sensory
polyneuropathy associated with impaired glucose tolerance. MUSCLE AND NERVE 24, 1225-1229
Novella SP, Inzucchi SE, Goldstein JM. The frequency of
undiagnosed diabetes in patients with idionpathic sensory neuropathy.
MUSCLE AND NERVE
A new treatment of Guillain Barre: CSF filtration
None can deny the need for an improved treatment of
Guillain-Barre; even with best management, some 10% of
patients are unable to walk a year later. This group, from
Ulm in Germany, have compared CSF filtration with plasma exchange in a randomised clinical trial of 37 patients.
CSF is filtered by withdrawing 30 to 50 mLs CSF through
a spinal catheter and then reinfused through a filter. At
each session, this withdrawal and reinfusion is repeated up
to six times. Such sessions are repeated for 5-15 consecutive days. There was no difference in clinical efficacy
between the two treatments; six months on, 80% in each
group could walk more than 5 metres unaided. CSF filtration was better tolerated; there was one case of pulmonary
oedema and one of hypovolaemic shock in the plasma
The investigators originally planned 40 patients in each
study arm, but as IVIG became increasingly available
recruitment tailed off and they had to stop the study prematurely. For this reason, the numbers are small and this
study should not change practice. But it is interesting to
speculate on how CSF filtration might be working. The
autoimmune response in Guillain Barre is believed to be
generated in the periphery and directed against peripheral nerve or root antigens. There is no evidence for intrathecal antibody synthesis. So why should sieving CSF help? In
a Nature Medicine article last year, the same group
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ANCR • VOLUME 1 NUMBER 5 NOVEMBER/DECEMBER 2001
described a CSF pentapeptide, QYNAD, that blocks sodium channels and thereby blocks neuronal conduction. They
showed in this study that CSF filtration transiently reduced
CSF levels of QYNAD. All very intriguing. -AJC
Wollinsky KH, Hulser PJ, Brinkmeier H, Aulkemeyer P,
Bossenecker W, Huber-Hartmann KH, Rohrbach P,
Schreiber H, Weber F, Kron M, Buchele G, Mehrkens HH,
Ludolph AC, Rudel R.
CSF filtration is an effective treatment of Guillain-Barre
syndrome: A randomized clinical trial
2001 Sep 11;57(5):774-80
Epilepsy surgery: Research uses of the waiting list
How do you do a randomised study to prove the worth of
surgery for temporal lobe epilepsy, when everyone knows
it works and you cannot ethically randomise patients to no
surgery? Normally it takes a year to work patients up for
surgery. The authors split patients into two groups. A: standard workup then surgery after a year. B: fast-track with
surgery within 4 weeks. The groups were compared over
the next year: prior to surgery for group A and after
surgery for group B. This gets round the problem of randomising patients to no surgery although follow-up is
In group A 8% became free of seizures impairing consciousness compared to 58% in postoperative patients.
This, in fact, is less good than other non-randomised postoperative studies of temporal lobe epilepsy surgery. There
were four post-operative complications, but only one
death, a sudden unexplained death in a patient in the
delayed surgery group. This study provides strong support
for the role of temporal lobe epilepsy surgery in selected
patients, but it is perhaps the design of the study that is
particularly intriguing and may be applicable to other surgical techniques, especially in the NHS! - MM
Wiebe S , Blume WT , Girvin JP , Eliasziw M for the effectiveness of surgery for temporal lobe epilepsy study
A randomized controlled trial of surgery for temporal
NEW ENGL J MED 2001;345:311-8
Calcium Channel (P/Q type) mutation linked to a
form of human epilepsy
As the field of channelopathies expands for the first time a
human form of epilepsy has been associated with a mutation on the gene encoding the alpha 1 subunit of the voltage gated Calcium channel, which is found on chromosome 19. To date spontaneously arising murine mutations
have been described with mutations in this gene which represent models of human absence epilepsy but up till now
no human mutations in this gene have given rise to epilepsy but have rather been described as giving rise to familial
hemiplegic migraine and episodic ataxia type 2. The case
in which this mutation has been described has a complex
phenotype with primary generalised epilepsy, episodic
and progressive ataxia and mild learning difficulties. The
mutation produces a stop codon producing complete loss
of the C terminal, which is required for bind to the other
sub-units which together usually form the pore region of
this Ca Channel. The patient was found to be heterozygous
for this mutation as all other described human Calcium
ANCR • VOLUME 1 NUMBER 5 NOVEMBER/DECEMBER 2001
channel (CACNA1A) mutations. This mutation was not
found in the parents (paternity confirmed genetically) or
200 healthy controls and the patient is the only child so
other cases as yet have not been described. Using sophisticated expression studies the role of the mutation in causing Ca Channel malfunction was confirmed. Furthermore
this effect was defined as being a dominant negative effect.
The importance of the ion channels in basic neurological
function is once again underlined and the role of drugs
modulating the function of these channels may provide
new avenues of treatment for some cases of epilepsy. - MM
Human epilepsy associated with dysfuntion of the brain
P/Q-type calcium channel.
AnneJouvenceau, Louise Eunson, Alexander Spaushus,
Venkataswaran Ramesh, Sameer Zuberi, Dimitri
Kullmann, Michael Hanna
Diagnostic criteria for multiple sclerosis
This paper presents the conclusions of the International
Panel on Multiple Sclerosis (MS) Diagnosis, convened in
London in July 2000. This is the first major review of MS
diagnostic criteria since those of Poser et al. with which
most neurologists will probably be familiar if not conversant, which were published in 1983 when use of MRI was
still in its infancy.
The importance of demonstrating dissemination of
lesions in time and space is reaffirmed, using either objective clinical evidence (symptoms alone are not enough), or
clinical and supporting paraclinical evidence (MRI, CSF,
VEP), the latter obtained using the highest quality, state-ofthe-art technology. Specific MR imaging criteria, absent in
Poser, are presented. Although the diagnosis can be made
on clinical grounds alone (i.e. two or more attacks with
objective clinical evidence of two or more lesions), more
stringent additional criteria apply as the clinical evidence
becomes weaker. Hence in clinically isolated syndromes
(monosymptomatic presentation), the diagnosis of MS
requires demonstration of dissemination in space (MRI,
MRI + CSF) and time (2nd attack, clinical evidence of a
second lesion). The diagnosis of primary progressive MS
remains problematic, requiring evidence of dissemination
in space (MRI, MRI + VEP) and time (MRI, clinical progression of disability over 1 year). No better explanation for
the clinical and paraclinical abnormalities must be available.
The outcome of using these criteria will be a diagnosis of
MS, “possible MS”, or “not MS”. Terminology familiar
from the Poser criteria (e.g. clinically definite, laboratory
supported) is dropped. The criteria aim to be of use to the
practising physician as well as for research purposes. It
seems likely that they will be widely accepted and supersede the Poser criteria.-AJL
McDonald WI, Compston A, Edan G et al
Recommended diagnostic criteria for multiple sclerosis:
guidelines from the International Panel on the Diagnosis
of Multiple Sclerosis
ANNALS OF NEUROLOGY 2001;50(1):121-127
Stereotactic surgery for tremor in multiple sclerosis
Many neurologists will have experienced the frustrating
sense of therapeutic impotence when attempting to treat
disabling tremor in patients with multiple sclerosis (MS).
Although a number of drugs have been tried, such as
carabamazepine, clonazepam, isoniazid, ondansetron,
primidone and propranolol, and even limb weights, lack of
meaningful benefit is not infrequent. Stereotactic surgery
has also been used, intermittently, for many years in this
situation, but few good prospective studies have been conducted, a deficiency partially answered by the current
study. Of 46 MS patients assessed, 33 (= 72%) were
excluded from surgery for various reasons. In the surgical
group (n = 13), stereotactic lesions were made in the thalamus, zona incerta or subthalamic nucleus.
Assessments made 3 and 12 months postoperatively
showed attenuation of contralateral upper limb postural
and kinetic tremor in all cases, irrespective of lesion site,
and in head tremor. Total tremor suppression was seen if
preoperative tremor frequency was > 3Hz, but total suppression was never seen if tremor frequency was ≤ 3Hz. By
1 year, 7/11 survivors had reduced tremor-related disability.
Surgery was associated with significant morbidity: postoperative hemiparesis, seizures, fatigue, increased bladder dysfunction, and depression were reported. However,
compared to control patients matched for duration and
severity of MS (but not necessarily with tremor), there was
no significant difference in the rate of disease progression
at 3 and 12 months postoperatively.
Although numbers are small, and patient assessments
were not blinded, nonetheless this is a significant study
showing that stereotactic lesional surgery can be beneficial
for MS tremor, but only for highly selected patient groups.
Moreover surgery is not without concurrent morbidity, but
this may be minimised, as selection criteria for the procedure are refined. It seems likely that stereotactic surgery
will become part of the standard therapeutic approach to
tremor in multiple sclerosis.-AJL
Alusi SH, Aziz TZ, Glickman S, Jahanshahi M, Stein JF,
Stereotactic lesional surgery for the treatment of tremor
in multiple sclerosis. A prospective case-controlled study.
Levodopa boosts the effects of physiotherapy after
Enhancement of motor recovery may be brought about by
an increased concentration of norepinephrine in the central nervous system. Animal models of stroke and some
small clinical trials have shown that treatment with amphetamines, whose action is to release norepinephrine, is effective in improving motor recovery when combined with
training or physiotherapy. However there seems to be little
impetus in the UK for larger scale trials leading to their use
in clinical practice.
Reluctance to use amphetamines may be because of the
risk of physical and psychological dependence or because
of potentially dangerous cardiovascular side effects. Is
there a way to increase norepinephrine safely? A group in
Munich have successfully tested a potential solution.
Instead of amphetamine, Levodopa in combination with a
decarboxylase inhibitor is used. Given orally, it is
metabolised to dopamine in the brain and converted to
However in the periphery metabolism of the norepinephrine is blocked by the decarboxylase inhibitor that
does not cross the blood-brain barrier.
53 patients were enrolled to a randomised double blind
trial. They were given single doses of 100mg levodopa or
placebo before every session of physiotherapy for three
weeks. For the following 3 weeks they had physiotherapy
without drug intervention. At the start of treatment the two
groups were similar except in side of stroke. A greater proportion of patients with right hemisphere strokes were in
the placebo group.
Motor recovery was measured using the Rivermead
Motor Assessment and was found to be significantly better
after 3 weeks of levodopa than placebo intervention. The
advantage was maintained at the end of the study, 3 weeks
after levodopa was stopped.
These results are very promising. In their report the
group put forward a number of possible mechanisms for
levodopa’s beneficial influence on recovery. Further work is
needed to identify how it works. In the future will this
method prove be an acceptable way to boost the effects of
physical therapy? -AJT
Effect of Levodopa in combination with physiotherapy on
functional recovery after stroke: a prospective, randomised, double-blind study.
Scheidtmann K, Fries W, Muller F, Koenig E.
2001: 358 September 8,2001: 787-790
Complimentary Journals Reviewed
We would like to thank the following publishers who have provided us with complimentary review subscriptions to their journals. For
subscription details please contact the relevant publisher direct.
Cerebrovascular Diseases, Neuroepidemiology
S. Karger AG - Medical and Scientific Publishers,Allschwilerstrasse 10, CH - 4009 Basel, SWITZERLAND.
Tel. 0041 61 306 11 11, Fax. 0041 61 306 12 34, E-Mail. [email protected] www.karger.com
Oxford University Press, Great Clarendon Street, Oxford, OX2 6DP. Tel. 01865 267154, Fax. 01865 267985.
Clinical Rehabilitation, Multiple Sclerosis
Arnold, 338 Euston Road, London NW1 3BH. Tel. 020 7873 6339, Fax. 020 7873 6325,
ANCR • VOLUME 1 NUMBER 5 NOVEMBER/DECEMBER 2001
If you would like to review books for ACNR, please contact Andrew Larner, Book Review Editor,
c/o [email protected]
Stroke: A Practical Guide To Management 2nd Edition
It is five years since the first edition of this benchmark
book hit the scenes. Benchmark because it was a comprehensive textbook of cerebrovascular disease written
by a close group of authors combining neurological, radiological and gerontological skills with pragmatism and
common sense. The second edition is no different and is
What makes this book so important is the clarity and
structure with which it is written. The style is such that
the reader could believe it is the writings of one individual, not seven, for it is not a book made up of individual
chapters written by different contributors. The constant
honing of all parts of the book until a consensus was
reached was certainly worthwhile.
Approximately 800 pages and 18 chapters long, with
clear text, tables, line drawings and photographs, the
book can either be used for reference or for education
and the personal development of a questioning
approach to every vascular case one might come
across. Rather than encouraging medicine by recipe the
authors use their commanding knowledge of the clinical
encounter and the weight (or sometimes lack of it) of evi-
dence to enable the reader to make sensible clinical
Much of the fabric of the book (for example the sections describing clinical features, pathology etc) remain
little changed but sections on treatments (post IST and
post NINDS and ECASS thrombolysis trials) are updated. Given that five of the seven authors are neurologists
one might have anticipated a slightly more comprehensive section on unusual causes of ischaemic stroke and
cerebral venous thrombosis but I appreciate that far
more readers of the book will be stroke physicians than
stroke neurologists. The reader will also find copious references to take a topic further if necessary.
This book should be open on the desk (rather than
hidden on a shelf) of all of us who see patients with cerebrovascular disease as a constant reminder to keep asking ourselves "What sort of stroke is it? What am I going
to do about it? What caused it? How can I stop it happening again?"
Authors: C P Warlow, MS
Dennis, J Van Gijn, G J
Hankey, PAG Sandercock, JM
Bamford, J M Wardlaw
Published by: Blackwell
ISBN No: 632054182
The Year in Neurology 2001
It is not possible for one person to read all the literature
on a single neurological disease, let alone for the practising neurologist to keep abreast of developments
across a range of diseases. For instance in the last eighteen months there have been (to consider some of the
diseases covered in this book) 2129 papers relevant to
multiple sclerosis, 2585 to Parkinson's disease, 4707 to
Alzheimer's and 5171 to epilepsy (according to
PubMed). Perhaps the best solution to this problem is a
publication such as ACNR, which regularly provides
reviews of major journals in the field. Another is the
annual "digest" of important papers selected by a team
of experts, such as this book. It has been developed, the
publishers say, "to provide the reader with a concise
focused resource of recent developments in the field"
and promises to be the first of an annual series. The
experts chosen to review the literature are
mainly from the UK and will be reasonably
familiar to those in their field. Their reviews
are presented attractively in a format that is
convenient for both reference and idle browsing. Each disease takes up a chapter, which
consists of a brief overview followed by literaKeeping
Massimo Feliciani, “La
ture reviews arranged into sensible
Up To Date
subtopics. Each chosen study is reviewed
Rome, Italy • Simon
briskly, to a set template that clearly distinLovestone, Institute of
guishes findings from interpretation.
Psychiatry, London, UK •
One can argue over the balance of the
Niall Quinn, Anette Schrag &
chapters: that on cervical dystonia is twice as
Matthew Walker, Institute of Neurology,
long as that on multiple sclerosis for instance.
London, UK • Tom Warner, Royal Free
And the reader looking for the most up-toHospital, London, UK • John Zajicek,
date account will be disappointed. Although
Derriford Hospital, Plymouth, UK
published in November 2001, there are no
contributions from the 2001 literature; all the
As the amount of published research
papers reviewed are from late 1999 to 2000.
in neurology increases, it becomes
This time lag is of course a problem with all
extremely difficult to keep up to date
book publishing (and where journals such as
with all the latest developments. The Year in
ACNR have the advantage). However this
Neurology alleviates this problem by encapsulating everything that
book has been produced remarkably rapidly,
the busy clinician needs to know, in one volume. This title offers you:
compared to many recent neurology texts; for
• Evaluation and critical
• Key papers for practice identiinstance the content of Clinical Trials in
appraisal of the full range of
fied and summarised
Neurology, edited by Roberto Guiloff and
recently published literature
published in 2001, was written in 1997. This
• The experience of several of
in the field
slight publication lag is a reasonable price to
the world’s leading centres of
pay for an accessible and authoritative distil• Single user-friendly volume
excellence in the field
lation of the recent neurological literature;
To order, or for further
and at £49.50 (US$80) has to be considered
Part 1: Cervical Dystonia
information on this, or our other
titles, please contact:
The Year in Neurology 2001
Part 2: Parkinson’s Disease
Part 3: Epilepsy
Part 4: Alzheimer’s Disease
Part 5: Multiple Sclerosis
ISBN: 0-9537339-5-5 • 325 pp
Illustrations • Hardback
Published September 2001
Clinical Publishing Services Ltd.,
Oxford Centre for Innovation,
Mill Street, Oxford, OX2 0JX, UK
Tel: +44 (0) 1865 811116
Fax: +44 (0) 1865 251550
Email: [email protected]
ANCR • VOLUME 1 NUMBER 5 NOVEMBER/DECEMBER 2001
Authors: Feliciani, M;
Lovestone, S; Quinn, N;
Schrag, A;Walker, M;Warner,
T; Zajicek, J.
Published by: Clinical
Publishing Services Ltd
ISBN No: 0-9537339-5-5
WIN A COPY OF THIS TITLE
For more information see reverse of
the reader enquiry sheet included with
S AV E O N T H E N E U R O LO G Y T I T L E S YO U N E E D
W I T H LW W & A C N R
ATLAS OF ADULT ELECTROENCEPHALOGRAPHY
Advances In Neurology, Volume 88
Warren Blume, MD & Masako Kaibara, MD,
Electroencephalography (EEG) is the study of brain electrical
activity and remains the primary diagnostic tool for epilepsy &
seizure disorders. These disorders are the most common neurological disease as they affect over a million individuals.
Thoroughly revised and updated, this atlas remains a “must have” for anyone performing
or interpreting EEGs in adults. This new edition shows readers how to maximise the usefulness of digital EEG and also features a special horizontal format, digital EEG and
expanded coverage of subdural EEG and EEG in the ICU and 500 clear as well as easy to
read EEG samples.
0-7817-2996-3 • 500 illus. • November 2001 • Hardback • 550 pages
Normal Retail Price: £120.00
LOCALIZATION IN CLINICAL NEUROLOGY
Paul W. Brazis, MD, Joseph C. Masdeu, MD
& Jose Biller, MD,
Clinical localization comprises a series of examination techniques
where clinical signs and symptoms are used to determine the
anatomical location of neurological disease. This updated fourth
edition is still the most practical reference available on localization
in clinical neurology.
Revised in it’s format the book now includes more tables and illustrations to aid in accurate diagnosis as well as a more didactic approach to the emphasis of the importance of
localization as a crucial tool in patient care. This is a “must have” book for neurologists,
residents in training and for the shelf of every neurology department library since the
book features concise but systematic explanations, easy to understand explanation of difficult concepts as well as full coverage of neurological signs ranging from obscure to the
most common. Also there are now more tables and figures, a new introductory chapter
and also a comparison of localization and imaging for accurate diagnosis.
0-7817-2843-6 • 100 illus. • September 2001 • Hardback • 512 pages
Normal Retail Price: £102.00
Rahman Pourmand, MD & Yadollah Harati, MD,
Neuromuscular disease is a major subspeciality within neurology and includes muscular
dystrophy, myasthenia gravis, amyotrophic lateral sclerosis, diabetic neuropathy and other
diseases. Some of these illness are rare while others more prevalent.
Together neuromuscular disorders account for half a million cases of neurological disease.
This volume explains the recent breakthrough in a way that is clinically relevant. The book
will be based on a symposium; with contributors being invited by the editors to contribute. All chapters will include sections on scientific advances, practical applications,
treatment strategies and future directions. The book will feature chapters by internationally recognised experts and will include coverage of innovative diagnostic methods, new
and effective therapies and new management strategies. Each of the chapters has three
main sections – namely scientific background, practical application and future directions.
CURRENT OPINION IN NEUROLOGY
Editor: Richard SJ Frackowiak
Deputy Editor: Anne B Young
Current Opinion distills the massive amount of primary literature
into reliable, concise and thoughtful analyses written by respected
The entire discipline is covered within structured sections so that
you receive a full update on all aspects of neurology every year.
Visit www.co-neurology.com for further information and to check out a sample issue.
Advances in Neuromuscular Disorders: A Historical Perspective • Pathogenesis of
Amyotrophic Lateral Sclerosis • Genetic Aspects of Amyotrophic Lateral Sclerosis
• Motor Unit Estimate • Diagnostic Criteria and Outcome Measurement of Amyotrophic
Lateral Sclerosis • Drug Therapy in Amyotrophic Lateral Sclerosis • Spinal Muscular
Atrophies • Diabetic Neuropathy • Immune Mediated Neuropathies • Genetically
Determined Neuropathies and Plexopathies • Neuropathic Pain • Myasthenia Gravis
• Lambert-Eaton Myasthenia Syndrome • Congenital Myasthenia Syndrome • Metabolic
Myopathies • Periodic Paralysis and Related Disorders • Idiopathic Inflammatory
Myopathies • Dystrophinopathies • FSH Syndrome • Limb-Girdle Muscular Dystrophies
• Myotonias • HIV Neuromyopathies • Critical Illness Neuromyopathies • INDEX
Normal Retail Price: £128.00
MERRITT’S NEUROLOGY HANDBOOK
Pietro Mazzoni, MD, PhD & Lewis P. Rowland, MD,
Designed for portability and quick reference on the wards and in other
clinical settings, this handbook presents the essentials of Merritt’s
Neurology, 10th edition. The book follows the text chapter by chapter and presents the key information on signs and symptoms, diagnostic tests, and neurologic disorders in an easy to scan numbered list
format. This pocket sized reference is sure to be perfect for residents
and practitioners needing clinical information from Merritt’s but in a
practical format for on the spot consultation. The book also features a
bulleted outline format for quick information access that is keyed to the main text book
by SIGNS AND SYMPTOMS, DIAGNOSTIC TESTS AND NEUROLOGICAL DISORDERS.
Symptoms of Neurological Disorders • How to Select Diagnostic Tests • Infections of the
Nervous System • Vascular Diseases • Disorders of Cerebrospinal and Brain Fluids
• Tumors • Trauma • Birth Injuries and Developmental Abnormalities • Genetic Diseases of
the Central Nervous System • Disorders of Mitochondrial DNA • Neurocutaneous
Disorders • Peripheral Neuropathies • Dementias • Ataxias • Movement Disorders • Spinal
Cord Diseases • Disorders of the Neuromuscular Junction • Myopathies • Demyelinating
Diseases • Autonomic Disorders • Paroxysmal Disorders • Systemic Diseases and General
Medicine • Environmental Neurology • Ethical and Legal Guidelines • INDEX
0-683-30496-8 • 40 illus. • September 2001 • Paperback • 500 pages
Normal Retail Price: £34.00
ISSN – 1350-7540 • Individual subscription $266
(6 issues per year) includes online access.
HANDBOOK OF MULTIPLE SCLEROSIS
Khurram Bashir, MD & John N. Whitaker, MD,
To order any of the above publications or any other
Lippincott Williams & Wilkins publications
email ACNR Bookservice at [email protected] or
fax 0131 313 1110
A concise guide to the evaluation and management of patients with
multiple sclerosis., this book’s coverage will begin with clearly written
reviews of the classification of human demyelinating diseases as well as
the epidemiology, pathology and pathogenesis of human sclerosis. The
authors will also explain the clinical symptoms and signs which occur
during the course of the diseases and present guidelines for diagnostic
workup and treatment and also offer specific recommendations for managing the physical and psychosocial aspects of multiple sclerosis.
0-7817-2754-5 • 36 illus. • November 2001 • Paperback • 288 pages
Normal Retail Price: £29.00
V I S I T
O U R
N E W
W E B S I T E
W W W
L W W
FOCUS ON PUBLISHERS
Need to keep updated? Here is the pick of latest publications
The Interactive Spine
Expert advice in the Neurosciences
The most up-to-date knowledge on the applications of Transcranial Magnetic Stimulation is combined with essential background information in the
forthcoming 'Handbook of Transcranial Magnetic
Stimulation' (Pascual-Leone, Davey, Rothwell,
Wasserman and Puri).Available in November 2001,
this indispensable guide brings together the related
basic science, fundamental principles and essential
procedures of TMS, with current information on
the technique. Expert authors provide readerfriendly guidance on this procedure for clinical and
research-based neurologists, neurophysiologists,
neuropsychologists and psychiatrists.
Other recent publications in this area include
‘Parkinson's Disease in the Older Patient’ - a practical guide to assessment and clinical management
and the 4th edition of ‘Uncommon Psychiatric
Syndromes’ - the definitive account of rare mental
For more information on these, and other related
publications from Arnold Publishers, contact
E.Mail [email protected] or call 0207
873 6355 for a catalogue.
New Second Edition
Stroke - A practical guide to management
Presenting a unique approach to stroke, both from
the uniformity and clarity of the style and the integrated clinical management which weaves together causation, presentation, diagnosis, management
and rehabilitation, the second edition of Stroke:
A practical guide to management has been
extensively revised and expanded to present
an authoritative reference for all health care
professionals involved in stroke care.
This highly acclaimed textbook, along
with a selection of other recently published titles in neurology, are now available
to readers of Advances in Clinical
Neuroscience and Rehabilitation at specially discounted prices.
To reserve your copies simply complete
and return the order form accompanying
the promotional leaflet inside this journal. Alternatively, contact the publisher
Blackwell Publishing Tel: 01865
206233, Fax: 01865 206026, or Email: [email protected] quoting reference Q/G00270/10.
clearly written and so well set out ... I can strongly recommend it to all those who deal with
stroke. Neurologists, neurosurgeons, vascular surgeons and trainees should all have a copy of it on
their shelves.” Journal of Clinical Neuroscience
“Charles Warlow and
and pupils are to
on this original
piece of work.'”
and his colleagues
from Edinburgh and
Utrecht are to be congratulated on producing
a book which will actually be useful to clinicians,
even neurologists, especially those who believe in
practicing properly scientific
clinical medicine.” Journal of
Neurology, Neurosurgery and
Reviews of the First Edition ...
“This is an important book ...The authors deserve
congratulations for their impressive achievement.”
“I cannot remember when last I read a book so
Primal Pictures has announced
the launch of its latest and most
ambitious product to date. The
Interactive Spine represents the
world's first computer graphic
model of the entire spinal column.
Primal Pictures is one of the
world leading developers and
publishers of 3D interactive
anatomy software on CD-ROM
and now on-line.The Interactive
Spine features 3D computer
graphic models of the spine,
allowing users to rotate, select
from a range of spinal models
and peel away over 20 layers of
anatomy from skin to bone! Full
anatomy, pathology and radiology text is illustrated by hundreds of slides and video clips.
The Interactive Spine is the ultimate resource for improving
patient education, enhancing
training sessions and transforming presentations.
Primal Pictures is offering
ACNR readers a special offer
price of £112.50 plus VAT and a
30-day no risk, money-back
For further information contact
Primal Pictures Ltd, 2nd Floor,
Tennyson House, 159-165 Great
Portland Street, London. W1W
5PA.Tel: 020 7637 1010, www.primalpictures.com
“This book is probably already a classic and
should be in every hospital library ...'” Medicine
The Year in Neurology
Clinical Publishing Services Ltd has published its newest
title, The Year in Neurology 2001. Providing the reader
with a concise overview of the latest developments in neurology, the title provides evaluation and critical appraisal of
the full range of recently published literature in the field.
This year's volume covers Cervical Dystonia, Parkinson's
Disease, Epilepsy, Alzheimer's Disease, and Multiple
For further information on this and related titles, visit
www.clinicalpublishing.co.uk, or contact the publishers at
Oxford Centre for Innovation, Mill Street, Oxford, OX2 0JX,
Tel: 01865 811116, Fax: 01865 251550 or
E-mail: [email protected]userve.com.
ANCR • VOLUME 1 NUMBER 5 NOVEMBER/DECEMBER 2001
WIN A COPY OF THIS TITLE!!
Clinical Publishing and ACNR magazine are pleased to
offer readers the chance to win a copy of The Year in
To enter, all you have to do is fill in the short survey on
the back of the reader enquiry/mailing sheet included with
this magazine, and fax it to 0131 313 1110. If you don't
have the insert sheet, just fax your details to the above
number, marking your fax "YEAR IN NEUROLOGY
New treatment for Schizophrenia
Sulpiride 200mg/5ml Oral Solution, previously supplied under its Specials manufacturers licence.
Sulpor is easy to swallow, sugar free in a suitably
flavoured base, packaged in an attractive blue
vignetted carton representing the Rosemont
Central Nervous System therapeutic group, has
easy to read pack information, and child resistant
tamper evident closures.
Sulpor is available from all major wholesalers.
For further information, freephone 0800 919312,
Fax. 0113 2460738.
Rosemont Pharmaceuticals are pleased to
announce the launch of Sulpor (200mg/5ml Oral
Solution Sulpiride) as a licensed product for the
treatment of chronic schizophrenia.
The initial dosage varies from 400mg to 800mg
twice daily, depending on the condition being treated.
The product is available at a strength of
200mg/5ml in 150ml bottles (£27/150ml) and
allows dosage flexibility to the prescriber. Sulpor
has the same formulation as the Rosemont
New marketing manager for Oxford Instruments
Oxford Instruments Medical
are pleased to announce Sue
Marketing Manager for its
Sue takes global responsibility for the Medelec range of
EEG, EMG and EP products
Instruments partnership with
Compumedics for sleep diagnostic instruments.
Sue Joins OI from 'Integra Neurosciences'
where for four years she was responsible for the
international marketing for "Selector", an ultrasonic aspirator for the removal of tumours, and
for European marketing for a variety of neurosurgical equipment and implants.
Prior to this Sue worked with Johnson &
Johnson Professional as a Product Manager for
Neuroendoscopy. Although starting originally in
skin-related research, she progressed to the sales
arena with Glaxo and Keymed (part of the
Olympus group) before joining J&J.
For further information contact Oxford Instruments
on Tel. 01483 770331.
Gait Trainer GT I - the
new development in
Call to reassess the significance of NAbs in MS patients treated with
Researchers at ECTRIMS called for physicians and
clinicians to recognise neutralising antibodies (NAbs)
as a primary consideration when starting interferonbeta treatment for MS.
Evidence confirms that high levels of therapyinduced NAbs may reduce or abolish the efficacy of
beta-interferon (IFN beta). Various studies presented
at ECTRIMS demonstrate that the type of Interferon,
dosage, dose frequency and route of administration
may each influence the rate of NAb development. For
example, IFN-beta 1a (Avonex) is administered once
a week by intra-muscular injection and the incidence
of NAb formation ranges from 2-8%. IFN-beta-1a
(Rebif) is administered three times a week by subcutaneous injection and generates levels of Nabs from
15-30%. Finally, over 40% of patients receiving IFNbeta-1b (Betaferon) administered sub-cutaneously
every other day will develop NAbs.
A clinical consensus also suggests that NAbs
caused by any of these products are cross-reactive, so
switching a patient to a less antigenic Interferon after
NAbs have been generated may not overcome their
negative effects. Clinical trials
demonstrate that IFN-beta-1a
(Avonex) is associated with the
lowest incidence of NAbs and is the
least immunogenic. Physicians and
clinicians should therefore consider
the long-term immunogenicity of
NAbs as major criteria when initiating MS treatment to ensure continued therapeutic efficacy. Many
ECTRIMS speakers also emphasised
a vital need for standardised IFN-antibody measurements and ongoing NAb monitoring during treatment.
"The clinical impact of NAbs is not generally seen
in the short-term since MS is a long-term chronic disease. Patients need to be followed up regularly for at
least a year for the effects to be reliably detected,"
noted Dr Jeffrey Greenstein of the Temple University
School of Medicine, Philadelphia, USA.
For further information contact Biogen on Tel. 01628
Web resource for epilepsy specialists
www.eucare.be (European Concerted Action and
Research in Epilepsy) is dedicated to providing
information and a contact point
for epilepsy professionals, and to
raising the profile of epilepsy
across Europe through educational and political actions. It was initiated to coincide with the launch
of the European White Paper on
Epilepsy, enabling a live webcast of
the event to reach a wide internet
audience. This technique has also been used to
transmit live webcasts of Eucare's satellite symposium at the WCN, and the parallel session
'Prevention of refractory epilepsy' at
the International Epilepsy Congress.
In addition to extending the live audience, webcasting allows Eucare
events to be archived, then viewed by
individuals at their convenience.
Free mouse! Registered members
of Eucare can apply for the chance to
receive the EUCARE mouse. See
www.eucare.be for more details.
Modern concepts of motor
learning favour a task-specific,
repetitive approach, ie. if someone wants to re-learn walking,
they have to walk. So far, conventional therapy requires the
strenuous effort of up to three
therapists to assist the gait of
severely disabled subjects
resulting in a non-sufficient
(seldom more than 100 steps)
and non-optimal practice. This
is the reason for the design of
the gait trainer: the harnesssecured patient is positioned
on two footplates, whose
movements simulate stance
and swing in a physiological
manner, a drive supports the
patient according to his abilities, and the highly relevant
trunk movements are controlled phase-dependently. By
themselves or with only a little
help, wheelchair-bound subjects can thus practice up to
1000 almost natural steps per
session. The gait trainer operates successfully in several
European countries, improving
gait ability in stroke, TBI, paraparetic,
For more information contact
Reha-Stim, Kastanienallee 32,
14050 Berlin, Germany, or use
the reader enquiry service
enclosed with this magazine.
ANCR • VOLUME 1 NUMBER 5 NOVEMBER/DECEMBER 2001
Laboratory favourite gets power boost
sion top boxes and downloadThe all-new Micro1401 Mk II from
able firmware updates are just
CED Ltd is an updated version of the
some of the new features
Micro1401 data acquisition unit, used
available with the Micro1401
in thousands of life-science laboratoMk II. CED Spike2 and Signal
ries world-wide. The Micro1401 estabsoftware means that the perlished itself as the standard laboratory
formance of the Micro1401
interface, bringing versatility and reliaMk II can be harnessed right
bility to research at an affordable price.
Used with Spike2 and Signal software,
the Micro1401 and its big brother the
Power1401 gave the researcher unparalleled performance and ease-of-use for neurological, physiological, pharmacological and many other
Now CED has updated the Micro1401 to bring
even greater performance and value-for-money. A
For further information contact Simon Gray,
16-bit 500kHz analogue-to-digital converter, builtin choice of USB or CED standard interfaces, Cambridge Electronic Design Ltd, Science Park, Milton
option of expandable memory, multi-system syn- Road, Cambridge CB4 0FE.Tel. 01223 420186, E-Mail.
chronisation for large numbers of channels, expan- [email protected]
2001 IPA Service to the Field Awardee
Professor Raymond Levy
has been awarded the
Service to the Field Award
from the IPA, to commemorate his lifetime contribution
Psychogeriatrics through his
work for IPA, especially as
president from 1995-1997.
Professor Levy was the From left to right: Alistair Burns, Edmond Chiu,
foundation Profesor of Raymond Levy
Psychiatry of Old Age at the
Institute of Psychiatry,
London, and is noted for his
groundbreaking work on
neuroimaging and cholinergic therapies in Alzheimer’s
He has mentored scores
of psychogeriatricians on 5
Cooler future for brain-injury patients
European neurologists and neurosurhas already successfully controlled fever
geons are at the forefront of treating
in 50 patients and reported that 89% of
patients with fever-related brain damage
patients treated had no temperature
using a new technology that reduces
value over 38ºC (or 100º F.). "The Alsius
core body temperature. Developed by
system is able to successfully control
AlsiusTM Corporation, the technology featemperature because cooling takes
place internally as opposed to conventures a heat-exchange catheter called
tional surface cooling methods such as
the Cool LineTM which connects to a
ice packs or blankets," said Prof.
sophisticated temperature control
Schmutzhard. "This is the future for
treating critical care patients with neuAt the January 2001 ANIM meeting in
Innsbruck, neurologists and intensive
Alsius technology has received CE
care clinicians from Leipzig, Innsbruck, Prof. Erich Schmutzhard
clearance in Europe and is currently
and Vienna reported how Alsius' new
investigational in the US.
approach showed signs of benefiting
For further information, please contact: George
patients admitted into Neuro ICU with severe
brain injury. Since then, physicians in Italy, Spain and Strang, Forth Medical Limited, Forth House, 42
Kingfisher Court, Hambridge Road, Newbury, Berkshire
Germany have been using AlsiusTM technology.
Innsbruck neurologist Prof. Erich Schmutzhard RG14 5SJ.
The AXIOM Artis MP multi purpose
Siemens Medical Solutions has
introduced a new concept that
improves the productivity of
many radiographic procedures.
Called AXIOM, the concept simplifies routine tasks and increases workflow by using advances
in information technology techniques.
The AXIOM concept has
been introduced because of the
increasing need to bring down
equipment life-cycle costs and
improve operational productivity - notably the more efficient
use of equipment and staff - by
employing the latest advances in
hardware and software. Making
substantial improvements to
image quality, ease of use, patient
care and equipment connectivity, all the equipment variants in
the AXIOM range make gains in
these four key areas by combining advances in hardware with
software. This improves image
quality for quicker and more
'Unchaining your workflow'
improves productivity from
diagnostics and therapy to continuing and ongoing care. This
also means that x-ray systems
and equipment can be 'seamlessly' integrated into a hospital network to facilitate faster data
exchange not just between
departments but, if necessary,
between remotely located sites.
Depending on requirements,
images and data from other
modalities and departments can
be made available at the touch
of a button. Such facilities not
only promote faster therapeutic
decisions, but also raise productivity.
For more information contact:
Mike Bell, Siemens Medical
Solutions,Tel. 01344 396317.
The British Neuroscience Association
‘Towards a better understanding of the nervous system in health
The BNA is the fastest growing learned society, with
nearly 2000 members, a rise of 40% since its relaunch as the
BNA in 1997 from the former Brain Research Association.
In addition to discounted journals and books and other
occasional 'special offers', the benefits of membership now include the
following: Reduced registration fees to the National Meeting and
One-Day Symposia, and FREE admission to many events; Regular
newsletter and other relevant mailings; Regular 'BNA News Email
Alert' service; Student prizes, and bursaries for attendance at BNA
ANCR • VOLUME 1 NUMBER 5 NOVEMBER/DECEMBER 2001
and FENS meetings; Free on-line access to European
Journal of Neuroscience; Concessionary (SFN membership
rate) registration fees and sponsored abstract forms for
Society for Neuroscience; Free advertising in 'BNA News
Email Alert', the BNA Newsletter and on the BNA Website.
For further information contact [email protected], or
see www.bna.org.uk. Membership application forms are also available from
either of these sources, or from the BNA Conference Office c/o New
Medical School, Ashton Street, Liverpool L69 3GE. Tel. 0151 794
4943/5449, Fax, 0151 794 5517. Membership fees are still only £45 per
annum (full member), £15 per annum (student member)!
Brief Prescribing Information. Presentation: Pale yellow tablets containing 25mg, 50mg, 100mg
and 200mg lamotrigine, and white dispersible/chewable tablets containing 2mg, 5mg, 25mg and
Uses: Monotherapy: Not recommended in children under 12 years. Adults and children over 12 years
for partial epilepsy with or without secondarily generalised tonic-clonic seizures and in primary generalised tonic-clonic seizures. Add-on therapy: Adults and children over 2 years for partial epilepsy with
or without secondary generalised tonic-clonic seizures and in primary generalised tonic-clonic
seizures. Seizures associated with Lennox-Gastaut syndrome.
Dosage and Administration: Initial dose and subsequent dose escalation should not be exceeded to
minimise the risk of rash. Monotherapy: Initial dose is 25mg daily for two weeks, followed by 50mg
daily for two weeks. Dose should be increased by a maximum of 50-100mg every 1-2 weeks until optimal response. Usual maintenance dose is 100-200mg/day in one dose, or two divided doses.
Add-on therapy: Adults and Children over 12 years: To sodium valproate with or without ANY other
antiepileptic drug (AED), initial dose 25mg every alternate day for two weeks, followed by 25mg/day
for two weeks. Dose should be increased by 25-50mg every 1-2 weeks until optimal response. Usual
maintenance dose 100 to 200mg/day in one dose, or two divided doses. To enzyme inducing AEDs
with or without other AEDs (but NOT valproate), initial dose is 50mg daily for two weeks, followed
by 100mg/day in two divided doses for two weeks. Dose should be increased by 100mg every
1-2 weeks until optimal response. Usual maintenance dose is 200 to 400mg/day given in two divided
doses. Children aged 2-12 years: To be dosed on a mg/kg basis until the adult recommended titration
dose is reached. Add-on to sodium valproate with or without ANY other AED, initial dose is
0.15mg/kg bodyweight/day given once a day for two weeks, followed by 0.3mg/kg/day given once a
day for two weeks. Dose should then be increased by a maximum of 0.3mg/kg every 1-2 weeks until
optimal response. Usual maintenance dose is 1 to 5mg/kg/day given in one dose, or two divided
doses. Add-on to enzyme-inducing AEDs with or without other AEDs (but NOT valproate) is
0.6mg/kg bodyweight/day given in two divided doses for two weeks, followed by 1.2mg/kg/day for two
weeks given in two divided doses. Dose should then be increased by a maximum of 1.2mg/kg every
1-2 weeks until optimal response. Usual maintenance dose is 5-15mg/kg/day given in two divided
doses. Weight of child should be monitored and dose adjusted as appropriate. If calculated dose
is 1-2mg/day then 2mg may be taken on alternate days for the first two weeks. Dose Escalation:
Starter packs covering the first four weeks treatment are available for adults and children over
12 years. When the pharmacokinetic interaction of any AED with Lamictal is unknown the dose escalation for Lamictal and concurrent sodium valproate should be used. Elderly patients: No dose adjustment required.
Contra-indications: Hypersensitivity to lamotrigine.
Precautions: Adverse skin reactions, mostly mild and self-limiting, may occur generally during the
first 8 weeks of treatment. Rarely, serious, potentially life threatening rashes including StevensJohnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. Patients should
be promptly evaluated and Lamictal withdrawn unless the rash is clearly not drug related. High initial dose, exceeding the recommended dose escalation rate, and concomitant use of sodium valproate
have been associated with an increased risk of rash. Patients who acutely develop symptoms suggestive of hypersensitivity such as rash, fever, lymphadenopathy, facial oedema, blood and liver abnormalities, flu-like symptoms, drowsiness or worsening seizure control, should be evaluated immediately and Lamictal discontinued if an alternative aetiology cannot be established. Hepatic
impairment: Dose reductions recommended. Withdrawal: Avoid abrupt withdrawal, except
for safety reasons. Pregnancy: Lamictal was not carcinogenic, mutagenic, teratogenic
or shown to impair fertility in animal studies. There are insufficient data available
on the use of Lamictal in human pregnancy to evaluate its safety. Lamictal should
not be used during pregnancy unless, in the opinion of the physician, the potential
benefits of treatment to the mother outweigh any possible risk to the developing foetus. Driving: As with all AEDs, the individual response should be considered.
Interactions: Antiepileptic drugs which alter certain metabolising enzymes in the liver
affect the pharmacokinetics of Lamictal (see Dosage and Administration). This is also important during AED withdrawal.
Side and Adverse Effects: With monotherapy: headache, tiredness, rash, nausea, dizziness, drowsiness, and insomnia. Other adverse experiences have included diplopia, blurred vision, conjunctivitis, GI disturbances, irritability/aggression, agitation, confusion, hallucinations and haematological
abnormalities. Also movement disorders such as tics, unsteadiness, ataxia,
nystagmus and tremor. Severe skin reactions including SJS and TEN have occurred rarely, with or
without signs of hypersensitivity syndrome. Elevations of liver function tests and rare reports of
Legal category: POM.
Basic NHS costs: £16.45 for Monotherapy Starter Pack of 42 x 25mg tablets (PL0003/0272);
£27.98 for Non-Valproate Starter Pack of 42 x 50mg tablets (PL0003/0273); £8.23 for Valproate
Starter Pack of 21 x 25mg tablets (PL0003/0272). £64.37 for pack of 56 x 100mg tablets
(PL0003/0274); £109.42 for pack of 56 x 200mg tablets (PL0003/0297). £21.95 for pack of 56 x 25mg
tablets (PL0003/0272). £37.31 for pack of 56 x 50mg tablets (PL0003/0273). £8.75 for pack of
28 x 5mg dispersible tablets (PL0003/0346). £21.95 for pack of 56 x 25mg dispersible tablets
(PL0003/0347). £64.37 for pack of 56 x 100mg dispersible tablets (PL0003/0348). £9.37 for pack of
30 x 2mg dispersible tablets (PL0003/0375).
Product Licence Holder: The Wellcome Foundation Ltd, Middlesex UB6 0NN. Lamictal is a Trade
mark of the Glaxo Wellcome Group of Companies.
Further information is available from GlaxoSmithKline UK Limited, Stockley Park West, Uxbridge,
Middlesex UB11 1BT.
Note: If changes in AED medication are to be made they should be completed before conception.9
The UK Pregnancy Register (0800 389 1248) is collecting prospective data on the effects of all
AEDs in pregnancy. Please phone for information or to register a patient.
©Glaxo Wellcome UK Limited, 2001.
Customer Services Freephone 0800 221441
1. Holdich T et al. Epilepsia 1991; 32 (Suppl. 1): 96.
2. Morrell MJ. Neurology 1998; 51 (Suppl. 4): S21-S27.
3. Fitton A, Goa KL. Drugs 1995; 50 (4): 691-713.
4. Patsalos PN, Sander JWAS. Drug Safety 1994; 11 (1): 37-67.
5. Messenheimer J et al. Drug Safety 1998; 18 (4): 281-296.
6. Brodie MJ et al. The Lancet 1995; 345: 476-479.
7. Reunanen M et al. Epilepsy Research 1996; 23: 149-155.
8. Steiner TJ et al. Epilepsia 1999; 40 (5): 601-607.
9. Crawford P et al. Seizure 1999; 8: 201-217.
treat her epilepsy,
Imagine you’re a woman diagnosed with epilepsy.
There are certain things you need to be assured of before starting monotherapy.
Will it affect my periods? Will I put on weight?
Unlike some other therapies, Lamictal can offer the reassurance a woman seeks.
Lamictal does not interact with the contraceptive pill.1,2
It is not associated with cosmetic side effects or menstrual disorders.3-5
Lamictal causes significantly less sedation than carbamazepine6,7 and phenytoin.8
In addition to these benefits – essential to women – it still provides the effective
seizure control you expect.6-8 What other AED can offer a woman so much?
GEN 26792-ALP/May 2001
Epilepsy treatment with women in mind