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NATURE REVIEWS | NEUROLOGY VOLUME 7 | NOVEMBER 2011 | 639

Department of
Neurology, School of
Medicine, Room 5.41,
5th Floor, Biomedical
Science Building, Trinity
College Dublin,
Dublin 2, Ireland
(O. Hardiman).
Department of
Neurology, Rudolf
Magnus Institute of
Neuroscience,
University Medical
Center Utrecht,
Heidelberglaan 100,
3508 GA Utrecht, The
Netherlands (L. H. van
den Berg). Prince of
Wales Clinical School,
University of New South
Wales, High Street,
Randwick, Sydney, NSW
2031, Australia
(M. C. Kiernan).
Correspondence to:
O. Hardiman
orla@hardiman.net
Clinical diagnosis and management
of amyotrophic lateral sclerosis
Orla Hardiman, Leonard H. van den Berg and Matthew C. Kiernan
Abstract | Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that results in progressive
loss of bulbar and limb function. Patients typically die from respiratory failure within 3 years of symptom
onset. The incidence of ALS in Europe is 2–3 cases per 100,000 individuals in the general population,
and the overall lifetime risk of developing the disease is 1:400. ALS is familial in 5% of cases, and
shows a Mendelian pattern of inheritance. ALS is recognized to overlap with frontotemporal dementia.
Diagnosis is made on clinical grounds, using internationally recognized consensus criteria, after exclusion
of conditions that can mimic ALS. The Revised ALS Functional Rating Scale is currently the most widely
used assessment tool; scores are used to predict survival, and have been employed extensively in clinical
trials. Riluzole remains the only effective drug, and extends the average survival of patients by 3–6 months.
Optimal treatment is based on symptom management and preservation of quality of life, provided in a
multidisciplinary setting. The discovery of further effective disease-modifying therapies remains a critical
need for patients with this devastating condition.
Hardiman, O. et al. Nat. Rev. Neurol. 7, 639–649 (2011); published online 11 October 2011; doi:10.1038/nrneurol.2011.153
Introduction
Amyotrophic lateral sclerosis (ALS) is one of the motor
neuron diseases. In the USA it is commonly known as
Lou Gehrig’s disease, after the baseball player diagnosed
with this disease in 1939. The clinical features of ALS are
those of progressive neurological deterioration involving
the corticospinal tract, brainstem and anterior horn cells
of the spinal cord.
1,2
Clinical, pathological and genetic
advances indicate heterogeneity in phenotype, patho-
logical substrate and genetic predisposition, suggesting
that ALS should be considered a syndrome rather than a
single disease entity.
3–5
Although the clinical presentation
and progression of ALS varies considerably, the course
is inexorably progressive, and over 60% of patients die
within 3 years of presentation. Of the remaining patients,
up to 10% survive for more than 8 years.
2
ALS is familial in 5% of cases, and shows a Mendelian
pattern of inheritance.
6
The clinical phenotype of
familial ALS is similar to that of the sporadic form of the
disease. At least 15 genes have been associated with
the various types of familial ALS, and variants in these
genes account for 30% of these cases.
3
Sporadic ALS is
considered to be a complex disease, in which genetic and
environmental factors combine to increase the risk of
developing the condition.
3
Identification of these genetic
and environmental risks has been challenging owing to
a combination of factors, including the relatively low
incidence rate of ALS, disease heterogeneity, genetic
diversity across populations, and reduced penetrance of
some mutations.
The establishment of multidisciplinary ALS clinics
and the development of population-based ALS regis-
ters have begun to present rich clinical, genotype and
epidemio logical data that can help to provide insights
into this heterogeneous disease.
7
In this Review, we
provide an over view of key advances in understand-
ing of the epidemio logy, clinical features, diagnosis and
management of this devastating disease.
Epidemiology
In populations of European extraction, ALS is more
common in men than in women by a ratio of 1.2–1.5:1.
7

This disparity is largely attributable to the increased fre-
quency of spinal-onset ALS in men.
8
In contrast to other
neurodegenerative diseases, such as Parkinson disease
and Alzheimer disease, the risk of developing ALS peaks
between the ages of 50 years and 75 years, and declines
thereafter.
7,9,10
This feature suggests that ALS is not a
disease of aging, but rather a disease for which age is one
of numerous risk factors. Careful evaluation of popula-
tions over a period of more than 10 years has indicated
that the adjusted age-specific incidence of the disease is
not increasing.
9
The incidence of ALS in Europe is 2–3 people per
100,000 of the general population, and the overall life-
time risk of developing the condition is 1:400.
11–13
Current
evidence suggests that the frequency of ALS is reduced
in populations of non-European or mixed ethnicity
13,14

and that genetic admixture might be protective.
14
A par-
ticularly high frequency of ALS cases that often present
with parkinsonism and dementia was first described in
1945 in the Chamorro tribe who live on the Pacific island
Competing interests
The authors declare no competing interests.
AMYOTROPHI C LATERAL SCLEROSI S
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of Guam.
15
A similarly high frequency of ALS has been
reported in two separate areas in the Kii peninsula of
Honshu island, Japan.
16
The frequency of ALS in Guam
has declined rapidly over the past five decades, although
elevated rates of Parkinson disease and dementia persist,
15

as do increased rates of ALS in parts of Japan.
8
A high
content of cyanotoxins has been reported in the diet of
the indigenous population in Guam. However, detailed
epidemiological and toxicological studies do not support
the hypothesis that these forms of ALS result from cyano-
toxic effects, and no environmental toxin has been con-
clusively identified.
17
The pathobiology underlying these
disease clusters remains unclear.
Environmental factors that confer an increased risk
of developing ALS outside of Guam and the Kii penin-
sula have also been difficult to identify.
18
Although many
case–control studies have attempted to establish exposure
risks, their findings have demonstrated little consensus.
This disparity is partly attributable to methodological
problems, including small sample sizes, and the use of
referral or prevalent cohorts rather than population-
based incident cohorts.
10,18
Clustering of ALS has been
identified in certain occupations, including in Italian
soccer players (although not in other athletes),
19,20
and
possibly individuals deployed in military service.
21,22

Other environmental factors that have been associated
with ALS include smoking
23,24
and exposure to pesticides,
lead, organic toxins, and electromagnetic radiation.
25

Large population-based case–control studies of incident
cohorts are needed to conclusively establish environ-
mental risk factors in ALS. To implement such studies
requires international collaboration; the European ALS
Consortium (EURALS) has recently initiated such a
collaboration using established ALS registers from the
EURALS group in Italy, Ireland and the Netherlands.
7
Presentation
Clinical features
Disease phenotype is often classified by the site of onset.
The majority (65%) of patients present with limb symp-
toms, while 30% present with symptoms of bulbar dys-
function in the form of dysarthria or dysphagia. 5% of
Key points
■ Amyotrophic lateral sclerosis (ALS) is a syndrome of progressive deterioration
involving the corticospinal tract, brainstem, and anterior horn cells of the
spinal cord
■ The risk of developing ALS peaks between the ages of 50 years and 75 years;
disease rates are elevated in populations of white European ancestry, and
reduced in mixed populations
■ No definitive test for ALS exists; the diagnosis is established by excluding other
causes of progressive upper motor neuron and lower motor neuron dysfunction
■ Up to 15% of patients with ALS have frontotemporal dementia, and a further
25% have evidence of cognitive impairment, mainly executive dysfunction
■ Clinical care is based on symptom management; however, riluzole, the only
available disease-modifying drug, improves patients’ survival early in the course
of the disease
■ Further improvements in survival will depend on advances in understanding the
origins and spread of this syndrome
patients have respiratory-onset disease.
7
Initial symp-
toms of weight loss and isolated emotional lability have
also been reported.
26,27
As motor neurons are affected segmentally in patients
with ALS, the initial clinical presentation depends on
where in the neuroaxis the disease is first manifest.
28

Symptom onset is usually asymmetrical. Neurological
examination generally reveals a combination of upper
motor neuron and lower motor neuron features; for
example, spasticity combined with wasting and fascicu-
lations (Figure 1).
2
Extraocular and sphincter muscles
are characteristically spared in patients with ALS, at least
until late in the disease,
29
although subtle changes in eye
movements have been reported.
30,31
Sensory examination
is generally normal, although some patients may describe
minor sensory symptoms.
2
In some patients with ALS, especially during the early
stages of disease, the characteristic combination of upper
motor neuron and lower motor neuron abnormalities
may be absent, leading to diagnostic uncertainty. Thus,
the majority of patients with ALS will have seen at least
two or three other specialists before they are formally
diagnosed, and the time from symptom onset to defini-
tive diagnosis is usually 9–15 months, regardless of the
standard of health care available.
32
Cognitive and behavioral impairment
Cognitive impairment is a frequent feature of ALS
33–38
and
consensus criteria have been proposed to categorize the
various forms of cognitive and behavioral impairment
associated with ALS.
34
Frontotemporal dementia, which
occurs in up to 15% of patients with ALS,
37
is charac terized
by personality change, irritability, poor insight, and per-
vasive deficits on frontal executive tests.
33,34
This form
of dementia is recognized to overlap with ALS in clini-
cal, radiological, pathological and genetic features.
33–38
A
mild form of executive impairment occurs in up to 20% of
patients with ALS.
37,38
Executive dysfunction is associated
with impaired judgment and impulsivity, and is a strong
negative prognostic indicator.
37,38
Behavioral impairment
in the absence of cognitive impairment can also occur,
34,36

and both cognitive and behavioral dysfunction can
precede or follow the onset of motor symptoms. Behavi oral
changes are frequently reported by spouses or relatives, but
might not be apparent during a formal clinical interview.
Behavioral impairment can be formally assessed using
carer-based instruments such as the Neuro psychiatric
Inventory or Frontal Systems Behavior Scale.
33,34,36
Currently, no definitive screening test for cognitive
impairment in ALS exists. Verbal fluency is a sensitive
marker, and a simple 2 min word-generation test can
help to identify patients in whom more-detailed neuro-
psychological evaluation might be required.
33,37–39
Patients
with severe deficits in verbal fluency are likely to exhibit
frontal and executive deficits on formal testing, although
the outcomes of these tests also depend on premorbid
intellectual ability.
38,40
Short batteries of tests, such as the
Mini Mental State Examination, are not sensitive enough
to detect frontotemporal syndromes and should not be
used for diagnostic purposes.
38
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NATURE REVIEWS | NEUROLOGY VOLUME 7 | NOVEMBER 2011 | 641
Diagnosis
Overlap with other neurodegenerative diseases
Overlap of ALS with other neurodegenerative conditions,
particularly Parkinson disease, has been recognized in
countries other than Guam.
41,42
An increased occurrence
of dementia has also been reported in some kindreds
that include patients with sporadic ALS.
43
The clinical
and pathogenic overlap between ALS and some other
neurodegenerative diseases tends to support the hypo-
thesis that a shared environmental and genetic suscep-
tibility underlies some neurodegenerative phenotypes.
44

However, large population-based, case–control studies
are required to establish the true familial aggregation of
neurodegenerative conditions.
Variations in phenotype
Although most clinical presentations of ALS are sub-
divided into bulbar-onset or spinal-onset disease, further
phenotypic subclassification is based on the degree of
upper motor neuron and lower motor neuron involve-
ment. Phenotypes include primary lateral sclerosis (PLS),
progressive muscular atrophy (PMA) and progressive
bulbar palsy (Table 1).
PLS is a diagnosis of exclusion in patients with a spo-
radic adult-onset upper motor neuron syndrome with a
duration of 4 years or more.
45
This syndrome is gener-
ally spinal in onset, although patients can occasionally
present with bulbar signs, and can progress to ALS.
Differentiating PLS from apparently sporadic pre-
sentations of hereditary spastic paraparesis can be dif-
ficult.
46,47
Differentiation is important, as hereditary
spastic paraparesis carries a more favorable prognosis
than PLS.
44,47
PMA is a heterogeneous syndrome that overlaps
with ALS. Although it is considered to carry a better
prognosis than typical ALS, approximately 30% of
patients with PMA develop upper motor neuron signs
within 18 months, and progress to a diagnosis of ALS.
48

Cortico spinal tract involvement is demonstrated on
autopsy in up to 50% of patients with an initial diagnosis
of PMA.
49
Patients with lower motor neuron syndromes and a
disease duration of 4 years or more usually have a favor-
able prognosis if muscle involvement has a segmental
distribution.
50
A prospective follow-up study established
that patients with segmental disease phenotypes do not
a b
Figure 1 | Clinical features of ALS. a | The ‘split hand’, in which disproportionate wasting of the first dorsal interossei
(and the underside thenar muscles, particularly the abductor pollicis brevis, not illustrated), with relative preservation of
the adductor digiti minimi is evident. This pattern of wasting is consistent with a cortical, motor neuronal origin of ALS. The
thenar muscles and the first dorsal interossei have extensive corticospinal connections, and might have increased energy
demands and also be susceptibility to excitotoxic effects. b | Patients with limb-onset ALS show prominent bilateral wasting
of the shoulder girdles, pectoral muscles and proximal upper arms, associated with brisk tendon reflexes. Abbreviation:
ALS, amyotrophic lateral sclerosis.
Table 1 | ALS and related phenotypes
Disease Clinical features Comments Median survival
ALS Multiple spinal segments affected
with both upper and lower motor
neuron signs
Most common adult-onset form of motor
neuron disease
3–5 years
Primary lateral
sclerosis
Upper motor neuron signs only Many patients eventually develop clinical or
electrophysiological signs of lower motor
neuron involvement; ALS develops in up to
77% of patients within 3–4 years
≥20 years for
patients who do not
progress to ALS
Progressive
muscular atrophy
Lower motor neuron signs only Variable evolution to ALS Typically 5 years, but
a subset survive for
≥20 years
Progressive bulbar
palsy
Speech and swallowing initially
affected, owing to lower motor
neuron involvement of cranial
nerves IX, X and XII
Symptoms include dysarthria, dysphagia and
dysphonia; aspiration pneumonia is usually the
cause of death
2–3 years
Abbreviation: ALS, amyotrophic lateral sclerosis.
AMYOTROPHI C LATERAL SCLEROSI S
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develop respiratory insufficiency or significant changes
in respiratory muscle strength, functional impairment,
or forced vital capacity.
50
Differential diagnosis and mimic syndromes
In patients diagnosed with ALS, the absence of disease
progression, the presence of an atypical history, or the
presence of unusual symptoms should trigger a search
for ‘mimic syndromes’ (Box 1).
51
Consideration of the
conditions that closely resemble ALS is important,
as the diagnosis of ALS is based primarily on clinical
examination. The two conditions most commonly mis-
taken for ALS are multifocal motor neuropathy with
conduction block, and cervical spondylotic myelo-
pathy.
51,52
Differentiating multifocal motor neuropathy
from ALS is especially important, as patients with this
neuropathy may benefit from intravenous immuno-
globulin treatment.
53
Generally, patients with common
mimic syndromes do not progress as rapidly as those
with ALS, and tend to survive for longer periods.
Spinobulbar muscular atrophy (Kennedy disease) is
also often misdiagnosed as ALS. Kennedy disease is an
X-linked disorder associated with an expansion of tri-
nucleotide repeats in the androgen receptor gene. The
clinical features of this condition include slowly pro-
gressive lower motor neuron signs in the bulbar region
and proximal limbs, and 50% of affected patients have
gynecomastia. A pure lower motor neuron syndrome
with a family history demonstrating no male-to-male
inheritance should, therefore, alert the physician to this
possible diagnosis. Nerve conduction studies can be
helpful to differentiate Kennedy disease from ALS, as the
sensory nerve action potentials are often absent in the
former. Progression of Kennedy disease is slower than
that of typical ALS, and patients have an almost normal
life expectancy.
54
Diagnostic criteria
The El Escorial criteria were developed in 1994 by the
World Federation of Neurology for research and clini-
cal trial purposes.
55
These guidelines were subsequently
revised in recognition of the importance of laboratory
testing, and were renamed the Airlie House criteria in
1998.
56
The role of neurophysiology in diagnostic catego-
rization has been further revised, and a subsidiary set of
indicators—the Awaji–Shima criteria—was introduced
in 2008, use of which improved diagnostic sensitivity
without increasing false-positive rates (Table 2).
57,58
The El Escorial and Airlie House criteria are based on
the degree of certainty of diagnosis. This is predicated
on clinical assessment, which requires the identification
of upper and lower motor neuron signs together in the
same topographical anatomical region in the brainstem,
or the cervical, thoracic or lumbosacral spinal cord. A
definite diagnosis of ALS requires the following: identi-
fication of lower motor neuron degeneration on clinical,
electro physiological or neuropathological examina-
tion; evidence of upper motor neuron degeneration by
clinical examination; and progression of the motor syn-
drome within a region or to other regions. In addition,
diagnosis requires the absence of electrophysiological
and pathological evidence of other disease processes
that might explain the signs of upper or lower motor
neuron degeneration, and the absence of neuroimaging
evidence of other disease processes that might explain
the observed clinical and electrophysiological signs
(Table 2). Although these criteria were never formally
validated, a series of inter-rater reliability studies have
shown that among experts, they are generally uniformly
applied and reproducible.
59,60
However, the criteria are
not designed for use in everyday clinical practice, and
Box 1 | Differential diagnoses of ALS
Hereditary conditions
■ Spinobulbar muscular atrophy (Kennedy disease)
■ Hereditary spastic paraparesis
■ Acid maltase deficiency
■ Facioscapulohumeral muscular dystrophy
■ Adrenomyeloneuropathy
■ Huntington disease
■ Hexosaminidase deficiency
Metabolic conditions and toxic effects
■ Hyperthyroidism
■ Hyperparathyroidism
■ Heavy metal intoxication
■ Lathyrism
■ Organophosphate toxic effects
Immune and/or infammatory conditions
■ Multifocal motor neuropathy with conduction block
■ Chronic inflammatory demyelinating polyneuropathy
■ Myasthenia gravis
■ Inclusion body myositis
■ Polymyositis
■ Multiple sclerosis
■ Paraneoplastic disorders
Structural disorders
■ Cervical spondylotic myelopathy
■ Syringomyelia or syringobulbia
■ Postirradiation myelopathy and/or plexopathy
■ Tumor
■ Cerebrovascular disease
Other neurodegenerative diseases
■ Corticobasal degeneration
■ Multiple system atrophy
■ Progressive supranuclear palsy
■ Parkinson disease
■ Huntington disease
Other motor neuron diseases
■ Primary lateral sclerosis
■ Progressive muscular atrophy
■ Spinal muscular atrophy
■ Post-polio spinal muscle atrophy
■ Benign fasciculation syndrome
■ Hirayama disease
Abbreviation: ALS, amyotrophic lateral sclerosis.
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NATURE REVIEWS | NEUROLOGY VOLUME 7 | NOVEMBER 2011 | 643
have been criticized as being excessively restrictive when
used to enroll patients in clinical trials.
61
Moreover, the
criteria were devised before recognition of the nonmotor
components of ALS, such as cognitive and behavioral
impairment. Further revisions to these criteria will be
required to take these features into account.
Diagnostic tests
No definitive diagnostic test for ALS exists. The com-
bination of suggestive clinical signs with negative labo-
ratory tests and imaging studies for other pathologies
supports the diagnosis, although disease progression is
a prerequisite.
Laboratory investigations
Routine investigation of a patient with apparently typical
ALS should include measurement of erythrocyte sedi-
mentation rate, serum and urine protein electro phoresis,
thyroid function tests, serum calcium and phosphate
measurements, and cerebrospinal fluid analysis (Box 2).
A heavy metal screen should be performed in individuals
with a potential history of exposure. β-hexosaminidase
deficiency (Tay–Sachs disease) is common in some
ethnic groups, and can mimic ALS. β-hexosaminidase
subunits α and β activity should be tested in patients of
Ashkenazi Jewish extraction (Box 2).
56
Electrodiagnostic studies
Electrodiagnostic studies are the most critical ancillary
tool in the investigation of ALS. Electromyography can
identify loss of lower motor neurons, the hallmark of
ALS,
62
and is particularly useful in clinically unaffected
regions (Box 2). The most frequently recognized abnor-
malities observed on electromyography are fasciculation,
spontaneous denervation discharges (fibrillation poten-
tials and positive sharp waves) indicative of ongoing
motor neuron loss, and polyphasic units indicative of
reinnervation. Fibrillation potentials and positive sharp
waves might not develop until one-third of the motor
neurons have been lost, although their presence in clini-
cally normal muscle tissue may facilitate an early diagno-
sis.
63
Transcranial magnetic stimulation, where available,
may help in the identification of patients with subclinical
upper motor neuron dysfunction.
64,65
Short-interval and
long-interval intracortical inhibition and peristimulus
time histograms might be useful to document the pres-
ence of ALS pathophysiology, but are not used routinely
in clinical settings.
66,67
Genetic testing
A systematic review of all familial ALS cases suggests
that up to 5% of cases follow a Mendelian pattern of
inheritance;
6
a total of 15 genes and loci have been iden-
tified (Table 3).
4
The clinical and pathological presenta-
tion of familial ALS is very similar to that of sporadic
cases. Correct identification of familial cases of ALS
can be challenging, as the lifetime risk of developing the
disease is 1:400.
11,12
The size of a given extended kindred
and the lifetime risk of developing ALS can be used to
calculate the risk. For any index case with a kindred of
17 first-degree and second-degree relatives, there is a 5%
chance that a second member of the kindred will also
develop sporadic ALS.
6,68
Conversely, the likelihood of a
Mendelian pattern of inheritance of the disease is greatly
increased when three affected members of a kindred
have been identified.
68
Among the 15 genes known to be
associated with ALS, only mutations in SOD1, TARDBP,
ANG, VCP and FUS are associated with typical ALS; the
remainder are associated with unusual phenotypes or
have been described in small numbers of kindreds.
4
Screening of patients with familial ALS for muta-
tions in these known genes might offer some benefit,
as preliminary evidence from mouse studies suggests
that passive immunization strategies can attenuate
disease progression in the SOD1 model.
69
Clinical trials
using antisense drugs,
70
arimoclomol (phase II–III
trials)
71
and pyrimethamine (phase I–II trials),
72
have
commenced. However, genetic screening of unaffected
Table 2 | Criteria for diagnosis of ALS
Criteria Definite ALS Probable ALS Possible ALS Suspected ALS
El Escorial criteria,
1994
51
Upper and lower motor
neuron signs in three regions
Upper and lower motor
neuron signs in at least two
regions, with upper motor
neuron signs rostral to
lower motor neuron signs
Upper and lower motor
neuron signs in one
region, upper motor
neuron signs alone in two
or more regions, or lower
motor neuron signs
rostral to upper motor
neuron signs
Lower motor
neuron signs
only, in two or
more regions
Revised Airlie
House criteria,
1998
52

(incorporating the
Awaji–Shima
criteria, 2008
53
)*
Clinical or
electrophysiological evidence,
demonstrated by the
presence of upper and lower
motor neuron signs in the
bulbar region and at least
two spinal regions, or the
presence of upper and lower
motor neuron signs in three
spinal regions
Clinical or
electrophysiological
evidence, demonstrated by
upper and lower motor
neuron signs in at least two
spinal regions, with some
upper motor neuron signs
necessarily rostral to the
lower motor neuron signs
Clinical or
electrophysiological signs
of upper and lower motor
neuron dysfunction in
only one region, or upper
motor neuron signs alone
in two or more regions, or
lower motor neuron signs
rostral to upper motor
neuron signs
NA
*These revised recommendations emphasize the equivalence of clinical and electrophysiological tests in establishing neurogenic changes in bodily regions.
Abbreviations: ALS, amyotrophic lateral sclerosis; NA, not applicable.
AMYOTROPHI C LATERAL SCLEROSI S
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members of ALS kindreds is currently of little utility,
as known mutations have limited penetrance, and the
risk of disease development in an asymptomatic carrier
cannot be determined.
Neuroimaging studies
MRI of the brain and spinal cord remains the most
useful neuroimaging technique in ALS (Box 2), mainly
to exclude syndromes that mimic ALS.
51,73
In some
patients with ALS, rounded foci of high signal intensity
are evident along the corticospinal tract and precentral
and frontal cortex on T2-weighted, fluid-attenuated
inversion recovery and proton-density-weighted MRI
sequences.
73–75
However, these MRI features are not
specific for ALS and correlate poorly with both disease
severity and the presence of upper motor neuron signs,
nor are they useful as markers of disease progression.
Advanced MRI techniques, including diffusion tensor
imaging, magnetization transfer, proton magnetic reso-
nance spectroscopy and resting functional MRI, in addi-
tion to voxel-based morphometry—a neuroimaging
analysis technique that uses statistical methods—might
be useful to identify specific ALS-associated pathol-
ogy in a noninvasive manner (Figure 2).
73
At present,
these techniques are primarily used as research tools,
although diffusion tensor imaging, voxel-based mor-
phometry and resting functional MRI have been used
in both cross-sectional and longitudinal studies of ALS,
and have the potential to be developed into sensitive
new neuro imaging techniques.
74–82
Prognostic factors
The site of ALS onset is of prognostic significance.
Disease starting in the limbs carries a better prognosis
than that starting in the bulbar region, and lower-limb
onset carries a better prognosis than upper-limb onset.
83

The flail-limb variant and isolated bulbar pheno type of
ALS also carry better prognoses than typical ALS.
84,85

Respiratory-onset disease carries the worst prog-
nosis.
83
Evolving evidence also suggests that a favorable
cardiovascular risk profile (for example, low levels of
C-reactive protein, LDL and homocysteine, and ele-
vated levels of HDL) is associated with declining lung
function (forced vital capacity) and accelerated disease
progression (Box 3).
86–88
Disease progression can be monitored using a variety of
clinical scales. The Revised ALS Functional Rating Scale
(ALSFRS-R, Supplementary Box 1, online) is currently the
most widely used measurement tool. Patients are scored
from 0 points (maximum disability) to 48 points (normal
functioning) for bulbar and limb symptoms, mobility and
respiratory function. A decline in the ALSFRS-R score is
a predictor of reduced survival.
89
This scale is employed
extensively in clinical trial assessment.
Patients who receive care at a multidisciplinary clinic
have a better prognosis and improved quality of life
compared with those attending a general neurology
clinic.
90–92
Clinical management
Evidence-based guidelines for the clinical management
of ALS have been published by the European Federa tion
of Neurological Societies
93
and the American Academy of
Neurology.
94,95
Despite over 30 phase II and phase III
clinical trials of promising agents,
96,97
riluzole remains the
only evidence-based disease-modifying drug for ALS.
98

More-efficient approaches to early phase clinical trials
are required to accelerate the identification and develop-
ment of useful agents for ALS.
96,97
Management of ALS is
other wise focused on symptom control and preservation
of quality of life.
Respiratory function
The majority of patients with ALS die from respiratory
failure, and the presence of respiratory muscle weakness
is an independent predictor of quality of life. Assessment
of respiratory insufficiency includes pulmonary function
Box 2 | Essential investigations in patients with ALS
Blood tests
■ Erythrocyte sedimentation rate
■ C-reactive protein
■ Hematological screen: full blood count
■ Liver function tests: alanine transaminase and
aspartate transaminase levels
■ Creatine kinase
■ Creatine
■ Electrolytes: Na
+
, K
+
, Cl

, Ca
2+
, PO
4
■ Glucose
■ Lactate dehydrogenase
■ Thyroid function tests: free tri-iodothyronine, free
thyroxine and thyroid stimulating hormone
■ Vitamins: B
12
, folate
■ Serum protein electrophoresis
■ Serum immunoelectrophoresis
■ β-hexosaminidase subunits α and β assay (where
clinically indicated)
■ Ganglioside GM-1 antibodies (where clinically
indicated)
■ Serum Borrelia titers and HIV tests (where clinically
indicated)
■ Celiac serology (where clinically indicated)
Cerebrospinal fuid tests
■ Cell count
■ Protein
■ Glucose
■ Oligoclonal bands (where clinically indicated)
Neurophysiology
■ Nerve conduction velocities
■ Sensory and motor amplitudes
■ Presence of focal motor conduction block
■ Features of denervation on electromyography
■ Motor unit morphology
Imaging studies
■ MRI and/or CT (head and neck, thoracic, lumbar)
■ Chest radiography
Abbreviation: ALS, amyotrophic lateral sclerosis.
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tests, overnight pulse oximetry, and measurement of
early morning arterial blood gases.
99
Forced vital capac-
ity is the most widely used assessment of respiratory
insuffi ciency in patients with ALS. Additional investi-
gations include the sniff nasal inspiratory pressure test,
which is a better predictor of nocturnal hy poxemia than
is vital capacity.
100
Noninvasive positive pressure ventilation (NIPPV)
should be considered at an early stage. If tolerated,
NIPPV extends survival, particularly in patients who are
able to use it for 5 h or more per day, and those without
severe bulbar dysfunction.
101
Treatment with NIPPV
also improves patients’ quality of life without increasing
caregiver burden or stress.
102
Overnight pulse oximetry
should be performed once use of NIPPV commences,
and patients should be reviewed at regular intervals by
a respiratory physician to ensure that pressure settings
are optimized.
103
Early symptoms of respiratory dysfunction should be
actively sought at each clinic visit. Techniques to reduce
the risk of aspiration should be introduced, including
suction machines, alteration in food texture and advice
regarding swallowing.
93–95
Tenacious secretions should
be treated by ensuring adequate hydration, the use of
muco lytic agents such as acetylcysteine (200–400 mg
three times daily), or the use of a saline nebulizer with
β-receptor antagonists (such as metoprolol or pro-
pranolol), ipratropium bromide or theophylline.
93–95

Suctioning is also helpful and, in some instances, a cough
insufflator can be of benefit in patients with reduced
peak cough expiratory flow (2–3 l/s or less).
104
Excessive
secretions can be treated with amitriptyline, hyoscine or
scopolamine patches.
93–95
When these first-line agents
are ineffective, botulinum toxin injected into the sali-
vary glands may be beneficial,
105
although caution is
recom mended in patients with signifi cant bulbar palsy,
as increased dysphagia may occur.
106
Other options
include subcutaneous glycopyrrolate infusion
107
and
salivary gland irradiation.
108
Nutritional support
Weight loss and malnutrition are common features of ALS
and are associated with a poor prognosis.
109
Weight loss
might be associated with hypermetabolism.
110
Conversely,
emerging evidence suggests that patients with triglyceride
and cholesterol levels commonly associated with increased
cardiovascular risk have improved survival.
86–88,110
Dysphagia increases the risk of insufficient calorie
intake, aspiration and choking. Dysphagia can be evalu-
ated using bedside clinical scales, video fluoroscopy
and fiberoptic examination.
111
Management includes
modification of food and fluid consistencies, postural
advice (for example, tucking the chin and flexing the
neck forward on swallowing to protect the airway), and
enteral feeding by gastrostomy.
93,95
The advantages of
gastrostomy include improved nutrition, although evi-
dence to support a substantial effect on survival remains
to be firmly established.
93,95
Use of radiological imaging
during insertion of the gastrostomy tube has been shown
to be superior to endoscopic gastrostomy in patients with
pronounced bulbar symptoms or respiratory compro-
mise.
112,113
In patients with evidence of respiratory insuffi-
ciency, noninvasive ventilation should be in troduced
before gastrostomy.
114
Table 3 | Known genes and loci implicated in familial ALS
Disease subtype Gene Locus Protein
ALS 1 SOD1 21q22.11 Superoxide
dismutase 1
ALS 2 (juvenile) ALS2 2q33–q35 Alsin
ALS 3 (autosomal-dominant) ND 18q21 ND
ALS 4 (childhood-onset or
adolescent-onset, slow
progression and sparing of
bulbar and respiratory muscles)
SETX 9q34 Probable helicase
senataxin
ALS 5 ND 15q15.1–q21.1 ND
ALS 6 FUS 16p11.2 Fused in sarcoma
ALS 7 ND 20p13 ND
ALS 8 VAPB 20q13 Vesicle-associated
membrane protein
(VAMP)-associated
protein B and C
ALS 9 ANG 14q11.1–q11.2 Angiogenin
ALS 10 TARDBP 1p36.22 TAR DNA-binding
protein 43
ALS 11 FIG4 6q21 Polyphosphoinositide
phosphate
ALS 12 OPTN 10p14 Optineurin
ALS 13 ATXN2 12q23-q24.1 Ataxin-2
ALS-X UBQLN2 Xp11.21 Ubiquilin-2
ALS with frontotemporal
dementia
C9orf72 9p21.1 Uncharacterized
protein C9orf72
ALS with inclusion body
myositis
VCP 9p13 Transitional
endoplasmic
reticulum ATPase
Abbreviations: ALS, amyotrophic lateral sclerosis; ND, not documented.
Prefrontal
dorsolateral cortex
Posterior cingulate Cerebellum
Figure 2 | Voxel-based morphometry image from a patient with ALS. This technique
is used to identify alterations in regional gray matter signal intensity by comparing
scans from age-matched healthy controls with those from patients with ALS. The
blue color indicates areas of significantly reduced gray matter volume in the
posterior cingulate, prefrontal dorsolateral cortex and cerebellum in a patient with
ALS. Abbreviation: ALS, amyotrophic lateral sclerosis.
AMYOTROPHI C LATERAL SCLEROSI S
© 2011 Macmillan Publishers Limited. All rights reserved
646 | NOVEMBER 2011 | VOLUME 7 www.nature.com/nrneurol
Quality of life
Quality of life is determined by the pleasure and satis-
faction an individual draws from living. Health-related
quality of life is determined by the influence that an
individual’s health has on their experience of living.
Measurement of either of these indicators in patients
with ALS is challenging owing to communication bar-
riers and cognitive deficits.
115
Generic quality of life
instruments (for example, the Sickness Impact Profile
or the Short Form [36] Health Survey) are of limited use
in patients with ALS.
116
Several ALS-specific health-related quality of life
scales have been generated (such as the ALS Assessment
Questionnaires ALSAQ-40 and ALSAQ-5).
117–119

Health-related quality of life declines in patients with
ALS commensurately with their physical decline,
120–124

and high levels of psychological distress occur in some
patients.
125,126
However, self-assessed quality of life
scores, although limited in their utility,
123
do not gen-
erally decline in patients with ALS—this observation
is attributed to a psychological response shift.
121
Strong
religious belief correlates with high self-reported quality
of life scores in both patients
127
and their carers.
128
Support for caregivers
As ALS progresses, an increasing and often unacknow-
l edged burden is borne by the patient’s primary carer,
from both a physical and an emotional perspective.
129–131

The burden of care may increase considerably if the
patient develops cognitive or behavioral impairments.
132

Supportive strategies that include counseling for family
members can be helpful.
93
In the late stages of the patient’s
illness, regular respite and psychological support should
be available for their primary carer.
93
Palliative care and end-of-life decisions
The rapidly progressive course of ALS means that the
patient’s level of disability changes over a timescale of
months rather years. The shift from a treatment paradigm
of cure to one of symptom management and palliation
can be difficult for both patients and doctors. A close
working relationship with the palliative care team can
enable the treating physician to accomplish this transfer
early in the course of the patient’s illness.
115
From the time
of diagnosis, patients should be provided with a realistic
projection of the trajectory of their disease, and as the
condition progresses they should be encouraged to con-
sider an advance directive (sometimes termed a ‘living
will’) to record their end-of-life decisions.
93,133
For the
majority who decide against invasive mechanical venti-
lation, assurances should be provided that palliative care
strategies can control symptoms in the terminal phase of
the illness.
93,115,133
Conclusions
Riluzole is the only drug proven to modify the course of
ALS, but this treatment achieves only a modest improve-
ment in survival.
98
Symptom control and preservation of
quality of life remain the cornerstones of management
for patients with ALS.
Advances in our understanding of ALS have reignited
research interest in this clinically heterogeneous disorder.
Despite the complexity of the disease, very real improve-
ments have been made in our understanding of the
pathophysiology of ALS that will undoubtedly translate
into tangible clinical benefits. For example, new research
clearly shows that the duration of survival for patients
with ALS is determined by many factors, including the
clinical phenotype, rate of disease progression, nutri-
tional status and its specialized management, and the
specialized management of respiratory failure. Further
improvements in survival will depend on advancements
in the understanding of the origins and progression of
this disease. In the meantime, an urgent need remains
for the identification of early biomarkers of disease onset
and progression, and efficient approaches to early-phase
clinical trials are required to accelerate the identification
and development of useful therapies for ALS.
Box 3 | Prognostic indicators in ALS
Favorable prognostic indicators
■ Age <50 years
■ Lower limb onset
■ Long interval from first symptom to diagnosis
■ Hyperlipidemia
■ Attendance at a multidisciplinary clinic
■ Variants, such as flail arm or flail leg, pure upper motor
neuron conditions, and pure lower motor
neuron conditions
Poor prognostic indicators
■ Age >65 years
■ Bulbar-onset disease
■ Respiratory-onset disease
■ Short interval from first symptom to diagnosis
■ Malnutrition
■ Impaired executive function
■ Low cardiovascular risk (a favorable lipid profile)
■ Rapidly declining Revised ALS Functional Rating
Scale scores
■ Forced vital capacity <50%
■ Sniff nasal inspiratory pressure <40 cm H
2
O
Abbreviation: ALS, amyotrophic lateral sclerosis.
Review criteria
We searched the PubMed (January 1966 to
December 2010), EMBASE (January 1980 to December
2010), and Cochrane Library databases for English-
language articles, using the following MeSH terms:
“amyotrophic lateral sclerosis” OR “motor neuron
disease” in combination with “diagnosis”, “phenotype”,
“clinical”, “epidemiology”, “prognosis”, “frontotemporal
dementia”, “cognition”,“genetics”, “imaging”,
“neurophysiology” and “management”. Further relevant
material was identified in the reference lists of key
reviews and major textbook chapters. The final reference
list was based on both originality and relevance to the
topics covered in this Review. Publications from the
past 5 years were prioritized, but we also included highly
regarded older publications.
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1. Charcot, J. M. De la sclérose latérale
amyotrophique [French]. Progrès Médical 2, 325
(1874).
2. Kiernan, M. C. et al. Amyotrophic lateral
sclerosis. Lancet 377, 942–955 (2011).
3. Deng, H. X. et al. FUS-immunoreactive inclusions
are a common feature in sporadic and non-SOD1
familial amyotrophic lateral sclerosis. Ann.
Neurol. 67, 739–748 (2010).
4. Beleza-Meireles, A. & Al-Chalabi, A. Genetic
studies of amyotrophic lateral sclerosis:
controversies and perspectives. Amyotroph.
Lateral Scler. 10, 1–14 (2009).
5. Beghi, E. et al. for the Eurals Consortium. The
epidemiology and treatment of ALS: focus on
the heterogeneity of the disease and critical
appraisal of therapeutic trials. Amyotroph.
Lateral Scler. 12, 1–10 (2011).
6. Byrne, S. et al. Rate of familial amyotrophic
lateral sclerosis: a systematic review and meta-
analysis. J. Neurol. Neurosurg. Psychiatry 82,
623–627 (2011).
7. Logroscino, G. et al. Incidence of amyotrophic
lateral sclerosis in Europe. J. Neurol. Neurosurg.
Psychiatry 81, 385–390 (2010).
8. Kuzuhara, S. Muro Disease: Amyotrophic lateral
sclerosis/parkinsonism-dementia complex in
Kii Peninsula of Japan. Brain Nerve 63,
119–129 (2011).
9. Chiò, A. et al. Epidemiology of ALS in Italy:
a 10-year prospective population-based study.
Neurology 72, 725–731 (2009).
10. O’Toole, O. et al. Epidemiology and clinical
features of amyotrophic lateral sclerosis in
Ireland between 1995 and 2004. J. Neurol.
Neurosurg. Psychiatry 79, 30–32 (2008).
11. Johnston, C. A. et al. Amyotrophic lateral
sclerosis in an urban setting: a population
based study of inner city London. J. Neurol. 253,
1642–1643 (2006).
12. Alonso, A., Logroscino, G., Jick, S. S. &
Hernán, M. A. Incidence and lifetime risk of
motor neuron disease in the United Kingdom:
a population-based study. Eur. J. Neurol. 16,
745–751 (2009).
13. Cronin, S., Hardiman, O. & Traynor, B. J. Ethnic
variation in the incidence of ALS: a systematic
review. Neurology 68, 1002–1007 (2007).
14. Zaldivar, T. et al. Reduced frequency of ALS in an
ethnically mixed population: a population-based
mortality study. Neurology 72, 1640–1650
(2009).
15. Steele, J. C. Parkinsonism-dementia complex of
Guam. Mov. Disord. 20 (Suppl. 12), S99–S107
(2005).
16. Kuzuhara, S. & Kokubo, Y. Atypical parkinsonism
of Japan: amyotrophic lateral sclerosis-
parkinsonism-dementia complex of the Kii
peninsula of Japan (Muro disease): an update.
Mov. Disord. 20 (Suppl. 12), S108–S113 (2005).
17. Steele, J. C. & McGeer, P. L. The ALS/PDC
syndrome of Guam and the cycad hypothesis.
Neurology 70, 1984–1990 (2008).
18. Sutedja, N. A. et al. What we truly know about
occupation as a risk factor for ALS: a critical and
systematic review. Amyotroph. Lateral Scler. 10,
295–301 (2009).
19. Chiò, A., Benzi, G., Dossena, M., Mutani, R. &
Mora, G. Severely increased risk of amyotrophic
lateral sclerosis among Italian professional
football players. Brain 128, 472–476 (2005).
20. Chio, A. et al. ALS in Italian professional soccer
players: the risk is still present and could be
soccer-specific. Amyotroph. Lateral Scler. 10,
205–209 (2009).
21. Kasarskis, E. J. et al. Clinical aspects of ALS in
Gulf War veterans. Amyotroph. Lateral Scler. 10,
35–41 (2009).
22. Horner, R. D. et al. Amyotrophic lateral sclerosis
among 1991 Gulf War veterans: evidence for a
time-limited outbreak. Neuroepidemiology 31,
28–32 (2008).
23. Armon, C. Smoking may be considered an
established risk factor for sporadic ALS.
Neurology 73, 1693–1698 (2009).
24. Alonso, A., Logroscino, G. & Hernán, M. A.
Smoking and the risk of amyotrophic lateral
sclerosis: a systematic review and meta-
analysis. J. Neurol. Neurosurg. Psychiatry 81,
1249–1252 (2010).
25. Sutedja, N. A. et al. Exposure to chemicals and
metals and risk of amyotrophic lateral sclerosis:
a systematic review. Amyotroph. Lateral Scler.
10, 302–309 (2009).
26. Ferguson, T. A. & Elman, L. B. Clinical
presentation and diagnosis of amyotrophic
lateral sclerosis. NeuroRehabilitation 22,
409–416 (2007).
27. Kiernan, M. C. et al. Amyotrophic lateral
sclerosis. Lancet 377, 942–955 (2011).
28. Ravits, J. M. & La Spada, A. R. ALS motor
phenotype heterogeneity, focality, and spread:
deconstructing motor neuron degeneration.
Neurology 73, 805–811 (2009).
29. Eisen, A., Kim, S. & Pant, B. Amyotrophic lateral
sclerosis (ALS): a phylogenetic disease of the
corticomotoneuron? Muscle Nerve 15, 219–224
(1992).
30. Donaghy, C. et al. Slow saccades in bulbar-onset
motor neurone disease. J. Neurol. 257,
1134–1140 (2010).
31. Donaghy, C. et al. Ocular fixation instabilities in
motor neurone disease. A marker of frontal
lobe dysfunction? J. Neurol. 256, 420–426
(2009).
32. Chiò, A. ISIS Survey: an international study on
the diagnostic process and its implications in
amyotrophic lateral sclerosis. J. Neurol.
246 (Suppl. 3), III1–III5 (1999).
33. Phukan, J., Pender, N. P. & Hardiman, O.
Cognitive impairment in amyotrophic lateral
sclerosis. Lancet Neurol. 6, 994–1003 (2007).
34. Strong, M. J. et al. Consensus criteria for the
diagnosis of frontotemporal cognitive and
behavioural syndromes in amyotrophic lateral
sclerosis. Amyotroph. Lateral Scler. 10, 131–136
(2009).
35. Strong, M. J. The syndromes of frontotemporal
dysfunction in amyotrophic lateral sclerosis.
Amyotroph. Lateral Scler. 9, 323–338 (2008).
36. Raaphorst, J., de Visser, M., Linssen, W. H.,
de Haan, R. J. & Schmand, B. The cognitive
profile of amyotrophic lateral sclerosis: A meta-
analysis. Amyotroph. Lateral Scler. 11, 27–37
(2010).
37. Elamin, M. et al. Executive dysfunction is a
negative prognostic indictor in patients with ALS
without dementia. Neurology 76, 1263–1269
(2011).
38. Phukan, J. et al. The syndrome of cognitive
impairment in amyotrophic lateral sclerosis:
a population-based study. J. Neurol. Neurosurg.
Psychiatry http://dx.doi.org/10.1136/
jnnp-2011-300188.
39. Abrahams, S. et al. Verbal fluency and executive
dysfunction in amyotrophic lateral sclerosis
(ALS). Neuropsychologia 38, 734–747 (2000).
40. Woolley, S. C. et al. Detecting frontotemporal
dysfunction in ALS: utility of the ALS Cognitive
Behavioral Screen (ALS-CBS). Amyotroph. Lateral
Scler. 11, 303–311 (2010).
41. Gilbert, R. M., Fahn, S., Mitsumoto, H. &
Rowland, L. P. Parkinsonism and motor neuron
diseases: twenty-seven patients with diverse
overlap syndromes. Mov. Disord. 25,
1868–1875 (2010).
42. Farníková, K., Kanovský, P., Nestrasil, I. &
Otruba, P. Coexistence of parkinsonism,
dementia and upper motor neuron syndrome in
four Czech patients. J. Neurol. Sci. 296, 47–54
(2010).
43. Fallis, B. A. & Hardiman, O. Aggregation of
neurodegenerative disease in ALS kindreds.
Amyotroph. Lateral Scler. 10, 95–98 (2009).
44. Przedborski, S., Vila, M. & Jackson-Lewis, V.
Neurodegeneration: what is it and where are
we? J. Clin. Invest. 111, 3–10 (2003).
45. Gordon, P. H. et al. The natural history of primary
lateral sclerosis. Neurology 66, 647–653
(2006).
46. Brugman, F. et al. Primary lateral sclerosis as a
phenotypic manifestation of familial ALS.
Neurology 64, 1778–1779 (2005).
47. Brugman, F. et al. Differentiation of hereditary
spastic paraparesis from primary lateral
sclerosis in sporadic adult-onset upper motor
neuron syndromes. Arch. Neurol. 66, 509–514
(2009).
48. Visser, J. et al. Disease course and prognostic
factors of progressive muscular atrophy. Arch.
Neurol. 64, 522–528 (2007).
49. Ince, P. G. et al. Corticospinal tract degeneration
in the progressive muscular atrophy variant of
ALS. Neurology 60, 1252–1258 (2003).
50. Van den Berg-Vos, R. M. et al. A long-term
prospective study of the natural course of
sporadic adult-onset lower motor neuron
syndromes. Arch. Neurol. 66, 751–757 (2009).
51. Traynor, B. J. et al. Amyotrophic lateral sclerosis
mimic syndromes: a population-based study.
Arch. Neurol. 57, 108–113 (2000).
52. Davenport, R. J., Swingler, R. J., Chancellor, A. M.
& Warlow, C. P. Avoiding false positive diagnoses
of motor neuron disease: lessons from the
Scottish Motor Neuron Disease Register.
J. Neurol. Neurosurg. Psychiatry 60, 147–151
(1996).
53. Cats, E. A. et al. Correlates of outcome and
response to IVIg in 88 patients with multifocal
motor neuropathy. Neurology 75, 818–825
(2010).
54. Finsterer, J. Perspectives of Kennedy’s disease.
J. Neurol. Sci. 298, 1–10 (2010).
55. Brooks, B. R. 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. 124 (Suppl.), 96–107 (1994).
56. Miller, R. G., Munsat, T. L., Swash, M. &
Brooks, B. R. Consensus guidelines for the
design and implementation of clinical trials in
ALS. World Federation of Neurology committee
on Research. J. Neurol. Sci. 169, 2–12 (1999).
57. de Carvalho, M. et al. Electrodiagnostic criteria
for diagnosis of ALS. Clin. Neurophysiol. 119,
497–503 (2008).
58. Schrooten, M., Smetcoren, C., Robberecht, W. &
Van Damme, P. Benefit of the Awaji diagnostic
algorithm for amyotrophic lateral sclerosis:
A prospective study. Ann. Neurol. 70, 79–83
(2011).
59. Forbes, R. B., Colville, S. & Swingler, R. J. Are the
El Escorial and Revised El Escorial criteria for
ALS reproducible? A study of inter-observer
agreement. Amyotroph. Lateral Scler. Other Motor
Neuron Disord. 2, 135–138 (2001).
60. Beghi, E. et al. Reliability of the El Escorial
diagnostic criteria for amyotrophic lateral
sclerosis. Neuroepidemiology 21, 265–270
(2002).
AMYOTROPHI C LATERAL SCLEROSI S
© 2011 Macmillan Publishers Limited. All rights reserved
648 | NOVEMBER 2011 | VOLUME 7 www.nature.com/nrneurol
61. Traynor, B. J. et al. Clinical features of
amyotrophic lateral sclerosis according to the
El Escorial and Airlie House diagnostic criteria:
a population-based study. Arch. Neurol. 57,
1171–1176 (2000).
62. Daube, J. R. Electrodiagnostic studies in
amyotrophic lateral sclerosis and other motor
neuron disorders. Muscle Nerve 23, 1488–1502
(2000).
63. Eisen, A. & Swash, M. Clinical neurophysiology
of ALS. Clin. Neurophysiol. 112, 2190–2201
(2001).
64. Triggs, W. J. et al. Transcranial magnetic
stimulation identifies upper motor neuron
involvement in motor neuron disease. Neurology
53, 605–611 (1999).
65. Mills, K. R. The natural history of central motor
abnormalities in amyotrophic lateral sclerosis.
Brain 126, 2558–2566 (2003).
66. Vucic, S., Howells, J., Trevillion, L. &
Kiernan, M. C. Assessment of cortical
excitability using threshold tracking techniques.
Muscle Nerve 33, 477–486 (2006).
67. Vucic, S. & Kiernan, M. C. Novel threshold
tracking techniques suggest that cortical
hyperexcitability is an early feature of motor
neuron disease. Brain 129, 2436–2446 (2006).
68. Byrne, S. et al. Proposed criteria for familial
amyotrophic lateral sclerosis. Amyotroph. Lateral
Scler. 12, 157–159 (2011).
69. Gros-Louis, F., Soucy, G., Larivière, R. &
Julien, J. P. Intracerebroventricular infusion of
monoclonal antibody or its derived Fab fragment
against misfolded forms of SOD1 mutant delays
mortality in a mouse model of ALS.
J. Neurochem. 113, 1188–1199 (2010).
70. Isis Pharmaceuticals [online], http://www.
isispharm.com/Pipeline/Patients.htm (2011).
71. Phase II/III randomized, placebo-controlled trial
of arimoclomol in SOD1 positive familial
amyotropic lateral sclerosis. ClinicalTrials.gov
[online], http://clinicaltrials.gov/ct2/show/NCT
00706147?term=Amyotrophic+lateral+
sclerosis&intr=arimoclomol&rank=1 (2011).
72. SOD1 inhibition by pyrimethamine in familial
amyotrophic lateral sclerosis (ALS). ClinicalTrials.
gov [online], http://clinicaltrials.gov/ct2/show/
NCT01083667?term=Amyotrophic+lateral+
sclerosis&intr=pyrimethamine&rank=1
(2011).
73. Turner, M. R., Kiernan, M. C., Leigh, P. N. &
Talbot, K. Biomarkers in amyotrophic lateral
sclerosis. Lancet Neurology 8, 94–109 (2009).
74. Hecht, M. J. et al. Hyperintense and hypointense
MRI signals of the precentral gyrus and
corticospinal tract in ALS: a follow-up
examination including FLAIR images. J. Neurol.
Sci. 199, 59–65 (2002).
75. Lulé, D., Ludolph, A. C. & Kassubek, J.
MRI-based functional neuroimaging in ALS:
an update. Amyotroph. Lateral Scler. 10,
258–268 (2009).
76. Unrath, A., Ludolph, A. C. & Kassubek, J. Brain
metabolites in definite amyotrophic lateral
sclerosis. A longitudinal proton magnetic
resonance spectroscopy study. J. Neurol. 254,
1099–1106 (2007).
77. Senda, J. et al. Progressive and widespread
brain damage in ALS: MRI voxel-based
morphometry and diffusion tensor imaging
study. Amyotroph. Lateral Scler. 12, 59–69
(2011).
78. Abrahams, S. et al. Frontotemporal white matter
changes in amyotrophic lateral sclerosis.
J. Neurol. 252, 321–331 (2005).
79. Woolley, S. C., Zhang, Y., Schuff, N.,
Weiner, M. W. & Katz, J. S. Neuroanatomical
correlates of apathy in ALS using 4 Tesla
diffusion tensor MRI. Amyotroph. Lateral Scler.
12, 52–58 (2011).
80. Lulé, D. et al. Neuroimaging of multimodal
sensory stimulation in amyotrophic lateral
sclerosis J. Neurol. Neurosurg. Psychiatry 81,
899–906 (2010).
81. Filippini, N. et al. Corpus Callosum involvement
is a consistent feature of amyotrophic lateral
sclerosis. Neurology 75, 1645–1652 (2010).
82. Agosta, F. et al. A longitudinal diffusion tensor
MRI study of the cervical cord and brain in
amyotrophic lateral sclerosis patients. J. Neurol.
Neurosurg. Psychiatry 80, 53–55 (2009).
83. Chiò, A. et al. Prognostic factors in ALS: A critical
review. Amyotroph. Lateral Scler. 10, 310–323
(2009).
84. Wijesekera, L. C. et al. Natural history and
clinical features of the flail arm and flail leg ALS
variants. Neurology 72, 1087–1094 (2009).
85. Burrell, J. R., Vucic, S. & Kiernan, M. C. Isolated
bulbar phenotype of amyotrophic lateral
sclerosis. Amyotroph. Lateral Scler. 12, 283–289
(2011).
86. Chiò, A. et al. Lower serum lipid levels are
related to respiratory impairment in patients
with ALS. Neurology 73, 1681–1685 (2009).
87. Dorst, J. et al. Patients with elevated triglyceride
and cholesterol serum levels have a prolonged
survival in amyotrophic lateral sclerosis.
J. Neurol. 258, 613–617 (2011).
88. Sutedja, N. A. et al. Beneficial vascular risk
profile is associated with amyotrophic lateral
sclerosis. J. Neurol. Neurosurg. Psychiatry 82,
638–642 (2011).
89. Traynor, B. J. et al. Functional outcome measures
as clinical trial endpoints in ALS. Neurology 63,
1933–1935 (2004).
90. Traynor, B. J., Alexander, M., Corr, B., Frost, E. &
Hardiman, O. Effect of a multidisciplinary
amyotrophic lateral sclerosis (ALS) clinic on ALS
survival: a population based study, 1996–2000.
J. Neurol. Neurosurg. Psychiatry 74, 1258–1261
(2003).
91. Van den Berg, J. P. et al. Multidisciplinary ALS
care improves quality of life in patients with
ALS. Neurology 65, 1264–1267 (2005).
92. Chiò, A. et al. Positive effects of tertiary centres
for amyotrophic lateral sclerosis on outcome and
use of hospital facilities. J. Neurol. Neurosurg.
Psychiatry 77, 948–950 (2006).
93. Andersen, P. M. 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. 8, 195–213 (2007).
94. Miller, R. G. 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 73,
1227–1233 (2009).
95. Miller, R. G. et al. Practice parameter update:
The care of the patient with amyotrophic lateral
sclerosis: drug, nutritional, and respiratory
therapies (an evidence-based review): report of
the Quality Standards Subcommittee of the
American Academy of Neurology. Neurology 73,
1218–1226 (2009).
96. Cudkowicz, M. E. et al. Toward more efficient
clinical trials for amyotrophic lateral sclerosis.
Amyotroph. Lateral Scler. 11, 259–265 (2010).
97. Lanka, V. & Cudkowicz, M. Therapy development
for ALS: lessons learned and path forward.
Amyotroph. Lateral Scler. 9, 131–140 (2008).
98. Miller, R. G., Mitchell, J. D., Lyon, M. &
Moore, D. H. Riluzole for amyotrophic lateral
sclerosis (ALS)/motor neuron disease (MND).
Cochrane Database of Systematic Reviews,
Issue 1. Art. No.: CD001447. doi:10.1002/
14651858.CD001447.pub2 (2007).
99. Hardiman, O. Management of respiratory
symptoms in ALS. J. Neurol. 258, 359–365
(2011).
100. Morgan, R. K. et al. Use of Sniff nasal-inspiratory
force to predict survival in amyotrophic lateral
sclerosis. Am. J. Respir. Crit. Care Med. 171,
269–274 (2005).
101. Bourke, S. C. et al. Effects of non-invasive
ventilation on survival and quality of life in
patients with amyotrophic lateral sclerosis:
a randomised controlled trial. Lancet Neurol. 5,
140–147 (2006).
102. Mustfa, N. et al. The effect of noninvasive
ventilation on ALS patients and their caregivers.
Neurology 66, 1211–1217 (2006).
103. Pinto, S. & De Carvalho, M. Is a four-hour use
of non-invasive ventilation enough to define
compliance? Amyotroph. Lateral Scler. 11,
250–252 (2010).
104. Sancho, J., Servera, E., Díaz, J. & Marín, J.
Efficacy of mechanical insufflation-exsufflation in
medically stable patients with amyotrophic lateral
sclerosis. Chest 125, 1400–1405 (2004).
105. Gilio, F. et al. Botulinum toxin type A for the
treatment of sialorrhoea in amyotrophic lateral
sclerosis: a clinical and neurophysiological
study. Amyotroph. Lateral Scler. 11, 359–363
(2010).
106. Winterholler, M. G., Erbguth, F. J., Wolf, S. &
Kat, S. Botulinum toxin for the treatment of
sialorrhoea in ALS: serious side effects of a
transductal approach. J. Neurol. Neurosurg.
Psychiatry 70, 417–418 (2001).
107. Cooper-Knock, J., Ahmedzai, S. H. & Shaw, P. The
use of subcutaneous glycopyrrolate in the
management of sialorrhoea and facilitating the
use of non-invasive ventilation in amyotrophic
lateral sclerosis. Amyotroph. Lateral Scler. http://
dx.doi.org/10.3109/17482968.2011.584195.
108. Neppelberg, E., Haugen, D. F., Thorsen, L. &
Tysnes, O. B. Radiotherapy reduces sialorrhea in
amyotrophic lateral sclerosis. Eur. J. Neurol. 14,
1373–1377 (2007).
109. Limousin, N. et al. Malnutrition at the time of
diagnosis is associated with a shorter disease
duration in ALS. J. Neurol. Sci. 297, 36–39
(2010).
110. Dupuis, L., Pradat, P. F., Ludolph, A. C. &
Loeffler, J. P. Energy metabolism in amyotrophic
lateral sclerosis. Lancet Neurol. 10, 75–82
(2011).
111. Kidney, D., Alexander, M., Corr, B., O’toole, O. &
Hardiman, O. Oropharyngeal dysphagia in
amyotrophic lateral sclerosis: neurological and
dysphagia specific rating scales. Amyotroph.
Lateral Scler. Other Motor Neuron Disord. 5,
150–153 (2004).
112. Thornton, F. J. et al. Amyotrophic lateral
sclerosis: enteral nutrition provision
—endoscopic or radiologic gastrostomy?
Radiology 224, 713–717 (2002).
113. Chiò, A. et al. Percutaneous radiological
gastrostomy: a safe and effective method of
nutritional tube placement in advanced ALS.
J. Neurol. Neurosurg. Psychiatry 75, 645–647
(2004).
114. Sancho, J. et al. Noninvasive respiratory muscle
aids during PEG placement in ALS patients with
severe ventilatory impairment. J. Neurol. Sci.
297, 55–59 (2010).
115. Bede, P. et al. Palliative care in amyotrophic
lateral sclerosis: a review of current international
guidelines and initiatives. J. Neurol. Neurosurg.
Psychiatry 82, 413–418 (2011).
REVI EWS
© 2011 Macmillan Publishers Limited. All rights reserved
NATURE REVIEWS | NEUROLOGY VOLUME 7 | NOVEMBER 2011 | 649
116. Neudert, C., Wasner, M. & Borasio, G. D. 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. 191, 103–109 (2001).
117. 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. 180, 94–100
(2000).
118. Jenkinson, C., Fitzpatrick, R., Brennan, C. &
Swash, M. Evidence for the validity and reliability
of the ALS assessment questionnaire: the
ALSAQ-40. Amyotroph. Lateral Scler. Other Motor
Neuron Disord. 1, 33–40 (1999).
119. Jenkinson, C. & Fitzpatrick, R. Reduced item set
for the amyotrophic lateral sclerosis
assessment questionnaire: development and
validation of the ALSAQ-5. J. Neurol. Neurosurg.
Psychiatry 70, 70–73 (2001).
120. Simmons, Z. et al. The ALSSQOL: balancing
physical and nonphysical factors in assessing
quality of life in ALS. Neurology 67, 1659–1664
(2006).
121. Hardiman, O., Hickey, A. & O’Donerty, L. J.
Physical decline and quality of life in amyotrophic
lateral sclerosis. Amyotroph. Lateral Scler. Other
Motor Neuron Disord. 5, 230–234 (2004).
122. De Groot, I. J., Post, M. W., Van Heuveln, T., Van
den Berg, L. H. & Lindeman, E. Cross-sectional
and longitudinal correlations between disease
progression and different health-related quality
of life domains in persons with amyotrophic
lateral sclerosis. Amyotroph. Lateral Scler. 8,
356–361 (2007).
123. Felgoise, S. H. et al. The SEIQoL-DW for
assessing quality of life in ALS: strengths
and limitations. Amyotroph. Lateral Scler. 10,
456–462 (2009).
124. Robbins, R. A., Simmons, Z., Bremer, B. A.,
Walsh, S. M. & Fischer, S. Quality of life in ALS is
maintained as physical function declines.
Neurology 56, 442–444 (2001).
125. Cupp, J. et al. Psychological health in patients
with ALS is maintained as physical function
declines. Amyotroph. Lateral Scler. 12, 290–296
(2011).
126. Felgoise, S. H. et al. Psychological morbidity in
ALS: the importance of psychological
assessment beyond depression alone.
Amyotroph. Lateral Scler. 11, 351–358 (2010).
127. Walsh, S. M., Bremer, B. A., Felgoise, S. H. &
Simmons, Z. Religiousness is related to quality
of life in patients with ALS. Neurology 60,
1527–1529 (2003).
128. Calvo, A. et al. Religiousness is positively
associated with quality of life of ALS caregivers.
Amyotroph. Lateral Scler. 12, 168–171 (2011).
129. Goldstein, L. H., Atkins, L., Landau, S., Brown, R.
& Leigh, P. N. Predictors of psychological
distress in carers of people with amyotrophic
lateral sclerosis: a longitudinal study. Psychol.
Med. 36, 865–875 (2006).
130. Gauthier, A. et al. A longitudinal study on quality
of life and depression in ALS patient-caregiver
couples. Neurology 68, 923–926 (2007).
131. Pagnini, F. et al. Existential well-being and
spirituality of individuals with amyotrophic lateral
sclerosis is related to psychological well-being of
their caregivers. Amyotroph. Lateral Scler. 12,
105–108 (2011).
132. Pagnini, F. et al. Burden, depression, and anxiety
in caregivers of people with amyotrophic lateral
sclerosis. Psychol. Health Med. 15, 685–693
(2010).
133. Oliver, D. J. & Turner, M. R. Some difficult
decisions in ALS/MND. Amyotroph. Lateral Scler.
11, 339–343 (2010).
Acknowledgments
O. Hardiman was funded by the European Union
Health Research 7
th
Framework Program, 2007–
2013, under grant agreement number 259,867,
and by the Health Research Board Ireland.
Author contributions
All authors contributed equally to the research of
data, discussion of content, writing, and review and/
or editing of the manuscript before submission.
Supplementary information
Supplementary information is linked to the online
version of the paper at www.nature.com/nrneurol
AMYOTROPHI C LATERAL SCLEROSI S
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