Pathology and Etiology

Amyotrophic lateral sclerosis (ALS), a term first coined by Charcot in 1875, is the prototypical disease among disorders of the motor neuron. It is a relentlessly progressive and fatal neurodegenerative disorder caused by loss of both upper motor neurons (UMN) and lower motor neurons (LMN). ALS is usually sporadic while 5 to 10% of cases are familial, usually following an autosomal dominant inheritance pattern.

The pathology of sporadic ALS is represented by the selective loss of motor neurons in the spinal cord and brain stem, and cortical motor neurons (Betz cells). Classic findings on spinal cord sections include the loss of anterior horns, with degeneration of the pyramidal tracts (crossed and uncrossed) and dramatic preservation of the dorsal columns and spinocerebellar tracts. Although all motor neurons ultimately degenerate, there is relative sparing of the oculomotor nuclei in the brain stem and Onuff nucleus in the lumbosacral cord. Microscopically, there is, in addition to the loss of anterior horn motor neurons, frequent accumulation of neurofilaments in surviving neurons and dilatation of axons (“spheroids”). The pathologic findings in familial ALS are identical to those in the sporadic form, except that Lewy-like bodies frequently are identified in surviving motor neurons.

Amyotrophic lateral sclerosis is a fatal disorder of unknown etiology. It is likely that there are initiating and propagating factors that lead to motor neuron cell death. Currently, there are five major hypotheses about the development of ALS, although many theories are interrelated:

Clinical Features

Amyotrophic lateral sclerosis, also known as motor neuron disease, Lou Gehrig disease, or maladie de Charcot, occurs in a fairly uniform distribution worldwide with no true differences in geographical incidence, except for small clusters in Guam, the Kii peninsula of Japan, and West New Guinea. The worldwide incidence of ALS is 0.6 to 2.6 per 100 000 population, and its lifetime risk is 1 in 1000. Since 5 to 10% of ALS cases are dominantly inherited, the risk to siblings of a patient with ALS is approximately 2.5 to 5%. The disorder affects both sexes, with a slight preponderance to males. The mean age of onset is 55 years, with a wide range from 17 to 77 years. The illness is fatal within 5 years in 80% of patients; however, some survive as long as 20 years. Patients with initial weakness in the bulbar muscles and older patients have a poorer prognosis for survival. Most patients with ALS die of respiratory failure and fewer than 10% of ALS patients in the United States choose long-term mechanical ventilation to sustain their lives.

More than two-thirds of patients with ALS present with weakness, atrophy, or both. The weakness involves one arm, one leg, or asymmetrically both legs in almost half of patients, while generalized weakness, bilateral upper extremities, or unilateral hemiparesis are less common. Bulbar manifestations are present at onset in a quarter of patients. Fasciculations, cramps, shortness of breath, head drop, or weight loss are rare initial presentations. UMN findings include weakness, spasticity, hyperreflexia, and Babinski and Hoffman signs. LMN findings are usually more pronounced and include weakness, muscle atrophy, fasciculations, and hyporeflexia. Bulbar manifestations in ALS typically include dysarthria, dysphagia, sialorrhea, aspiration, and pseudobulbar affect (inappropriate, spontaneous, forced laughing, crying, or yawning).

A typical patient with ALS is a man in his fifties in whom asymmetrical weakness and atrophy of the muscles develop in one limb, usually those in one hand or one foot. The weakness progresses over time to adjacent myotomes in the same limb and thence to the contralateral limb or the other limb on the same side. The weakness ultimately generalizes to involve all limb, bulbar and respiratory muscles. At its advanced stage, there is usually generalized diffuse muscular atrophy and weakness, fasciculations, spasticity with hyperreflexia, and possibly dysphagia and dysarthria. In typical ALS, there is sparing of sphincteric function, eye movement, sensory function, and cognitive capability.

The diagnosis of ALS is based on the presence of a progressive disorder with the characteristic combination of upper and lower motor neuron involvement. Many criteria have been proposed but most are inadequate, particularly those pertaining to early diagnosis and the definition of upper motor neuron involvement. Among them, the revised El Escorial diagnostic criteria currently are the most widely accepted for the diagnosis of ALS (Table C19-1).

Table C19-1 Revised El-Escorial Criteria for the Diagnosis of Amyotrophic Lateral Sclerosis

Nerve Conduction Studies

Although the major changes in ALS are seen on needle EMG, nerve conduction studies (NCS) should be done in all patients with suspected ALS to exclude other possible causes of weakness. Sensory NCSs are normal, although a subtle decrease in SNAP amplitudes has been reported in a few studies. Motor NCSs may show abnormalities that vary with the stage of disease. Normal study results are not uncommon early in the disease course. Later, low-amplitude CMAPs are frequently revealed; these may be regional (i.e., the result of motor conduction studies performed on weakened limb(s) because of anterior horn cell loss). In more advanced stages of the disease, diffusely low CMAP amplitudes with normal SNAP amplitudes, so called “low motor-normal sensory pattern,” is characteristic. This NCS pattern is not specific for the diagnosis and may be seen in spinal muscular atrophies, diffuse myelopathies or polyradiculopathies, axonal motor polyneuropathies, presynaptic neuromuscular junction disorders, and severe myopathies (see Figure C17–13). In contrast to CMAP amplitudes, motor conduction velocities, distal latencies, and F wave latencies are usually normal in ALS until significant degrees of axon loss have occurred, when mild slowing may be detected due to the loss of large and fast conducting axons. This slowing is proportional to the reduction in CMAP amplitude, and the conduction velocity does not decrease to less than 70 to 80% of the lower limit of normal. Motor conduction block, or significant CMAP temporal dispersion, should raise the suspicion of another disorder that may, at times, mimic motor neuron disease: multifocal motor neuropathy with conduction block.

Needle EMG

Needle EMG is the most powerful tool in confirming the diagnosis of ALS. Needle EMG findings in motor neuron disease in general and in ALS in particular are dependent on the extent of lower motor neuron degeneration. Changes seen on needle EMG consist of abnormal spontaneous activity and loss of motor neurons; this loss is characterized by impaired MUAP recruitment and altered MUAP configuration that is consistent with reinnervation.

Fasciculation potentials are sporadic or quasi-rhythmic, spontaneous (involuntary) contractions of a group of muscle fibers that are innervated by a single motor unit. They can be of any shape and size, depending on the motor units from which they arise (Figure C19-1). They reflect irritability of the motor unit and usually originate from the distal nerve terminals, with spread by axon reflex to other parts of the unit. They frequently are visible on inspection. During needle EMG, fasciculation potentials are characterized by a random firing pattern. Fasciculations are particularly prominent in patients with ALS and have been closely linked to the disease since its first description by Charcot. Using simultaneous multichannel EMG recordings from different sites and muscles, it has been estimated that more than 90% of patients with ALS have fasciculations.

Figure C19-1 Fasciculation potentials recorded, in raster mode, from the vastus lateralis in a patient with motor neuron disease. Note that the sweep speed is set at 20 ms/division. Note that the morphology of the potentials is of motor units but with extreme variability in configuration among the individual discharges and their irregular firing pattern. Individual fasciculation potential may recur irregularly (arrows and arrowheads).

Although fasciculation potentials are extremely common in ALS, they also occur in other lower motor neuron disorders (radiculopathies and peripheral polyneuropathies), with the use of anticholinesterase medication, in hyperthyroidism and hypocalcemia, and in healthy muscles (particularly the calves). Thus, fasciculation potentials are nonspecific and may be benign, unless they are accompanied by fibrillation potentials or by MUAP changes.

Because they can occur in healthy individuals, an attempt has been made to distinguish “benign” from “malignant” fasciculations. On average, malignant fasciculations have a slower rate of discharge and higher amplitudes compared with the benign ones. However, these differences are not sufficient to provide a reliable method of distinguishing between them. The best way to differentiate is to look for accompanying changes on needle EMG, such as fibrillation potentials, impaired recruitment, and MUAP configuration abnormalities.

Fibrillation potentials are spontaneous action potentials of denervated muscle fibers that usually fire regularly. They can take one of two forms: a brief spike or a long-duration positive wave. They are seen most commonly in processes associated with axonal or neuronal loss, although they may occur in necrotizing myopathies. In ALS, the identification of fibrillation potentials is extremely important because they confirm the occurrence of axonal loss and support the suspicion that the accompanied fasciculation potentials are pathologic. Because fibrillation potentials are abolished by sprouting, which usually is an active process early in the disease course, these potentials can be of limited number and of scattered distribution during the first stages of ALS. In general, fibrillation potentials are more prominent in rapidly progressive than in slowly progressive motor neuron disease.

Reduced MUAP recruitment is caused by degeneration and loss of motor neurons in ALS, with the result that only a few can be activated voluntarily. The activated motor units fire more rapidly as anterior horn cells are lost (Figure C19-2). This EDX finding always is abnormal but, when isolated, does not mean automatically that axonal loss has occurred because it may happen if there is demyelination anywhere along the motor axon that results in the block of conduction transmission. In ALS patients, slow recruitment frequency (poor activation) of MUAPs in limbs where UMN loss predominates may also be evident but is a less frequent finding.

Figure C19-2 Reduced recruitment with maximal effort from the biceps muscle of a 55-year-old man with ALS revealing a single unit, with long duration and high amplitude, firing rapidly at a rate of 20 Hz. Note that the sweep speed is set at 20 ms/division.

Reinnervated MUAPs dominate as collateral sprouting increases the number of muscle fibers per motor unit resulting in increased duration and amplitude MUAPs (Figure C19-2). Also, because of conduction slowing along the newly formed collateral sprouts, muscle fiber action potentials become asynchronous. This results in increased polyphasic MUAPs (more than four phases). Thus, a mixture of MUAPs often is seen on needle EMG, dependent on the stage of illness. Normal MUAPs are intermixed with polyphasic MUAPs, with or without satellite potentials (Figure C19-3), and with long-duration, high-amplitude MUAPs (Figure C19-4). Moment-to-moment MUAP amplitude variation, representing motor unit instability, may also be appreciated.

Figure C19-3 Polyphasic motor unit potential (MUAP) with satellite (linked) potentials, also called complex MUAP.

(From Daube J. AAEM minimonograph 11: needle electromyography in clinical electromyography. Muscle Nerve 1991;14:685–700, with permission.)

Figure C19-4 Relative average durations and amplitudes of some motor unit potentials (MUAPs) seen in myopathic and neurogenic disorders.

(From Daube J. AAEM minimonograph 11: needle electromyography in clinical electromyography. Muscle Nerve 1991;14:685–700, with permission.)

In summary, the findings on needle EMG are variable and depend on the stage of illness. At any one point in a patient’s illness, sampling many muscles in four limbs and the head often reveals a mixture of the following findings (listed in worsening severity):

Other Electrodiagnostic Tests

Other EDX tests sometimes used in the assessment of ALS including repetitive nerve stimulation, single fiber EMG and motor unit number estimate. Repetitive stimulation of motor nerves at a slow rate may result in a modest decrement of the CMAP in many patients with ALS, usually by less than 20 to 25%. This decrement is more likely to occur during recording of a denervated muscle, particularly in patients with rapidly progressive ALS. Single-fiber EMG reveals a marked increase in fiber density (2–10 times), which is consistent with collateral sprouting. Jitter analysis is abnormal in 90% of patients with ALS. Both increased fiber density and abnormal jitter are seen more commonly in muscles with denervation than in healthy muscles. Finally, motor unit number estimation (MUNE), is a promising technique with potentials in studies of the natural history and prognosis of ALS, and of the response to experimental treatment. MUNE is a technique that measures the approximate number of LMNs innervating a single muscle or a small group of muscles. At least four methods for this have been described; In general, MUNE count is determined through division of the supramaximal CMAP amplitude or area by the mean surface-recorded motor unit potential amplitude or area. At this time, there is no role for MUNE in the routine diagnosis of ALS.

Electrodiagnostic Criteria

Amyotrophic lateral sclerosis is a clinical disorder in which the EDX study plays a major role in supporting the diagnosis and in excluding entities that can mimic ALS. Electrophysiologic confirmation of ALS requires evidence of a widespread LMN degeneration, and hence the needle EMG examination should be performed on three or more regions of the neuraxis and should assess all the major segments in the limbs examined. When the bulbar region is assessed, changes must be observed in at least one muscle (including tongue, jaw muscles, and facial muscles). Needle EMG of the tongue is difficult due to failure to achieve adequate relaxation which results in inability to appreciate fibrillation or fasciculation potentials. Also, the tongue MUAPs normally are small and may appear similar to fibrillation potentials. The thoracic segment can only be assessed by needle EMG of the thoracic paraspinal muscles at or below the T6 level, and occasionally the abdominal muscles. Evaluation of higher thoracic segments may be misleading as denervation changes derived from lower cervical segments may manifest as far caudally as the T6 level.

The criteria proposed by Lambert in 1969 had been the most widely accepted for the diagnosis of ALS. These criteria require fibrillation with fasciculation potentials in three limbs, with the head counting as a “limb.” El Escorial criteria have adopted these standards with some revisions. Table C19-4 provides a summary of definitive EDX criteria for ALS.

Table C19-4 Electrodiagnostic Criteria for the Diagnosis of Amyotrophic Lateral Sclerosis (ALS)

* Regions are defined as follows: brain stem (bulbar), cervical (upper limbs), thoracic (back and abdomen), and lumbosacral (lower limbs). Involvement in a region is without regard to right or left side, but location is indicative of the level of neuraxis involved.

† Motor conduction velocities may be slowed but should not be lower than 70 to 80% of lower limits of normal values, in nerves with very low CMAP amplitudes (less than 50% of the lower limits of normal or less than 30% of normal mean).

The aforementioned criteria are fulfilled at the time of diagnosis in approximately two-thirds of patients with ALS. However, a significant proportion of patients with a clinical diagnosis of ALS fail to show these findings on EDX testing, particularly on initial studies. This is caused by the following limitations:

Thus, clinicians must understand the drawbacks of EDX study and use this test as an adjunct to clinical examination. Sequential EDX examinations are sometimes necessary to confirm progression and worsening of denervation in the affected limb(s), and even more importantly, to document evidence of dissemination of denervation. In practical terms, it frequently is more important for the electromyographer to test extensively an asymptomatic or mildly symptomatic limb than a limb with severe atrophy and weakness because the documentation of denervational changes in all limbs is essential to show dissemination of disease and to solidify the diagnosis.

Although the role of EDX study in ALS is complementary to the clinical suspicion, there are many advantages associated with use of the EDX examination that: