Diagnosis of Amyotrophic Lateral Sclerosis and Other Forms of Motor Neuron Disease - UpToDate

27.03.
2024 01:52 Diagnosis of amyotrophic lateral sclerosis and other forms of motor neuron disease - UpToDate
Official reprint from UpToDate®

www.uptodate.com © 2024 UpToDate, Inc. and/or its affiliates. All Rights Reserved.
Diagnosis of amyotrophic lateral sclerosis and other

forms of motor neuron disease
AUTHORS: Lauren B Elman, MD, Leo McCluskey, MD, MBE
SECTION EDITOR: Jeremy M Shefner, MD, PhD
DEPUTY EDITOR: Richard P Goddeau, Jr, DO, FAHA
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2024.

This topic last updated: Oct 18, 2023.
INTRODUCTION
Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive, presently incurable

neurodegenerative disorder that causes muscle weakness, disability, and eventually death.
This topic will review the clinical evaluation and laboratory testing needed to support the
diagnosis of ALS and other forms of motor neuron disease as well as the differential
diagnosis of ALS. Other aspects of ALS are discussed separately. (See "Clinical features of
amyotrophic lateral sclerosis and other forms of motor neuron disease" and "Epidemiology
and pathogenesis of amyotrophic lateral sclerosis" and "Familial amyotrophic lateral
sclerosis" and "Symptom-based management of amyotrophic lateral sclerosis" and "Disease-
modifying treatment of amyotrophic lateral sclerosis".)
CLINICAL EVALUATION
ALS is one of multiple degenerative motor neuron diseases that are clinically defined based
on the involvement of upper and/or lower motor neurons. ALS is the most common form of
acquired motor neuron disease. Clinical manifestations of ALS include the presence of upper
motor neuron and lower motor neuron signs, progression of disease, and the absence of an
alternative explanation. There is no single diagnostic test that can confirm or entirely exclude
the diagnosis of motor neuron disease.
History — The diagnosis of ALS is suggested when there are progressive symptoms
consistent with upper and lower motor neuron dysfunction that present in one of four body
segments (cranial/bulbar, cervical, thoracic, and lumbosacral) followed by spread to other
https://www.uptodate.com/contents/diagnosis-of-amyotrophic-lateral-sclerosis-and-other-forms-of-motor-neuron-disease/print 1/34
27.03.2024 01:52 Diagnosis of amyotrophic lateral sclerosis and other forms of motor neuron disease - UpToDate
segments over a period of months to years. The course is not relapsing and remitting but
rather is insidiously progressive. Involuntary weight loss and muscle wasting unrelated to
nutrition may also occur.
The signs and symptoms associated with ALS are described in the tables for limb ( table 1),
bulbar ( table 2), axial ( table 3), and respiratory ( table 4) locations.
In this setting, the diagnosis of ALS is further suggested by an absence of associated

neuropathic or radiculopathic pain, sensory loss, sphincter dysfunction, ptosis, or extraocular
muscle dysfunction. While sensory symptoms may occur in 20 to 30 percent of patients with
ALS, the sensory examination is usually normal. (See "Clinical features of amyotrophic lateral
sclerosis and other forms of motor neuron disease", section on 'Sensory symptoms'.)
Phenomena considered to exclude the diagnosis of ALS are ocular motility disturbances
including supranuclear gaze paresis, tremor or other involuntary movements, cerebellar
ataxia, extrapyramidal symptoms, and autonomic dysfunction. However, if one or more of
these features occurs in the setting of otherwise typical ALS, this may be considered an ALS-
plus syndrome. (See "Clinical features of amyotrophic lateral sclerosis and other forms of
motor neuron disease", section on 'ALS-plus syndrome'.)
Cognitive dysfunction does not exclude the diagnosis of ALS. Frontotemporal behavioral or
executive dysfunction can precede or follow the onset of motor symptoms in up to 40
percent of patients with ALS. In most cases, the symptoms are mild and possibly only
detectable with formal cognitive testing. However, overt frontotemporal lobar dementia
occurs in approximately 5 to 10 percent of patients with ALS and may be more common in
patients with bulbar-onset ALS [1-4]. (See "Frontotemporal dementia: Clinical features and
diagnosis".)
Since approximately 10 percent of ALS cases are related to a genetic variant (ie, familial ALS),
the history should include a thorough family history focused on any known diagnoses of ALS,
other motor disorders, dementia, schizophrenia, and other neurodegenerative diseases. (See
"Familial amyotrophic lateral sclerosis" and "Clinical features of amyotrophic lateral sclerosis
and other forms of motor neuron disease", section on 'ALS-plus syndrome'.)
Physical examination — The presence of both upper and lower motor neuron signs in
multiple segments is required for the diagnosis of ALS. These are described in the tables for
limb ( table 1), bulbar ( table 2), axial ( table 3), and respiratory ( table 4) signs and
symptoms associated with ALS.
Lower motor neuron signs include the following:
● Weakness
● Fasciculations ( movie 1)
● Muscular atrophy ( movie 2)

● Decreased muscle tone (flaccidity) and reduced or absent reflexes
Upper motor neuron signs include the following:
● Increased tone (spasticity) and increased extremity deep-tendon reflexes ( movie 3)

● The presence of any reflexes in muscles that are profoundly weak and wasted
● Pathologic reflexes such as crossed adductors, a jaw jerk, Hoffman sign, or Babinski
sign [5]
● The syndrome of pseudobulbar affect, which consists of inappropriate laughing, crying,
and/or forced yawning
The Babinski sign (reflex great toe extension, often with fanning of the small toes, with
lateral plantar stimulation) is present in approximately one-half of patients with ALS [6] but is
a definitive indicator of upper motor neuron pathology when present ( movie 4). In the
absence of upper motor neuron pathology, lateral plantar stimulation produces reflex toe
flexion without other leg or foot movement. Triple flexion, which is a manifestation of upper
motor neuron disease, occurs when plantar stimulation produces reflex great toe extension,
flexion of the knee, and flexion of the hip; in some cases, only the contraction of the tensor
fasciae latae may be seen because of total loss of distal motor function [5].
DIAGNOSIS
The diagnosis of ALS is considered in patients with gradually progressive weakness occurring
without associated pain or sensory impairment. The diagnosis of ALS is made in patients
who meet diagnostic criteria assessed by history and physical examination, supported by
electrodiagnostic studies, and not excluded by neuroimaging and laboratory studies. (See
'Diagnostic criteria' below and 'Diagnostic evaluation' below.)
Diagnostic criteria — The criteria used for the diagnosis of ALS have evolved over time [7].
For many years, the clinical standard was the revised El Escorial World Federation of
Neurology criteria, also known as the Airlie House criteria ( algorithm 1) [8,9]. Key features
of these criteria include upper and lower motor neuron signs and progression of symptoms
over time. The El Escorial criteria have been validated pathologically [10].
The revised El Escorial criteria were designed for research purposes to ensure appropriate
inclusion of patients into clinical trials and allow assignment of diagnostic certainty. They
were further adapted (the Awaji criteria) to better incorporate electromyography information
and improve diagnostic sensitivity [11]. Based on diagnostic certainty of the clinical
evaluation, patients may be categorized as having "definite ALS," "probable ALS," or "possible
ALS." However, the complexity and moderate inter-rater reliability when applying these
criteria have been criticized [12,13]. Additionally, categories of diagnostic certainty do not
necessarily predict disease progression [14,15].
Consensus diagnostic criteria were proposed in 2019 to address these concerns and simplify
the diagnosis [16]. These simplified diagnostic criteria (termed "Gold Coast criteria") for ALS
include:
● Progressive upper and lower motor neuron symptoms and signs in one limb or body
segment, OR
● Progressive lower motor neuron symptoms and signs in at least two body segments,
AND
● Absence of electrophysiologic, neuroimaging, and pathologic evidence of other disease

processes that might explain the signs of lower and/or upper motor neuron
degeneration
An advantage of the Gold Coast criteria is the establishment of the diagnosis of ALS for
patients with isolated lower motor neuron signs. It also establishes the diagnosis for patients
who would be labeled with "possible ALS" by the El Escorial criteria. This represents a
simplification of the diagnostic process without the likelihood of excluding patients with the
disease.
In a retrospective study of 506 patients with suspected ALS, the diagnostic sensitivity of the
Gold Coast criteria was similar to the revised El Escorial and Awaji criteria for definite,
probable, or possible ALS (92 versus 90 and 89 percent, respectively) [17]. The Gold Coast
criteria was more sensitive than the revised El Escorial or Awaji criteria for definite or
probable ALS, including those with lower limb and bulbar-onset ALS. The specificity was
similar among the three criteria.
Related forms of ALS — The clinical evaluation of patients with signs and symptoms of
motor neuron disease may suggest the diagnosis of a related form of motor neuron disease
in patients who do not meet diagnostic criteria for ALS. In some of these patients, the
evolution of symptoms may eventually progress to meet diagnostic criteria for ALS; in others,
symptoms remain consistent with a more restricted phenotype of motor neuron disease.
These related forms of motor neuron disease include:
● Progressive muscular atrophy – This progressive disorder is clinically limited to lower

motor neurons. If two regions of the body are involved clinically or
electrophysiologically, then ALS can be diagnosed based on Gold Coast criteria. If upper
motor neuron signs appear over time, the disease is referred to as lower motor
neuron–onset ALS. (See "Clinical features of amyotrophic lateral sclerosis and other
forms of motor neuron disease", section on 'Progressive muscular atrophy'.)
● Primary lateral sclerosis – This is a progressive disorder that is clinically limited to the
upper motor neurons. Consensus diagnostic criteria for primary lateral sclerosis require
presence of exclusively upper motor neuron signs in at least two of three body regions
(bulbar, upper extremity, lower extremity) and the absence of both sensory symptoms
and lower motor neuron dysfunction. Duration of progressive symptoms should be for
at least four years since symptom onset [15]. If lower motor neuron signs appear
before this time, then the diagnosis converts to upper motor neuron–onset ALS. (See
"Clinical features of amyotrophic lateral sclerosis and other forms of motor neuron
disease", section on 'Primary lateral sclerosis'.)
● Progressive bulbar palsy – This is a progressive motor neuron disorder of cranial

muscles. When both upper and lower motor neuron findings are present, the disorder
meets Gold Coast criteria for the diagnosis of ALS. In nearly all cases, upper and/or
lower motor neuron abnormalities will eventually spread to limb, axial, and/or
respiratory motor neurons, and these patients may meet criteria for ALS. In this
circumstance, the designation is changed to bulbar-onset ALS. (See "Clinical features of
amyotrophic lateral sclerosis and other forms of motor neuron disease", section on
'Progressive bulbar palsy'.)
● Flail arm (or leg) syndrome – This syndrome presents with progressive lower motor
neuron weakness of the arms. Similarly, flail leg syndrome involves lower motor neuron
weakness of the legs. When both arms or both legs are involved, this is similar to
progressive muscular atrophy, as described above, and can be called ALS. (See "Clinical
features of amyotrophic lateral sclerosis and other forms of motor neuron disease",
section on 'Flail arm syndrome'.)
● ALS-plus syndrome – This is the designation for patients who meet the clinical criteria
for ALS and also have features of other disorders that have historically excluded the
diagnosis of ALS, such as autonomic insufficiency, extrapyramidal features,
supranuclear gaze paresis, and cerebellar ataxia. (See "Clinical features of amyotrophic
lateral sclerosis and other forms of motor neuron disease", section on 'ALS-plus
syndrome'.)
DIAGNOSTIC EVALUATION
Electrodiagnostic studies — We recommend electrodiagnostic testing with nerve

conduction studies and electromyography (EMG) in all patients with suspected ALS. While
ALS is primarily a clinical diagnosis, sensory and motor nerve conduction studies and EMG
are a standard part of the evaluation of motor neuron disease. Electrodiagnostic studies are
most helpful when clinical evidence supporting the diagnosis of ALS is limited or conflicting.
Electrodiagnostic criteria — The following principles have been emphasized regarding

electrodiagnostic evidence of lower motor neuron disease in patients with suspected ALS
[18]:
● In general, the electrodiagnostic evaluation includes multiple motor and sensory

conduction studies in two or more limbs and needle examination of multiple muscles in
three limbs, the midthoracic paraspinal region, and the bulbar region.
● Motor conduction block should be absent.
● Motor conduction velocities should be normal in the arm and leg. However, loss of
motor axons with resulting reduction of the compound muscle action potential (CMAP)
amplitude may be associated with mild slowing of conduction velocity.
● Sensory amplitudes and velocities in the arm and leg should be normal or preserved in
relationship to motor amplitudes.
● Evidence of acute or ongoing muscle denervation, as indicated by the presence of

fibrillation potentials and positive sharp waves, should be present in multiple muscles
of the regions examined. Per the Awaji Island consensus criteria, fasciculations are
considered indicative of an acute or ongoing denervation in muscles demonstrating
evidence of chronic denervation.
● Evidence of chronic denervation and reinnervation should be present in multiple

muscles in one or more limbs and may also be present in bulbar and thoracic muscles.
Electromyography — The EMG findings in ALS combine features of acute and chronic
denervation and reinnervation [19,20].
● Acute denervation findings include fibrillations and positive sharp waves. The Awaji
Island criteria [21] allowed fasciculations in muscles with neurogenic change to be
considered equivalent to fibrillations and positive sharp waves.
● Fasciculation potentials may appear in denervated muscle and represent spontaneous

firing of motor units that are not voluntarily recruited. Fasciculations may be visible to
the naked eye when they occur on the surface of muscles ( movie 1 and movie 5).
● Chronic denervation and reinnervation findings include large-amplitude, long-duration,

complex motor unit action potentials (MUAPs) with neurogenic recruitment and a
reduced interference pattern. Instability of MUAPs indicative of recent reinnervation is
considered an important indication of ongoing denervation and reinnervation by the
Awaji criteria.
The EMG abnormalities noted in muscles of patients with ALS are not pathognomonic for the
disease but can be seen in any disease causing chronic and ongoing denervation. However,
the diagnosis of ALS should be suggested by the observation of similar abnormalities in
multiple muscles of proximal and distal limbs, in the absence of radiologic demonstration of
corresponding nerve root compression considered significant enough to cause the
abnormality.
Nerve conduction studies — Sensory and motor nerve conduction studies are most often
normal in ALS, though CMAP amplitudes may be reduced in severely atrophic and
denervated muscles [19,20,22].
Motor unit number estimation is a nerve conduction-based method that assesses the
number of viable motor axons innervating small hand or foot muscles [23]. Although this
technique has applications to many diseases, it has been applied most successfully to ALS
[23-26]. Motor unit numbers drop prior to the onset of clinical weakness, and changes in this
measure can be used as an outcome measure in clinical trials [25].
Other electrodiagnostic techniques — In addition to routine nerve conduction studies

and electromyography, other electrodiagnostic techniques may be performed in select
patients being evaluated for ALS. These studies can improve the diagnostic yield of testing
and may help identify or exclude alternative diagnoses. (See 'Differential diagnosis' below.)
● Repetitive nerve stimulation – Repetitive nerve stimulation is a nerve conduction

technique that assesses the integrity of the neuromuscular junction and is useful for
the diagnosis of disorders such as myasthenia gravis and the Lambert-Eaton
myasthenic syndrome [27,28]. Thus, repetitive nerve stimulation may be useful if these
conditions are a consideration in the differential diagnosis during the evaluation of
suspected motor neuron disease.
Repetitive nerve stimulation may be normal or abnormal in patients with ALS, since the
physiology of ongoing denervation with reinnervation can cause unstable transmission
through the neuromuscular junction, which manifests as an abnormal decrement in the
CMAP amplitude [29-35]. Occasionally, the presence of a decrement on repetitive
stimulation can cause diagnostic confusion.
● Single-fiber EMG – Single-fiber EMG is used to measure jitter (an evaluation of

neuromuscular junction function) and fiber density (an electrophysiologic assessment
of reinnervation following denervation). Jitter may be abnormally increased in the
presence of ongoing reinnervation and newly formed, unstable neuromuscular
junctions [19,36].
Increased fiber density is a nonspecific finding that may be present in any muscle that
has undergone denervation and reinnervation. Collateral sprouting increases the
number of muscle fibers within the territory of reinnervated motor units. As a result,
adjacent muscle fibers within any region of a denervated/reinnervated muscle are more
likely to be part of the same motor unit.
● Transcranial magnetic stimulation – External stimulation with a magnet over the

motor cortex, cervical spine, and lumbosacral spine produces a CMAP that can be
recorded from the surface. The difference between the latency of the response elicited
by cranial versus cervical or cranial versus lumbosacral stimulation is called the central
motor conduction time and is a reflection of the integrity of central motor pathways.
Slowing of central motor conduction time has been reported in patients with ALS.
Another measure, cortical hyperexcitability, may be an early and specific feature of ALS
[37].
Transcranial magnetic stimulation (TMS) remains a largely experimental technique and

is not used or routinely available for clinical diagnosis. However, correlation with clinical
upper motor neuron signs has been noted [38-45]. One preliminary study found that
the TMS threshold tracking technique to detect cortical hyperexcitability in patients with
suspected ALS had a reasonable sensitivity and specificity (73 and 81 percent,
respectively) to distinguish ALS from non-ALS disorders at an early stage of disease
[46]. In work by the same group, the addition of a range of TMS and EMG parameters to
clinical criteria to generate an ALS diagnostic index (ALSDI) improved diagnostic
accuracy for early ALS compared with the Awaji criteria [47]. If further validated, tools
like the ALSDI may help to improve the certainty with which clinicians can differentiate
ALS from mimics at an early stage of disease, when new therapies are most likely to be
effective [48].
Additional diagnostic studies — We recommend neuroimaging and routine laboratory

testing in all patients with suspected ALS to exclude alternative diagnoses. Other diagnostic
testing is performed for selected patients. There is no single diagnostic test that can confirm
or entirely exclude the diagnosis of motor neuron disease. However, neuroimaging and
laboratory studies are often important to exclude alternative diagnoses.
Neuroimaging — Neuroimaging has traditionally been used to exclude other possible

diagnoses in the evaluation of suspected ALS. Magnetic resonance imaging (MRI) is the
preferred modality, unless there is a contraindication. Brain MRI should be performed
whenever bulbar disease is present. Cervical and lumbosacral spine MRI can be used to
evaluate lower motor neuron findings in the arms and legs.
When evaluating upper motor neuron findings, MRI should be performed in all segments
rostral to the clinical findings; this includes the brain, cervical spine, and thoracic spine when
upper motor neuron findings are in the legs. Conventional MRI is usually normal in ALS,
although increased signal in the corticospinal tracts on T2-weighted and fluid-attenuated
inversion recovery images and hypointensity of the motor cortex on both T2-weighted and
T2*-susceptibility-weighted images may be seen [49-53].
Experimental imaging techniques to detect upper motor neuron disease in ALS include
magnetic resonance spectroscopy and diffusion tensor imaging [54-57]. Magnetic resonance
spectroscopy provides biochemical and metabolic information in the form of a spectrum
obtained in a region of interest or in the whole brain. The three major peaks observed on an
in vivo proton magnetic resonance spectrum are from N-acetyl aspartate (NAA), choline
(Cho), and creatine (Cr). NAA is thought to correlate with neuronal integrity. The data are
presented either quantitatively or as ratios.
The balance of evidence has shown reduced NAA levels or lower ratios of NAA:Cr, NAA:Cho,
or NAA:Cr+Cho in the motor cortex and corticospinal tract of patients with ALS [55,56,58,59].
Correlation with clinical parameters was not consistently achieved in earlier studies, but one
study evaluating whole-brain magnetic resonance spectroscopic imaging found that
reductions in NAA along the corticospinal tract correlated with disability [59].
Diffusion tensor imaging is a structural neuroimaging technique that measures the extent
and direction of water diffusion. Diffusion of brain water has been shown to have strong
directionality (anisotropy) in white matter [60,61]. Diffusion anisotropy is the result of
restricted diffusion of water molecules across myelinated white matter fibers compared with
diffusion along the fibers. Patients with ALS have been shown to have decreased fractional
anisotropy and increased mean diffusivity in the corticospinal tracts at multiple levels and in
the corpus callosum [54,55,62-65].
Laboratory testing — Laboratory testing of blood, urine, and sometimes cerebrospinal

fluid (CSF) is performed during the evaluation of motor neuron disease. Routine laboratory
work usually includes complete blood count with differential, electrolytes including calcium
and phosphate, liver function tests, thyroid studies, creatine phosphokinase, erythrocyte
sedimentation rate, antinuclear antibody, rheumatoid factor, vitamin B12, anti-GM1
antibody, serum protein electrophoresis with immunofixation, and urine protein
electrophoresis with immunofixation.
● In ALS, creatine phosphokinase may be elevated up to approximately 1000 units/L on

the basis of denervation.
● In patients with an elevated serum calcium level, the serum parathyroid hormone level
should be checked. ALS is rarely associated with primary hyperparathyroidism [66].
● Identification of a serum paraprotein should prompt further work-up with a 24-hour

urine protein electrophoresis, a skeletal survey, and computed tomography (CT) of the
chest, abdomen, and pelvis to look for myeloma and lymphoma. In such cases, referral
to a hematologist/oncologist for bone marrow biopsy may be appropriate.
● In some cases, testing for Lyme disease may be appropriate in regions where it is
endemic (see "Nervous system Lyme disease"). This is particularly important in the
following situations:
• When the clinical manifestations include radicular or neuropathic pain and/or

unilateral peripheral facial palsy
• When sensory signs and symptoms are present
• When MRI of the brain demonstrates multiple white matter signal hyperintensities
• When MRI of the brain and spine demonstrates meningeal signal change and/or
enhancement
● Testing for HIV may be appropriate, particularly in younger patients, at-risk individuals,
and those with atypical features. (See "Acute and early HIV infection: Clinical
manifestations and diagnosis", section on 'Neurologic findings'.)
● Screening for heavy metals in the blood and urine is not required if there is no known
occupational exposure. Only lead intoxication has been reported to cause a condition
resembling lower motor neuron–predominant ALS. This condition has been largely
eliminated through monitoring of occupational exposure [67].
● There is generally no need to send paraneoplastic antibody panels in patients

suspected of having ALS; however, anti-glutamic acid decarboxylase (GAD) antibody
testing may be indicated in the setting of significant upper motor neuron disease.
● Testing for the antibodies found in myasthenia gravis (acetylcholine receptor antibodies
and muscle-specific tyrosine kinase [MuSK] antibodies) and Lambert-Eaton myasthenic
syndrome (voltage-gated calcium channel antibodies) is appropriate in the right clinical
setting and is particularly appropriate in patients with bulbar dysfunction or any ocular
motility disturbance. (See "Diagnosis of myasthenia gravis" and "Lambert-Eaton
myasthenic syndrome: Clinical features and diagnosis", section on 'VGCC antibody
testing'.)
● Lumbar puncture and CSF analysis should be performed if there is clinical suspicion for
Lyme disease, HIV infection, or chronic inflammatory demyelinating polyneuropathy.
● Lumbar puncture for CSF analysis that includes cytology and a search for systemic
malignancy should be considered in lower motor neuron disorders with symptoms that
have progressed over a period of less than two years. This recommendation is based on
our clinical experience and the knowledge that multiple types of cancer can produce a
subacutely progressive lower motor disorder by direct infiltration of the meninges,
motor roots, and cranial nerves. (See "Clinical features and diagnosis of leptomeningeal
disease from solid tumors".)
Elevated levels of CSF neurofilament are found in patients with ALS, suggesting a possible
future role for neurofilament as CSF biomarkers of ALS [68,69].
Genetic testing — Genetic testing has not traditionally been a routine part of the
diagnostic evaluation in ALS. However, familial ALS (FALS) accounts for approximately 10
percent of all ALS cases. Clinical genetic testing for FALS is available to look for variants in a
number of genes, and it is now possible to identify the pathogenic variant in approximately
80 percent of patients with FALS. Autosomal-dominant inheritance is the most common
pattern in hereditary ALS. (See "Familial amyotrophic lateral sclerosis", section on 'Autosomal
dominant'.)
Issues related to genetic testing in ALS are evolving rapidly as clinical trials targeted to
certain genetically mediated forms of ALS are becoming a reality. (See "Familial amyotrophic
lateral sclerosis", section on 'Who should be tested?'.)
Neuromuscular ultrasound — Limited evidence suggests that the use of muscle

ultrasound to detect fasciculations can aid in the diagnosis of ALS. (See "Diagnostic
ultrasound in neuromuscular disease", section on 'Dynamic changes in diseased muscle'.)
In one prospective unblinded report of 81 patients with sporadic ALS, fasciculations were
detected at a significantly higher rate by ultrasound compared with needle EMG in a variety
of muscles including the tongue (60 versus 0 percent), biceps brachii (88 versus 66 percent),
and tibialis anterior (83 versus 45 percent) [70]. Consequently, the proportion of patients
who fulfilled Awaji diagnostic criteria for definite or probable ALS using information from
both EMG and ultrasound was modestly higher compared with EMG alone (79 versus 74
percent).
Another small study found that ultrasound can identify nerve and muscle atrophy in patients
with ALS compared with controls, but these findings are recognized as nonspecific because
they occur in a variety of neuropathic and myopathic disorders [71].
Thus, additional research is needed to determine the true utility of neuromuscular

ultrasound in the diagnosis of ALS [72].
Muscle biopsy — Muscle biopsy is not a routine part of the diagnostic evaluation of ALS but
may be performed if myopathy is suspected on clinical, electrodiagnostic, or serologic
grounds.
Findings on muscle biopsy in ALS are the nonspecific findings of chronic denervation with
reinnervation. Denervated fibers may appear shrunken, angular, and darkly staining. Fiber-
type grouping is a prominent finding that reflects reinnervation. Muscle cell type (fast, slow,
or intermediate twitch) is determined by the innervating motor neuron and leads to
characteristic staining intensities. Normally, different fiber types are distributed randomly
within the muscle, leading to a variegated appearance. With reinnervation, the likelihood
that adjacent fibers will be innervated by the same motor neuron increases, leading to
groups of adjacent fibers having the same staining characteristics.
DIFFERENTIAL DIAGNOSIS
A complete evaluation should be aimed at eliminating the possibility that signs or symptoms
may be accounted for by an alternative diagnosis ( table 5).
Multifocal motor neuropathy — Multifocal motor neuropathy (MMN), also known as MMN
with conduction block, is characterized by lower motor neuron signs that often present in a
bibrachial pattern. (See "Multifocal motor neuropathy".)
The typical clinical presentation of MMN is one of subacute onset with asymmetric weakness
and lower motor neuron signs producing arm and hand weakness without associated
sensory loss. The neuronal involvement in MMN is typically patchy, with some nerves
unaffected and others severely involved. Motor nerve conduction studies usually show
evidence of conduction block. Sensory conduction through the same segment of nerve is
normal. Elevated titers of anti-GM1 antibodies are present in 30 to 80 percent of patients.
(See "Multifocal motor neuropathy", section on 'Clinical features'.)
MMN is a particularly important diagnosis to consider as the condition is treatable with

intravenous immune globulin and other forms of immunosuppression. (See "Multifocal
motor neuropathy", section on 'Treatment'.)
Cervical radiculomyelopathy — Cervical spondylosis with nerve root compression can

cause the combination of lower motor neuron signs at the level of abnormality with upper
motor neuron signs below it. This condition often includes dermatomal or distal sensory
abnormalities and sphincter dysfunction, but these features may be absent. Cervical
magnetic resonance imaging (MRI) establishes the diagnosis. (See "Cervical spondylotic
myelopathy".)
Benign fasciculations — Spontaneous fasciculations may occur in up to 70 percent of

people [73]. A smaller proportion of this group will experience relatively frequent
fasciculations that may be widespread or relatively focal and may be accompanied by
cramps. Long-term follow-up of patients with excess fasciculations who have a normal
examination and normal electromyography (EMG) suggests that this is a truly benign
condition and does not confer an increased risk for the development of motor neuron
disease [74-76]. (See "Overview of electromyography", section on 'Fasciculations'.)
Inflammatory myopathies — Polymyositis, dermatomyositis, immune-mediated

necrotizing myopathy, overlap syndromes with rheumatologic disease, antisynthetase
syndromes, and inclusion body myopathy comprise the inflammatory myopathies. Weakness
of voluntary muscles and dysphagia along with elevated levels of creatine phosphokinase
may occur in each of these conditions. However, inflammatory myopathies may also present
with skin findings, interstitial lung disease, and arthralgias. Muscle biopsy and antibody
testing is usually required for diagnosis of these disorders. Electrophysiologic findings
consistent with myopathy are often seen, but motor unit morphology and recruitment in
end-stage myopathy can appear similar to findings characteristic of chronic denervation.
(See "Overview of and approach to the idiopathic inflammatory myopathies".)
Post-polio syndrome — Post-polio syndrome is a condition that occurs many years after
partial or full clinical recovery from viral poliomyelitis. It is characterized by neurologic and
musculoskeletal complaints. Progressive weakness with or without atrophy may occur in
segments that were affected at the time of initial infection. Upper motor neuron signs do not
occur. The condition may also include pain in muscles or joints and generalized fatigue. The
diagnosis of post-polio syndrome is clinical and is based on slow progression of the above
clinical findings [77,78]. (See "Poliomyelitis and post-polio syndrome", section on 'Post-polio
syndrome'.)
Monomelic amyotrophy — Monomelic amyotrophy, also known as focal amyotrophy, is a

condition that presents clinically with early onset of focal atrophy and weakness, most
commonly of a single hand and arm and rarely of a leg.
One form of monomelic amyotrophy known as Hirayama disease progresses over one to five
years (less commonly over eight years) and then plateaus [67,79-84]. Cervical spine MRI in
the neutral and flexed positions characteristically shows asymmetric flattening of the cord in
the neutral position, anterior displacement of the dura during flexion, and a prominent
posterior epidural venous plexus [85-87]. The proposed mechanism is repeated transient
ischemia of the spinal cord due to forward displacement of the dura on the cord with neck
flexion [88]. Some patients with monomelic amyotrophy have generalized joint hypermobility
that may contribute to excessive cervical joint flexion and extension [89]. Management is
controversial. While most opt for clinical observation, use of a cervical collar and surgical
decompression with fusion have been described in the literature.
Another form of self-limited arm weakness, known as the O'Sullivan–McLeod syndrome,

progresses over a longer period of 25 to 40 years [90].
Both Hirayama disease and O'Sullivan–McLeod syndrome are male-predominant disorders

that affect one or occasionally both upper extremities with weakness that is distal (90
percent) more commonly than proximal (10 percent). Recovery does not occur, but both
conditions are considered to be benign since they do not progress to systemic motor neuron
disease [67,91-93].
While usually sporadic, familial cases of upper-extremity monomelic amyotrophy have been
reported [80,84,94-96].
Lower-extremity monomelic amyotrophy is much less common. It is male predominant with

weakness that is most often present asymmetrically in the gastrocnemius, peronei, and
hamstrings more commonly than in the quadriceps. Progression occurs over a few years and
is followed by a clinical plateau [91].
Hereditary spastic paraplegia — Hereditary spastic paraplegia is a large group of inherited

neurologic disorders in which the prominent feature is a progressive upper motor neuron
spastic weakness of the legs that is similar to that seen in ALS and primary lateral sclerosis.
However, unlike those conditions, patients with hereditary spastic paraplegia often have
urinary urgency and high arched feet. Some forms of hereditary spastic paraplegia may be
associated with cerebellar dysfunction, optic atrophy, and peripheral neuropathy (SPG7) or
with cognitive decline, upper-extremity weakness, dysarthria, nystagmus, and thinning of
the corpus callosum on MRI (SPG11). (See "Disorders affecting the spinal cord", section on
'Hereditary spastic paraplegias'.)
Spinobulbar muscular atrophy — An expansion of an unstable cytosine-adenine-guanine

(CAG) tandem repeat in exon 1 of the androgen receptor gene on chromosome Xq11-12
occurs in males with spinobulbar muscular atrophy (also known as Kennedy disease) [97].
This X-linked disorder is characterized by onset from ages 20 to 60 years of slowly
progressive weakness and atrophy affecting facial, bulbar, and limb muscles that may be
predominantly asymmetric, symmetric, proximal, or distal. There is degeneration of lower
motor neurons in brainstem nuclei and spinal cord. Associated endocrine disturbances
include late-onset gynecomastia, defective spermatogenesis, and a hormonal profile
consistent with androgen resistance. The androgen receptor gene contains an expansion in
the number of glutamine repeats in the N-terminal region ( figure 1) from the usual 20
glutamines to >40 repeats [98]. The pathogenesis is not fully understood, but accumulating
evidence suggests that neuronal degeneration and death are related to accumulation of the
toxic expanded androgen receptor [97].
Myasthenia gravis — Myasthenia gravis occasionally can present as a bulbar syndrome with
dysphagia and dysarthria but without the ptosis or ocular motility disturbance that
commonly accompanies myasthenia. This presentation can mimic bulbar-onset ALS. The
absence of upper or lower motor neuron bulbar signs, the presence of ocular findings, and a
history of diurnal variation of symptoms weigh in favor of myasthenia gravis. In addition, it is
more common for myasthenia to present with ptosis and ocular dysmotility, in which case it
is unlikely to be confused with bulbar ALS. (See "Clinical manifestations of myasthenia
gravis".)
Testing for acetylcholine receptor-binding antibodies should be performed on all patients if

myasthenia gravis is suspected. Testing for muscle-specific tyrosine kinase (MuSK) antibodies
should be pursued if acetylcholine receptor antibodies are negative. The diagnosis of
myasthenia gravis is discussed in detail separately. (See "Diagnosis of myasthenia gravis".)
Repetitive nerve stimulation and single-fiber EMG of facial muscles may be abnormal in both
myasthenia gravis and bulbar-onset ALS with lower motor neuron facial weakness. Cranial
muscles such as the tongue, masseter, or sternocleidomastoid will demonstrate
electrophysiologic evidence of denervation and reinnervation in bulbar-onset ALS. (See
'Other electrodiagnostic techniques' above.)
Hyperthyroidism — There is no evidence of an association between hyperthyroidism and

motor neuron disease. However, clinical features in patients with thyrotoxicosis may include
upper motor neuron signs related to pyramidal tract dysfunction and lower motor neuron
signs related to a peripheral neuropathy; these may overlap with those of ALS. (See
"Neurologic manifestations of hyperthyroidism and Graves' disease", section on 'Motor
neuron manifestations'.)
Others — Other conditions to consider in the differential diagnosis of ALS ( table 5)

include the following [99]:
● Adult-onset spinal muscular atrophy

● Late-onset Tay-Sachs disease (GM2 gangliosidosis)
● Motor neuron syndromes with lymphoproliferative disorders
● Motor neuron syndromes in lung, breast, and other cancers
● Radiation brainstem injury/radiation myelopathy
● Intraspinal lesions (eg, syringomyelia, syringobulbia, or tumor)
Lymphoma, lung cancer, and breast cancer can produce an indirect paraneoplastic
degeneration of the motor neurons that is most commonly subacute to chronic. (See
"Paraneoplastic syndromes affecting spinal cord, peripheral nerve, and muscle", section on
'Subacute motor neuronopathy'.)
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Motor neuron
disease".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th
grade reading level, and they answer the four or five key questions a patient might have
about a given condition. These articles are best for patients who want a general overview
and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are
longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th
grade reading level and are best for patients who want in-depth information and are
comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to
print or email these topics to your patients. (You can also locate patient education articles on
a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
● Basics topic (see "Patient education: Amyotrophic lateral sclerosis (ALS) (The Basics)")
SUMMARY AND RECOMMENDATIONS
● Key clinical features – Clinical manifestations of amyotrophic lateral sclerosis (ALS)

include the presence of upper motor neuron and lower motor neuron signs,
progression of disease, and the absence of an alternative explanation. Motor
impairment may involve limb ( table 1), bulbar ( table 2), axial ( table 3), and
respiratory ( table 4) function. Cognitive change related to frontotemporal
dysfunction may be the presenting symptom in a small subset of patients. (See 'Clinical
evaluation' above and "Clinical features of amyotrophic lateral sclerosis and other forms
of motor neuron disease".)
● Diagnosis – The diagnosis of ALS is made in patients who meet diagnostic criteria
assessed by history and physical examination, supported by electrodiagnostic studies,
and not excluded by neuroimaging and laboratory studies. (See 'Diagnosis' above.)
The criteria used for the diagnosis of ALS have evolved over time. The revised El Escorial
World Federation of Neurology criteria, also known as the Airlie House criteria, include
upper and lower motor neuron signs and progression of symptoms over time
( algorithm 1) [8,9]. The Gold Coast criteria simplify the revised El Escorial criteria for
ALS. (See 'Diagnosis' above.)
● Electrodiagnostic studies – We recommend electrodiagnostic testing with nerve

conduction studies and electromyography (EMG) in all patients with suspected ALS.
Sensory and motor nerve conduction studies are most often normal in ALS, although
compound muscle action potential (CMAP) amplitudes may be reduced in severely
atrophic and denervated muscles. EMG typically reveals combined features of acute
and chronic denervation in ALS. (See 'Electrodiagnostic studies' above.)
● Additional diagnostic testing – We recommend neuroimaging and routine laboratory

testing in all patients with suspected ALS to exclude alternative diagnoses. Other
diagnostic testing is performed for selected patients.
• Neuroimaging – Magnetic resonance imaging (MRI) evaluation should include all

segments rostral to the clinical findings; this includes the brain, cervical spine, and
thoracic spine when upper motor neuron findings are in the legs. Conventional MRI
is usually normal in ALS. (See 'Neuroimaging' above.)
• Routine laboratory testing – Routine testing of blood and urine is used for all
patients to exclude alternative diagnoses. Lumbar puncture for cerebrospinal fluid
analysis is performed if there is clinical suspicion for the diagnosis of chronic
inflammatory demyelinating polyneuropathy, Lyme disease, HIV infection, or
lymphoma or if there is a rapidly progressive isolated lower motor neuron
syndrome. Additional laboratory testing may be required in certain clinical settings.
(See 'Laboratory testing' above.)
• Other testing for some patients
- Genetic testing is not a required part of the diagnostic evaluation in ALS but can
be helpful in making the diagnosis in familial ALS, which accounts for
approximately 10 percent of all ALS cases. (See 'Genetic testing' above.)
- Muscle biopsy is not a routine part of the diagnostic evaluation of ALS but
should be performed if there is clinical suspicion of inflammatory myopathy.
(See 'Muscle biopsy' above and 'Differential diagnosis' above.)
● Differential diagnosis – The differential diagnosis of ALS is extensive ( table 5). This
includes multifocal motor neuropathy, cervical radiculomyelopathy, benign
fasciculations, inflammatory myopathies, post-polio syndrome, monomelic
amyotrophy, hereditary spastic paraplegia, spinobulbar muscular atrophy, myasthenia
gravis, and hyperthyroidism. (See 'Differential diagnosis' above.)
Use of UpToDate is subject to the Terms of Use.
REFERENCES
1. Lomen-Hoerth C. Characterization of amyotrophic lateral sclerosis and frontotemporal

dementia. Dement Geriatr Cogn Disord 2004; 17:337.
2. Strong MJ, Lomen-Hoerth C, Caselli RJ, et al. Cognitive impairment, frontotemporal

dementia, and the motor neuron diseases. Ann Neurol 2003; 54 Suppl 5:S20.
3. Lomen-Hoerth C, Murphy J, Langmore S, et al. Are amyotrophic lateral sclerosis patients
cognitively normal? Neurology 2003; 60:1094.
4. Lomen-Hoerth C, Anderson T, Miller B. The overlap of amyotrophic lateral sclerosis and

frontotemporal dementia. Neurology 2002; 59:1077.
5. Mitsumoto H, Chad DA, Pioro EP. Amyotrophic lateral sclerosis. In: Contemporary Neurol
ogy Series, 49, FA Davis Company, 1998.
6. LANDAU WM, CLARE MH. The plantar reflex in man, with special reference to some
conditions where the extensor response is unexpectedly absent. Brain 1959; 82:321.
7. Feldman EL, Goutman SA, Petri S, et al. Amyotrophic lateral sclerosis. Lancet 2022;
400:1363.
8. 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 Suppl:96.
9. Brooks BR, Miller RG, Swash M, et al. El Escorial revisited: revised criteria for the
diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron
Disord 2000; 1:293.
10. Chaudhuri KR, Crump S, al-Sarraj S, et al. The validation of El Escorial criteria for the
diagnosis of amyotrophic lateral sclerosis: a clinicopathological study. J Neurol Sci 1995;
129 Suppl:11.
11. Boekestein WA, Kleine BU, Hageman G, et al. Sensitivity and specificity of the 'Awaji'
electrodiagnostic criteria for amyotrophic lateral sclerosis: retrospective comparison of
the Awaji and revised El Escorial criteria for ALS. Amyotroph Lateral Scler 2010; 11:497.
12. Forbes RB, Colville S, Swingler RJ. 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 2001; 2:135.
13. Johnsen B, Pugdahl K, Fuglsang-Frederiksen A, et al. Diagnostic criteria for amyotrophic
lateral sclerosis: A multicentre study of inter-rater variation and sensitivity. Clin
Neurophysiol 2019; 130:307.
14. Traynor BJ, Codd MB, Corr B, et al. Clinical features of amyotrophic lateral sclerosis
according to the El Escorial and Airlie House diagnostic criteria: A population-based
study. Arch Neurol 2000; 57:1171.
15. Turner MR, Barohn RJ, Corcia P, et al. Primary lateral sclerosis: consensus diagnostic
criteria. J Neurol Neurosurg Psychiatry 2020; 91:373.

16. Shefner JM, Al-Chalabi A, Baker MR, et al. A proposal for new diagnostic criteria for ALS.
Clin Neurophysiol 2020; 131:1975.
17. Hannaford A, Pavey N, van den Bos M, et al. Diagnostic Utility of Gold Coast Criteria in
Amyotrophic Lateral Sclerosis. Ann Neurol 2021; 89:979.
18. Shefner JM. Amyotrophic lateral sclerosis. In: Office Practice of Neurology, 2nd ed, Samu
els MA, Feske SK (Eds), Churchill Livingstone, 2003. p.548.
19. Daube JR. Electrodiagnostic studies in amyotrophic lateral sclerosis and other motor
neuron disorders. Muscle Nerve 2000; 23:1488.
20. Krivickas LS. Amyotrophic lateral sclerosis and other motor neuron diseases. Phys Med
Rehabil Clin N Am 2003; 14:327.
21. Costa J, Swash M, de Carvalho M. Awaji criteria for the diagnosis of amyotrophic lateral
sclerosis:a systematic review. Arch Neurol 2012; 69:1410.
22. de Carvalho M, Swash M. Nerve conduction studies in amyotrophic lateral sclerosis.
Muscle Nerve 2000; 23:344.
23. Olney RK, Lomen-Hoerth C. Motor unit number estimation (MUNE): how may it
contribute to the diagnosis of ALS? Amyotroph Lateral Scler Other Motor Neuron Disord
2000; 1 Suppl 2:S41.
24. Shefner JM, Gooch CL. Motor unit number estimation in neurologic disease. Adv Neurol
2002; 88:33.
25. Gooch CL, Shefner JM. ALS surrogate markers. MUNE. Amyotroph Lateral Scler Other
Motor Neuron Disord 2004; 5 Suppl 1:104.
26. de Carvalho M, Scotto M, Lopes A, Swash M. Quantitating progression in ALS. Neurology
2005; 64:1783.
27. LAMBERT EH, MULDER DW. Electromyographic studies in amyotrophic lateral sclerosis.
Proc Staff Meet Mayo Clin 1957; 32:441.
28. MULDER DW, LAMBERT EH, EATON LM. Myasthenic syndrome in patients with
amyotrophic lateral sclerosis. Neurology 1959; 9:627.
29. Henderson RD, Daube JR. Decrement in surface-recorded motor unit potentials in
amyotrophic lateral sclerosis. Neurology 2004; 63:1670.
30. Jillapalli D, Shefner JM. Single motor unit variability with threshold stimulation in patients
with amyotrophic lateral sclerosis and normal subjects. Muscle Nerve 2004; 30:578.
31. Wang FC, De Pasqua V, Gérard P, Delwaide PJ. Prognostic value of decremental
responses to repetitive nerve stimulation in ALS patients. Neurology 2001; 57:897.
32. Killian JM, Wilfong AA, Burnett L, et al. Decremental motor responses to repetitive nerve
stimulation in ALS. Muscle Nerve 1994; 17:747.
33. Denys EH, Norris FH Jr. Amyotrophic lateral sclerosis. Impairment of neuromuscular
transmission. Arch Neurol 1979; 36:202.
34. Brown WF, Jaatoul N. Amyotrophic lateral sclerosis. Electrophysiologic study (number of
motor units and rate of decay of motor units). Arch Neurol 1974; 30:242.
35. Carleton SA, Brown WF. Changes in motor unit populations in motor neurone disease. J
Neurol Neurosurg Psychiatry 1979; 42:42.
36. Cui LY, Liu MS, Tang XF. Single fiber electromyography in 78 patients with amyotrophic
lateral sclerosis. Chin Med J (Engl) 2004; 117:1830.
37. Vucic S, Cheah BC, Yiannikas C, Kiernan MC. Cortical excitability distinguishes ALS from
mimic disorders. Clin Neurophysiol 2011; 122:1860.
38. de Carvalho M, Dengler R, Eisen A, et al. Electrodiagnostic criteria for diagnosis of ALS.
Clin Neurophysiol 2008; 119:497.
39. Pohl C, Block W, Träber F, et al. Proton magnetic resonance spectroscopy and
transcranial magnetic stimulation for the detection of upper motor neuron
degeneration in ALS patients. J Neurol Sci 2001; 190:21.
40. Schulte-Mattler WJ, Müller T, Zierz S. Transcranial magnetic stimulation compared with
upper motor neuron signs in patients with amyotrophic lateral sclerosis. J Neurol Sci
1999; 170:51.
41. Kaufmann P, Mitsumoto H. Amyotrophic lateral sclerosis: objective upper motor neuron
markers. Curr Neurol Neurosci Rep 2002; 2:55.
42. Kaufmann P, Pullman SL, Shungu DC, et al. Objective tests for upper motor neuron
involvement in amyotrophic lateral sclerosis (ALS). Neurology 2004; 62:1753.
43. Pouget J, Trefouret S, Attarian S. Transcranial magnetic stimulation (TMS): compared
sensitivity of different motor response parameters in ALS. Amyotroph Lateral Scler
Other Motor Neuron Disord 2000; 1 Suppl 2:S45.
44. Miscio G, Pisano F, Mora G, Mazzini L. Motor neuron disease: usefulness of transcranial
magnetic stimulation in improving the diagnosis. Clin Neurophysiol 1999; 110:975.
45. Floyd AG, Yu QP, Piboolnurak P, et al. Transcranial magnetic stimulation in ALS: utility of
central motor conduction tests. Neurology 2009; 72:498.
46. Menon P, Geevasinga N, Yiannikas C, et al. Sensitivity and specificity of threshold
tracking transcranial magnetic stimulation for diagnosis of amyotrophic lateral sclerosis:
a prospective study. Lancet Neurol 2015; 14:478.
47. Geevasinga N, Howells J, Menon P, et al. Amyotrophic lateral sclerosis diagnostic index:
Toward a personalized diagnosis of ALS. Neurology 2019; 92:e536.
48. Lacomis D, Gooch C. Upper motor neuron assessment and early diagnosis in ALS:
Getting it right the first time. Neurology 2019; 92:255.
49. Chan S, Shungu DC, Douglas-Akinwande A, et al. Motor neuron diseases: comparison of
single-voxel proton MR spectroscopy of the motor cortex with MR imaging of the brain.
Radiology 1999; 212:763.
50. Oba H, Araki T, Ohtomo K, et al. Amyotrophic lateral sclerosis: T2 shortening in motor
cortex at MR imaging. Radiology 1993; 189:843.
51. Cosottini M, Donatelli G, Ricca I, et al. Iron-sensitive MR imaging of the primary motor
cortex to differentiate hereditary spastic paraplegia from other motor neuron diseases.
Eur Radiol 2022; 32:8058.
52. Roeben B, Wilke C, Bender B, et al. The motor band sign in ALS: presentations and
frequencies in a consecutive series of ALS patients. J Neurol Sci 2019; 406:116440.
53. Adachi Y, Sato N, Saito Y, et al. Usefulness of SWI for the Detection of Iron in the Motor
Cortex in Amyotrophic Lateral Sclerosis. J Neuroimaging 2015; 25:443.
54. Turner MR, Grosskreutz J, Kassubek J, et al. Towards a neuroimaging biomarker for
amyotrophic lateral sclerosis. Lancet Neurol 2011; 10:400.
55. Wang S, Melhem ER, Poptani H, Woo JH. Neuroimaging in amyotrophic lateral sclerosis.
Neurotherapeutics 2011; 8:63.
56. Verma G, Woo JH, Chawla S, et al. Whole-brain analysis of amyotrophic lateral sclerosis
by using echo-planar spectroscopic imaging. Radiology 2013; 267:851.
57. Hornberger M, Kiernan MC. Emergence of an imaging biomarker for amyotrophic lateral
sclerosis: is the end point near? J Neurol Neurosurg Psychiatry 2016; 87:569.
58. Govind V, Sharma KR, Maudsley AA, et al. Comprehensive evaluation of corticospinal
tract metabolites in amyotrophic lateral sclerosis using whole-brain 1H MR
spectroscopy. PLoS One 2012; 7:e35607.
59. Stagg CJ, Knight S, Talbot K, et al. Whole-brain magnetic resonance spectroscopic
imaging measures are related to disability in ALS. Neurology 2013; 80:610.
60. Pierpaoli C, Basser PJ. Toward a quantitative assessment of diffusion anisotropy. Magn
Reson Med 1996; 36:893.
61. Basser PJ, Pajevic S, Pierpaoli C, et al. In vivo fiber tractography using DT-MRI data. Magn
Reson Med 2000; 44:625.
62. Iwata NK, Aoki S, Okabe S, et al. Evaluation of corticospinal tracts in ALS with diffusion
tensor MRI and brainstem stimulation. Neurology 2008; 70:528.
63. Menke RA, Abraham I, Thiel CS, et al. Fractional anisotropy in the posterior limb of the
internal capsule and prognosis in amyotrophic lateral sclerosis. Arch Neurol 2012;
69:1493.
64. Filippini N, Douaud G, Mackay CE, et al. Corpus callosum involvement is a consistent
feature of amyotrophic lateral sclerosis. Neurology 2010; 75:1645.
65. Müller HP, Turner MR, Grosskreutz J, et al. A large-scale multicentre cerebral diffusion
tensor imaging study in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry
2016; 87:570.
66. Jackson CE, Amato AA, Bryan WW, et al. Primary hyperparathyroidism and ALS: is there a
relation? Neurology 1998; 50:1795.
67. Rowland LP. Diagnosis of amyotrophic lateral sclerosis. J Neurol Sci 1998; 160 Suppl 1:S6.
68. Reijn TS, Abdo WF, Schelhaas HJ, Verbeek MM. CSF neurofilament protein analysis in the
differential diagnosis of ALS. J Neurol 2009; 256:615.
69. Steinacker P, Feneberg E, Weishaupt J, et al. Neurofilaments in the diagnosis of
motoneuron diseases: a prospective study on 455 patients. J Neurol Neurosurg
Psychiatry 2016; 87:12.
70. Misawa S, Noto Y, Shibuya K, et al. Ultrasonographic detection of fasciculations markedly
increases diagnostic sensitivity of ALS. Neurology 2011; 77:1532.
71. Cartwright MS, Walker FO, Griffin LP, Caress JB. Peripheral nerve and muscle ultrasound
in amyotrophic lateral sclerosis. Muscle Nerve 2011; 44:346.
72. Swash M, Carvalho Md. Muscle ultrasound detects fasciculations and facilitates
diagnosis in ALS. Neurology 2011; 77:1508.
73. REED DM, KURLAND LT. MUSCLE FASCICULATIONS IN A HEALTHY POPULATION. Arch
Neurol 1963; 9:363.
74. Mitsikostas DD, Karandreas N, Coutsopetras P, et al. Fasciculation potentials in healthy
people. Muscle Nerve 1998; 21:533.
75. de Carvalho M, Swash M. Fasciculation potentials: a study of amyotrophic lateral
sclerosis and other neurogenic disorders. Muscle Nerve 1998; 21:336.
76. Blexrud MD, Windebank AJ, Daube JR. Long-term follow-up of 121 patients with benign
fasciculations. Ann Neurol 1993; 34:622.
77. Sunnerhagen KS, Grimby G. Muscular effects in late polio. Acta Physiol Scand 2001;
171:335.
78. Chasens ER, Umlauf MG. Post-polio syndrome. Am J Nurs 2000; 100:60.
79. Rowland LP. Progressive muscular atrophy and other lower motor neuron syndromes of
adults. Muscle Nerve 2010; 41:161.
80. HIRAYAMA K, TSUBAKI T, TOYOKURA Y, OKINAKA S. Juvenile muscular atrophy of
unilateral upper extremity. Neurology 1963; 13:373.
81. Hirayama K. [Juvenile non-progressive muscular atrophy localized in the hand and
forearm--observations in 38 cases]. Rinsho Shinkeigaku 1972; 12:313.
82. Pradhan S. Bilaterally symmetric form of Hirayama disease. Neurology 2009; 72:2083.
83. Hosokawa T, Fujieda M, Wakiguchi H, Oosaki Y. Pediatric Hirayama disease. Pediatr

Neurol 2010; 43:151.
84. Hirayama K, Tomonaga M, Kitano K, et al. Focal cervical poliopathy causing juvenile
muscular atrophy of distal upper extremity: a pathological study. J Neurol Neurosurg
Psychiatry 1987; 50:285.
85. Lehman VT, Luetmer PH, Sorenson EJ, et al. Cervical spine MR imaging findings of
patients with Hirayama disease in North America: a multisite study. AJNR Am J
Neuroradiol 2013; 34:451.
86. Tsukita K, Sakamaki-Tsukita H. Hirayama disease: oblique amyotrophy and characteristic

magnetic resonance imaging findings. QJM 2018; 111:583.
87. Boruah DK, Prakash A, Gogoi BB, et al. The Importance of Flexion MRI in Hirayama
Disease with Special Reference to Laminodural Space Measurements. AJNR Am J
Neuroradiol 2018; 39:974.
88. Hirayama K, Tokumaru Y. Cervical dural sac and spinal cord in juvenile muscular atrophy
of distal upper extremity. Neurology 2000; 54:1922.
89. Chen K, Yang Y, Zhu D, et al. Association of joint hypermobility with range of cervical
motion and its impact on the motor unit loss in patients with Hirayama disease. Muscle
Nerve 2023; 68:729.
90. O'Sullivan DJ, McLeod JG. Distal chronic spinal muscular atrophy involving the hands.
Clin Exp Neurol 1977; 14:256.
91. Di Muzio A, Delli Pizzi C, Lugaresi A, et al. Benign monomelic amyotrophy of lower limb:
a rare entity with a characteristic muscular CT. J Neurol Sci 1994; 126:153.
92. Gourie-Devi M, Nalini A. Long-term follow-up of 44 patients with brachial monomelic
amyotrophy. Acta Neurol Scand 2003; 107:215.
93. Verma A, Bradley WG. Atypical motor neuron disease and related motor syndromes.
Semin Neurol 2001; 21:177.
94. Sobue I, Saito N, Iida M, Ando K. Juvenile type of distal and segmental muscular atrophy
of upper extremities. Ann Neurol 1978; 3:429.
95. Tandan R, Sharma KR, Bradley WG, et al. Chronic segmental spinal muscular atrophy of
upper extremities in identical twins. Neurology 1990; 40:236.
96. Nalini A, Lokesh L, Ratnavalli E. Familial monomelic amyotrophy: a case report from
India. J Neurol Sci 2004; 220:95.
97. Finsterer J. Perspectives of Kennedy's disease. J Neurol Sci 2010; 298:1.

98. La Spada AR, Wilson EM, Lubahn DB, et al. Androgen receptor gene mutations in X-
linked spinal and bulbar muscular atrophy. Nature 1991; 352:77.
99. Kiernan MC, Vucic S, Cheah BC, et al. Amyotrophic lateral sclerosis. Lancet 2011;
377:942.
Topic 5138 Version 46.0
GRAPHICS
Limb signs and symptoms associated with amyotrophic lateral sclerosis
Upper motor neuron signs Upper motor neuron symptoms

Spasticity Stiffness, slowness, and incoordination of
movement
Slowed rapid alternating movements
Hand and/or arm
Increased reflexes
Difficulty performing activities of daily
"Preserved" reflexes in weak/atrophic muscles
living
Distal spread of arm reflexes
Difficulty manipulating small objects or
Hoffman sign writing
Crossed adduction Leg and/or foot
Upgoing toe Gait dysfunction
Triple flexion Slow, stiff gait; difficulty turning

Gait disorder Legs "heavy"
Spastic Poor balance and falling
Lower motor neuron signs Spontaneous clonus
Weakness Spontaneous flexor spasms
Intrinsic hand weakness Lower motor neuron symptoms

Foot drop Weakness and atrophy
Proximal arm and leg weakness Arm and/or hand

Poor heel and/or toe walking Difficulty performing activities of daily
living
Poor rise from chair
Poor squat Difficulty manipulating small objects or

writing
Gait disorder
Leg and/or foot
Steppage
Difficulty arising from chairs or from floor
Waddling
Difficulty climbing stairs
Reduced reflexes
Foot drop
Muscle atrophy and fasciculations
Tripping, falling
Fasciculations
Cramps
Graphic 72454 Version 3.0
Bulbar signs and symptoms associated with amyotrophic lateral sclerosis
Increased jaw reflex Jaw stiffness with difficulty opening the mouth
Jaw spasticity Spontaneous clenching or biting
Facial diparesis (may be Trismus

asymmetric)
Spontaneous jaw clonus
Increased facial reflexes
Dysphagia
Palmomental sign
Tongue incoordination disrupts the oral phase
Poor palatal elevation
Pharyngeal muscle incoordination disrupts the pharyngeal
Slow tongue movement phase
Lower motor neuron signs Dysarthria
Weak masseter and/or Labial, lingual, and/or pharyngeal components

pterygoids Spastic with slow, strained speech
Difficulty maintaining jaw closure Laryngospasm
Facial diparesis (may be Often triggered by secretions (eg, saliva) or food particles
asymmetric)
Rapid onset
Poor palatal elevation
"Squeezing" feeling, inability to speak, strained speech
Tongue weakness
Short-lived, less than 30 seconds
Muscle atrophy and
fasciculations Pseudobulbar affect
Inappropriate laughing, crying, and/or yawning
Affective response >> emotional trigger
Mood incongruent
Sialorrhea (drooling)
Difficulty managing pharyngeal secretions
Lower motor neuron symptoms

Incomplete eye closure
Difficulty opening and/or closing the jaw
Difficulty chewing
Disarticulation of the temporomandibular joint when severe
Poor lip closure and seal
May contribute to sialorrhea when severe
Dysphagia
Tongue weakness disrupts the oral phase
Pharyngeal muscle weakness disrupts the pharyngeal phase
Coughing and choking induced by drinking, eating, or saliva

secretion
Often thin liquids followed by solids and thick liquids
Dysarthria
Labial, lingual, and/or pharyngeal components
Slurred, nasal, and/or hoarse speech
Hoarseness
Axial signs and symptoms associated with amyotrophic lateral sclerosis
Absent abdominal reflexes Stiffness and imbalance
Lower motor neuron signs Lower motor neuron symptoms
Neck extension weakness Neck extensors
Truncal extension weakness; bent spine Difficulty holding up the head
Abdominal protuberance When severe produces head drop
Increased lumbar lordosis Truncal extensors
Difficulty maintaining an erect posture
Lumbar extensors
Increased lumbar lordosis
Abdominal wall muscles
Abdominal protuberance
Cramps
Respiratory signs and symptoms associated with amyotrophic lateral

sclerosis
Lower motor neuron signs Lower motor neuron symptoms
Tachypnea Dyspnea and/or orthopnea
Vocal and speech Low speech volume
Reduced vocal volume Weak cough
Shortened sentences Sleep disordered breathing
Frequent breath pauses Frequent nocturnal awakenings, possibly with note of

dyspnea
Use of accessory respiratory
muscles Excessive daytime sleepiness and/or fatigue
Abdominal paradox Morning headache
Confusion
Hallucinations
Revised El Escorial and Awaji diagnostic criteria for amyotrophic lateral

sclerosis
ALS: amyotrophic lateral sclerosis; EMG: electromyography.
From: Quinn C, Elman L. Amyotrophic lateral sclerosis and other motor neuron diseases. Continuum 2020; 26:1323. DOI:
10.1212/CON.0000000000000911. Copyright © 2020 American Academy of Neurology. Reproduced with permission from
Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited.
Differential diagnosis of amyotrophic lateral sclerosis
Disease Distinguishing features
Multifocal motor neuropathy Multifocal nerve conduction block, very high GM1 ganglioside
antibody titers
Cervical spondylosis or Sensory symptoms and signs, Lhermitte's symptom, LMN signs at
extramedullary tumor with level(s) of compression and UMN signs in legs, sphincter dysfunction,
compressive radiculopathy MRI of spine shows significant cord compression with intrinsic spinal
and myelopathy cord signal abnormality
Benign fasciculations No weakness or atrophy, no electromyographic abnormality of motor

unit morphology
Inclusion body myositis Disproportionate finger flexor weakness, no UMN signs, slow
progression, diagnosis requires muscle biopsy, electromyography
usually with myopathic features
Primary lateral sclerosis A clinical variant of ALS: Spastic paraparesis, often with pseudobulbar
palsy, prominent spasticity and hyperreflexia, no LMN signs
Progressive bulbar palsy A clinical variant of ALS: Bulbar involvement predominates,

pronounced dysarthria and dysphagia, limb musculature mostly
spared
Progressive muscular atrophy A clinical variant of ALS: Muscle weakness and atrophy with no UMN
signs
Myasthenia gravis Diplopia, ptosis, ocular dysmotility, weakness improved by

acetylcholinesterase inhibitors, no UMN or LMN features
Monomelic (benign focal) Onset usually in youth, slow and self limited course, no UMN features
amyotrophy
Hereditary spinal muscular Symmetric, slow course, no UMN signs, usually diagnostic changes
atrophy detected in the survival motor neuron 1 gene (SMN1)
Hereditary spastic paraplegia Slowly progressive lower extremity spastic UMN weakness, minimal or
no LMN symptoms and/or signs, sphincter dysfunction, sensory
symptoms and signs, HSP gene positive if available
Post-polio progressive Slow course, no UMN signs

muscular atrophy
Spinobulbar muscular X-linked recessive disorder, slow progression, expansion of a CAG

atrophy (Kennedy disease) trinucleotide repeat (>40 CAGs) in the androgen receptor gene
Late-onset Tay-Sachs disease Late adolescent and early adult onset, progressive atrophic paralysis,
(GM2 gangliosidosis) hexosaminidase A deficiency
Motor neuron syndromes Lymphoma (Hodgkin or non-Hodgkin), multiple myeloma, chronic

with lymphoproliferative lymphocytic leukemia, Waldenström macroglobulinemia; some have
disorders paraproteinemia
Motor neuron syndromes in May improve on treatment of the tumor, may be paraneoplastic or
lung, breast, and other coincidental
cancers
Radiation brainstem History of radiation therapy for cancer, location of injury within the
injury/radiation myelopathy radiation ports, delay of months to a few years from treatment, LMN
symptoms and signs at the level of the injury, possible UMN symptom
and signs below the injury, possible sensory symptoms and signs
below the level of the injury (eg, Lhermitte sign), self limited: does not
progress to a diffuse LMN/UMN disorder
Thyrotoxic myopathy with Overt or covert hyperthyroidism

fasciculations
Intraspinal tumors and other Imaging studies show syringomyelia, syringobulbia, or intraspinal
lesions tumors
ALS: amyotrophic lateral sclerosis; LMN: lower motor neuron; UMN: upper motor neuron.
Modified from: Layzer RB. Chapter 415. Hereditary and acquired intrinsic motor neuron diseases. In: Bennett and Plum (Eds),
Cecil Textbook of Medicine, W.B. Saunders, Philadelphia 1999.
Human androgen receptor
Schematic diagram of the human androgen receptor structure as deduced from cDNA. The protein
contains 917 amino acids, and the positions of the homopolymeric glutamine (Gln), proline (Pro), and
glycine (Gly) repeat sequences and of the DNA- and hormone-binding domains are indicated using
the numbering coordinates of Tilley WD, Marcelli M, Wilson JD, McPhaul MJ. Proc Natl Acad Sci U S A
1989; 86:327.
Contributor Disclosures
Lauren B Elman, MD Grant/Research/Clinical Trial Support: Abbvie Pharmaceuticals [ALS]; Amylyx
[ALS]; Avidity Biosciences [FSHD]; Biogen [ALS]; Biohaven Pharmaceuticals [ALS]; Clene Nanomedicine
[ALS]; Denali Therapeutics [ALS]; Harmony Biosciences [Myotonic Dystrophy]; MLBio Solutions [LGMD];
Prilenia Therapeutics [ALS]; Ra Pharmaceuticals [ALS]; Seelos Therapeutics [ALS]. Consultant/Advisory
Boards: Apellis Pharmaceuticals [ALS]; Biogen [ALS, SMA]; Edgewise Therapeutics [Duchenne/Becker
Muscular Dystrophy]; PTC Therapeutics [Duchenne muscular dystrophy]; Roche/Genentech [SMA]. All of
the relevant financial relationships listed have been mitigated. Leo McCluskey, MD, MBE No relevant
financial relationship(s) with ineligible companies to disclose. Jeremy M Shefner, MD,
PhD Grant/Research/Clinical Trial Support: AB Sciences [ALS]; Amylyx [ALS]; Biogen [ALS]; Cytokinetics
Incorporated [ALS]; Ionis [ALS]; Mitsubishi Tanabe Pharma America [ALS]; PTC [ALS]; QurAlis [ALS];
Sanofi [ALS]; Wave Life Sciences [ALS]. Consultant/Advisory Boards: AcuraStem [ALS]; Amylyx [ALS];
Annexon [ALS]; Apellis [ALS]; Clene [ALS]; Cytokinetics [ALS]; Denali [ALS]; Eikonizo [ALS]; GSK [ALS];
Mitsubishi Tanabe Pharma America [ALS]; Neurosense [ALS]; Novartis [ALS]; Revalesio [ALS]; RRD [ALS];
Swanbio [ALS]; Vertex [DMD]. All of the relevant financial relationships listed have been
mitigated. Richard P Goddeau, Jr, DO, FAHA No relevant financial relationship(s) with ineligible
companies to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these
are addressed by vetting through a multi-level review process, and through requirements for
references to be provided to support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.
Conflict of interest policy

Diagnosis of Amyotrophic Lateral Sclerosis and Other Forms of Motor Neuron Disease - UpToDate

Uploaded by

Copyright:

Available Formats

You might also like

Diagnosis of Amyotrophic Lateral Sclerosis and Other Forms of Motor Neuron Disease - UpToDate

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Diagnosis of Amyotrophic Lateral Sclerosis and Other Forms of Motor Neuron Disease - UpToDate

Uploaded by

Copyright:

Available Formats

27.03.

Official reprint from UpToDate®

Diagnosis of amyotrophic lateral sclerosis and other

Literature review current through: Feb 2024.

Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive, presently incurable

In this setting, the diagnosis of ALS is further suggested by an absence of associated

Lower motor neuron signs include the following:

● Muscular atrophy ( movie 2)

Upper motor neuron signs include the following:

● Increased tone (spasticity) and increased extremity deep-tendon reflexes ( movie 3)

● Absence of electrophysiologic, neuroimaging, and pathologic evidence of other disease

● Progressive muscular atrophy – This progressive disorder is clinically limited to lower

● Progressive bulbar palsy – This is a progressive motor neuron disorder of cranial

Electrodiagnostic studies — We recommend electrodiagnostic testing with nerve

Electrodiagnostic criteria — The following principles have been emphasized regarding

● In general, the electrodiagnostic evaluation includes multiple motor and sensory

● Motor conduction block should be absent.

● Evidence of acute or ongoing muscle denervation, as indicated by the presence of

● Evidence of chronic denervation and reinnervation should be present in multiple

● Fasciculation potentials may appear in denervated muscle and represent spontaneous

● Chronic denervation and reinnervation findings include large-amplitude, long-duration,

Other electrodiagnostic techniques — In addition to routine nerve conduction studies

● Repetitive nerve stimulation – Repetitive nerve stimulation is a nerve conduction

● Single-fiber EMG – Single-fiber EMG is used to measure jitter (an evaluation of

● Transcranial magnetic stimulation – External stimulation with a magnet over the

Transcranial magnetic stimulation (TMS) remains a largely experimental technique and

Additional diagnostic studies — We recommend neuroimaging and routine laboratory

Neuroimaging — Neuroimaging has traditionally been used to exclude other possible

Laboratory testing — Laboratory testing of blood, urine, and sometimes cerebrospinal

● In ALS, creatine phosphokinase may be elevated up to approximately 1000 units/L on

● Identification of a serum paraprotein should prompt further work-up with a 24-hour

• When the clinical manifestations include radicular or neuropathic pain and/or

● There is generally no need to send paraneoplastic antibody panels in patients

Neuromuscular ultrasound — Limited evidence suggests that the use of muscle

Thus, additional research is needed to determine the true utility of neuromuscular

MMN is a particularly important diagnosis to consider as the condition is treatable with

Cervical radiculomyelopathy — Cervical spondylosis with nerve root compression can

Benign fasciculations — Spontaneous fasciculations may occur in up to 70 percent of

Inflammatory myopathies — Polymyositis, dermatomyositis, immune-mediated

Monomelic amyotrophy — Monomelic amyotrophy, also known as focal amyotrophy, is a

Another form of self-limited arm weakness, known as the O'Sullivan–McLeod syndrome,

Both Hirayama disease and O'Sullivan–McLeod syndrome are male-predominant disorders

Lower-extremity monomelic amyotrophy is much less common. It is male predominant with

Hereditary spastic paraplegia — Hereditary spastic paraplegia is a large group of inherited

Spinobulbar muscular atrophy — An expansion of an unstable cytosine-adenine-guanine

Testing for acetylcholine receptor-binding antibodies should be performed on all patients if

Hyperthyroidism — There is no evidence of an association between hyperthyroidism and

Others — Other conditions to consider in the differential diagnosis of ALS ( table 5)

● Adult-onset spinal muscular atrophy

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

SUMMARY AND RECOMMENDATIONS

● Key clinical features – Clinical manifestations of amyotrophic lateral sclerosis (ALS)

● Electrodiagnostic studies – We recommend electrodiagnostic testing with nerve

● Additional diagnostic testing – We recommend neuroimaging and routine laboratory

• Neuroimaging – Magnetic resonance imaging (MRI) evaluation should include all

• Other testing for some patients

Use of UpToDate is subject to the Terms of Use.

1. Lomen-Hoerth C. Characterization of amyotrophic lateral sclerosis and frontotemporal