Seminar

Amyotrophic lateral sclerosis

J D Mitchell, G D Borasio

Amyotrophic lateral sclerosis (known in the UK as motor neuron disease) is a devastating illness with uncertain
pathogenesis. In this Seminar, we review its natural history, clinical features, diagnostic criteria, variant and mimic
syndromes, genetic forms, and epidemiology. Several hypotheses about causes of the disorder are discussed, such as
excitotoxicity and oxidant stress, and we review past and present putative disease-modifying treatments.
Disease-management strategies, from telling the patient about their illness to end-of-life decisions and palliative care,
are presented. We review options for control of the main symptoms of amyotrophic lateral sclerosisincluding
dysphagia, dysarthria, respiratory distress, pain, and psychological disordersand care in the terminal phase. The
need for good psychosocial and spiritual care of patients and families is emphasised. We conclude with an overview
of some current major issues and future prospects, ranging from the search for disease markers to challenging
developments such as stem-cell and gene therapy.
Amyotrophic lateral sclerosis (known in the UK as motor
neuron disease) is a devastating illness for patients,
relatives, and carers. It is also one of the most puzzling
diseases in medicine in terms of our understanding of its
pathogenesis.

Natural history, clinical features, and

epidemiology
Natural history
Amyotrophic lateral sclerosis is one of the major
neurodegenerative diseases alongside Alzheimers
disease and Parkinsons disease. It is a progressive
disorder that involves degeneration of the motor system
at all levels. Involvement of other elements of the nervous
system has been described, particularly at post mortem,
but motor-system involvement is most important in
relation to clinical features noted during life. Overlap
with other neurodegenerative diseases is sometimes
seen; some patients have associated frontotemporal
dementia.1

(bulbar palsy), upper motor neuron (pseudobulbar palsy),

or both. Bulbar palsy is associated with upper and lower
facial weakness and poverty of palatal movement with
wasting, weakness, and fasciculation of the tongue.
Pseudobulbar palsy is characterised by emotional lability
(also known as pathological laughing or crying), brisk jaw
jerk, and dysarthria.
Cervical-onset amyotrophic lateral sclerosis presents
with upper-limb symptoms, either bilateral or unilateral.
Proximal weakness can present as diculty with tasks
associated with shoulder abduction (eg, hair washing,
combing, etc), and distal weakness can manifest with
impairment of activities requiring pincer grip. Upper
limb signs might also be upper motor neuron, lower
motor neuron, or both. The arm can be strikingly wasted
with profuse fasciculation and brisk reexes.
Lumbar onset implies degeneration of the anterior-horn
cells of the lumbar enlargement and is associated with
lower motor neuron symptoms and signs in the legs,
such as a tendency to trip (foot drop) or diculty on stairs
(proximal weakness).

Lancet 2007; 369: 203141

Motor Neurone Disease Care
and Research Centre, Royal
Preston Hospital, Fulwood,
Preston PR2 9HT, UK
(Prof J D Mitchell MD); and
Interdisciplinary Centre for
Palliative Medicine and Motor
Neurone Disease Research
Group, Department of
Neurology, Munich University
Hospital, Grosshadern,
D-81366 Munich, Germany
(G D Borasio MD)
Correspondence to:
Prof J D Mitchell
Douglas.Mitchell@lthtr.nhs.uk

Clinical features
The clinical features of amyotrophic lateral sclerosis are
indicative of the loss of neurons at all levels of the motor
systemfrom the cortex to the anterior horn of the
spinal cord. Physical signs of this disorder thus
encompass both upper motor neuron and lower motor
neuron ndings. Objective sensory ndings are
incompatible with a diagnosis of amyotrophic lateral
sclerosis unless they can be accounted for by neurological
comorbidity. The course of the disorder is inexorably
progressive, with 50% of patients dying within 3 years of
onset. The clinical features can be considered in relation
to neurological regions or levels: bulbar, cervical, and
lumbar. A fourth thoracic level is sometimes mentioned
but is rarely an issue in routine clinical practice, except in
relation to paraspinal electromyography (EMG).
Bulbar-onset patients present with slurring of speech
(dysarthria), diculty swallowing (dysphagia), or both.
Exclusion of other potentially treatable diseases is
importanteg, oesophageal carcinoma and myasthenia
gravis. Bulbar involvement can be lower motor neuron
www.thelancet.com Vol 369 June 16, 2007

Search strategy and selection criteria

The literature search was aimed at nding papers relevant to
this Seminar dating back to 2000. Medline and Embase were
used as the basis of this search. Papers relating to
amyotrophic lateral sclerosis were sought with the terms:
ALS, MND, amyotrophic lateral sclerosis, motor
neuron(e) disease, and motorneuron disease. Papers on
motor neuron disease identied with this strategy were
further selected for relevance by seeking those containing the
following terms: epidemiology, natural history,
management, dysphagia, sialorrhoea, riluzole, pain,
depression, ventilation, symptom control, psychosocial
care, spiritual care, palliative care, stem cells,
excitotoxicity, glutamate, superoxide, and familial.
Additional paperssome from before 2000known to us
through our knowledge of published work relating to
amyotrophic lateral sclerosis were included when judged
appropriate.

2031

Seminar

Variant syndromes
Progressive muscular atrophy is a lower motor neuron
syndrome without upper motor neuron signs. The
relation between progressive muscular atrophy and
amyotrophic lateral sclerosis has been debated
extensively. Some patients with progressive muscular
atrophy progress fairly slowly, prompting the suggestion
that the disorder is a variant of spinal muscular atrophy,
a much less aggressive motor neuron disease. Other
aected individuals presenting with progressive
muscular atrophy eventually develop full amyotrophic
lateral sclerosis.
Conversely, primary lateral sclerosis is a pure upper
motor neuron disease without lower motor neuron
involvement. This entity has also been debated widely. In
a review of 39 patients with primary lateral sclerosis,
16 remained free of lower motor neuron signs throughout
their clinical course but 13 eventually presented with
evidence of lower motor neuron involvement,2 suggesting
that a substantial proportion of these individuals develop
amyotrophic lateral sclerosis before death.

be in the distribution of individual nerves. Cranial

nerves and respiratory muscles are rarely aected.
Upper motor neuron signs are absent and the disease
can be very slowly progressive, over a period of up to
30 years. The neurophysiological hallmark is the nding
of conduction blocks. IgM anti-GM1 ganglioside
antibodies are frequently positive. Great improvement
with immunomodulatory treatment can take place even
in patients with severe weakness. Intravenous immunoglobulin is usually the rst treatment of choice. Some
researchers also suggest benet from cyclophosphamide,
but a high risk of serious adverse events is present with
this drug. Findings of Cochrane systematic reviews
have not recorded clear evidence from randomised
controlled trials of the best treatment. Use of
corticosteroids has been associated with deterioration.
Little or no evidence is available about drugs less toxic
than cyclophosphamide, such as azathioprine,
interferon beta, rituximab, ciclosporin, and plasma
exchange.4,5

Epidemiology and genetic forms

Mimic syndromes
Slow progression and absence of upper motor neuron
signs strongly suggest mimic syndromes. Although
technically a variant of spinal muscular atrophy,
bulbospinal muscular atrophy (Kennedys syndrome)an
X-linked recessive lower motor neuron syndrome with
bulbar involvementcan be confused with amyotrophic
lateral sclerosis. Tongue wasting and fasciculation,
gynaecomastia, testicular atrophy, and infertility are
characteristic ndings. Some patients also have a primary
sensory neuronopathy. Kennedys syndrome links to
Xq11-q12 and is associated with a CAG repeat sequence
in the androgen receptor gene.3
Multifocal motor neuropathy is an important
dierential diagnosis because it is potentially treatable.
Weakness generally aects distal arm muscles and can

The incidence of sporadic amyotrophic lateral sclerosis is

between 15 and 20 per 100 000 population per year,
giving a prevalence of around 6 per 100 000. Males are
usually aected more than females (ratio about 16:1).
Areas with an apparently higher prevalence of an
amyotrophic lateral sclerosis-like disease compared with
other regionsnotably around the Pacic rim (eg,
Guam)have long been a source of interest to
epidemiologists. The role of methylaminoalanine in
these foci is of particular interest. Research suggests a
cyanobacterial origin for methylaminoalanine in cycad
tissue with resultant biomagnication in the food chain.
The traditional diet of the Chamorro population, who live
on the Pacic island of Guam, includes the fruit bat,
which feeds on cycad seeds and has been reported to
bioaccumulate methylaminoalanine.6

Designation

Locus

Gene

Inheritance

Comment

ALS 1

21q22.1

Copper/zinc superoxide dismutase (SOD1)

Autosomal dominant

Many (about 100) mutations now

described

ALS 2

2q33

ALS2: a guanine nucleotide exchange factor for

RAB5A, a key regulator of endocytosis

Autosomal recessive

Upper motor neuron features might be

prominent

ALS 3

18q21

Not known

Autosomal dominant

..

ALS 4

9q34

Senataxin (SETX): could have RNA and DNA

helicase activities and act in DNA repair pathways

Autosomal dominant

Onset age might be younger than 25 years,

slow progression, normal lifespan?

ALS 5

15q15.1-q21.1

Not known

Autosomal recessive

..

ALS 6

16q12.1-q12.2

Not known

Autosomal dominant

..

ALS 7

20pter

Not known

Autosomal dominant

..

ALS 8

20q13.3

Vesicle-associated membrane
protein/synaptobrevin-associated membrane
protein B (VAPB) gene

Autosomal dominant

Possible founder eect

Lower motor
neuron disease,
dynactin type

2p13

Dynactin 1 gene (DCTN1)

Autosomal dominant

Very slowly progressive, upper motor

neuron signs only

Table 1: Summary of familial amyotrophic lateral sclerosis variants

2032

www.thelancet.com Vol 369 June 16, 2007

Seminar

Increased age of onset, low forced vital capacity, short

time from rst symptom to presentation, and bulbar
onset are all adverse prognostic indicators.7 A host of
environmental factors have been investigated as potential
risk factors for amyotrophic lateral sclerosis.
Unfortunately, many studies to date have been
insuciently powered.8 Putative physical and toxic risk
factors have also been reviewed,9 again without any clear
pointers emerging. Substantially raised risks of
developing amyotrophic lateral sclerosis have been
reported in Italian professional football players.10
Increased risks have also been suggested in military
personnel.11 Although potential associations between
amyotrophic lateral sclerosis and smoking have been
discussed, evidence for this link remains unclear.12,13
510% of patients have a positive family history for
amyotrophic lateral sclerosis. These kindreds usually
show an autosomal-dominant pattern of inheritance.
Autosomal-recessive forms have also been described,
particularly from highly consanguineous populations in
north Africa.14 Between 10% and 20% of autosomaldominant patients have mutations in the copper/zinc
superoxide dismutase (SOD1) gene on chromosome 21.
Other linkages have also been reported in people with
familial amyotrophic lateral sclerosis but the genetic
lesion in most of these aected individuals remains
unknown. Table 1 summarises potential variants and
linkages of the familial disorder. Additionally, several
other genetic mutations have been reported to alter the
risk of developing sporadic amyotrophic lateral sclerosis.
These include angiogenin (14q11.2), vascular endothelial
growth factor (6p12), survival motor neuron (5q12.2-q13.3),
neurolament protein (22q12.2), and charged
multivesicular body protein 2B (2p11.2).15

Panel 1: Summary of revised El Escorial criteria17

Denite
Lower motor neuron and upper motor neuron signs in three
regions
Probable
Lower motor neuron and upper motor neuron signs in two
regions
Probable with laboratory support
Lower motor neuron and upper motor neuron signs in one
region or upper motor neuron signs in one or more regions
with EMG evidence of acute denervation in two or more limbs
Possible
Lower motor neuron and upper motor neuron signs in one
region
Suspected
Lower motor neuron signs only in one or more regions or
upper motor neuron signs only in one or more regions
All categories need evidence of disease progression and absence of sensory signs not
explicable on the basis of comorbidity.

the short form 3621 or the amyotrophic lateral sclerosis

specic questionnaire, the ALSAQ 40,22 and thus they
correlate well with functional rating scales. However,
patients with amyotrophic lateral sclerosis seem to prefer
individual quality-of-life scales, such as the schedule for
evaluation of individual quality of life-direct weighting.23
Individual quality of life is dependent on factors other
than physical functioning24,25 and does not necessarily
deteriorate, despite progressing disability.26

Causal and pathogenetic hypotheses

Diagnostic criteria, clinical rating scales, and
quality-of-life measurement
The El Escorial diagnostic criteria for amyotrophic lateral
sclerosis were developed in the late 1980s16 and have
subsequently been revised.17 Panel 1 shows the essential
features of the revised criteria. Although intended as an
aid to research and slightly more restrictive than the
burden of proof usually applied in clinical practice, these
criteria do provide a structured approach to assessment
of people suspected of having amyotrophic lateral
sclerosis, which can enhance objectivity in clinical
practice and facilitates clinical studies.
Several functional rating scales have also been
developed over the past 2025 years. These include the
Norris scale,18 the Appel amyotrophic lateral sclerosis
rating scale,19 and the amyotrophic lateral sclerosis
functional rating scale.20 This latter scale is, at present,
the most widely used in clinical trials.
Many assessment scales have been used to measure
quality of life in the broadest sense in individuals with
amyotrophic lateral sclerosis. Most are actually designed
to assess general or disease-specic health status, such as
www.thelancet.com Vol 369 June 16, 2007

Many causal and pathogenetic hypotheses for

amyotrophic lateral sclerosis have been proposed over
the years, ranging from heavy-metal toxic eects27 to
environmental and occupational exposures.28 Despite
extensive research, the disorder remains poorly
understood in terms of a unifying causal hypothesis and,
indeed, might turn out to be a common end-stage
phenotype of diverse causes. Current work focuses
largely on excitotoxicity and oxidant stress. Viral hypotheses drawing from the role of poliovirus in poliomyelitis
have been pursued extensively without positive evidence
emerging.
Excitotoxicity is the process by which aminoacid
neuromodulators such as glutamate become toxic when
present at supraphysiological concentrations. Other
potential excitotoxins include AMPA (-amino-hydroxy5-methylisoxasole-4 propionic acid) and kainate.
Excitotoxins are thought to precipitate neuronal death by
triggering excessive calcium inux into the motor
neuron, which is mediated at membrane level, and
stimulating an intraneuronal cascade mechanism
including free-radical intermediates, ultimately resulting
2033

Seminar

Drug

Mechanism

Dose and route

Trial design

Status/outcome

Ref

AEOL-10150

Antioxidant

Dose not known, subcutaneous

Not known

Phase I clinical trial status: pivotal phase II/III

trials planned

53

Brain-derived
neurotrophic factor
(BDNF)

Neurotrophin

25 or 100 g/kg

Randomised, placebocontrolled,
dose-ranging trial

Failed to show benet for primary endpoints

45, 46

25, 60, 150, 400, or

1000 g/day, intrathecal

Randomised, double-blind, sequential,

dose-escalation study

Intrathecal BDNF well tolerated in doses of up to

150 g/day; few patients did not permit
conclusions on eectiveness

Ciliary neurotrophic
factor (CNTF)

Neurotrophin

05, 2, or 5 g/kg per day

Double-blind, placebo-controlled,
dose-ranging trial

No benecial eect on progression; adverse

events and deaths increased in 5 g/kg group

15 or 30 g/kg, subcutaneous

Randomised, placebo-controlled,
dose-ranging, double-blind trial

No signicant dierence between CNTF and

placebo; side-eects sucient to limit use in
many cases

44

Creatine

Stabilise mitochondrial
function

Creatine monohydrate 10 g/day

Double-blind, placebo-controlled,
sequential trial

Did not have a benecial eect on survival or

disease progression

55

Gabapentin

Antiexcitotoxic agent

3600 mg/day

Randomised, placebo-controlled trial

No evidence of benecial eect on disease

progression or symptoms

58

Glatiramer acetate

Immunosuppressant

Randomised controlled trial

Status uncertain; further studies needed

52

Interferon beta 1A

Immunomodulatory agent

12 mIU, subcutaneously, three

times a week

Randomised, placebo-controlled trial

The results of this pilot study suggest that

interferon beta 1A is not eective

59

Lamotrigine

Glutamate release inhibitor

300 mg/day, oral

Double-blind, placebo-controlled,
crossover

No evidence of eectiveness

51

Minocycline

Inhibits glial and caspase

activation

Up to 400 mg/day, oral

Compound, with and without riluzole

Status not yet clear; further trials planned

49, 50

ONO 2506 (Cereact)

Astrocyte stabilising drug

12 g/day, oral

Compound, with and without riluzole

Results pending

48

Pentoxifylline

Tumour necrosis factor

inhibitor

12 g/day

Double-blind, randomised,
placebo-controlled, multicentre trial

Not benecial and should be avoided in patients 54

treated with riluzole

Recombinant IGF-I

Neurotrophin

005 and 01 mg/kg per day,

subcutaneous

Placebo-controlled dose ranging trial

Interpretation of trial results jeopardised by trial

design, further studies in progress

43

Riluzole

Glutamate release inhibitor

100 mg/day, oral

Placebo-controlled dose-ranging trial

Modestly eective

29

Topiramate

Antiexcitotoxic agent

Up to 800 mg/day

Double-blind, placebo-controlled,
multicentre, randomised clinical trial

Did not alter decline in forced vital capacity and 57

amyotrophic lateral sclerosis functional rating
scale or aect survival; further studies of
topiramate up to 800 mg/day are not warranted

Vitamin E

Antioxidant

tocopherol (500 mg twice a day) Randomised, placebo-controlled trial

Xaliproden

Enhancement of nerve
growth factor gene
expression

1 and 2 mg/day, oral

No eect on survival and motor function

Random allocation to one or two doses of No evidence of eectiveness

xaliproden or placebo; two sub-studies:
one with all patients taking riluzole, the
other with no patients taking riluzole

56
47

Table 2: Some putative disease-modifying treatments for amyotrophic lateral sclerosis

in neuronal death. The excitotoxic and free-radical

theories are, thus, not mutually exclusive. The excitotoxic
hypothesis has led to the identication of riluzole, a
glutamate-release inhibitor, as the rst licensed
disease-modifying treatment for amyotrophic lateral
sclerosis.29 Attempts to develop antioxidant strategies for
the disorder have, by contrast, been disappointing.30
Other pathogenetic hypotheses have centred on
dysregulation of intracellular calcium,31 axonal transport
defects,32 and protein aggregation.33
Early investigations seeking a potential role for free
radicals in the pathogenesis of amyotrophic lateral
sclerosis34 became much more tightly focused after Rosen
published his report of the chromosome 21 SOD1 gene
mutation in some families with a history of familial
amyotrophic lateral sclerosis.35 This mutation has since
been recorded in individuals with apparently sporadic
disease,36 but some of these patients were subsequently
shown to be related in a much earlier generation
2034

(common founder eect).37 Although more than 10 years

have elapsed since Rosens paper, the link between the
SOD1 gene mutation and amyotrophic lateral sclerosis
remains unclear. Copper chaperone proteins have been
discussed in this context,38 and the putative toxic gain of
function of mutant SOD1 remains elusive despite intense
research.39 Whether neuronal death in amyotrophic
lateral sclerosis is due to apoptosis is also still a matter of
debate.40 Two essential issues that need to be remembered
are: 1) SOD1 is associated with no more than 20% of total
cases of familial amyotrophic lateral sclerosis, and the
familial disease only accounts for 510% of amyotrophic
lateral sclerosis cases; and 2) the mutant SOD1 enzyme is
expressed in all tissues from birth to death.
Why do people with SOD1 gene mutations live a
substantial proportion of their normal lifespan
(generally >60%) as apparently healthy individuals before
they develop a catastrophic degenerative disorder aecting
a very specic neuronal population, which will result in
www.thelancet.com Vol 369 June 16, 2007

Seminar

death within less than 5% of the typical lifespan? One

possible answer could reside in the notion of selective
motor neuron vulnerability, which might be related to a
reduced amount of calcium-binding proteins in motor
neurons,41 although the size of the motor neuron and
resultant energy requirements, length of the motor
neuronal axon, and molecular prole of glutamate
receptors might also be important. Identication of
TDP43 as the major ubiquitinated protein in both
frontotemporal dementia and sporadic amyotrophic
lateral sclerosis suggests a range of disorders with similar
pathological mechanisms, culminating in the progressive
degeneration of dierent selectively vulnerable neurons.42

Management
Disease-modifying treatments
Many putative disease-modifying strategies for
amyotrophic lateral sclerosis have been tested in clinical
trials (table 2),29,4359 but only one drug (riluzole) has so far
been licensed. One of the actions of riluzole is as a
glutamate-release inhibitor acting on sodium channels.60
In this context, riluzole has similar pharmacological
properties to lamotrigine. It prolongs the lifespan of
patients with amyotrophic lateral sclerosis by an average
of 3 months. Findings of an initial trial in individuals
with this disorder suggested that riluzole was more
eective in bulbar-onset than limb-onset patients.61 This
result was not repeated in a second, larger, dose-ranging
trial.62 After publication of a Cochrane systematic review29
and an assessment by the UKs National Institute for
Clinical Excellence,63 further studies were recommended
to investigate aspects of the potential eectiveness of
riluzole in amyotrophic lateral sclerosis. This work has
not yet been done but some observational, survey, and
audit data64 for the so-called real-world clinical use of
riluzole have been reported, which suggest a longer
survival time than that recorded in randomised controlled
trials, a nding that needs conrmation.
Nerve growth factors (neurotrophins) have also been
investigated as disease-modifying treatments for
amyotrophic lateral sclerosis. Neurotrophins are thought
to have a key role in maintenance of neuronal viability,
prompting suggestions that they might be able to rescue
dying motor neurons.
Recombinant insulin-like nerve growth factor 1 is a
naturally occurring peptide with multitarget neurotrophic
potential on motor neurons. Two randomised placebocontrolled trials of this peptide in patients with
amyotrophic lateral sclerosis have been completed to
date, which were seriously compromised by awed trial
design. A Cochrane review43 has been undertaken, and
the eectiveness of recombinant insulin-like nerve
growth factor 1 for treatment of this disorder remains
unproven, although the drug might be modestly eective.
Hopefully, a current trial in North America will provide
new insights into the eectiveness of this peptide in
amyotrophic lateral sclerosis.
www.thelancet.com Vol 369 June 16, 2007

Ciliary neurotrophic factor and brain-derived

neurotrophic factor have both shown promising results
in vitro and in animal models. However, ndings of
clinical trials with parenteral and (for brain-derived
neurotrophic factor) intrathecal administration have
been disappointing (table 2).4446

Symptom control and palliative care

Palliative care for patients with amyotrophic lateral
sclerosis, which includes all measures aimed at relief of
symptoms and improvement of quality of life,65 starts
with communication of diagnosis and goes all the way to
bereavement counselling (gure). Panel 2 includes all
the main symptoms of the disorder. Despite rst attempts
at establishing evidence-based guidelines,66,67 standards
of palliative treatment in patients with amyotrophic
lateral sclerosis are still largely based on expert opinion68,69
and dier between countries.70 If possible, aected
individuals should be referred to the closest multidisciplinary clinic for amyotrophic lateral sclerosis.71 Early
cooperation between the treating doctor and the local
palliative care or hospice team can be of invaluable help
for patients and families.72
Communicating a diagnosis of amyotrophic lateral
sclerosis is one of the most important tasks for the doctor.
Callous delivery of the diagnosis can be detrimental to
the therapeutic relationship and might negatively aect
psychological adjustment to bereavement.73 The patient
should dictate the pace and depth of the information ow
and the doctor has the task of responding appropriately
to the patients cues.74 The issue of complementary
treatments should be discussed proactively.75
At onset of symptoms of dyspnoea or chronic nocturnal
hypoventilation, or when forced vital capacity drops
below 50%, the patient should be oered information
Breaking the news

Psychological support

Symptomatic treatment

Percutaneous endoscopic gastrostomy

home ventilation

End-of-life decisions

Terminal phase and death

Bereavement counselling

Figure: Course of palliative care in amyotrophic lateral sclerosis

2035

Seminar

Panel 2: Symptoms attributable to amyotrophic lateral

sclerosis
Direct (owing to motor neuronal degeneration)
Weakness and atrophy
Fasciculations and muscle cramps
Spasticity
Dysarthria
Dysphagia
Dyspnoea
Emotional lability
Indirect (as a result of primary symptoms)
Psychological disturbances
Sleep disturbances
Constipation
Drooling
Thick mucous secretions
Symptoms of chronic hypoventilation
Pain

about the terminal phase, since at this point most people

worry that they will choke to death. This fear can be
relieved by describing the mechanism of terminal
hypercapnic coma and the resultant peaceful death
during sleep.76 At the same time, aected individuals
should be asked about their wishes in the event of a
terminal respiratory failure. Since a tracheostomy can
result eventually in a so-called locked-in syndrome and
death on an intensive-care unit, most patients will usually
refuse it. This refusal should be incorporated into an
advance directive,77 which should be reviewed at
appropriate intervals because preferences of patients
with amyotrophic lateral sclerosis for life-sustaining
treatments can change over time.78
Control of dysphagia requires an adjustment in diet
consistency (recipe books for patients with amyotrophic
lateral sclerosis are available from several lay associations).
Specic swallowing techniques can help to prevent
aspiration.79 When oral food intake becomes intolerable
because of choking, percutaneous endoscopic gastrostomy should be undertaken.80 In patients with a forced
vital capacity less than 50%, gastrostomy placement
should be done after institution of non-invasive ventilation because of the increased risk of respiratory
insuciency.81 Alternatively, a radiologically inserted
gastrostomy can be considered.82
Dysarthria can lead to complete loss of oral communication. Speech therapy is helpful initially if
progression is slow. Modern computer technology can
enable even quadriplegic patients to communicate
eectively.83 First attempts at directly exploiting brain
electric currents to control computers have shown
encouraging results.84
Dyspnoea can be a very distressing symptom in patients
with amyotrophic lateral sclerosis and most aected
individuals die from respiratory failure. Dyspnoeic attacks
2036

usually have a pronounced anxiety component and are

best managed by short-acting benzodiazepines (lorazepam
sublingual 0510 mg). Particularly in chronic dyspnoea,
the feeling of shortness of breath is best treated with
morphine (start with 2550 mg orally or 12 mg
subcutaneously or intravenously every 4 h). Titration of
the morphine dose against the clinical eect will almost
never lead to life-threatening respiratory depression.85
Symptoms of chronic nocturnal hypoventilation, such
as disordered sleep and daytime fatigue, can arise
months to years before terminal respiratory failure and
greatly reduce quality of life.86 Non-invasive ventilation is
an ecient and cost-eective palliative measure for
these symptoms.87,88 Diculties with mechanical
ventilation are usually not related to cost or technical
issues but to increasing care needs of patients. Slow
progression, good communication skills, mild bulbar
involvement, strong motivation on the patients part,
and a supportive family environment are factors that
argue in favour of initiation of non-invasive ventilation.
To be eective, this strategy needs to be administered for
at least 4 h a day, preferably at night.89 If a patient requests
discontinuation of this ventilation treatment, the doctor
has a legal and ethical duty to honour the request and to
provide appropriate drugs such as morphine and
benzodiazepines, to prevent dyspnoea and to ensure a
peaceful death.90,91
Thick mucous secretions, which result from a combination of diminished uid intake and reduced coughing
pressure, are dicult to treat. N-acetylcysteine is useful in
some cases. Suction is usually not fully eective unless
done via a tracheostomy. Manually assisted coughing
techniques and mechanical insuation-exsuation can
both be of help.92
Most patients with amyotrophic lateral sclerosis
undergo a phase of reactive depression after their
diagnosis and need counselling. Full-edged major
depression is infrequent (around 10%) but self-reported
depressive symptoms arise in 4475% of aected
individuals.93,94 Clinically signicant depression should
be looked for and treated at all disease stages. Selective
serotonin reuptake inhibitors are most frequently used;
however, amitriptyline has its advantages in amyotrophic
lateral sclerosis because it might exert favourable eects
on other symptoms such as drooling, emotional lability,
and sleep disturbance. Since concordance of depression
and distress levels between patients and caregivers is
high, attention to the mental health of the caregiver can
alleviate the patients distress as well.95
Pathological laughing or crying happens in up to
50% of patients. It is not a mood disorder but rather an
abnormal display of aect, which can be very disturbing
in social situations. The symptom responds well to drugs
(table 3). A combination of dextromethorphan and
quinidine has been shown to be eective in a randomised
study, but further research on the long-term side-eects
and tolerability are needed.96
www.thelancet.com Vol 369 June 16, 2007

Seminar

Other symptoms of amyotrophic lateral sclerosis that

can be relieved by appropriate drugs include muscle
cramps, fasciculations, spasticity, and drooling. Table 3
shows treatment options. The dose of antispasticity drugs
needs to be titrated against clinical eect, since a
moderate degree of spasticity is usually better for mobility
than a fully accid paresis. For patients with drooling
refractory to treatments listed in table 3, botulinum toxin
injections97 or irradiation of the salivary glands98 can be
considered.
Up to 73% of patients with amyotrophic lateral sclerosis
complain of pain.99 Musculoskeletal pain typically arises
in the later stages of the disease due to atrophy and
altered tone around joints. Furthermore, muscle contractures and joint stiness (eg, frozen shoulder) can be
painful. Treatment includes physiotherapy, non-steroidal
anti-inammatory drugs, and opioids. Skin pressure
pain due to immobility needs special attention by nursing
care.100

Psychosocial care
According to US data, many patients with amyotrophic
lateral sclerosis show an interest in physician-assisted
suicide.93 Although suicidal actions are fairly rare in
people with this disorder,76 20% of aected individuals in
the Netherlands have died through active euthanasia or
Dosage*
Fasciculations and muscle cramps
Mild
Magnesium

5 mmol up to three times a day

Vitamin E

400 IE twice a day

Severe
Quinine sulphate

200 mg twice a day

Carbamazepine

200 mg twice a day

Phenytoin

100 mg up to three times a day

Spasticity
Baclofen

1080 mg

Tizanidine

624 mg

Memantine

1060 mg

Tetrazepam

100200 mg

Drooling

Spiritual care and bereavement

The importance of spiritual care is usually underestimated.103 Findings of a study suggested that spirituality
or religiousness might aect use of percutaneous
endoscopic gastrostomy and non-invasive ventilation in
patients with amyotrophic lateral sclerosis, and spiritual
care can be a source of comfort to aected individuals.25
Spiritual care should encompass the whole family as a
means of preventing complicated bereavement.

Terminal phase
In a retrospective survey of 171 patients with amyotrophic
lateral sclerosis, more than 90% died peacefully, mostly
in their sleep, and none choked to death.76 Without
mechanical ventilation, the death process usually begins
with the individual slipping from sleep into coma due to
increasing hypercapnia. Restlessness or signs of dyspnoea
should be treated with morphine (beginning with
2550 mg orally or 12 mg subcutaneously or
intravenously every 4 h). Oxygen should be administered
only if symptomatic hypoxia is recorded. If anxiety is
present or suspected it should be treated with lorazepam
sublingual (beginning with 1025 mg) or midazolam
orally or subcutaneously (starting at 12 mg). The dose
should be increased until satisfactory symptom control is
achieved.104 According to the ndings of a meta-analysis,
there is virtually no risk of shortening life with these
measures.85

Future prospects
Diagnostic markers and markers of disease progression

Amitriptyline

10150 mg

Transdermal hyoscine patches

12 patches

Glycopyrrolate

0102 mg subcutaneously or
intramuscularly three times a day

Atropine or benzatropine

025075 mg or 12 mg

Pathological laughing or crying

Amitriptyline

physician-assisted suicide.101 Assessment of patients for

hopelessness and early institution of non-pharmacological
interventions aimed at maintaining hope and a sense of
meaning in life is probably the best way to prevent wishes
for hastened death.
When asked about the most important aspects of their
quality of life, 100% of people with amyotrophic lateral
sclerosis mentioned their family.23 The burden of care on
relatives sometimes exceeds that of the patients and
deserves particular attention.102 Patients associations can
provide invaluable help and assistance.

10150 mg

Fluvoxamine

100200 mg

Lithium carbonate

400800 mg

Levodopa

500600 mg

Drugs are listed for every symptom in order of recommendation. *Usual range of
adult daily dose; some patients might need higher doseseg, of antispastic drugs.

Table 3: Symptomatic drugs in amyotrophic lateral sclerosis

www.thelancet.com Vol 369 June 16, 2007

Although there is still no strongly eective diseasemodifying treatment for amyotrophic lateral sclerosis,
the ow of potential drugs continues. Thus, a
methodology that permits rapid testing of new potential
treatments, including markers of disease progression, is
needed. Spirometry is an important measure that can be
used to assess rate of progression in clinical trials of
amyotrophic lateral sclerosis, but the reliability of this
test is uncertain particularly in patients with prominent
bulbar involvement. Sni nasal pressure is currently
being assessed as an alternative. Maximum voluntary
isometric contraction has been investigated as a better
way to achieve objective measurement of muscle strength
than hand-held myometry. However, only t patients can
2037

Seminar

be tested with this method and it is dependent on

observer training. Strategies to establish the number of
surviving motor units include motor unit number
estimation and the neurophysiological index. The
methodology needed for motor unit number estimation
can be time consuming and the calculation complex,
whereas the neurophysiological index is easily calculated
from standard data obtained when calculating motor
conduction velocity.105 Potential methods of detecting
and quantifying subclinical upper motor neuron
involvement, such as transcranial magnetic stimulation106
and tractography,107 a magnetic resonance-based strategy
encompassing diusion tensor-weighted imaging
technology, have also been discussed as possible
progression markers for clinical trials.

The way forward

Stem-cell treatment

Because of the shortage of satisfactory disease-modifying

treatments, early diagnosis of amyotrophic lateral
sclerosis has traditionally not been imperative. It will,
however, be increasingly important for any attempts to
develop more eective treatments. Encouragingly,
ndings of high-throughput technologies have shown
potential proteomic and metabolic targets that might be
used as disease-specic biomarkers. Such indicators
could provide opportunities for early diagnosis and
surrogate markers to monitor disease progression in
clinical trials.116 A reliable method of showing subclinical
upper motor neuron involvement would also be an
important advance in clinical trial methodology.
Eective disease-modifying treatments for amyotrophic
lateral sclerosis might include drug delivery via viral
vectors or intrathecal administration. Viral vectors can
also be used to accomplish gene transfer aimed at
silencing a mutant gene, interfering with RNA, or
replacing a defective gene. Such interventions are already
underway in animal models.117 Future treatments might
also entail multimodality regimens, as exemplied by
approaches to antituberculous and cancer chemotherapy.
Since amyotrophic lateral sclerosis is likely to remain a
progressive and fatal disease for several years, if not
decades, further research into palliative care and
symptom control will be of primary importance to
improve quality of life of patients and their families.
Although there has been substantial progress in our
understanding of the disorder in the past 25 years, we are
still some distance from fullling the aim of the Motor
Neurone Disease Association to achieve a World Free of
ALS. To quote Oscar Wilde, the truth is rarely pure and
never simple, and we would also do well to remember
the words of Winston Churchill: This is not the end. It is
not even the beginning of the end. But it is, perhaps, the
end of the beginning.

The potential restorative mechanisms of stem-cell

treatment are still uncertain. In addition to replacement
of lost cells, other processes including cell fusion,
neurotrophic factor release, endogenous stem-cell
proliferation, and transdierentiation could be
important.111,112 The feasibility and safety of implantation
of autologous mesenchymal stem cells into the spinal
cord has been tested in amyotrophic lateral sclerosis. No
major adverse events arose, but there was no evidence of
ecacy.113 The study was viewed largely as being
premature and ethically questionable.114 Increases in

Conict of interest statement

JDM received speakers honoraria from several pharmaceutical
companies, including Aventis, the manufacturer of riluzole, and
Cephalon, the manufacturer of IGF-I, up until 2002. He was also an
investigator in the dose-ranging trial of riluzole and in studies on IGF-I
(Cephalon), Xaliproden (Sano), and ONO 2506 (Ono) but did not
participate in data analysis or report preparation for any of these studies.
He was chairman of the UK motor neuron disease interest group
(funded by Aventis and Amgen) between 1998 and 2002. GDB was an
investigator in three trials (European IGF-I trial, riluzole open-label trial,
and Xaliproden trial) and lead author of the European IGF-I trial. He
received the customary study fees for his centre and speakers fees from
Cephalon, Rhone-Poulenc Rorer, and Sano.

Novel methods of delivery of putative

disease-modifying treatments
A recurring theme in the discussion of potential
disease-modifying treatments for amyotrophic lateral
sclerosis is the need to ensure that the investigational
substance is delivered to the site of the disease
processie, the motor neuronas eciently as
possible. This targeting might not be achieved with oral
treatments or parenteral administration. Adenoassociated
virus expressing IGF-I has been used as a means of
delivering IGF-I to motor neurons by injecting the virus
into respiratory and limb muscles in G39A SOD1
transgenic mice.108 This strategy has been reported to
prolong survival in this mouse model even if treatment
was started after the animals had developed clinical
features of amyotrophic lateral sclerosis. Similarly, one
injection of a lentiviral vector expressing vascular
endothelial growth factor delayed onset and slowed
progression of amyotrophic lateral sclerosis in
SOD1 transgenic mice even when treatment was only
initiated at the onset of paralysis. This vector increased
the life expectancy of these mice by 30% without toxic
side-eects, making it one of the most eective
treatments so far reported in an animal model.109
Intrathecal administration of recombinant vascular
endothelial growth factor in G39A SOD1 transgenic rats
has also been reported to delay the onset of paralysis and
prolong survival.110

2038

donor-derived DNA have been reported after allogeneic

haemopoietic stem-cell transplantation in amyotrophic
lateral sclerosis, but the therapeutic potential remains
uncertain.115 Much work remains to be done before
stem-cell treatment can ever be regarded as even an
experimental therapeutic modality in amyotrophic lateral
sclerosis.

www.thelancet.com Vol 369 June 16, 2007

Seminar

Acknowledgments
We thank Debra Thornton of the Royal Preston Hospital Library for help
with the literature search. The work of the Preston MND Care and
Research Centre is supported by the UK Motor Neurone Disease
Association (MNDA), George Barton Trust, and the UK Department of
Health. The sponsors had no role in the preparation of this Seminar.

23

References
1
Neary D, Snowden JS, Mann DM. Cognitive change in motor
neurone disease/amyotrophic lateral sclerosis (ALS/ALS).
J Neurol Sci 2000; 180: 1520.
2
Gordon PH, Cheng B, Katz IB, et al. The natural history of primary
lateral sclerosis. Neurology 2006; 66: 64753.
3
Kennedy WR, Alter M, Sung JH. Progressive proximal spinal and
bulbar muscular atrophy of late onset: a sex-linked recessive trait.
Neurology 1968; 18: 67180.
4
van Schaik IN, van den Berg LH, de Haan R, Vermeulen M.
Intravenous immunoglobulin for multifocal motor neuropathy.
Cochrane Database Syst Rev 2005; 2: CD004429.
5
Umapathi T, Hughes RA, Nobile-Orazio E, Lger JM.
Immunosuppressant and immunomodulatory treatments for
multifocal motor neuropathy. Cochrane Database Syst Rev 2005; 3:
CD003217.
6
Ince PG, Codd GA. Return of the cycad hypothesis: does the
amyotrophic lateral sclerosis/parkinsonism dementia complex
(ALS/PDC) of Guam have new implications for global health?
Neuropathol Appl Neurobiol 2005; 31: 34553.
7
Haverkamp LJ, Appel V, Appel SH. Natural history of amyotrophic
lateral sclerosis in a database population: validation of a scoring
system and a model for survival prediction. Brain 1995; 118: 70719.
8
Armon C. Environmental risk factors for amyotrophic lateral
sclerosis. Neuroepidemiology 2001; 20: 269.
9
Mitchell JD. Amyotrophic lateral sclerosis: toxins and environment.
Amyotroph Lateral Scler Other Motor Neuron Disord 2000; 1: 23550.
10 Chio A, Benzi G, Dossena M, Mutani R, Mora G. Severely increased
risk of amyotrophic lateral sclerosis among Italian professional
football players. Brain 2005; 128: 47276.
11 Weisskopf MG, OReilly EJ, McCullough ML, et al. Prospective study
of military service and mortality from ALS. Neurology 2005; 64: 3237.
12 Weisskopf MG, McCullough ML, Calle EE, Thun MJ, Cudkowicz M,
Ascherio A. Prospective study of cigarette smoking and
amyotrophic lateral sclerosis. Am J Epidemiol 2004; 160: 2633.
13 Qureshi MM, Hayden D, Urbinelli L, et al. Analysis of factors that
modify susceptibility and rate of progression in amyotrophic lateral
sclerosis (ALS). Amyotrophic Lateral Sclerosis 2006; 7: 17382.
14 Figlewicz DA, Orrell RW. The genetics of motor neuron diseases.
Amyotroph Lateral Scler Other Motor Neuron Disord 2003; 4: 22531.
15 Parkinson N, Ince PG, Smith MO, et al. ALS phenotypes with
mutations in CHMP2B (charged multivesicular body protein 2B).
Neurology 2006; 67: 107477.
16 World Federation of Neurology Research Group on Neuromuscular
Diseases Subcommittee on Motor Neuron Disease. The El Escorial
criteria for the diagnosis of amyotrophic lateral sclerosis.
J Neurol Sci 1994; 124 (suppl): 96107.
17 World Federation of Neurology Research Group on Motor Neuron
Diseases. El Escorial revisited: revised criteria for the diagnosis of
amyotrophic lateral sclerosis. http://www.wfnals.org/guidelines/
1998elescorial/elescorial1998.htm (accessed Feb 18, 2007).
18 Hillel AD, Miller RM, Yorkston K, McDonald E, Norris FH,
Konikow N. Amyotrophic lateral sclerosis severity scale.
Neuroepidemiology 1989; 8: 14250.
19 Appel V, Stewart SS, Smith G, Appel SH. A rating scale for
amyotrophic lateral sclerosis: description and preliminary
experience. Ann Neurol 1987; 22: 32833.
20 ALS CNTF treatment study (ACTS) phase III study group. The
amyotrophic lateral sclerosis functional rating scale: assessment of
activities of daily living in patients with amyotrophic lateral
sclerosis. Arch Neurol 1996; 53: 14147.
21 Ware JE, Sherbourne CD. A 36-item short-form health survey (SF-36):
conceptual framework and item selection. Med Care 1992; 30: 47383.
22 Jenkinson C, Levvy G, Fitzpatrick R, Garratt A. The amyotrophic
lateral sclerosis assessment questionnaire (ALSAQ-40): tests of data
quality, score reliability and response rate in a survey of patients.
J Neurol Sci 2000; 180: 94100.

25

www.thelancet.com Vol 369 June 16, 2007

24

26

27
28

29

30

31

32
33

34

35

36

37

38

39

40

41

42

43

44

45
46

Neudert C, Wasner M, Borasio GD. Patients assessment of quality

of life instruments: a randomised study of SIP, SF-36 and
SEIQoL-DW in patients with amyotrophic lateral sclerosis.
J Neurol Sci 2001; 191: 10309.
Simmons Z, Bremer BA, Robbins RA, et al. Quality of life in ALS
depends on factors other than strength and physical function.
Neurology 2000; 55: 38892.
Murphy PL, Albert SM, Weber C, et al. Impact of spirituality and
religiousness on outcomes in patients with ALS. Neurology 2000; 55:
158184.
Neudert C, Wasner M, Borasio GD. Individual quality of life is not
correlated with health-related quality of life or physical function in
patients with amyotrophic lateral sclerosis. J Palliat Med 2004; 7:
55157.
Mitchell JD. Heavy metals and trace elements in amyotrophic
lateral sclerosis. Neurol Clin 1987; 5: 4360.
Armon C. An evidence-based medicine approach to the evaluation
of the role of exogenous risk factors in sporadic amyotrophic lateral
sclerosis. Neuroepidemiology 2003; 22: 21728.
Miller R, Mitchell J, Lyon M, Moore D. Riluzole for amyotrophic
lateral sclerosis (ALS)/motor neuron disease (MND).
Cochrane Database Syst Rev 2007; 1: CD001447.
Orrell RW, Lane RJ, Ross M. Antioxidant treatment for amyotrophic
lateral sclerosis/motor neuron disease. Cochrane Database Syst Rev
2005; 1: CD002829.
von Lewinski F, Keller BU. Ca+, mitochondria and selective
motoneuron vulnerability: implications for ALS. Trends Neurosci
2005; 28: 494500.
Chevalier-Larsen E, Holzbaur EL. Axonal transport and
neurodegenerative disease. Biochim Biophys Acta 2006; 1762: 1094108.
Strong MJ, Kesavapany S, Pant HC. The pathobiology of
amyotrophic lateral sclerosis: a proteinopathy?
J Neuropathol Exp Neurol 2005; 64: 64964.
Mitchell JD, Jackson MJ, Pentland B. Indices of free radical activity
in the cerebrospinal uid in motor neurone disease.
J Neurol Neurosurg Psychiat 1987; 50: 91922.
Rosen DR, Siddique T, Patterson D, et al. Mutations in Cu/Zn
superoxide dismutase gene are associated with familial amyotrophic
lateral sclerosis. Nature 1993; 362: 5962.
Jones CT, Swingler RJ, Simpson SA, Brock DJ. Superoxide
dismutase mutations in an unselected cohort of Scottish
amyotrophic lateral sclerosis patients. J Med Genet 1995; 32: 29092.
Ceroni M, Malaspina A, Poloni TE, et al. Clustering of ALS patients
in central Italy due to the occurrence of the L84F SOD1 gene
mutation. Neurology 1999; 53: 106471.
Silahtaroglu AN, Brondum-Nielsen K, Gredal O, et al. Human CCS
gene: genomic organization and exclusion as a candidate for
amyotrophic lateral sclerosis (ALS). BMC Genet 2002; 3: 5.
Andersen PM. Amyotrophic lateral sclerosis associated with
mutations in the CuZn superoxide dismutase gene.
Curr Neurol Neurosci Rep 2006; 6: 3746.
Bacman SR, Bradley WG, Moraes CT. Mitochondrial involvement in
amyotrophic lateral sclerosis: trigger or target? Mol Neurobiol 2006;
33: 11331.
Alexianu ME, Ho BK, Mohamed AH, La Bella V, Smith RG,
Appel SH. The role of calcium-binding proteins in selective
motoneuron vulnerability in amyotrophic lateral sclerosis.
Ann Neurol 1994; 36: 84658.
Neumann M, Sampathu DM, Kwong LK, et al. Ubiquitinated
TDP-43 in frontotemporal lobar degeneration and amyotrophic
lateral sclerosis. Science 2006; 314: 13033.
Mitchell JD, Wokke JH, Borasio GD. Recombinant human
insulin-like growth factor I (rhIGF-I) for amyotrophic lateral
sclerosis/motor neuron disease. Cochrane Database Syst Rev 2002; 3:
CD002064.
Bongioanni P, Reali C, Sogos V. Ciliary neurotrophic factor (CNTF)
for amyotrophic lateral sclerosis/motor neuron disease.
Cochrane Database Syst Rev 2004; 3: CD004302.
The BDNF Study Group (Phase III). A controlled trial of recombinant
methionyl human BDNF in ALS. Neurology 1999; 52: 142733.
Ochs G, Penn RD, York M, et al. A phase I/II trial of recombinant
methionyl human brain derived neurotrophic factor administered
by intrathecal infusion to patients with amyotrophic lateral sclerosis.
Amyotroph Lateral Scler Other Motor Neuron Disord 2000; 1: 20106.

2039

Seminar

47

48
49

50

51

52
53
54

55

56

57

58

59
60
61
62

63

64

65

66

67

68

69

70

2040

Meininger V, Bensimon G, Bradley WR, et al. Ecacy and safety of

xaliproden in amyotrophic lateral sclerosis: results of two phase III
trials. Amyotroph Lateral Scler Other Motor Neuron Disord 2004; 5:
10717.
de Paulis T. ONO-2506 (Ono). Curr Opin Investig Drugs 2003; 4: 86367.
Gordon PH, Moore DH, Gelinas DF, et al. Placebo-controlled phase
I/II studies of minocycline in amyotrophic lateral sclerosis.
Neurology 2004; 62: 184547.
Pontieri FE, Ricci A, Pellicano C, Benincasa D, Buttarelli FR.
Minocycline in amyotrophic lateral sclerosis: a pilot study.
Neurol Sci 2005; 26: 28587.
Ryberg H, Askmark H, Persson LI. A double-blind randomized
clinical trial in amyotrophic lateral sclerosis using lamotrigine:
eects on CSF glutamate, aspartate, branched-chain amino acid
levels and clinical parameters. Acta Neurol Scand 2003; 108: 18.
Gordon PH, Doorish C, Montes J, et al. Randomized controlled phase
II trial of glatiramer acetate in ALS. Neurology 2006; 66: 111719.
Orrell RW. AEOL-10150 (Aeolus). Curr Opin Investig Drugs 2006; 7:
7080.
Meininger V, Asselain B, Guillet P, et al. Pentoxifylline in ALS: a
double-blind, randomized, multicentre, placebo-controlled trial.
Neurology 2006; 66: 8892.
Groeneveld GJ, Veldink JH, van der Tweel I, et al. A randomized
sequential trial of creatine in amyotrophic lateral sclerosis.
Ann Neurol 2003; 53: 43745.
Desnuelle C, Dib M, Garrel C, Favier A. A double-blind,
placebo-controlled randomized clinical trial of alpha-tocopherol
(vitamin E) in the treatment of amyotrophic lateral sclerosis.
Amyotroph Lateral Scler Other Motor Neuron Disord 2001; 2: 918.
Cudkowicz ME, Shefner JM, Schoenfeld DA, et al. A randomized,
placebo-controlled trial of topiramate in amyotrophic lateral
sclerosis. Neurology 2003; 61: 45664.
Miller RG, Moore DH 2nd, Gelinas DF, et al. Phase III randomized
trial of gabapentin in patients with amyotrophic lateral sclerosis.
Neurology 2001; 56: 8438.
Beghi E, Chio A, Inghilleri M, et al. A randomized controlled trial of
recombinant interferon beta-1a in ALS. Neurology 2000; 54: 46974.
Anon. Riluzole (monograph). In: Dollery C, ed. Therapeutic drugs,
2nd edn. Edinburgh: Churchill Livingstone, 1999: R3741.
Bensimon G, Lacomblez L, Meininger V. A controlled trial of riluzole
in amyotrophic lateral sclerosis. N Engl J Med 1994; 330: 58591.
Lacomblez L, Bensimon G, Leigh PN, Guillet P, Meininger V.
Dose-ranging study of riluzole in amyotrophic lateral sclerosis.
Lancet 1996; 347: 142531.
National Institute for Clinical Excellence. Guidance on the use of
riluzole (Rilutek) for the treatment of motor neurone disease:
technology appraisal guidance 20, January 2001. Available from:
http://www.nice.org.uk/page.aspx?o=ta020 (accessed Feb 18, 2007).
Mitchell JD, OBrien MR, Joshi M. Audit of outcomes in motor
neuron disease (MND) patients treated with riluzole.
Amyotroph Lateral Scler Other Motor Neuron Disord 2006; 7: 6771.
Oliver D, Borasio GD, Walsh D. Palliative care in amyotrophic
lateral sclerosis: from diagnosis to bereavement, 2nd edn. Oxford:
Oxford University Press, 2006.
Miller RG, Rosenberg JA, Gelinas DF, et al. Practice parameter: the
care of the patient with amyotrophic lateral sclerosis (an
evidence-based review)report of the Quality Standards
Subcommittee of the American Academy of Neurology, ALS
Practice Parameters Task Force. Neurology 1999; 52: 131123.
Andersen PM, Borasio GD, Dengler R, et al. EFNS task force on
management of amyotrophic lateral sclerosis: guidelines for
diagnosing and clinical care of patients and relatives: an
evidence-based review with good practice points. Eur J Neurol 2005;
12: 92138.
Mitsumoto H, Bromberg M, Johnston W, et al. Promoting
excellence in end-of-life care in ALS. Amyotroph Lateral Scler Other
Motor Neuron Disord 2005; 6: 14554.
Simmons Z. Management strategies for patients with amyotrophic
lateral sclerosis from diagnosis through death. Neurologist 2005; 11:
25770.
Borasio GD, Shaw PJ, Hardiman O, et al. Standards of palliative care
for patients with amyotrophic lateral sclerosis: results of a European
survey. Amyotroph Lateral Scler Other Motor Neuron Disord 2001; 2:
15964.

71

72
73

74
75

76

77

78

79

80

81

82

83

84

85
86

87

88

89

90
91
92

93

Van den Berg JP, Kalmijn S, Lindeman E, et al. Multidisciplinary

ALS care improves quality of life in patients with ALS. Neurology
2005; 65: 126467.
Borasio GD, Voltz R, Miller RG. Palliative care in amyotrophic
lateral sclerosis. Neurol Clin 2001; 19: 82947.
McMurray A, Harris A. Bereavement. In: Oliver D, Borasio GD,
Walsh D, eds. Palliative care in amyotrophic lateral sclerosis: from
diagnosis to bereavement, 2nd edn. Oxford: Oxford University
Press, 2006: 30123.
Borasio GD, Sloan R, Pongratz DE. Breaking the news in
amyotrophic lateral sclerosis. J Neurol Sci 1998; 160: 12733.
Wasner M, Klier H, Borasio GD. The use of alternative medicine by
patients with amyotrophic lateral sclerosis. J Neurol Sci 2001; 191:
15154.
Neudert C, Oliver D, Wasner M, Borasio GD. The course of the
terminal phase in patients with amyotrophic lateral sclerosis.
J Neurol 2001; 248: 61216.
Borasio GD, Voltz R. Advance directives. In: Oliver D, Borasio GD,
Walsh D, eds. Palliative care in amyotrophic lateral sclerosis: from
diagnosis to bereavement, 2nd edn. Oxford: Oxford University
Press, 2006: 5561
Silverstein MD, Stocking CB, Antel JP, et al. Amyotrophic lateral
sclerosis and life-sustaining therapy: patients desires for
information, participation in decision making, and life-sustaining
therapy. Mayo Clin Proc 1991; 66: 90613.
Wagner-Sonntag E, Prosiegel M. Dysphagia. In: Oliver D,
Borasio GD, Walsh D, eds. Palliative care in amyotrophic lateral
sclerosis: from diagnosis to bereavement, 2nd edn. Oxford: Oxford
University Press, 2006: 95109.
Kasarskis EJ, Scarlata D, Hill R, Fuller C, Stambler N,
Cedarbaum JM. A retrospective study of percutaneous endoscopic
gastrostomy in ALS patients during the BDNF and CNTF trials.
J Neurol Sci 1999; 169: 11825.
Gregory S, Siderowf A, Golaszewski AL, McCluskey L. Gastrostomy
insertion in ALS patients with low vital capacity: respiratory support
and survival. Neurology 2002; 58: 48587.
Chio A, Galletti R, Finocchiaro C, et al. Percutaneous radiological
gastrostomy: a safe and eective method of nutritional tube
placement in advanced ALS. J Neurol Neurosurg Psychiatry 2004; 75:
64547.
Scott A, McPhee M. Speech and language therapy. In: Oliver D,
Borasio GD, Walsh D, eds. Palliative care in amyotrophic lateral
sclerosis: from diagnosis to bereavement, 2nd edn. Oxford: Oxford
University Press, 2006: 21327.
Kubler A, Nijboer F, Mellinger J, et al. Patients with ALS can use
sensorimotor rhythms to operate a brain-computer interface.
Neurology 2005; 64: 177577.
Sykes N, Thorns A. The use of opioids and sedatives at the end of
life. Lancet Oncol 2003; 4: 31218.
Lyall RA, Gelinas DF. Dyspnoea and respiratory problems. In:
Oliver D, Borasio GD, Walsh D, eds. Palliative care in amyotrophic
lateral sclerosis: from diagnosis to bereavement, 2nd edn. Oxford:
Oxford University Press, 2006: 6393.
Bourke SC, Tomlinson M, Williams TL, Bullock RE, Shaw PJ,
Gibson GJ. Eects of non-invasive ventilation on survival and
quality of life in patients with amyotrophic lateral sclerosis: a
randomised controlled trial. Lancet Neurol 2006; 5: 14047.
Mustfa N, Walsh E, Bryant V, et al. The eect of non-invasive
ventilation on ALS patients and their caregivers. Neurology 2006; 66:
121117.
Kleopa KA, Sherman M, Neal B, Romano GJ,
Heiman-Patterson T. Bipap improves survival and rate of
pulmonary function decline in patients with ALS. J Neurol Sci
1999; 164: 8288.
American Academy of Neurology. Assisted suicide, euthanasia, and
the neurologist. Neurology 1998; 50: 59698.
Borasio GD, Voltz R. Discontinuation of life support in patients
with amyotrophic lateral sclerosis. J Neurol 1998; 245: 71722.
Sancho J, Servera E, Diaz J, Marin J. Ecacy of mechanical
insuation-exsuation in medically stable patients with
amyotrophic lateral sclerosis. Chest 2004; 125: 140005.
Ganzini L, Johnston WS, McFarland BH, et al. Attitudes of
patients with amyotrophic lateral sclerosis and their care givers
toward assisted suicide. N Engl J Med 1998; 339: 96773.

www.thelancet.com Vol 369 June 16, 2007

Seminar

94

95

96

97

98
99

100
101

102

103

104
105

Rabkin JG, Albert SM, Del Bene ML, et al. Prevalence of depressive
disorders and change over time in late-stage ALS. Neurology 2005;
65: 6267.
Rabkin JG, Wagner GJ, Del Bene M. Resilience and distress among
amyotrophic lateral sclerosis patients and caregivers. Psychosom Med
2000; 62: 27179.
Brooks BR, Thisted RA, Appel SH, et al. Treatment of pseudobulbar
aect in ALS with dextromethorphan/quinidine: a randomized
trial. Neurology 2004; 63: 136470.
Giess R, Naumann M, Werner E, et al. Injections of botulinum
toxin A into the salivary glands improve sialorrhoea in amyotrophic
lateral sclerosis. J Neurol Neurosurg Psychiatry 2000; 69: 12123.
Stalpers LJ, Moser EC. Results of radiotherapy for drooling in
amyotrophic lateral sclerosis. Neurology 2002; 58: 1308.
Oliver D. The quality of care and symptom control: the eects on
the terminal phase of ALS/MND. J Neurol Sci 1996; 139 (suppl):
13436.
Newrick PG, Langton-Hewer R. Pain in motor neuron disease.
J Neurol Neurosurg Psychiatry 1985; 48: 83840.
Veldink JH, Wokke JH, van der Wal G, Vianney de Jong JM,
van den Berg LH. Euthanasia and physician-assisted suicide among
patients with amyotrophic lateral sclerosis in the Netherlands.
N Engl J Med 2002; 346: 163844.
Gallagher D, Monroe B. Psychosocial care. In: Oliver D,
Borasio GD, Walsh D, eds. Palliative care in amyotrophic lateral
sclerosis: from diagnosis to bereavement, 2nd edition. Oxford:
Oxford University Press, 2006: 14368.
Lambert R. Spiritual care. In: Oliver D, Borasio GD, Walsh D, eds.
Palliative care in amyotrophic lateral sclerosis: from diagnosis to
bereavement, 2nd edn. Oxford: Oxford University Press, 2006:
16985.
OBrien T, Kelly M, Saunders C. Motor neurone disease: a hospice
perspective. BMJ 1992; 304: 47173.
de Carvalho M, Chio A, Dengler R, Hecht M, Weber M, Swash M.
Neurophysiological measures in amyotrophic lateral sclerosis:
markers of progression in clinical trials.
Amyotroph Lateral Scler Other Motor Neuron Disord 2005; 6: 1728.

www.thelancet.com Vol 369 June 16, 2007

106 Mills KR. The natural history of central motor abnormalities in

amyotrophic lateral sclerosis. Brain 2003; 126: 255866.
107 Aoki S, Iwata NK, Masutani Y, et al. Quantitative evaluation of the
pyramidal tract segmented by diusion tensor tractography:
feasibility study in patients with amyotrophic lateral sclerosis.
Radiat Med 2005; 23: 19599.
108 Kaspar BK, Llado J, Sherkat N, Rothstein JD, Gage FH. Retrograde
viral delivery of IGF-1 prolongs survival in a mouse ALS model.
Science 2003; 301: 83942.
109 Azzouz M, Ralph GS, Storkebaum E, et al. VEGF delivery with
retrogradely transported lentivector prolongs survival in a mouse
ALS model. Nature 2004; 429: 41317.
110 Storkebaum E, Lambrechts D, Dewerchin M, et al. Treatment of
motoneuron degeneration by intracerebroventricular delivery of
VEGF in a rat model of ALS. Nat Neurosci 2005; 8: 8592.
111 Silani V, Corbo M. Cell-replacement therapy with stem cells in
neurodegenerative diseases. Curr Neurovasc Res 2004; 1: 28389.
112 Silani V, Cova L, Corbo M, Ciammola A, Polli E. Stem-cell therapy
for amyotrophic lateral sclerosis. Lancet 2004; 364: 20002.
113 Mazzini L, Fagioli F, Boccaletti R, et al. Stem cell therapy in
amyotrophic lateral sclerosis: a methodological approach in
humans. Amyotroph Lateral Scler Other Motor Neuron Disord 2003; 4:
15861.
114 Silani V, Leigh N. Stem therapy for ALS: hope and reality.
Amyotroph Lateral Scler Other Motor Neuron Disord 2003; 4: 810.
115 Appel SH, Engelhardt JI, Henkel JS, et al. Allogeneic
haematopoietic stem cell transplantation in ALS.
Amyotroph Lateral Scler Other Motor Neuron Disord 2004; 5 (suppl 2):
54.
116 Bowser R, Cudkowicz M, Kaddurah-Daouk R. Biomarkers for
amyotrophic lateral sclerosis. Expert Rev Mol Diagn 2006; 6: 38798.
117 Federici T, Boulis NM. Gene-based treatment of motor neuron
diseases. Muscle Nerve 2006; 33: 30223.

2041