Diagnosis of amyotrophic lateral sclerosis and other forms of motor neuron disease

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 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 5^th to 6^th 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 10^th to 12^th 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.)