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      Drugs & Diseases > Neurology

      Amyotrophic Lateral Sclerosis Workup

      Updated: Aug 18, 2023
      • Author: Carmel Armon, MD, MSc, MHS; Chief Editor: Nicholas Lorenzo, MD, CPE, MHCM, FAAPL  more...
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      Workup

      Approach Considerations

      Amyotrophic lateral sclerosis (ALS) may not lend itself to a quick definitive diagnosis early in its presentation. Often, neurologists need many months to exclude all other possible diagnoses in a patient presenting with upper and lower motor neuron signs. In some cases the diagnosis is fairly obvious even in its early stages.

      Nerve conduction studies and needle electromyography (EMG) are useful for confirming the diagnosis of ALS and for excluding peripheral conditions that resemble ALS.

      Laboratory tests are performed primarily to rule out other disease processes; results generally are normal in ALS.

      Biochemical markers in blood are used almost routinely to identify diseases that could mimic ALS. Examination of cerebrospinal fluid usually is not necessary unless the patient has a pure upper motor neuron (UMN) or pure lower motor neuron (LMN) presentation, in which case it can be helpful in excluding inflammatory conditions, neoplastic infiltrations, or infections.

      Genetic testing

      Genetic testing may be performed to identify genetic defects in some familial types of ALS, as well as other inherited motor neuron diseases. In the future, genetic testing may become more routine, given recent research showing that in some populations the C9orf72 mutation is present in a high proportion of patients with no family history of ALS.

      The role of genetic testing in patients with sporadic disease has been debated among ALS experts. [167] Patients with sporadic disease who are considering genetic testing should take the time, through genetic counseling, to study the implications for themselves and for their first-degree relatives, Ideally, the first-degree relatives should be involved in the counseling process as the results of genetic testing impact them more than they impact the patient. In some centers, genetic testing is routine for all patients with ALS. It has been advocated as necessary for all patients entering clinical trials, as treatment responses may vary based on patients’ genetic profiles. A current instance under evaluation is the effectiveness of lithium in patients with ALS. After initial enthusiasm, it was shown to be ineffective in several large placebo-controlled studies. [239, 240, 241]

      It then appeared, in a post-hoc analysis, that there may be a subgroup of patients, those who are homozygous for the C-allele at SNP rs12608932 in UNC13A, in whom lithium might be effective. A clinical trial has been registered to explore this possibility. [242]

      Imaging

      Imaging studies need to be tailored to the patient’s clinical presentation. Neuroimaging may include computed tomography (CT) scanning or magnetic resonance imaging (MRI) of the brain and spinal cord.

      Muscle or nerve biopsy

      Muscle biopsy is needed only rarely but may be considered if the presentation of ALS is atypical. The results will confirm the presence of signs of denervation and reinnervation or may lead to an alternative diagnosis, such as inclusion body myositis.

      The presence of small, angular fibers is consistent with neurogenic atrophy (denervation). Fiber-type grouping is consistent with reinnervation.

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      Needle Electromyography and Nerve Conduction Studies

      It is common to examine at least 3 levels—cervical/thoracic/lumbar paraspinal muscles—and bulbar muscles, as follows:

      • Most involved limb first: Two or more weak muscles with different innervation

      • Distal muscles of other possibly abnormal extremities

      • If other levels are not abnormal, then check bulbar muscles

      EMG may show fibrillation and fasciculation potentials. The motor units may be polyphasic and have high amplitude and long duration.

      Motor unit recruitment

      The pattern of recruitment of motor units may be abnormal due to loss of anterior horn cells and a reduction in the number of viable motor axons to activate the muscle(s) involved. This loss results in increased firing frequency of surviving motor units, because fewer anterior horn cells (motor axons) are available to be activated as the amount of effort increases.

      Muscle innervation

      Recently reinnervated muscles demonstrate variability of morphology on needle EMG examination. This is because of sprouting nerve terminals that are unmyelinated, have slower conduction, and may cause intermittent conduction block. Increased polyphasia of voluntary motor unit action potentials is a result of asynchronous firing of reinnervated, unmyelinated muscle fibers resulting from slowed terminal nerve conduction.

      Over time, the voluntary motor unit action potentials increase in size and duration because of collateral sprouting, bringing more muscle fibers into the motor unit. With maturation of the terminal sprouting, voluntary motor unit action potentials increase in size in reinnervated muscle fibers, restoring their size and a greater degree of motor firing synchrony due to myelinization of terminal nerve fibers and more rapid terminal nerve conduction.’

      Denervation

      Signs of active and chronic denervation are likely to be observed. Fibrillation potentials and positive sharp waves represent active denervation. Chronic denervation is demonstrated by evidence of large motor unit potentials with increased duration and amplitude, as well as polyphasic potentials, reduced recruitment, a reduced interference pattern with firing rates higher than 10 Hz, and unstable motor unit potentials.

      Multispike and fasciculation potentials

      Complex, repetitive discharges occur in ALS of long duration, as they do in other chronic neurogenic atrophic conditions. These are regularly discharging multispike potentials that are time-locked. Other than an EMG finding associated with a chronic neurogenic atrophic condition, this finding has no other unique significance.

      Fasciculation potentials are seen frequently but not invariably in ALS. Their presence is not specific to ALS; they may occur in other conditions, some completely benign.

      Conduction studies

      Motor and sensory nerve conduction studies are performed primarily to rule out other disorders. In patients with predominantly LMN findings, the presence of conduction block may point to treatable diseases such as multifocal motor neuropathy or motor chronic inflammatory demyelinating polyneuropathy.

      Sensory nerve conduction studies are usually normal. Less than 10% of patients with ALS have abnormal sural sensory nerve conduction studies. Patients over age 60 years commonly lose the sural sensory nerve action potential (SNAP), but this is attributable to normal aging.

      In late stages of ALS, LMN involvement may be extensive; in such cases, compound muscle action potentials may be reduced. Hallmark findings in the electrodiagnosis of ALS are normal sensory nerve conduction studies and abnormal motor nerve conduction studies, with reduced motor compound muscle action potentials.

      Neuromuscular transmission instability of collateral nerve terminal sprouts in ALS patients presents as a decrement with slow repetitive stimulation. This instability is present in less than 50% of patients with ALS. The decrement in ALS is usually less than 10%. In contrast, compound muscle action potential decrements greater than 20% on repetitive stimulation of motor nerves are seen in myasthenia gravis. In ALS, this is usually a late finding, whereas in myasthenia gravis, this is an early finding.

      Electrophysiologic features compatible with UMN involvement include an increase of up to 30% in central motor conduction time determined by cortical magnetic stimulation. However, central electrophysiologic studies are currently not part of the routine evaluation of patients with ALS, because whether emergence of central studies abnormalities precedes that of clinical signs of UMN involvement has not been determined.

      Low or irregular firing rates of a few voluntary motor unit action potentials on maximal effort may be seen during routine needle examination of UMNs. However, this feature is nonspecific. It may be seen in other settings if patients have difficulty activating specific muscles because of UMN disease, pain inhibition, or poor cooperation.

      Motor unit number estimate

      The motor unit number estimate (MUNE) is a nerve conduction study technique that can quantify the numbers of motor units innervating an individual muscle. [168] It may be used to help with the diagnostic process in rare cases in which clinical or electrodiagnostic LMN involvement otherwise cannot be shown. For example, MUNE showing numbers below the lower limit of normal in distal upper and lower extremity muscles establishes the diagnosis as ALS.

      MUNE may be used to separate patients into faster and slower ALS progression groups. [169] However, other measures of disease progression that are easier to obtain, such as those derived using the ALS Functional Rating Scale-Revised (ALSFRS-R), may serve this purpose. Also, patients the author has surveyed have reflected ambivalence or reluctance at the prospect of receiving prognostic information early in the course of the disease, which is when such information is of greatest relevance. [157]

      MUNE is appealing as a quantifiable, physiologic measure of disease progression that is independent of patient effort and is a measure of pure LMN involvement. Nevertheless, the error inherent in the estimation process precludes its use as the primary measure of efficacy of putative, mechanism-specific interventions to slow disease progression.

      Characteristics of other neuropathies

      Multifocal motor mononeuropathy

      Other disease processes may be suggested by their characteristic electrophysiologic presentation. Multifocal motor mononeuropathy may be suggested by the following:

      • Motor conduction block in multiple nerves

      • Motor conduction velocities less than 70% of the lower limit of normal, and distal motor latencies greater than 30% of the upper limit of normal values

      Chronic inflammatory demyelinating polyradiculoneuropathy

      This condition may be suggested by the features listed above, together with the following:

      • Low sensory nerve action potential amplitudes with slow conduction if not attributable to entrapment syndromes or known concomitant pathology, such as diabetes

      • F-wave or H-wave latencies greater than 30% above established normal values

      Sensorimotor peripheral neuropathy

      A generalized axonal sensorimotor peripheral neuropathy may be suggested if motor and sensory fibers appear affected equally without excessive slowing or if sensory fibers are affected more than motor fibers. However, it must be recognized that mild sensory abnormalities may be found occasionally in patients with ALS without sensory symptoms and that the lower limits of normal in persons aged 60 years or older are lower than those for younger individuals.

      Inclusion body myositis

      Inclusion body myositis may be suggested by a characteristic pattern of distribution of affected muscles and by a mixed pattern of large and small motor unit potentials on needle examination. Other myopathies may also be suggested if small, rapidly firing motor unit potentials are found, rather than those characteristic of a neurogenic process.

      Primary lateral sclerosis and monomelic amyotrophy

      Primary lateral sclerosis may be suggested if LMN involvement is minimal or absent, particularly if that remains the case 3 years (or more conservatively, 5 years) after clinical onset of disease. Monomelic amyotrophy may be suggested if no evidence of disease is found outside 1 limb several years after its onset.

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      Laboratory Studies

      Laboratory tests sometimes ordered in the evaluation of a patient with possible ALS include anti-ganglioside M1 (anti-GM1) antibodies, as these can be seen in patients with multifocal motor neuropathy with conduction block. Vitamin B12 and folate levels, HIV status, Lyme serology, and creatine phosphokinase (CPK) determinations may also be performed when indicated by clinical circumstances. The CPK level may be elevated in ALS, but this is not a diagnostic finding.

      The following tests may also be considered:

      • Serum protein electrophoresis and immunoelectrophoresis

      • Syphilis tests

      • Thyroid function tests

      • Parathyroid hormone assay

      • Vitamin B1 assay

      • Genetic testing (especially in familial cases)

      If myasthenia gravis is under consideration, antiacetylcholine receptor antibody and anti-muscle specific kinase (MuSK) antibody assays should be ordered.

      Urinary 24-hour collections for heavy metals may be requested if there is reason to suspect recent exposure. Hexosaminidase A in urine may be checked when adult Tay-Sachs is suspected strongly.

      Lyme disease serology may be considered if clinical data suggest that the patient had untreated Lyme disease. However, the history, rather than laboratory testing, drives the diagnosis in Lyme disease.

      Genetic testing

      In patients with familial ALS, genetic testing may be requested after appropriate counseling. The results of genetic testing may affect not only the patient, but family members as well.

      Tests for the SOD1, TARDBP (coding for TDP-43), FUS, ANG, C9orf72, and FIG4 genes, as well as for the gene causing Kennedy disease, are available commercially. Patients with other forms of familial ALS may be referred to receive further information from centers with a research interest in familial ALS.

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      CT Scanning and MRI

      Brain or spinal MRI may be done to rule out structural lesions and neurologic conditions that sometimes account for early clinical features seen in patients suspected of having ALS (eg, multiple sclerosis, brainstem strokes, tumors, spinal radiculopathy). Results of these studies generally are normal in patients with ALS.

      Magnetic resonance spectroscopy may also be used, but it has a high false-negative rate. CT scanning with myelography may be needed in patients in whom an MRI cannot be performed safely (eg, because of the presence of a pacemaker, an implantable defibrillator, or metal fragments).

      The value of positron emission tomography (PET) scanning and functional MRI in ALS is being investigated. Imaging studies may not be necessary in patients presenting with advanced disease.

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      Functional Assessment

      ALS typically progresses within the area first affected and then to adjacent, contiguous regions. As it progresses, patients’ function and independence diminish. When respiratory muscles are affected, patients may be supported using noninvasive or invasive measures. The majority of patients die of ventilatory failure, most having chosen not to opt for long-term invasive mechanical ventilation. Less than 5% of patients die of other causes, such as a heart attack, a serious infection, or blood clots that migrate to the lungs.

      The pace of disease progression varies from patient to patient, and the symptoms depend on the muscles affected. Regular monitoring of the patient’s course assists in directing treatment.

      Standardized assessment of patients with ALS was facilitated by the development of the ALS Functional Rating Scale, a 10-item standardized questionnaire. [170] It was revised to give greater weight to respiratory involvement and became the 12-item ALSFRS-R, [171, 172] which is used extensively.

      In the ALSFRS-R, functions mediated by cervical, trunk, lumbosacral, and respiratory muscles are each assessed by 3 items. Each item is scored from 0-4, with 4 reflecting no involvement by the disease and 0 reflecting maximal involvement. The item scores are added to give a total.

      Total scores reflect the impact of ALS, as follows:

      • >40 (minimal to mild)

      • 39-30 (mild to moderate)

      • < 30 (moderate to severe)

      • < 20 (advanced disease)

      For an individual patient, loss of only 8-10 points on the ALSFRS-R may have severe implications; eg, if respiratory or bulbar function bears the brunt of the losses. A minor limitation of the scale is that it has a floor effect in terms of measuring disease progression in quadriparetic, ventilator-dependent patients.

      Most physicians caring for patients with ALS use a measure of the patient’s breathing ability to follow the course of their disease. In the United Kingdon, a governmental clinical guideline exists for monitoring respiratory weakness, with clear points for referral or intervention.

      Of the tests of pulmonary function, vital capacity is used most commonly. Additional measures, such as maximal inspiratory and expiratory pressures, arterial blood gas measurements, and overnight oximetry, may provide earlier evidence of dysfunction. Comparison of vital capacity in the upright and supine positions may also provide an earlier indication of weakening ventilatory muscle strength.

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