Seminar

Amyotrophic lateral sclerosis

Matthew C Kiernan, Steve Vucic, Benjamin C Cheah, Martin R Turner, Andrew Eisen, Orla Hardiman, James R Burrell, Margaret C Zoing
Lancet 2011; 377: 94255
Published Online
February 7, 2011
DOI:10.1016/S01406736(10)61156-7
Neuroscience Research
Australia and Prince of Wales
Clinical School, University of
New South Wales, Sydney,
Australia (Prof M C Kiernan DSc,
B C Cheah MBiostat,
J Burrell MBBS, M C Zoing BNurs);
Western Clinical School,
University of Sydney, Sydney,
Australia (S Vucic PhD); Nueld
Department of Clinical
Neurosciences, University
of Oxford, Oxford, UK
(M R Turner PhD); Division of
Neurology, Department of
Medicine, University of British
Columbia Vancouver,
Vancouver, Canada
(Prof A Eisen MD); and
Trinity College Institute of
Neuroscience, Dublin, Ireland
(Prof O Hardiman MD)
Correspondence to:
Prof Matthew C Kiernan,
Neuroscience Research Australia,
Barker Street, Randwick, Sydney,
NSW 2031 Australia
m.kiernan@unsw.edu.au

Amyotrophic lateral sclerosis (ALS) is an idiopathic, fatal neurodegenerative disease of the human motor system. In
this Seminar, we summarise current concepts about the origin of the disease, what predisposes patients to develop
the disorder, and discuss why all cases of ALS are not the same. In the 150 years since Charcot originally described
ALS, painfully slow progress has been made towards answering these questions. We focus on what is known about
ALS and where research is headingfrom the small steps of extending longevity, improving therapies, undertaking
clinical trials, and compiling population registries to the overarching goals of establishing the measures that guard
against onset and finding the triggers for this neurodegenerative disorder.

Introduction
Since the 1990s, there has been growing scientific and
clinical interest in amyotrophic lateral sclerosis (ALS).
Advances in our understanding of the glutamate
neurotransmitter system and the discovery of causal genes
linked to the development of familial ALS have stimulated
research interest, problems associated with clinical
heterogeneity have been identified, and survival in ALS is
now understood to be dependent on several factors,
including clinical presentation (phenotype), rate of disease
progression, early presence of respiratory failure, and the
nutritional status of patients.
Extending life expectancy in ALS seems to be dependent
on improving our understanding of its pathogenesis,
which will lead to the development of early and specific
diagnostic methods. There is a crucial need to formulate
therapies that not only slow disease progression, but also
deal with the secondary consequences of malnutrition
and respiratory failure. At present, no definitive diagnostic
test or biomarker for ALS exist, and neurologists rely on
only clinical criteria for diagnosis. The development of
novel biomarkers to objectively assess disease progression
holds the promise of greatly refining therapeutic trial
design and reducing trial costs. Furthermore, the power
of population registries is being increasingly recognised
as an essential adjunct to improved clinical assessment
techniques. These collaborative endeavours will inevitably
lead to a better understanding of ALS and its often
Search strategy and selection criteria
We searched Medline (1966, to December, 2009), EmBase
(1980, to December, 2009), and the Cochrane Library using
the search terms amyotrophic lateral sclerosis or motor
neurone disease in combination with diagnosis,
epidemiology, fronto-temporal dementia, imaging,
neurophysiology, management, and neuroprotection.
Further articles were included from reference lists, review
articles, and major textbook chapters. Abstracts and reports
from relevant meetings were also included. The final reference
list was generated on the basis of originality and relevance to
the topics covered in this Seminar. Emphasis was placed on
publications from the past 5 years, but did not exclude
commonly referenced and highly regarded older publications.

942

unpredictable progression, and will lead to the

development of guidelines for improved care of patients.
In this Seminar, we provide an up-to-date overview of the
key developments across the ALS specialty.

Epidemiology and molecular genetics

Several factors have complicated epidemiological studies
in ALS, including determination of a specific date of
disease onset and the potentially long duration between
onset of pathological changes and manifestation of
clinical disease. This prodomal period between disease
onset and presentation of symptoms possibly indicates
the redundancy of neuronal populations. As a
consequence, a range of epidemiological studies with
rigorous designs and the use of unbiased patient cohorts
have provided varying levels of evidence in support of
dierent causative mechanisms of disease.1,2 Populationbased studies have established that the incidence of ALS
in Europe is fairly uniform at 216 per 100 000 personyears.3 Although ALS aects people worldwide, an exact
incidence of this disease is not yet known.4 Men have a
higher incidence of disease (30 per 100 000 person-years;
95% CI 2833) than do women (24 per 100 000 personyears; 95% CI 2226), although the incidence between
men and women is about the same in familial disease.
The overall population-based lifetime risk of ALS is
1:400 for women and 1:350 for men. Peak age at onset is
5863 years for sporadic disease and 4752 years for
familial disease. Incidence decreases rapidly after 80 years
of age.3
Although the ALS phenotype might seem similar
across populations, there are subtle dierences in clinical
presentation across European registries.3 There is
evidence from population-based studies that suggest that
ALS is less common in individuals of mixed ancestral
origin than in individuals of Spanish origin.4 In a
population-based mortality study from Cuba,5 disease
rates were 60% lower than in European and North
American populations, lending support to previous
observations of reduced frequency of ALS in those of
Hispanic origin in North America.
About 510% of ALS is familial, with a Mendelian
pattern of inheritance. To date, 13 genes and loci of
major eect have been identified, many since 2009.6,7 Of
the known genes, mutations in SOD1 (encodes for
www.thelancet.com Vol 377 March 12, 2011

Seminar

copper/zinc ion-binding superoxide dismutase),

TARDBP (also known as TDP-43; encodes for TAR DNA
binding protein), FUS (encodes fusion in sarcoma),
ANG (encodes angiogenin, ribonuclease, RNase A
family, 5), and OPTN (encodes optineurin) cause a
typical clinical phenotype. Mutations in SOD1 induce a
toxic gain of function, although the pathophysiology
remains unclear. Both TDP-438 and FUS9,10 (also known
as TLS [translated in liposarcoma]) are multifunctional
proteins involved in gene expression and regulation,
including transcription, RNA splicing, transport, and
translation. FUS and TDP-43 are also involved in the
processing of small regulatory RNAs (microRNAs) and
in RNA maturation and splicing. ANG is a hypoxiaresponsive gene, which regulates RNA transcription.11
OPTN is a causative gene of primary open-angle
glaucoma. ALS-causing mutations of OPTN abolish the
inhibition of activation of NFB, and change the
cytoplasmic distribution of optineurin.
Mutations in SOD1 account for 20% of familial ALS12
and 5% of apparently sporadic disease. Mutations in
TARDBP account for 510% of familial ALS, mutations in
FUS for 5%, and mutations in ANG for about 1%.
The remaining 90% of people diagnosed with ALS are
classified as having sporadic disease. For these patients,
results from family aggregation studies have identified
an overlap between ALS and common neurodegenerative
disorders, suggesting the existence of susceptibility genes
that might increase the overall risk of neurodegeneration
among relatives.13 However, attempts to establish the
complex genetic basis for sporadic ALS by identifying
susceptibility genes have had little success. Results from
candidate gene studies have identified several
susceptibility genes,7 although the relative contribution
of every identified at risk gene rarely exceeds an odds
ratio of 20, and the mechanism by which risk is
conferred is not known.
Despite the disappointing findings in several recent
genome-wide association studies of sporadic ALS,4 a few
possible genes have been identified. The main problem
has been low power due to small sample sizes, with
candidates being accordingly dicult to replicate in a
second population.7 The recent identification of two new
susceptibility genes through collaborative research14
suggests that further genes and pathways could be
identified with increasingly eective cooperation
between research groups. However, the poor track
record of whole-genome association studies has led to a
reconsideration of the common disease, common
variant hypothesis in favour of a common disease,
multiple rare variant hypothesis.

Clinical phenotypes and prognosis

The varied presentations of ALS15 are also crucial to
the understanding and development of measures of
disease progression.16 The identification of specific
phenotypes has important implications for patients,
www.thelancet.com Vol 377 March 12, 2011

Figure 1: Clinical features of muscles wasting in a patient with ALS

Proximal and symmetrical upper limb wasting (A) results in an inability to lift arms against gravity (man-in-thebarrel or flail-arm variant ALS). Note the recessions above and below the scapular spine (B), indicating wasting of
supraspinatus and infraspinatus muscles, as well as substantial loss of deltoid muscle. As a consequence, the
glenohumeral joint becomes prominent, and prone to subluxation. (C) Disproportionate wasting of the thenar
muscles combined with the first dorsal interossei, the so-called split-hand, is a typical feature in ALS.17 Although the
mechanisms underlying this disproportionate wasting of hand muscles are unclear, a corticomotoneuronal origin has
been proposed.17 Specifically, the thenar muscles and first dorsal interossei receive more extensive corticospinal
connections and thereby might be prone to glutamate-mediated excitotoxicity.18 (D) Substantial wasting of the
tongue muscles in bulbar-onset ALS. Note the absence of palatal elevation present on vocalisation. Diculty with
mouth opening and dysphagia might require supplementary feeding through a percutaneous endoscopic
gastrostomy. In further support of a corticomotoneuronal hypothesis, the tongue is often disproportionately aected
in comparison to other oropharyngeal musculature in patients with bulbar-onset ALS. As with the thenar muscles in
the hand, the tongue receives more extensive cortical input than other muscle groups in the oropharyngeal area.
ALS=amyotrophic lateral sclerosis.

particularly with regards to prognosis and survival, but

also for their enrolment in clinical trials.
The main presentations of ALS include: (1) limb-onset
ALS with a combination of upper and lower motor
neuron (UMN and LMN) signs in the limbs; (2) bulbaronset ALS, presenting with speech and swallowing
diculties, and with limb features developing later in the
course of the disease (figure 1); (3) the less common
primary lateral sclerosis with pure UMN involvement; and (4) progressive muscular atrophy, with pure
LMN involvement.19
The clinical hallmark of ALS is the presence of UMN
and LMN features involving brainstem and multiple
spinal cord regions of innervation. Patients can present
with bulbar-onset disease (about 25%) or limb-onset
disease (about 70%), or with initial trunk or respiratory
involvement (5%), subsequently spreading to involve
other regions.20 Atypical modes of presentation can include
weight loss, which is an indicator of a poor prognosis,
cramps and fasciculations in the absence of muscle
943

Seminar

Astrocyte
Impaired
glutamate
intake
Microglia
Secretion of
toxic factors
Presynaptic
neuron
Release of
inflammatory
mediators

Mitochondrial
dysfunction
Glutamate
excitotoxicity

2K+

3Na+

Ca2+

SOD1 aggregates

Neurofilament
accumulation

Mutant SOD1

Pump
dysfunction

Dysfunction of axonal
transport systems

Increased
oxidative stress
Mutations in
TARDBP, FUS,
SOD1 genes

TARDBP/FUS

Figure 2: Cellular and molecular processes mediating neurodegeneration in ALS

The mechanisms underlying neurodegeneration in ALS are multifactorial and operate through inter-related molecular and genetic pathways. Specifically, neurodegeneration in ALS might result
from a complex interaction of glutamate excitoxicity, generation of free radicals, cytoplasmic protein aggregates, SOD1 enzymes, combined with mitochondrial dysfunction, and disruption of
axonal transport processes through accumulation of neurofilament intracellular aggregates. Mutations in TARDBP and FUS result in formation of intracellular aggregates, which are harmful to
neurons. Activation of microglia results in secretion of proinflammatory cytokines, resulting in further toxicity. Ultimately, motor neuron degeneration occurs through activation of
calcium-dependent enzymatic pathways. ALS=amyotrophic lateral sclerosis.

weakness, emotional lability, and frontal lobe-type

cognitive dysfunction.21
In terms of presentation, UMN disturbance involving
the limbs leads to spasticity, weakness, and brisk deep
tendon reflexes. By contrast, LMN limb features include
fasciculations, wasting, and weakness. Bulbar UMN
dysfunction results in spastic dysarthria, which is
characterised by slow, laboured, and distorted speech,
often with a nasal quality.22 The gag and jaw jerk can
be pathologically brisk. Bulbar LMN dysfunction can
be identified by tongue wasting, weakness, and
fasciculations, accompanied by flaccid dysarthria and
later dysphagia. Flaccid dysarthria results in nasal
speech caused by palatal weakness, hoarseness, and a
weak cough.22
ALS is relentlessly progressive50% of patients die
within 30 months of symptom onset and about 20% of
944

patients survive between 5 years and 10 years after

symptom onset.23 Older age at symptom onset, early
respiratory muscle dysfunction, and bulbar-onset disease
are associated with reduced survival, whereas limb-onset
disease, younger age at presentation, and longer diagnostic
delay are independent predictors of prolonged survival.23
Some ALS subtypes tend to lead to a better prognosis.
Specifically, flail-limb variant ALS (figure 1A, figure 1B)
and progressive muscular atrophy, both predominantly
LMN forms, are characterised by slower progression
than other forms of ALS.23,24 In the pure bulbar palsy
phenotype, which typically aects women older than
65 years of age with disease remaining localised to
oropharyngeal musculature and with UMN features
predominating,23 the prognosis varies from 24 years.
Additionally, patients with primary lateral sclerosis
progress more slowly than do patients with classic
www.thelancet.com Vol 377 March 12, 2011

Seminar

ALS.19,23 A definite diagnosis of primary lateral sclerosis

should be delayed for at least 4 years from disease onset,
given that development of LMN signs can occur even if
the initial presentation appears that of a pure spastic
syndrome.25 Distinguishing these phenotypes from the
typical ALS phenotype has implications for clinical trials
of putative disease-modifying therapies.
Fatigue and reduced exercise capacity are common
symptoms in ALS26 and, ultimately, most patients need
assistance with activities of daily living. Dysphagia
develops in most patients with ALS, with consequent
weight loss and malnutrition associated with poor
prognosis.27 Respiratory compromise eventually develops
in most cases of ALS, leading to exertional dyspnoea,
orthopnoea, hypoventilation with resultant hypercapnia,
and early morning headaches.28 Death becomes imminent
once patients develop dyspnoea at rest. Progressive
weakening of the respiratory muscles leads to respiratory
failure, often precipitated by pneumonia.

Overlap with frontotemporal dementia

The recent identification of TDP-43-positive ubiquitinated
cytoplasmic inclusions in almost all cases of ALS, and
more than half of patients with frontotemporal
dementia (FTD), has rekindled interest in the overlap
between these progressive neurodegenerative syndromes.29
Although reported in early descriptions, overt cognitive
symptoms and frank dementia were previously thought to
be uncommon symptoms of ALS. Conversely, a few
patients with FTD develop ALS.30 Familial clustering of
both disorders is also well recognised, with cases of FTD
or ALS or coincident FTD-ALS presenting in families. The
genes that cause these familial clusters are not yet known,
but results from linkage studies have identified a common
locus on chromosome 9.3135
Cognitive deficits might initially have a subtle
appearance and are often overlooked, but with appropriate
cognitive and neuropsychological assessment, 2050% of
patients with ALS fulfil the consensus criteria for probable
or definite FTD.36 The most commonly encountered
deficits involve executive function,37 either aecting
language or personality, with the cognitive profile most
closely resembling that of behavioural-variant FTD. In
terms of clinical implications, problems with judgment,
impulsivity, and a general deterioration in the ability to
undertake routine daily tasks can develop into dicult
problems with management of patients.38 Impaired verbal
fluency, which is more prominent in patients with
pseudobulbar disease, inevitably hinders the simple task
of patients being able to communicate their needs.
Cognitive, and particularly executive dysfunction, can also
adversely aect patient compliance with treatment,
decision-making abilities, and potentially raise ethical
and medico-legal concerns.37
In further support of overlap between these two
diseases, structural abnormalities, and specifically
frontotemporal atrophy, have been identified by voxelwww.thelancet.com Vol 377 March 12, 2011

Panel 1: Controversy in ALSwhere does the disease begin?

Despite Charcots initial observation of concomitant UMN and LMN pathological
changes in ALS, the question of where ALS begins has not been established.
Resolution of this question might enhance the understanding of the pathophysiology
of ALS and has diagnostic and therapeutic importance.
The dying-forward hypothesis proposes that ALS is mainly a disorder of
corticomotoneurons, which connect monosynaptically with anterior horn cells,
mediating anterograde degeneration of anterior horn cells via glutamate
excitotoxicity.
Support for a dying-forward hypothesis includes:
Results from transcranial magnetic stimulation studies documenting that cortical
hyperexcitability is an early feature in patients with sporadic ALS and precedes the
clinical onset of familial ALS.
Clinical observations that: (1) motor neurons without a monosynaptic connection
with corticomotoneurons, such as the oculomotor, abducens, and Onufs nuclei,
are typically spared in ALS; (2) the absence of a naturally occurring animal model of
ALS is ascribed to a paucity of corticomotoneuronal-anterior horn cell
connections; and (3) pure LMN forms of ALS are rare, whereas subclinical UMN
involvement is invariably detected with transcranial magnetic stimulation studies.
The dying-back hypothesis proposes that ALS begins within the muscle cells or at
the neuromuscular junction. Specifically, there is deficiency of a motor neurotrophic
hormone, which is normally released by postsynaptic cells and retrogradely
transported up the presynaptic axon to the cell body where it exerts its eects.
Support for the dying-back hypothesis includes:
Observations that synaptic denervation precedes the onset of motor neuron
degeneration.
Synaptic denervation is mediated by accumulation of mutant SOD1 protein in
Schwann cells.
By contrast with the dying-forward and dying-back hypotheses, some investigators
have proposed that UMN and LMN degeneration occur independently.
ALS=amyotrophic lateral sclerosis. LMN=lower motor neuron. UMN=upper motor neuron.

based morphometry MRI in patients with ALS and

FTD-ALS. Bilateral atrophy of the motor and premotor
cortices can develop,30,39 although patients with FTD-ALS
typically have more severe frontotemporal atrophy than
do patients with ALS alone.31,39 From a functional
perspective, frontotemporal hypometabolism has been
characterised in patients with ALS and FTD-ALS by
use of 2-fluoro-2-deoxy-D-glucose PET.33 This frontotemporal atrophy seems to be associated with neuronal
loss and cortical gliosis on post-mortem pathology. As
for most patients with sporadic ALS, intraneuronal
inclusions (TDP-43-positive) are present in half of
patients with FTD.32,40 FUS-positive inclusions have been
recently identified in patients with ubiquitin-positive,
TDP-43-negative FTD and in patients with familial ALS
caused by mutations in FUS39,40further emphasising
the pathological overlap between ALS and FTD.

Pathophysiological mechanisms
The pathophysiological mechanisms underlying the
development of ALS seem multifactorial (figure 2), with
emerging evidence of a complex interaction between
genetic and molecular pathways.4143 ALS might be an
945

Seminar

Motor cortex

Dying
forward
hypothesis

Anterograde degeneration
mediated via glutamate
excitotoxicity

Lateral
reticular
nucleus

Excitatory
interneuron

Propriospinal
neuron

Deficiency of motor
neurotrophic factor

Inhibitory
interneuron

Dying back
hypothesis

Anterior
horn cell

Figure 3: The dying-forward and dying-back hypotheses

adult manifestation of a developmental disorder of the

human motor system. Specifically, in a Swedish casecontrol study,1 low maternal age and high maternal age,
and exposure to younger siblings, were associated with
increased risk of developing ALS. Additionally, the
development of the human motor system might
potentially be perturbed during childhood by increased
exposure to childhood infections, as occurs in families
with young children. Various environmental risk factors
for ALS have also been suggested, including a lifetime
of intensive sport or physical exertion44 and active service
in the US armed forces.45 In a retrospective study of
football players from the Italian professional leagues,
the standardised morbidity ratios were increased for
development of ALS, particularly younger-onset
disease.46 For unknown reasons, footballers who played
for more than 5 years, particularly in an active midfield
position, were at highest risk of developing ALS. A
cluster of ALS cases has also been reported in amateur
football players from England.47
With regards to smoking, cigarettes might have a dosedependent eect on the subsequent development of
ALS.48 Neurotoxins, including -methyl-amino-L-alanine,
were associated with the development of an epidemic of
ALS-Parkinsons disease on the island of Guam.49 This
946

neurotoxic aminoacid was concentrated in the brains of

patients with ALS-Parkinsons disease and entered the
human food chain by consumption of flying foxes. These
bats, a delicacy of native Guamanians, the Chamorro,
feed on cycad seeds that have high concentrations of
-methyl-amino-L-alanine.49
No clear consensus has emerged to link SOD1 mutations
to the premature death of motor neurons. Current
understanding links genetic mutations to a toxic gain of
function of the SOD1 enzyme,41 with generation of free
radicals that eventually leads to cell injury and death.5053
Additionally, SOD1 mutations induce conformational
instability and misfolding of the SOD1 peptide, resulting
in formation of intracellular aggregates51,54 that inhibit
normal proteosomic function, disrupting axonal transport
systems and vital cellular functions.50,51,55
Glutamate-induced excitotoxicity has been implicated
in ALS pathogenesis. Glutamate is the main excitatory
neurotransmitter in the CNS, and binds to ionotropic
N-methyl-D-aspartate (NMDA) receptors and -amino-3hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA)
receptors on the postsynaptic membrane.56,57 Excessive
activation of these postsynaptic receptors by glutamate,
known as glutamate-induced excitotoxicity, can incite
neurodegeneration through activation of calciumdependent enzymatic pathways.58,59 Glutamate-induced
excitotoxicity can also result in generation of free
radicals, which in turn can cause neurodegeneration by
damaging intracellular organelles and upregulating
proinflammatory mediators.60,61
The mechanism by which glutamate-induced
excitotoxicity mediates motor neuron degeneration in
human beings remains unclear (panel 1, figure 3). A
so-called dying-forward process has been proposed,
whereby UMN mediate anterograde degeneration of
LMN by glutamate-induced excitotoxic processes.62,63
In addition to glutamate-induced excitotoxicity,
structural abnormalities of mitochondria, dysfunction of
the sodium/potassium ion pump, autophagy, and
disrupted axonal transport systems have all been
implicated in the pathogenesis of ALS.6470 Non-neuronal
cells, such as astrocytes and microglia, might also directly
contribute to neurodegeneration through mechanisms
including insucient release of neurotrophic factors,
secretion of neurotoxic mediators, and modulation of
glutamate receptor expression (known as non-cell
autonomous neurodegeneration).71
Of further relevance, TDP-43 was recognised as a major
component of ubiquitinated cytoplasmic protein
aggregates in almost all patients with sporadic ALS,
but not in the nucleus, as in normal neurons.
Although there were questions about whether such
aggregates triggered neurodegeneration in ALS,
mutations in TARDBP were reported in 3% of familial
ALS and 15% of patients with sporadic ALS, suggesting
that TDP-43 aggregates have a central role in triggering ALS.8,72 Evidence for the pathogenicity of
www.thelancet.com Vol 377 March 12, 2011

Seminar

TARDBP mutations was suggested when mutations

identified in highly conserved regions of DNA were not
evident in controls, and segregated with the disease.8,72
Given that TDP-43 binds both DNA and RNA,
mutations in TARDBP could result in dysregulation of
RNA processing.
Identification of FUS mutations on chromosome 16
associated with familial forms of ALS lends further
support to this theory. FUS aggregates were not evident
in patients with pathological changes in TDP-43 or
SOD1, indicating a novel disease pathway.10 Although the
identification of a causative eect between mutations in
the TARDBP and FUS genes and ALS was a major leap
in understanding ALS pathogenesis, several factors need
to be resolved. Do mutations in these DNA/RNA-binding
proteins indicate a toxic gain or loss of function?73 Does
neurotoxicity result from the misfolded proteins
overwhelming the cells protein surveillance pathways or
from sequestration of vital proteins and genomic
material by TDP-43 and FUS aggregates? And what is
the association between previously established pathophysiological mechanisms and the TDP-43 and
FUS proteins?

Diagnosis
Without a diagnostic test for ALS, clinicians mostly rely
on identifying the combination of UMN and LMN signs
in the same body region, with subsequent evidence of
disease progression to other regions. The El Escorial
criteria,74 revised in 1997,75 use a combination of UMN
and LMN signs to establish levels of diagnostic certainty.
Clinical trial investigators have tended to enrol patients
with either probable or definite ALS according to the
El Escorial criteria, highlighting their universality,
although inclusion of these diagnostic features as
enrolment criteria might be argued as restrictive.76
Furthermore, these criteria can have poor sensitivity,
particularly in the early stages of ALS when patients are
most likely to benefit from therapeutic intervention.77
Because of these criticisms, the criteria have been
modified to help early diagnosis78 and to optimise
levels of diagnostic certainty, important in the clinical
trial setting.79
There is often a long delay before a definitive diagnosis
is reached, partly because of the insidious onset of
symptoms, with the median time to diagnosis of about
14 months.80 Unusual clinical presentations, a low index
of suspicion, and misinterpretation of neurophysiological or neuroradiological findings are common causes
of diagnostic uncertainty.15 Unfortunately, diagnostic
delay can lead to use of inappropriate therapies, a
delay in starting appropriate pharmacological and
symptomatic therapies, and problems in dealing with
psychosocial factors.
The diagnosis of ALS is devastating for the patient and
family members, and must be handled sensitively. Patients
and family members can carry the emotional burden of an
www.thelancet.com Vol 377 March 12, 2011

Panel 2: Dierential diagnosis of ALS and appropriate investigations

Disorders of motor neurons
Spinal muscular atrophy (SMN gene deletion assay)
X-linked spinobulbar muscular atrophy (Kennedys disease; increased CAG repeats in
DNA from blood)
Poliomyelitis or post-polio syndrome (history, NCS, electromyography)
Hexosaminidase A deficiency (white-cell enzyme testing)
Disorders of motor nerves
Multifocal motor neuropathy (NCS, electromyography, ganglioside GM1 antibodies)
Chronic inflammatory demyelinating neuropathy (NCS, lumbar puncture)
Cramp-fasciculation syndrome (NCS, electromyography)
Neuromyotonia (antibodies to voltage-gated potassium channels)
Hereditary spastic paraparesis plus (gene mutation testing)
Hereditary motor neuropathy with pyramidal features
Radiculoplexopathy (NCS, electromyography, MRI)
Paraneoplastic syndrome (serum markers, imaging, bone marrow biopsy sample)
Heavy metal poisoning (urine or blood screens)
Mononeuritis multiplex (NCS, electromyography, vasculitic screen, serology)
Disorders of neuromuscular junction
Myasthenia gravis (acetylcholine receptor antibodies, MuSK antibodies, repetitive
stimulation, single-fibre electromyography)
Lambert-Eaton myasthenic syndrome (repetitive stimulation)
Structural CNS and spinal lesions
Syringomyelia or syringobulbia (MRI)
Tabes dorsalis (syphilis serology)
Multiple sclerosis (MRI, oligoclonal bands, evoked responses)
Monomelic spinal muscular atrophy (Hirayamas disease; electromyography, MRI)
Lyme disease (Lyme serology)
Human T-lymphotropic virus-1 (HIV)
Myopathy
Inclusion body myositis (electromyography, CK, muscle biopsy sample)
Polymyositis (electromyography, CK, muscle biopsy sample, autoimmune screens)
Dermatomyositis (electromyography, CK, skin, and muscle biopsy sample)
Polyglucosan body disease (NCS, electromyography, muscle or nerve biopsy sample)
Endocrine
Thyrotoxicosis (thyroid function tests, electromyography, muscle biopsy sample)
Hyperparathyroidism (calcium ion and parathyroid testing)
Subacute combined degeneration (vitamin B12 concentrations)
Coeliac disease (serum testing, bowel biopsy sample)
ALS=amyotrophic lateral sclerosis. CK=creatine kinase. NCS=nerve conduction studies. MuSK=muscle-specific tyrosine kinase.

insensitively delivered diagnosis for the entire disease

course, and initial indecision about the diagnosis in
atypical cases can delay the process of accepting the
terminal prognosis of the disease. Scheduling a followup appointment soon after diagnosis is beneficial to
answer questions not dealt with during the initial
consultation and can help provide further information
about support networks, which are well established in
most developed nations.81
Although rare, the existence of several disorders
that mimic ALS necessitates a thorough diagnostic
947

Seminar

B
Surviving motor unit
Collateral sprouts from
surviving motor axon
reinnervating denervated
muscle fibres
Degenerated motor unit

Figure 4: Investigation findings in ALS

(A) Biopsy sample of the left vastus lateralis muscle from a patient with ALS, stained with ATPase pH 94. The biopsy
sample highlights grouped atrophic fibres with both type I and type II fibres (mixed-type fibres, encompassed by red
box). (B) Pathophysiology of motor unit degeneration and reinnervation; with superimposition (C) of ten traces
demonstrating the typically large, polyphasic, unstable (complex) motor units observed in established ALS (sweep
duration 50 ms), with late components, indicating some re-innervation. ALS=amyotrophic lateral sclerosis.

assessment, which usually includes structural imaging

and neurophysiological and laboratory investigations, to
reduce the likelihood of an incorrect diagnosis (panel 2).20
In cases of pure LMN syndromes, genetic testing for
Kennedys disease, an X-linked bulbospinal atrophy, and
spinal muscular atrophy is important.82 Muscle biopsy
samples can be of further diagnostic value for excluding
unusual myopathies such as polyglucosan body disease83
or for confirming the presence of ALS by indicating
atrophy of mixed-fibre types (figure 4A).84
Routine neurophysiological investigations of patients
with ALS include nerve conduction studies, electromyography, and, less commonly, transcranial magnetic
stimulation.20,85 Nerve conduction studies are essential
to exclude disorders that mimic ALS, particularly
demyelinating motor neuropathies.86 Motor nerve
conduction is normal in the early stages of ALS, but
in advanced disease the compound muscle action
potential amplitude becomes reduced, indicating
denervation.87 Sensory nerve conduction is typically
normal in patients with ALS, dierentiating ALS from
demyelinating neuropathies.88 Prominent abnormalities
of sensory nerve conduction studies should raise
suspicion of an alternative diagnosis. In patients
presenting with predominantly LMN findings, treatable
disorders such as multifocal motor neuropathy should
be taken into account, with indication of conduction
block in at least two motor nerves outside the common
entrapment sites.89
In addition to nerve conduction studies, electromyography is useful for the identification of LMN loss
(figure 4B). The electromyographical findings indicating
LMN loss include fibrillation potentials, positive sharp
waves, and chronic neurogenic changes (figure 4C).86,90
These electromyographical abnormalities have been
948

recently incorporated into the revised El Escorial criteria

to help with the diagnosis of ALS, complementing the
clinical features of LMN involvement.90 Fibrillation
potentials and positive sharp waves can be evident in
muscles that seem clinically normal.86 Electromyography
can therefore help with an early diagnosis by establishing
the presence of subclinical LMN involvement.
Motor units that survive can fire spontaneously as
fasciculation potentials, clinically visible as involuntary
muscle twitchinga typical feature of ALS.91 When
detected in the tongue, fasciculations are highly specific
for ALS.92 The presence of fasciculations in the absence
of other electromyographical findings should be
interpreted with caution and can be a sign of less serious
disorders, especially benign cramp-fasciculation
syndrome.93 Conversely, recently revised consensus
guidelines (known as the Awaji Island criteria) have
recommended that fasciculations should be thought to
be equivalent to fibrillation potentials in individuals with
clinically suspected ALS.90 Furthermore, fasciculations in
ALS are complex (malignant), indicating re-innervation,
and have diagnostic importance when combined with
chronic neurogenic changes (figure 4C).
There is discussion about how successful clinicians are
at diagnosing ALS when using the combined approaches
of clinical assessment and laboratory investigation. This
matter was taken into account by the Scottish ALS registry,
which identified a false positive rate of 8%.15 Other data
from population-based studies have reported similar falsepositive rates, with a false-negative rate approaching 44%.94,95
In false-positive cases, the main reasons for diagnostic
revision included failure to progress, development of
atypical features, and results of follow-up neurophysiological
and neuroradiological investigations.15,94 Multifocal motor
neuropathy was the most frequent disorder misdiagnosed
as ALS, followed by Kennedys disease.94

Advances in neuroimaging
The greatest contribution of neuroimaging to the
diagnostic pathway in ALS so far has been the ability of
MRI to exclude alternative pathological causes. However,
the imaging discipline is evolving, and multimodal
neuroimaging has made major progress in the
confirmation that ALS is a multisystem cerebral
neurodegenerative disorder.96 The key neuroimaging
findings, some with potential as biomarkers, are
discussed in panel 3.

Management and prevention

Riluzole, an inhibitor of glutamate release, is a diseasemodifying (neuroprotective) therapy for patients with
ALS (panel 4). In two large randomised controlled trials,
riluzole extended survival of patients by 36 months.126128
This benefit seemed greater for management of patients
in specialised multidisciplinary ALS clinics than in other
settings,129 with most beneficial eects seen in patients
with moderate functional impairment.130
www.thelancet.com Vol 377 March 12, 2011

Seminar

Panel 3: Key neuroimaging findings in ALS

MRI corticospinal tract hyperintensity
Hyperintensity of the corticospinal tracts as seen on MRI can be
prominent in ALS,85,97 but this feature is not specific to the
disease (figure 5A).
Cerebral atrophy detection with MRI
Voxel-based morphometry has quantified grey and white
matter to detect cerebral atrophy in patients with ALS98 linked
to cognitive impairment,99 with notable dierences in regional
emphasis between patients with sporadic disease and those
with familial disease who have a longer life expectancy.100
3-Dimensional rendering of the brain by use of MRI might also
serve to highlight focal abnormality (figure 6).
Magnetic resonance spectroscopy
The measurement of proton-containing metabolites such as
N-acetylaspartate (expressed as a ratio with creatine/
phosphocreatine or choline) has served as a marker of neuronal
loss. Patients with ALS have a reduced primary motor cortex
N-acetylaspartate to creatine ratio compared with controls,101
and use of magnetic resonance spectroscopy seems particularly
sensitive in the detection of upper motor neuron dysfunction,
distinguishing patients with progressive muscular atrophy
from those with ALS.102
Diusion tensor imaging
Diusion tensor imaging can be used to exploit the sensitivity
of MRI to identify the direction of water diusion, which is
expected to be restricted (ie, anisotropic) within intact neuronal
pathways and more diuse (isotropic) in regions of reduced
integrity. Quantifiable measures such as fractional anisotropy
and mean diusivity are powerful surrogate markers of
neuronal pathological changes,103 and inter-connectivity
between neuronal pathways can be mapped using the allied
technique of tractography (figure 5B).104 Use of diusion tensor
imaging can detect reduced fractional anisotropy within the
corticospinal tract of patients with ALS.105
Functional studies
Results of PET activation studies with 2-18fluoro-2-deoxy-Dglucose and H215O have indicated widespread extramotor
changes in patients with ALS,106 with frontal deficits linked to
neuropsychological impairment,107 providing clear application to

Symptomatic treatments remain the cornerstone of

management for patients with ALS (panel 5).28 For
some patients, these treatments not only alleviate
symptoms but also improve survival and quality of
life.131 Optimum care for patients with ALS is provided
within a multidisciplinary environment where
physiotherapists, occupational therapists, speech
therapists, respiratory physicians, gastroenterologists,
and social workers collaborate to guide symptomatic
management through the course of disease.132
Multidisciplinary models of care have developed as a
predictor of survival, reducing the risk of death by 45%
www.thelancet.com Vol 377 March 12, 2011

the emerging clinicopathological overlap between ALS and

FTD.108 Non-invasive study of brain activation by functional MRI
exploits dierences in the resonant properties of
oxyhaemoglobin versus deoxyhaemoglobin (blood oxygenation
level dependent [BOLD]-functional MRI). By analysing wholebrain BOLD-functional MRI activity in the resting state,
functionally interconnected brain regions can be identified.109
Results from studies in patients with ALS have shown both
default mode and sensorimotor network activation changes.110
This technique has the potential to further delineate the
extramotor cerebral pathological changes in patients with ALS.
Molecular imaging
Receptor ligand PET has been used to study molecular
mechanisms in ALS. Data from 11C-flumazenil PET have
indicated reduced inhibitory GABAergic cortical eects in ALS,111
in keeping with the hypothesis of cortical hyperexcitability as a
fundamental aspect of ALS pathogenesis.112 Use of the
benzodiazepine receptor PET ligand 11C-PK11195 revealed
widespread microglial activation in ALS,113 supported by the
finding of inflammatory biomarkers in the cerebrospinal fluid.114
The pronounced frontotemporal reductions in the binding of
the 5-HT1A receptor ligand 11C-WAY100635 in patients with
ALS,115 and data from neuropathological receptor studies that
revealed similar changes in FTD,116 suggest that serotonergic
mechanisms warrant further study in relation to pathogenesis.
Finally, paramagnetic properties of small particles of iron oxide,
which can be used as intravenous contrast agents, might
indicate the start of the era of molecular MRI,117 with potential
to understand inflammatory mechanisms118 and therapeutic
stem-cell tracking.119
Detection of presymptomatic markers of disease
The poor definition of the population at risk for sporadic ALS
impedes attempts to identify an early, presymptomatic
diagnostic biomarker. Results from a diusion tensor imaging
study of presymptomatic patients with a highly penetrant
dominant SOD1 gene mutation revealed changes in the posterior
limb of the internal capsule not seen in healthy controls, which
might be among the earliest detectable changes.120
ALS=amyotrophic lateral sclerosis. FTD=frontotemporal dementia.

at 5 years. Compared with patients managed in a

general neurology clinic, patients managed in a
specialised clinic had a better quality of life, possibly
attributable to more eective use of resources, with
benefits derived after a single visit.132
Respiratory function and nutrition are crucial
symptomatic concerns for patients with ALS, with
respiratory failure being the main cause of death.81 Expert
consensus guideline recommendations have been
developed for key care concerns in ALS, including
respiratory management, nutrition, and palliative care.81,131
A positive outlook should be emphasised.133
949

Seminar

Panel 4: Controversy in ALSclinical trials

Although clinical trials of ALS have been done since the 1980s, riluzole is the only drug of
proven ecacy for treatment of this disorder. The failure of ALS clinical trials to lead to
substantial benefits has been attributed to several potential design problems at preclinical
and clinical levels:
Preclinical
Inappropriate mouse model. Until recently, the SOD1 mouse model has been the
benchmark for testing potential neuroprotectants in ALS.121 However, as SOD1
mutations account for about 2% of all ALS cases, the mouse model might have little
relevance to human sporadic disease. Furthermore, this model undergoes a series of
stereotypical changes that begin with hind limb weakness. The recent development
of mouse models with mutations in the gene encoding TDP-43 is a potential
advance in therapeutic development for ALS, providing basic scientists with a new,
perhaps more relevant, platform for studying novel therapies.122
Inappropriate timing of introducing drugs and dosing problems. Some investigators
have studied the eects of presymptomatic delivery of drugs on disease onset.123
Although this timing might contribute towards understanding the subclinical
processes that underlie motor neuron degeneration, it seems to be of little relevance
for treatment of sporadic ALS. Many preclinical studies have also examined ultra-high
doses of drugs that would probably translate into plasma concentrations far beyond
that tolerable by human patients. Some investigators have advocated that the highest
tolerable dose should not be assumed to produce the best outcome.124
Clinical
Trial design. There is increasing need for more eective screening of pharmacological
drugs during phase 2 trials because after this period of clinical development a
decision is made to proceed with confirmatory testing (ie, a phase 3 trial) or to reject
the drug as ineective. The distinction between phase 2 and phase 3 trials in ALS
becomes blurred, because providing preliminary evidence of drug ecacy in this
disease at the phase 2 level is dicult. The absence of an eective biomarker is a
major contributing reason. Therefore, the dilemma remains whether to use ecient
statistical strategies for minimising trial duration and sample size, to increase the
chance of proceeding with a phase 3 trial (ie, higher false-positive rate), or to do
phase 3 clinical trials tailored as phase 2 clinical trials (ie, higher false-negative rate).
The latter approach is perhaps one that is now rarely done, given recent advances in
statistical design.125 Investigators are also proceeding with phase 3 clinical trials, even
in the absence of preliminary evidence of ecacy in human patients.
Choice of primary endpoint. Changes in the primary endpoint establish whether a trial
will be successful. The choice of the correct primary endpoint in ALS clinical trials has
been debated. Trials that use functional scales and measures of strength as primary
endpoints have dominated the field, whereas trials mainly concerned with improved
survival of patients have been few and far between recently. The design and clinical
benefits of the former include: smaller sample size, shorter trial duration, and clinically
meaningful treatment eects. Nevertheless, measurement of survival might be the
only means of determining whether a treatment eect truly exists, given the large
extent of motor neuron loss from the time of symptom onset. For example, riluzole
has small but significant eects on the function of patients, detectable with sample
sizes far beyond that required to realise its survival benefit.
ALS=amyotrophic lateral sclerosis.

Respiratory failure indicates combined degeneration of

central respiratory centres and motor neurons contributing
to the phrenic nerve. Respiratory compromise is commonly
present at diagnosis in patients with ALS.28 Nocturnal
hypoxia, and associated symptoms of lethargy, loss of
950

Figure 5: Standard and experimental MRI sequences in patients with ALS

(A) T2-weighted FLAIR sequence shows hyperintense corticospinal tracts in a
patient with ALS on this coronal view (arrows), but this feature is neither
sensitive nor specific in the absence of other more obvious clinical symptoms.
(B) Diusion tensor tractography is a research-based MRI technique that has
potential to study extramotor and motor neuronal pathway involvement in ALS
(superior oblique cut-out brain section viewed from left). In this patient with an
unusual ALS phenotype that included prominent aphasia, reconstruction of the
temporal lobe white matter projection fibres indicated that there were fewer
fibres on the left (blue) compared with the right (red) side. ALS=amyotrophic
lateral sclerosis. FLAIR=Fluid-attenuated inversion-recovery.

Figure 6: 3-Dimensional MRI of a brain of a patient with primary lateral

sclerosis, as shown from above
Arrows show visibly widened precentral sulci with relative atrophy of the adjacent
gyri, notably the motor strips. Macroscopic atrophy as seen here is rare in patients
with typical ALS, but is more frequently noted in those with primary lateral
sclerosis, who have a predominantly upper motor neuron burden of disease. This
figure highlights the late stage of a corticomotoneuronal process postulated to
be inherent in ALS more generally. ALS=amyotrophic lateral sclerosis.

concentration, morning headaches, and unrefreshed sleep

are consequences of central dysfunction. Diaphragmatic
weakness can be diagnosed with spirometry, with vital
capacity undergoing a progressive decline over the course
of disease. Measures of inspiratory muscle strength, such
as maximum inspiratory pressure and sni nasal
inspiratory pressure, are more accurate predictors of
respiratory dysfunction than is vital capacity, and might be
more feasible in patients with substantial facial muscle
weakness (ie, who are unable to form a tight lip seal).28,81
Although undertaking polysomnography might be the
optimum approach to identify nocturnal hypoxic
episodes, nocturnal pulse oximetry is usually adequate
in patients with ALS.81 Non-invasive ventilation improves
quality of life in patients with ALS and improves
survival.134 Guidelines for instituting non-invasive
ventilation rely on a combination of symptoms that
www.thelancet.com Vol 377 March 12, 2011

Seminar

Panel 5: Symptomatic care in ALS

Weakness and disability
Orthotics (eg, ankle foot orthosis, neck collars)
Physiotherapy
Adaptive aids (eg, walking frame, wheelchair)
Dysphagia
Assessment by speech therapist and dietitian
Safe swallowing techniques and modified diet
Insertion of gastrostomy tube
Dyspnoea and poor cough
Ventilatory support
Morphine or benzodiazepines
Chest physiotherapy
Suction machine
Manually assisted coughing techniques
Pain (ie, musculoskeletal pain and cramps, fasciculations
and spasticity, skin pressure pain caused by immobility)
Physiotherapy, NSAIDs
Muscle relaxants (baclofen, botulinum toxin)
Anticonvulsants (eg, gabapentin)
Re-positioning and pressure area care
Opioid drugs
Pressure-relieving cushions and mattress
Dysarthria
Assessment by speech pathologist
Communication aids
Educate family and caregivers

Thickened saliva
Natural remedies (eg, papaya)
Ensure adequate hydration
Saline nebulisers; nebulised N-acetylcysteine
Suctioning of the mouth
Mouth care
Emotional lability
Educate patients with ALS and caregivers
Amitriptyline
Benzodiazepines
Dextromethorphan hydrobromide/quinidine sulfate
Depression and anxiety
Counselling
Benzodiazepines
Antidepressants
Sleep disturbance
Treat underlying problem
Respiratory review, non-invasive ventilation
Benzodiazepines, tricyclic antidepressants
Constipation
Dietary changes (eg, increase fluid and fibre intake)
Use formulations high in bran, bulk, or fibre
Regular oral aperients (Movicol [Norgine, the Netherlands]
or suppositories).
ALS=amyotrophic lateral sclerosis. Data from Andersen and colleagues81 and Miller and
colleagues.131

Cognitive changes (frontal lobe dysfunction or dementia)

Explain symptomatology to caregivers and family
Antidepressant therapies
Sialorrhoea
Anticholinergic antidepressants (eg, amitriptyline)
Anticholinergic drugs (eg, glycopyrronium bromide)
Botulinum toxin injections
Radiation of salivary glands
Mouth-care products
Suction

signify respiratory muscle weakness (dyspnoea and

orthopnoea), along with signs of respiratory muscles
weakness, including substantial desaturation on
overnight oximetry, increased partial pressure of carbon
dioxide (PCO2) of less than 65 mm Hg and reduced
forced vital capacity of less than 80% or sni nasal
inspiratory pressure of less than 40 cmH2O.28,81 Patients
with substantial bulbar impairment and sialorrhoea
might not tolerate non-invasive ventilation, and
appropriate management of secretions is crucial.28 In
patients with ALS who are intolerant of non-invasive
ventilation, when this form of ventilation is no longer
sucient because of progressive respiratory muscle
weakness, invasive ventilation via tracheostomy is an
www.thelancet.com Vol 377 March 12, 2011

option.81 Although invasive ventilation prolongs survival,

this approach is rarely used in most countries because of
the practical challenges involved, the expense, and the
profound loss of quality of life.135 In terms of symptomatic
therapy, subcutaneous morphine provides great relief in
patients who have dyspnoea at rest.81,136
Malnutrition is a key determinant of prognosis.137 The
development of malnutrition in ALS is multifactorial,
and includes reduced food intake secondary to dysphagia,
as well as hypermetabolism.81,138 About 5060% of patients
with ALS have a hypermetabolic state,139,140 which seems
to be stable over the course of the disease and is
dependent on age, sex, and fat-free mass.139 The increase
in metabolic rate, as measured by resting energy
951

Seminar

Panel 6: Controversy in ALSalternative and o-label

treatments
Given the terminal nature of ALS, the fact that patients are
often willing to experiment with unproven therapies is not
surprising. Popular alternative and o-label treatments have
included insulin-life growth factor-1, lithium carbonate,70
minocycline,144 and stem-cell therapy. Patients should take
caution when starting alternative and o-label treatments.
As identified by some ALS clinical trials, some treatments can
accelerate the progression of muscle weakness and
negatively aect survival.

For more on ALSUntangled see

http://www.alsuntangled.com/
index.html

To keep the ALS community informed of available

alternative and o-label treatments, an internet-based
initiative, ALSUntangled, has been established recently.145
ALSUntangled enables the exchange of information about
new alternative and o-label treatments between patients
with ALS and clinicians. Patients with ALS are encouraged to
share newly hypothesised alternative and o-label
treatments, as the goal of this initiative is to consolidate and
convey information about cost, scientific and ethical basis,
and potential benefits and risks of every so-called treatment.
ALS=amyotrophic lateral sclerosis.

expenditure, is associated with reduced survival.139

Although the mechanisms that underlie a hypermetabolic
state are unclear, dysfunction of muscle mitochondria is
implicated in the pathogenesis of ALS.141
Insertion of a percutaneous gastrostomy tube ensures
sucient caloric and fluid intake, and should be oered to
patients who have substantial weight loss, even in the
absence of dysphagia.81 Implementing a gastrostomy
should be discussed early in the disease course because
morbidity increases when vital capacity is less than 50%.142
Attention to the many symptoms that might develop
during the course of the disease is essential to improve
the quality of life for patients with ALS (panel 5).143 The
terminal phase of ALS can be associated with restlessness,
anxiety, pain, and dyspnoea, and well coordinated multidisciplinary palliative care is needed. Finally, patients
might also seek alternative treatments (panel 6), often
with little evidence of benefit for ALS, and at great
personal financial cost.146

Conclusions
Let us keep looking, in spite of everything. Let us keep
searching. It is indeed the best method of finding, and
perhaps thanks to our eorts, the verdict we will give
such a patient tomorrow will not be the same we must
give this man today.
Charcot (1889)

By contrast with the previous century of little progress,

the recent developments in understanding, particularly
with regards to the genetics, clinical phenotypes, and
952

more general pathophysiology of ALS, encourage realistic

hope that new treatment approaches will emerge.
Contributors
BCC and MCZ did the literature search and contributed to sections on
management and prevention of ALS. OH and MRT contributed to the
review of the literature and the writing of the paper. MCK did the
literature review, coordinated authors writing, revision, and editing,
wrote the first draft, prepared figures, and finalised the manuscript.
JRB wrote the section on clinical phenotypes and on FTD-ALS, and
was involved in revising the manuscript. SV searched the literature,
was involved in writing and proofreading the paper, and helped
prepare the figures. AE contributed to the sections on management
and prevention of ALS and to the writing of the paper.
Conflicts of interest
OH has consulted for ONO Pharmaceuticals and KNOPP
Pharmaceuticals, and has received research support from
Sanofi-Aventis and Serono Pharmaceuticals. OH has received advisory
board fees from Novartis, Biogen, and Merck Sorono, and has received
travel and accommodation sponsorship from Merck Sorono. She is the
inventor of a patent held by the Royal College of Surgeons in Ireland
for the use of angiogenin as a therapeutic in ALS. Funding sources
include the National Health and Medical Research Council of Australia
(project grants 510233 and 568743; MCK); the Motor Neurone Disease
Research Institute of Australia (MCK); the Irish Health Research Board
(OH); American ALS Association (OH); the Irish Motor Neurone
Disease Research Foundation (OH); and the Medical Research Council
(Lady Edith Wolfson Clinician Scientist Fellowship; MRT). SV has
received the Clive and Vera Ramacciotti grant and the Charles Viertel
grant, and has received fees for advisory board from Merck Serono
Australia, Novartis Australia, and Biogen (not related to the topic
covered in this paper). BCC, AE, JRB, and MCZ declare that they have
no conflicts of interest.
Acknowledgments
The authors gratefully acknowledge the input of Marcus Cremonese for
illustrations, Pamela Dawes and the Medical Illustrations Unit, Prince of
Wales Hospital, Australia, for clinical photography, and Ricarda Menke
for the image analysis and assistance in production of the MRI figures.
References
1
Fang F, Kamel F, Sandler DP, Sparen P, Ye W. Maternal age,
exposure to siblings, and risk of amyotrophic lateral sclerosis.
Am J Epidemiol 2008; 167: 128186.
2
Sutedja NA, Veldink JH, Fischer K, et al. Exposure to chemicals
and metals and risk of amyotrophic lateral sclerosis: a systematic
review. Amyotroph Lateral Scler 2009; 10: 30209.
3
Logroscino G, Traynor BJ, Hardiman O, et al. Incidence
of amyotrophic lateral sclerosis in Europe.
J Neurol Neurosurg Psychiatry 2009; 81: 38590.
4
Cronin S, Hardiman O, Traynor BJ. Ethnic variation in the
incidence of ALS: a systematic review. Neurology 2007; 68: 100207.
5
Zaldivar T, Gutierrez J, Lara G, Carbonara M, Logroscino G,
Hardiman O. Reduced frequency of ALS in an ethnically mixed
population: a population-based mortality study. Neurology 2009;
72: 164045.
6
Maruyama H, Morino H, Ito H, et al. Mutations of optineurin
in amyotrophic lateral sclerosis. Nature 2010; 465: 22326.
7
Beleza-Meireles A, Al-Chalabi A. Genetic studies of amyotrophic
lateral sclerosis: controversies and perspectives.
Amyotroph Lateral Scler 2009; 10: 114.
8
Sreedharan J, Blair IP, Tripathi VB, et al. TDP-43 mutations in
familial and sporadic amyotrophic lateral sclerosis. Science 2008;
319: 166872.
9
Kwiatkowski TJ Jr, Bosco DA, Leclerc AL, et al. Mutations in the
FUS/TLS gene on chromosome 16 cause familial amyotrophic
lateral sclerosis. Science 2009; 323: 120508.
10 Vance C, Rogelj B, Hortobagyi T, et al. Mutations in FUS, an RNA
processing protein, cause familial amyotrophic lateral sclerosis
type 6. Science 2009; 323: 120811.
11 Greenway MJ, Andersen PM, Russ C, et al. ANG mutations
segregate with familial and sporadic amyotrophic lateral sclerosis.
Nat Genet 2006; 38: 41113.

www.thelancet.com Vol 377 March 12, 2011

Seminar

12
13
14
15

16
17
18
19
20

21
22
23
24
25
26
27
28
29
30
31
32
33
34
35

36
37

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.
Fallis BA, Hardiman O. Aggregation of neurodegenerative disease
in ALS kindreds. Amyotroph Lateral Scler 2009; 10: 9598.
van Es MA, Veldink JH, Saris CG, et al. Genome-wide association
study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for
sporadic amyotrophic lateral sclerosis. Nat Genet 2009; 41: 108387.
Davenport RJ, Swingler RJ, Chancellor AM, Warlow CP. Avoiding
false positive diagnoses of motor neuron disease: lessons from the
Scottish Motor Neuron Disease Register.
J Neurol Neurosurg Psychiatry 1996; 60: 14751.
Ringel SP, Murphy JR, Alderson MK, et al. The natural history
of amyotrophic lateral sclerosis. Neurology 1993; 43: 131622.
Kuwabara S, Sonoo M, Komori T, et al. Dissociated small hand
muscle atrophy in amyotrophic lateral sclerosis: frequency, extent,
and specificity. Muscle Nerve 2008; 37: 42630.
Van Damme P, Dewil M, Robberecht W, Van Den Bosch L.
Excitotoxicity and amyotrophic lateral sclerosis.
Neurodegener Dis 2005; 2: 14759.
Gordon PH, Cheng B, Katz IB, et al. The natural history of primary
lateral sclerosis. Neurology 2006; 66: 64753.
Vucic S, Burke D, Kiernan MC. Diagnosis of motor neuron
disease. In: Kiernan MC, ed. The Motor Neuron Disease
Handbook. Sydney: Australasian Medical Publishing Company
Limited, 2007: 89115.
Ferguson TA, Elman LB. Clinical presentation and diagnosis of
amyotrophic lateral sclerosis. NeuroRehabilitation 2007; 22: 40916.
Duy JR, Peach RK, Strand EA. Progressive apraxia of speech
as a sign of motor neuron disease. Am J Speech Lang Pathol 2007;
16: 198208.
Talbot K. Motor neuron disease: the bare essentials.
Pract Neurol 2009; 9: 30309.
Vucic S, Kiernan MC. Abnormalities in cortical and peripheral
excitability in flail arm variant amyotrophic lateral sclerosis.
J Neurol Neurosurg Psychiatry 2007; 78: 84952.
Gordon PH, Cheng B, Katz IB, et al. The natural history of primary
lateral sclerosis. Neurology 2006; 66: 64753.
Stambler N, Charatan M, Cedarbaum JM, Group ACTS. Prognostic
indicators of survival in ALS. Neurology 1998; 50: 6672.
Ramirez C, Piemonte MEP, Callegaro D, Da Silva HCA. Fatigue
in amyotrophic lateral sclerosis: frequency and associated factors.
Amyotroph Lateral Scler 2008; 9: 7580.
Leigh PN, Abrahams S, Al-Chalabi A, et al. The management of
motor neurone disease. J Neurol Neurosurg Psychiatry 2003; 74: S3247.
Neumann M, Sampathu DM, Kwong LK, et al. Ubiquitinated
TDP-43 in frontotemporal lobar degeneration and amyotrophic
lateral sclerosis. Science 2006; 314: 13033.
Lomen-Hoerth C, Anderson T, Miller B. The overlap of amyotrophic
lateral sclerosis and frontotemporal dementia. Neurology 2002;
59: 107779.
Morita M, Al-Chalabi A, Andersen PM, et al. A locus on
chromosome 9p confers susceptibility to ALS and frontotemporal
dementia. Neurology 2006; 66: 83944.
Vance C, Al-Chalabi A, Ruddy D, et al. Familial amyotrophic lateral
sclerosis with frontotemporal dementia is linked to a locus on
chromosome 9p13.221.3. Brain 2006; 129: 86876.
Le Ber I, Camuzat A, Berger E, et al. Chromosome 9p-linked
families with frontotemporal dementia associated with motor
neuron disease. Neurology 2009; 72: 166976.
Laaksovirta H, Peuralinna T, Schymick JC, et al. Chromosome 9p21
in amyotrophic lateral sclerosis in Finland: a genome-wide
association study. Lancet Neurol 2010; 9: 97885.
Shatunov A, Mok K, Newhouse S, et al. Chromosome 9p21 in
sporadic amyotrophic lateral sclerosis in the UK and seven other
countries: a genome-wide association study. Lancet Neurol 2010;
9: 98694.
Ringholz GM, Appel SH, Bradshaw M, Cooke NA, Mosnik DM,
Schulz PE. Prevalence and patterns of cognitive impairment in
sporadic ALS. Neurology 2005; 65: 58690.
Flaherty-Craig C, Eslinger P, Stephens B, Simmons Z. A rapid
screening battery to identify frontal dysfunction in patients with
ALS. Neurology 2006; 67: 207072.

www.thelancet.com Vol 377 March 12, 2011

38

39
40
41
42
43
44
45
46
47

48
49
50

51
52
53

54

55
56
57
58
59
60
61

Merrilees J, Klapper J, Murphy J, Lomen-Hoerth C, Miller BL.

Cognitive and behavioral challenges in caring for patients with
frontotemporal dementia and amyotrophic lateral sclerosis.
Amyotroph Lateral Scler 2010; 11: 298302.
Neumann M, Kwong LK, Lee EB, et al. Phosphorylation of S409/410
of TDP-43 is a consistent feature in all sporadic and familial forms
of TDP-43 proteinopathies. Acta Neuropathol 2009; 117: 13749.
Abrahams S, Leigh PN, Goldstein LH. Cognitive change in ALS:
a prospective study. Neurology 2005; 64: 122226.
Vucic S, Kiernan MC. Pathophysiology of degeneration in familial
amyotrophic lateral sclerosis. Curr Mol Med 2009; 9: 25572.
Pasinelli P, Brown RH. Molecular biology of amyotrophic lateral
sclerosis: insights from genetics. Nat Rev Neurosci 2006;
7: 71023.
Neusch C, Bahr M, Schneider-Gold C. Glia cells in amyotrophic
lateral sclerosis: new clues to understanding an old disease?
Muscle Nerve 2007; 35: 71224.
Harwood CA, McDermott CJ, Shaw PJ. Physical activity as an
exogenous risk factor in motor neuron disease (MND): a review of
the evidence. Amyotroph Lateral Scler 2009; 10: 191204.
Kasarskis EJ, Lindquist JH, Coman CJ, et al. Clinical aspects of
ALS in Gulf War veterans. Amyotroph Lateral Scler 2009; 10: 3541.
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.
Wicks P, Ganesalingham J, Collin C, Prevett M, Leigh NP,
Al-Chalabi A. Three soccer playing friends with simultaneous
amyotrophic lateral sclerosis. Amyotroph Lateral Scler 2007;
8: 17779.
Gallo V, Bueno-De-Mesquita HB, Vermeulen R, et al. Smoking and
risk for amyotrophic lateral sclerosis: analysis of the EPIC cohort.
Ann Neurol 2009; 65: 37885.
Cox PA, Sacks OW. Cycad neurotoxins, consumption of flying foxes,
and ALS-PDC disease in Guam. Neurology 2002; 58: 95659.
Bruijn LI, Beal MF, Becher MW, et al. Elevated free nitrotyrosine
levels, but not protein-bound nitrotyrosine or hydroxyl radicals,
throughout amyotrophic lateral sclerosis (ALS)-like disease
implicate tyrosine nitration as an aberrant in vivo property of one
familial ALS-linked superoxide dismutase 1 mutant.
Proc Natl Acad Sci USA 1997; 94: 760611.
Bruijn LI, Houseweart MK, Kato S, et al. Aggregation and motor
neuron toxicity of an ALS-linked SOD1 mutant independent from
wild-type SOD1. Science 1998; 281: 185154.
Bruijn LI, Miller TM, Cleveland DW. Unraveling the mechanisms
involved in motor neuron degeneration in ALS.
Annu Rev Neurosci 2004; 27: 72349.
Liu R, Althaus JS, Ellerbrock BR, Becker DA, Gurney ME.
Enhanced oxygen radical production in a transgenic mouse model
of familial amyotrophic lateral sclerosis. Ann Neurol 1998;
44: 76370.
Zetterstrom P, Stewart HG, Bergemalm D, et al. Soluble misfolded
subfractions of mutant superoxide dismutase-1s are enriched in
spinal cords throughout life in murine ALS models.
Proc Natl Acad Sci USA 2007; 104: 1415762.
Williamson TL, Cleveland DW. Slowing of axonal transport is a very
early event in the toxicity of ALS-linked SOD1 mutants to motor
neurons. Nat Neurosci 1999; 2: 5056.
Watkins JC, Evans RH. Excitatory amino acid transmitters.
Annu Rev Pharmacol Toxicol 1981; 21: 165204.
Heath PR, Shaw PJ. Update on the glutamatergic neurotransmitter
system and the role of excitotoxicity in amyotrophic lateral sclerosis.
Muscle Nerve 2002; 26: 43858.
Meldrum B, Garthwaite J. Excitatory amino acid neurotoxicity and
neurodegenerative disease. Trends Pharmacol Sci 1990; 11: 37987.
Regan RF, Panter SS, Witz A, Tilly JL, Giard RG. Ultrastructure
of excitotoxic neuronal death in murine cortical culture.
Brain Res 1995; 705: 18898.
Maher P, Davis JB. The role of monoamine metabolism in oxidative
glutamate toxicity. J Neurosci 1996; 16: 6394401.
Hensley K, Mhatre M, Mou S, et al. On the relation of oxidative
stress to neuroinflammation: lessons learned from the G93A-SOD1
mouse model of amyotrophic lateral sclerosis.
Antioxid Redox Signal 2006; 8: 207587.

953

Seminar

62
63

64

65

66
67
68
69
70
71
72
73
74

75

76
77

78
79
80
81

82
83

954

Eisen A, Kim S, Pant B. Amyotrophic lateral sclerosis (ALS):

a phylogenetic disease of the corticomotoneuron? Muscle Nerve
1992; 15: 21924.
Browne SE, Yang L, DiMauro JP, Fuller SW, Licata SC, Beal MF.
Bioenergetic abnormalities in discrete cerebral motor pathways
presage spinal cord pathology in the G93A SOD1 mouse model
of ALS. Neurobiol Dis 2006; 22: 599610.
Wong PC, Pardo CA, Borchelt DR, et al. An adverse property of a
familial ALS-linked SOD1 mutation causes motor neuron disease
characterized by vacuolar degeneration of mitochondria. Neuron
1995; 14: 110516.
Lederer CW, Torrisi A, Pantelidou M, Santama N, Cavallaro S.
Pathways and genes dierentially expressed in the motor cortex
of patients with sporadic amyotrophic lateral sclerosis.
BMC Genomics 2007; 8: 26.
Wiedemann FR, Manfredi G, Mawrin C, Beal MF, Schon EA.
Mitochondrial DNA and respiratory chain function in spinal cords
of ALS patients. J Neurochem 2002; 80: 61625.
Sasaki S, Iwata M. Mitochondrial alterations in the spinal cord
of patients with sporadic amyotrophic lateral sclerosis.
J Neuropathol Exp Neurol 2007; 66: 1016.
Ellis DZ, Rabe J, Sweadner KJ. Global loss of Na,K-ATPase and its
nitric oxide-mediated regulation in a transgenic mouse model of
amyotrophic lateral sclerosis. J Neurosci 2003; 23: 4351.
Sasaki S, Iwata M. Impairment of fast axonal transport in the
proximal axons of anterior horn neurons in amyotrophic lateral
sclerosis. Neurology 1996; 47: 53540.
Fornai F, Longone P, Cafaro L, et al. Lithium delays progression
of amyotrophic lateral sclerosis. Proc Natl Acad Sci USA 2008;
105: 205257.
Staats KA, Van Den Bosch L. Astrocytes in amyotrophic lateral
sclerosis: direct eects on motor neuron survival. J Biol Phys 2009;
35: 33746.
Van Deerlin VM, Leverenz JB, Bekris LM, et al. TARDBP mutations
in amyotrophic lateral sclerosis with TDP-43 neuropathology: a
genetic and histopathological analysis. Lancet Neurol 2008; 7: 40916.
Rutherford NJ, Zhang YJ, Baker M, et al. Novel mutations in
TARDBP (TDP-43) in patients with familial amyotrophic lateral
sclerosis. PLoS Genet 2008; 4: e1000193.
Brooks BR. El Escorial World Federation of Neurology criteria for
the diagnosis of amyotrophic lateral sclerosis. Subcommittee on
Motor Neuron Diseases/Amyotrophic Lateral Sclerosis of the World
Federation of Neurology Research Group on Neuromuscular
Diseases and the El Escorial Clinical limits of amyotrophic lateral
sclerosis workshop contributors. J Neurol Sci 1994; 124: 96107.
Miller RG, Munsat TL, Swash M, Brooks BR. Consensus guidelines
for the design and implementation of clinical trials in ALS. World
Federation of Neurology committee on Research. J Neurol Sci 1999;
169: 212.
Kiernan MC. Motor neuron disease: a Pandoras box. MJA 2003;
178: 31112.
Traynor BJ, Codd MB, Corr B, Forde C, Frost E. Hardiman O.
Clinical features of Amyotrophic Lateral Sclerosis according to the
El Escorial and Airlie House Diagnostic Criteria. Arch Neurol 2000;
57: 117176.
Ross MA, Miller RG, Berchert L, et al. Toward earlier diagnosis of
amyotrophic lateral sclerosis: revised criteria. rhCNTF ALS Study
Group. Neurology 1998; 50: 76872.
Beghi E, Balzarini C, Bogliun G, et al. Reliability of the El Escorial
diagnostic criteria for amyotrophic lateral sclerosis.
Neuroepidemiology 2002; 21: 26570.
Chio A. ISIS Survey: an international study on the diagnostic
process and its implications in amyotrophic lateral sclerosis.
J Neurol 1999; 246 (suppl 3): III15.
Andersen PM, Borasio GD, Dengler R, et al. Good practice in the
management of amyotrophic lateral sclerosis: clinical guidelines.
An evidence-based review with good practice points. EALSC
Working Group. Amyotroph Lateral Scler 2007; 8: 195213.
Rocha JA, Reis C, Simoes F, Fonseca J, Mendes Ribeiro J.
Diagnostic investigation and multidisciplinary management in
motor neuron disease. J Neurol 2005; 252: 143547.
Vucic S, Pamphlett R, Wills EJ, Yiannikas C. Polyglucosan body
disease myopathy: an unusual presentation. Muscle Nerve 2007;
35: 53639.

84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102

103
104

105
106
107
108
109

Baloh RH, Rakowicz W, Gardner R, Pestronk A. Frequent atrophic

groups with mixed-type myofibers is distinctive to motor neuron
syndromes. Muscle Nerve 2007; 36: 10710.
Winhammar JM, Rowe DB, Henderson RD, Kiernan MC.
Assessment of disease progression in motor neuron disease.
Lancet Neurol 2005; 4: 22938.
Eisen A, Swash M. Clinical neurophysiology of ALS.
Clin Neurophysiol 2001; 112: 2190201.
Daube JR. Electrodiagnostic studies in amyotrophic lateral sclerosis
and other motor neuron disorders. Muscle Nerve 2000; 23: 1488502.
Eisen A. Clinical electrophysiology of the upper and lower motor
neuron in amyotrophic lateral sclerosis. Sem Neurol 2001;
21: 14154.
Olney RK, Lewis RA, Putnam TD, Campellone JV Jr. Consensus
criteria for the diagnosis of multifocal motor neuropathy.
Muscle Nerve 2003; 27: 11721.
de Carvalho M, Dengler R, Eisen A, et al. Electrodiagnostic criteria
for diagnosis of ALS. Clin Neurophysiol 2008; 119: 497503.
Gubbay SS, Kahana E, Zilber N, Cooper G, Pintov S, Leibowitz Y.
Amyotrophic lateral sclerosis. A study of its presentation and
prognosis. J Neurol 1985; 232: 295300.
Li TM, Day SJ, Alberman E, Swash M. Dierential diagnosis
of motoneurone disease from other neurological conditions.
Lancet 1986; 2: 73133.
Hart IK, Maddison P, Newsom-Davis J, Vincent A, Mills KR.
Phenotypic variants of autoimmune peripheral nerve
hyperexcitability. Brain 2002; 125: 188795.
Traynor BJ, Codd MB, Corr B, Forde C, Frost E, Hardiman O.
Amyotrophic lateral sclerosis mimic syndromes: a population-based
study. Arch Neurol 2000; 57: 10913.
Belsh JM, Sciman PL. The amyotrophic lateral sclerosis (ALS)
patient perspective on misdiagnosis and its reprecussions.
J Neurol Sci 1996; 60: 11016.
Turner MR, Kiernan MC, Leigh PN, Talbot K. Biomarkers in
amyotrophic lateral sclerosis. Lancet Neurol 2009; 8: 94109.
Goodin DS, Rowley HA, Olney RK. Magnetic resonance imaging
in amyotrophic lateral sclerosis. Ann Neurol 1988; 23: 41820.
Ellis CM, Suckling J, Amaro E Jr, et al. Volumetric analysis reveals
corticospinal tract degeneration and extramotor involvement in
ALS. Neurology 2001; 57: 157178.
Chang JL, Lomen-Hoerth C, Murphy J, et al. A voxel-based
morphometry study of patterns of brain atrophy in ALS and
ALS/FTLD. Neurology 2005; 65: 7580.
Turner MR, Hammers A, Allsop J, et al. Volumetric cortical loss
in sporadic and familial amyotrophic lateral sclerosis.
Amyotroph Lateral Scler 2007; 8: 34347.
Pioro EP, Antel JP, Cashman NR, Arnold DL. Detection of cortical
neuron loss in motor neuron disease by proton magnetic resonance
spectroscopic imaging in vivo. Neurology 1994; 44: 193338.
Gredal O, Rosenbaum S, Topp S, Karlsborg M, Strange P,
Werdelin L. Quantification of brain metabolites in amyotrophic
lateral sclerosis by localized proton magnetic resonance
spectroscopy. Neurology 1997; 48: 87881.
Beaulieu C. The basis of anisotropic water diusion in the nervous
systema technical review. NMR Biomed 2002; 15: 43555.
Ciccarelli O, Catani M, Johansen-Berg H, Clark C, Thompson A.
Diusion-based tractography in neurological disorders: concepts,
applications, and future developments. Lancet Neurol 2008;
7: 71527.
Sage CA, Peeters RR, Gorner A, Robberecht W, Sunaert S.
Quantitative diusion tensor imaging in amyotrophic lateral
sclerosis. Neuroimage 2007; 34: 48699.
Kew JJ, Leigh PN, Playford ED, et al. Cortical function in
amyotrophic lateral sclerosis. A positron emission tomography
study. Brain 1993; 116: 65580.
Ludolph AC, Langen KJ, Regard M, et al. Frontal lobe function
in amyotrophic lateral sclerosis: a neuropsychologic and positron
emission tomography study. Acta Neurol Scand 1992; 85: 8189.
Phukan J, Pender NP, Hardiman O. Cognitive impairment in
amyotrophic lateral sclerosis. Lancet Neurol 2007; 6: 9941003.
Damoiseaux JS, Rombouts SA, Barkhof F, et al. Consistent
resting-state networks across healthy subjects.
Proc Natl Acad Sci USA 2006; 103: 1384853.

www.thelancet.com Vol 377 March 12, 2011

Seminar

110 Mohammadi B, Kollewe K, Samii A, Krampfl K, Dengler R,

Munte TF. Changes of resting state brain networks in amyotrophic
lateral sclerosis. Exp Neurol 2009; 217: 14753.
111 Turner MR, Hammers A, Al Chalabi A, et al. Distinct cerebral
lesions in sporadic and D90A SOD1 ALS: studies with [11C]
flumazenil PET. Brain 2005; 128: 132329.
112 Vucic S, Nicholson GA, Kiernan MC. Cortical hyperexcitability may
precede the onset of familial amyotrophic lateral sclerosis.
Brain 2008; 131: 154050.
113 Turner MR, Cagnin A, Turkheimer FE, et al. Evidence of
widespread cerebral microglial activation in amyotrophic lateral
sclerosis: an [(11)C](R)-PK11195 positron emission tomography
study. Neurobiol Dis 2004; 15: 60109.
114 Mitchell RM, Freeman WM, Randazzo WT, et al. A CSF biomarker
panel for identification of patients with amyotrophic lateral
sclerosis. Neurology 2009; 72: 1419.
115 Turner MR, Hammers A, Al Chalabi A, et al. Distinct cerebral
lesions in sporadic and D90A SOD1 ALS: studies with [11C]
flumazenil PET. Brain 2005; 128: 132329.
116 Bowen DM, Procter AW, Mann DM, et al. Imbalance of a
serotonergic system in frontotemporal dementia: implication
for pharmacotherapy. Psychopharmacology 2008; 196: 60310.
117 Shapiro EM, Skrtic S, Sharer K, Hill JM, Dunbar CE, Koretsky AP.
MRI detection of single particles for cellular imaging.
Proc Natl Acad Sci USA 2004; 101: 1090106.
118 Jander S, Schroeter M, Saleh A. Imaging inflammation in acute
brain ischemia. Stroke 2007; 38: 64245.
119 Sykova E, Jendelova P. In vivo tracking of stem cells in brain
and spinal cord injury. Prog Brain Res 2007; 161: 36783.
120 Ng MC, Ho JT, Ho SL, et al. Abnormal diusion tensor in
nonsymptomatic familial amyotrophic lateral sclerosis with
a causative superoxide dismutase 1 mutation.
J Magn Reson Imaging 2008; 27: 813.
121 Gurney ME, Pu H, Chiu AY, et al. Motor neuron degeneration in
mice that express a human Cu,Zn superoxide dismutase mutation.
Science 1994; 264: 177275.
122 Wegorzewska I, Bell S, Cairns NJ, Miller TM, Baloh RH. TDP-43
mutant transgenic mice develop features of ALS and
frontotemporal lobar degeneration. Proc Natl Acad Sci USA 2009;
106; 1880914.
123 Benatar M. Lost in translation: treatment trials in the SOD1 mouse
and in human ALS. Neurobiol Dis 2007; 26: 113.
124 Leigh PN, Meininger V, Bensimon G, Cudkowicz M, Robberecht W.
Minocycline for patients with ALS. Lancet Neurol 2008; 7: 11920.
125 Schoenfeld DA, Cudkowicz M. Design of phase II ALS clinical
trials. Amyotroph Lateral Scler 2008; 9: 1623.
126 Miller RG, Mitchell JD, Lyon M, Moore DH. Riluzole for
amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND).
Cochrane Database Syst Rev. 2007; 1: CD001447.
127 Bensimon GL, Lacomblez L, Meininger V. A controlled trial of
riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group.
N Engl J Med 1994 330: 58591.
128 Lacomblez L, Bensimon G, Leigh PN, Guillet P, Meininger V.
Dose-ranging study of riluzole in amyotrophic lateral sclerosis.
ALS/Riluzole Study Group II. Lancet 1996; 347: 142531.
129 Traynor BJ, Alexander M, Corr B, Frost E, Hardiman O. An
outcome study of riluzole in amyotrophic lateral sclerosis-a
population-based study in Ireland, 19962000. J Neurol 2003;
250: 47379.

www.thelancet.com Vol 377 March 12, 2011

130 Bensimon G, Lacomblez L, Delumeau JC, Bejuit R, Trunet P,

Meininger V. A study of riluzole in the treatment of advanced stage
or elderly patients with amyotrophic lateral sclerosis. J Neurol 2002;
249: 60915.
131 Miller RG, Jackson CE, Kasarskis EJ, et al. Practice parameter
update: the care of the patient with amyotrophic lateral sclerosis:
multidisciplinary care, symptom management, and cognitive/
behavioral impairment (an evidence-based review): report of the
Quality Standards Subcommittee of the American Academy of
Neurology. Neurology 2009; 73: 122733.
132 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.
133 Sathasivam S. Managing patients with amyotrophic lateral sclerosis.
Eur J Intern Med 2009; 20: 35558.
134 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.
135 Bourke SC, Gibson GJ. Non-invasive ventilation in ALS: current
practice and future role. Amyotroph Lateral Scler Other Motor Neuron
Disord 2004; 5: 6771.
136 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. Eur J Neurol
2005; 12: 92138.
137 Desport JC, Torny F, Lacoste M, Preux PM, Couratier P.
Hypermetabolism in ALS: correlations with clinical and paraclinical
parameters. Neurodegener Dis 2005; 2: 20207.
138 Funalot B, Desport JC, Sturtz F, Camu W, Couratier P. High
metabolic level in patients with familial amyotrophic lateral
sclerosis. Amyotroph Lateral Scler 2009; 10: 11317.
139 Desport JC, Torny F, Lacoste M, Preux PM, Couratier P.
Hypermetabolism in ALS: correlations with clinical and paraclinical
parameters. Neurodegener Dis 2005; 2: 20207.
140 Bouteloup C, Desport JC, Clavelou P, et al. Hypermetabolism in
ALS patients: an early and persistent phenomenon. J Neurol 2009;
256: 123642.
141 Dupuis L, Gonzalez de Aguilar JL, Echaniz-Laguna A, et al. Muscle
mitochondrial uncoupling dismantles neuromuscular junction and
triggers distal degeneration of motor neurons. PLoS One 2009;
4: e5390.
142 Shaw AS, Ampong MA, Rio A, et al. Survival of patients with ALS
following institution of enteral feeding is related to pre-procedure
oximetry: a retrospective review of 98 patients in a single centre.
Amyotroph Lateral Scler 2006; 7: 1621.
143 Brownlee A, Palovcak M. The role of augmentative communication
devices in the medical management of ALS. NeuroRehabilitation
2007; 22: 44550.
144 Gordon PH, Moore DH, Miller RG, et al. Ecacy of minocycline in
patients with amyotrophic lateral sclerosis: a phase III randomised
trial. Lancet Neurol 2007; 6: 104553.
145 The ALSUntangled Group. ALSUntangled update 1: investigating a
bug (Lyme disease) and a drug (Iplex) on behalf of people with ALS.
Amyotroph Lateral Scler 2009; 10: 24850.
146 Wasner M, Klier H, Borasio GD. The use of alternative medicine by
patients with amyotrophic lateral sclerosis. J Neurol Sci 2001;
191: 15154.

955