There are a heterogeneous group of motor neuron disorders that are rare but nonetheless important to recognize, because they often can mimic the presentation of amyotrophic lateral sclerosis (ALS). These often are referred to as atypical motor neuron disorders . Although many of the atypical motor neuron disorders share some features with ALS, they often can be distinguished by their clinical and electrophysiologic characteristics ( Boxes 28–1 and 28–2 ).
Acute onset
Paralytic poliomyelitis
West Nile encephalitis
Non-myotomal pattern of weakness
Multifocal motor neuropathy with conduction block
Absence of significant muscle wasting in chronically weak limbs
Multifocal motor neuropathy with conduction block
Predominantly lower motor neuron signs
Multifocal motor neuropathy with conduction block
Kennedy’s disease
Spinal muscular atrophy
Radiation injury
Paralytic poliomyelitis
West Nile encephalitis
Monomelic amyotrophy
Presence of sensory symptoms and/or signs
HTLV-1-associated myelopathy
Adult polyglucosan body disease
Late-onset Tay–Sachs disease (adult-onset hexosaminidase A deficiency)
Bladder or bowel dysfunction
HTLV-1-associated myelopathy
Adult polyglucosan body disease
Cerebellar, extrapyramidal, cognitive, and/or psychiatric dysfunction
Late-onset Tay–Sachs disease (adult-onset hexosaminidase A deficiency)
Hereditary spastic paraplegia (complicated)
Adult polyglucosan body disease
Duration of illness longer than 5 years
Kennedy’s disease
Radiation injury
Late-onset Tay–Sachs disease (adult-onset hexosaminidase A deficiency)
Spinal muscular atrophies
Hereditary spastic paraplegia
Adult polyglucosan body disease
Onset of illness before age 40 years
Late-onset Tay–Sachs disease (adult-onset hexosaminidase A deficiency)
Familial amyotrophic lateral sclerosis
Spinal muscular atrophy
Hereditary spastic paraplegia
Monomelic amyotrophy
Positive family history
Kennedy’s disease
Late-onset Tay–Sachs disease (adult-onset hexosaminidase A deficiency)
Familial amyotrophic lateral sclerosis
Spinal muscular atrophy
Hereditary spastic paraplegia
Adult polyglucosan body disease
History of radiation therapy
Motor neuron disease associated with radiation injury
History of malignancy
Paraneoplastic motor neuron disease (especially lymphoma)
History of old poliomyelitis
Postpoliomyelitis syndrome
History of electrical injury
Motor neuron disease associated with electrical injury
History of human immunodeficiency virus infection
Retrovirus-associated motor neuron disorder
HTLV-1, human T cell lymphotropic virus-type 1.
Conduction block on motor nerve conduction studies (not at entrapment sites)
Multifocal motor neuropathy with conduction block
Markedly slowed conduction velocities or prolonged distal latencies (not at entrapment sites)
Multifocal motor neuropathy with conduction block
Sensory nerve conduction abnormalities
Kennedy’s disease
Adult polyglucosan body disease
Late-onset Tay–Sachs disease (adult-onset hexosaminidase A deficiency)
Multifocal motor neuropathy with conduction block (rare)
West Nile encephalitis (rare)
Myokymic discharges
Radiation injury
Prominent complex repetitive discharges
Late-onset Tay–Sachs disease (adult-onset hexosaminidase A deficiency)
Facial fasciculations/grouped repetitive motor unit discharges with activation
Kennedy’s disease
Acute or subacute neuropathic pattern on needle electromyogram
Paralytic poliomyelitis, including West Nile encephalitis
One of the most important atypical motor neuron disorders that can be confused with motor neuron disease is the immune-mediated motor neuropathy multifocal motor neuropathy with conduction block (MMNCB). Strictly speaking, this is a disorder of the motor nerve and as such is discussed in detail in Chapter 26 . Patients present with progressive, asymmetric weakness and wasting that often affect the distal upper extremity muscles first. Weakness is in the distribution of named motor nerves, often with sparing of other nerves in the same myotome (clinical multifocal motor neuropathy). This pattern is not seen in ALS or its progressive muscular atrophy variant, in which the entire myotome is characteristically affected at the same time. Occasional patients have weakness without wasting, a finding usually associated with pure demyelination. The disease is slowly progressive, with a male predilection, generally presenting before the fifth decade. Definite upper motor neuron signs are absent, although retained or inappropriately brisk reflexes for the degree of weakness and wasting may be seen. Bulbar function and sensation are characteristically spared. Mild or transient sensory symptoms may be present. The characteristic finding on motor nerve conduction studies is that of conduction block, temporal dispersion, or both, along the motor nerves. Other signs of demyelination also may be seen, including slowed conduction velocities, absent or impersistent F responses, and prolonged distal motor latencies. Sensory conduction studies are typically normal.
Other than multifocal motor neuropathy with conduction block, atypical motor neuron disorders are seen most often in association with certain viral infections or as the result of specific genetic mutations. Rarely, atypical motor neuron disorders are seen as a remote effect of some neoplasms or as a result of electrical injuries or radiation. Because the prognosis in ALS is uniformly poor compared with these atypical motor neuron disorders, it is essential that the correct diagnosis is reached. In addition, some are potentially treatable; in others, genetic counseling is important.
Infectious Motor Neuron Disorders
Paralytic Poliomyelitis and Postpolio Syndrome
Paralytic poliomyelitis was once a common cause of acute lower motor neuron dysfunction. In the United States from 1951 to 1955, an average of more than 15,000 cases occurred per year. Through widespread use of the oral polio vaccine, the incidence of acute poliomyelitis has been drastically reduced. Most cases now are associated with the live attenuated virus in the oral polio vaccine and occur either in vaccine recipients or in individuals who are in contact with vaccine recipients, especially immunocompromised patients. Other cases occur in travelers to areas where poliomyelitis is endemic; in 2011, these countries were Afghanistan, India, Nigeria, and Pakistan. Sporadic outbreaks have also occurred in other underdeveloped countries. In rare, sporadic cases, infection presumably is due to incomplete immunization status. Most sporadic cases are no longer associated with the poliovirus but are the result of coxsackievirus, echovirus, or enterovirus infection.
Patients with acute poliomyelitis present with fever, headache, myalgias, and gastrointestinal disturbance. Weakness, wasting, and depressed reflexes begin to appear during the first or second week of the illness. The distribution of weakness typically is asymmetric, and the lower extremities are most commonly involved. The upper extremities, trunk, diaphragm, and bulbar muscles are occasionally involved. Sensation and autonomic function are spared. Cerebrospinal fluid (CSF) typically shows a lymphocytic pleocytosis, often in the range of 100 to 200 cells per cubic millimeter (rarely, polymorphonuclear leukocytes may be seen early), during the preparalytic phase of the illness. Pleocytosis, while invariably present in the preparalytic phase of the illness, tends to clear with the onset of the weakness. The CSF protein level is commonly elevated within the first several weeks of the illness, whereas CSF glucose is normal. Cultures from CSF usually fail to isolate the virus, although the virus can commonly be isolated from the stool if it is obtained within the first 10 days of the paralysis. In addition, antibody titers from the acute and convalescent phases may allow virus identification.
Weakness associated with poliomyelitis now is seen most often in the electromyography (EMG) laboratory not as an acute process but in patients with postpolio syndrome (PPS). PPS occurs in at least one fourth of previously infected patients, usually 25 to 30 years after the attack of acute poliomyelitis. Patients develop pain, fatigue, and weakness, often most prominent in the muscle groups previously affected by the poliomyelitis. However, muscles that were clinically normal may develop symptoms, reflecting the diffuse underlying nature of the previous poliomyelitis. The etiology of PPS is not completely known, but it is most likely related to the normal aging process (i.e., most individuals lose some motor neurons after age 55 years) superimposed on chronically denervated muscles. Patients with PPS and worsening symptoms often are referred to the EMG laboratory to exclude a new, superimposed process, such as radiculopathy, entrapment neuropathy, myopathy, or motor neuron disease as a source of increased fatigue, pain, and weakness.
West Nile Encephalitis
Over the past several years, there have been an increasing number of reports of a “polio-like” syndrome associated with West Nile encephalitis. The responsible virus, which is a member of the flavivirus family and is composed of a single strand of RNA, was first isolated in 1937 in northern Uganda. In nature, the virus is transmitted between birds by mosquitoes ( Figure 28–1 ). Jays, blackbirds, finches, warblers, sparrows, and crows appear to be most important in maintaining the infection. Most infections in humans occur by way of a mosquito bite, although cases have been reported following transplanted organs and infected blood products. Because the disease is primarily spread to humans by mosquitoes, patients typically are affected in the summer and early fall.
Fortunately, most infections with the West Nile virus are asymptomatic, with only one in 150 infections resulting in neurologic involvement. The elderly and the immunocompromised appear to be at highest risk. After an incubation period of several days, a nonspecific flulike illness develops, often with fever, headache, and joint and muscle pain. In some patients there may be additional features suggestive of West Nile infection, including retro-orbital pain, facial congestion, and rash. Definitive diagnosis is made by the presence of immunoglobulin M antibodies in CSF or serum.
In patients with neurologic involvement, a combination of encephalitis, meningitis, and myelitis can occur. Diffuse weakness is common and often thought to be due to the encephalitis. Other patterns of weakness are also seen, among them monoplegia, flaccid quadriplegia, bulbar weakness, and respiratory weakness. In some patients, an acute segmental flaccid paralysis has been described as an initial presentation of West Nile virus, even in the absence of meningitis or encephalitis. Such cases initially were attributed to Guillain–Barré syndrome, although it now is clear that the weakness more likely was due to anterior horn cell disease. In patients in whom electrodiagnostic (EDX) studies have been performed, nerve conduction studies show reduced compound muscle action potential (CMAP) amplitudes with relatively intact sensory conduction studies. No evidence of demyelination is present. Rarely, patients have had abnormal sensory conduction studies, suggesting involvement of the dorsal root ganglia or peripheral sensory nerve as well. Needle EMG shows evidence of axonal loss. The pattern of findings depends on when the study is performed in relationship to the start of the illness.
Thus, in addition to coxsackievirus, echovirus, and enterovirus, West Nile virus can be added to the list of infectious agents that can result in an acute infection of the anterior horn cells. Thus, paralytic poliomyelitis is best regarded as a clinical syndrome that can be caused by a variety of viruses, not simply the poliovirus.
Retrovirus-Associated Motor Neuron Disorders
Human immunodeficiency virus (HIV) is associated with a variety of neuromuscular disorders, including peripheral neuropathies, myopathies, and radiculopathies. Experimental studies in mice have shown that retroviruses can induce a lower motor neuron syndrome in mice and suggest a relationship between retroviruses and the pathogenesis of motor neuron disease. There are rare reports of patients with HIV infection and classic ALS, or a clinical syndrome resembling primary lateral sclerosis, without any other explanation for their symptoms. Other patients have had restricted lower motor neuron signs. Some reports have noted improvement or complete remission of the syndrome in these patients when they are treated with highly active antiretroviral therapy.
Another retrovirus, the human T cell lymphotropic virus-type 1 (HTLV-1), is well known to be associated with spastic paraparesis in endemic areas (i.e., the Caribbean basin, southwest Japan, southeast United States, southern Italy, and sub-Saharan Africa) in a syndrome known as HTLV-1-associated myelopathy or Tropical Spastic Paraparesis (HAM/TSP). Along with spastic paraparesis, patients usually have bladder dysfunction and minor sensory symptoms. A motor neuron syndrome mimicking ALS is also observed in a series of patients with HTLV-1 infection. The presence of spastic paraparesis or even typical ALS symptoms, with minor sensory findings or bladder dysfunction, especially in an endemic area for HTLV-1, should prompt a search for HTLV-1 antibodies.
Inherited Motor Neuron Disorders
Familial Amyotrophic Lateral Sclerosis (FALS)
Approximately 10% of cases of ALS are familial. Inheritance is usually autosomal dominant. Over 10 different genes have been identified, with the most common being a mutation in the superoxide dismutase ( SOD-1 ) gene on chromosome 21. The SOD-1 gene mutation accounts for 15–20% of FALS. Other more commonly identified genes include the fused-in-sarcoma ( FUS ) and the TAR (transactive response) DNA-binding protein ( TDP-43 ) genes. These two genes account for approximately 3–5% and 1–3% of FALS, respectively. Most recently, the gene encoding ubiquilin 2 has been found to be a cause of X-linked FALS. In addition, inclusions containing ubiquilin 2 have been found in a large number of ALS patients suggesting a common pathology. Ubiquilin 2 is involved in the protein degradation pathway. Recently, a mutation in the chromosome 9 open reading frame 72 ( C9ORF72 ) gene, resulting in an expanded hexanucleotide repeat in a noncoding region of the gene, was found in a large percent of patients with familial ALS (23%) or frontotemporal dementia (12%). The clinical presentation and prognosis of patients with FALS are similar to sporadic cases. One should consider the diagnosis of FALS in patients with ALS and a known family history or in patients with an early clinical presentation. Commercial DNA testing is available for the more common genetic mutations. Very rarely a patient with sporadic ALS (i.e., no family history) is reported with one of these mutations.
Spinal Muscular Atrophy
A large number of inherited spinal muscular atrophies (SMA) result in selective degeneration of the lower motor neurons. The characteristic clinical presentation is that of progressive, symmetric, proximal muscle weakness and atrophy, without upper motor neuron signs. Most are recessively inherited and linked to the survival motor neuron 1 ( SMN1 ) gene on chromosome 5q. Among the various types, the most severe form occurs in infancy (Werdnig–Hoffmann disease), usually resulting in death before age 2 years. Others present in early childhood or during adolescence or adulthood (Kugelberg–Welander disease) and have a much better prognosis. Although occasionally confused with ALS, adult-onset SMA is more commonly mistaken clinically for a myopathy. Direct DNA deletion analysis is now commercially available but does not detect all cases.
Although proximal muscles are most frequently involved, other anatomic variants have been described, including scapuloperoneal, facioscapulohumeral, and generalized forms. In addition, there is a rare distal SMA (also known as distal hereditary motor neuropathy or neuronopathy) that presents with a clinical phenotype similar to Charcot–Marie–Tooth polyneuropathy, although with a notable lack of sensory symptoms or findings. This variant often is referred to as the spinal form of Charcot–Marie–Tooth.
X-Linked Bulbospinal Muscular Atrophy (Kennedy’s Disease)
The one inherited SMA that deserves special attention, because it can easily be confused with the progressive bulbar palsy variant of ALS, is X-linked bulbospinal muscular atrophy (Kennedy’s disease). It affects only men and has its onset between the third and fifth decades of life, followed by a slow progression. Because there frequently is no obvious family history in X-linked disorders, many of these cases at first appear to be sporadic.
Some patients complain of exercise-induced muscle cramps and hand tremors several years before weakness develops. Proximal muscles are affected first, followed by bulbar involvement, which may become marked. Dysarthria and dysphagia are associated with atrophy and weakness of facial, jaw, and glossal muscles. Because of the prominent bulbar involvement, Kennedy’s disease can be difficult to differentiate from the bulbar variant of ALS. A classic and striking clinical feature is the presence of facial fasciculations, most prominent around the mouth and chin. Fasciculations are present at rest, but they are more prominent with contraction and are best elicited by having the patient whistle or blow out the cheeks. Facial fasciculations are reported in more than 90% of case reports. Distal muscles are affected later in the course. Reflexes typically are hypoactive or absent. There are no long-tract signs. Sensory loss or sensory symptoms are rare. Although not universal, most patients have gynecomastia, and some have other endocrine abnormalities, including diabetes and infertility .
Laboratory test results are normal except for a modestly elevated creatine kinase (CK) level (often 500–1500 IU), which is higher than the mild elevation typically seen in SMA or other motor neuron disorders. Nerve conduction studies often show normal motor studies. However, the CMAP amplitudes may be low if they are recorded from weak and wasted muscles. Most patients have low-amplitude or absent sensory nerve action potentials (SNAPs), which reflect the association of Kennedy’s disease with degeneration of the dorsal root ganglia. This finding is very important because it is not seen in ALS and is an important clue in the recognition of Kennedy’s disease . Needle EMG shows neurogenic changes, including increased insertional activity and reduced recruitment of large, prolonged duration, polyphasic motor unit action potentials (MUAPs) in affected muscles. Needle EMG examination of the facial muscles may show grouped repetitive motor unit discharges, which occur with mild activation of the facial muscles. Because these discharges occur with mild voluntary contraction rather than spontaneously, they are distinguished from myokymic or neuromyotonic discharges and are quite characteristic of Kennedy’s disease.
Despite prominent bulbar weakness and the corresponding risk of aspiration, longevity usually is not affected. Consequently, the correct diagnosis is important both for prognosis and for its value in genetic counseling. The diagnosis should be suspected in any male patient with motor neuron disease who presents with proximal and bulbar weakness, a positive family history, facial fasciculations, or gynecomastia and whose EDX studies show abnormal sensory studies in addition to the typical widespread neuronopathic pattern on needle EMG. An unusually elevated CK level is often an important clue as well. DNA testing is commercially available. The gene is an androgen receptor gene with an expansion of a trinucleotide repeat (CAG).
Hereditary Spastic Paraplegia
Hereditary spastic paraplegia, also known as familial spastic paraparesis , consists of a diverse group of genetic disorders characterized by progressive spasticity and sometimes weakness of the lower extremities. They are classified by their type of inheritance (autosomal dominant, autosomal recessive, or X-linked) and whether the spasticity is the sole manifestation of the disorder, termed uncomplicated or pure spastic paraplegia, or whether there are other accompanying abnormalities (termed complicated spastic paraplegia). These other manifestations may include ataxia, dementia, mental retardation, optic neuropathy, retinopathy, peripheral neuropathy, amyotrophy, extrapyramidal dysfunction, deafness, or ichthyosis. The clinical presentation, which includes age of onset, degree of deficit, and associated symptoms, varies both within and between families.
The diagnosis usually is straightforward if there is a known family history of pure progressive spastic paraparesis. If there is no known family history, other diagnoses are considered, including HTLV-1-associated myelopathy (see earlier), and most often the primary lateral sclerosis variant of ALS.
Adult-Onset Hexosaminidase A Deficiency (Late-Onset Tay–Sachs Disease)
Hexosaminidase A is a lysosomal enzyme important in the metabolism of gangliosides. Deficiency of this enzyme results in an abnormal accumulation of GM2 ganglioside, leading to nerve cell degeneration. The adult-onset form of hexosaminidase A deficiency (also known as late-onset Tay–Sachs disease ) is a rare recessively inherited disorder, only recognized in the late 1970s. In some affected individuals, the disorder can be mistaken for ALS or one of its variants, although most patients have coexistent cerebellar disturbances, about half have psychiatric disturbance (especially psychosis and depression), and approximately 25% have an axon loss sensorimotor polyneuropathy. The adult-onset form is quite different from the well-known rapidly progressive infantile form of hexosaminidase A deficiency, known as infantile Tay–Sachs disease. An absolute deficiency of hexosaminidase A causes infantile Tay–Sachs disease , whereas a partial deficiency results in the late-onset form.
Although the disorder affects multiple systems, nearly every affected patient has lower motor neuron involvement. Weakness and atrophy initially involve the lower extremities and are more prominent in the proximal muscles. In the upper extremities, there is a predilection for involvement of certain muscles, especially the triceps. It is not uncommon for patients to initially be misdiagnosed as adult-onset SMA. In one case series, nine of 14 patients also had upper motor neuron signs, but severe spasticity is rare. Cerebellar signs are common, including dysarthria, truncal ataxia, and dysmetria. If cerebellar signs are not prominent, however, the neurologic picture can mimic SMA or the progressive muscular atrophy variant of ALS, or classic ALS when upper and lower motor neuron signs predominate.
EDX studies usually show normal motor conduction studies, unless they are recorded from weak muscles, in which case the CMAP amplitudes are low, with normal or slightly slowed conduction velocities. Sensory nerve conduction studies are also usually normal, but may be abnormal in approximately 25% of patients, consistent with an axonal loss polyneuropathy. The needle EMG examination shows abnormal spontaneous activity including fasciculation and fibrillation potentials. Complex repetitive discharges (CRDs) may be especially prominent . Large, polyphasic MUAPs with reduced recruitment are seen in affected muscles.
Adult-onset hexosaminidase A deficiency should be considered in the differential diagnosis of any patient presenting with lower motor neuron disease, especially if there are coexistent cerebellar and/or psychiatric signs, or a family history of similarly affected siblings. A definitive diagnosis is made by measuring hexosaminidase A activity in serum, leukocytes, or fibroblasts.
Adult Polyglucosan Body Disease
Adult polyglucosan body disease (APGBD) is an exceedingly rare neurologic disorder; fewer than 30 cases have been reported. The clinical presentation includes progressive upper and lower motor neuron dysfunction, sensorimotor peripheral neuropathy, gait disturbance, urinary incontinence, and dementia. All components of the disorder may not be present initially, and motor symptoms may predominate. The pathologic hallmark of the disease is the presence of a large number of polyglucosan bodies, which structurally resemble Lafora bodies or corpora amylacea, in central and peripheral neuronal processes and astrocytes. Some cases appear to be sporadic and some familial (usually autosomal recessive), with a high proportion occurring in families of Ashkenazi Jewish descent. The presumed cause of adult polyglucosan body disease is genetic, especially in patients of Ashkenazi Jewish descent. A mutation in the glycogen branching enzyme gene, causing a deficiency of the glycogen branching enzyme, has been described in Ashkenazi Jewish patients with adult polyglucosan body disease.
The diagnosis should be suspected in patients with progressive upper and lower motor neuron dysfunction that resembles typical ALS, but which is accompanied by urinary incontinence, sensorimotor polyneuropathy, and dementia. If dementia and the motor neuron dysfunction are prominent, one should also consider frontotemporal dementia (see above) in addition to APGBD in the differential diagnosis. However, unlike frontotemporal dementia, in APGBD some distal sensory loss may be found on clinical exam. EDX studies reveal mild to moderate slowing of motor nerve conduction velocity and low-amplitude or absent SNAPs. Extensive white matter abnormalities often are seen on brain magnetic resonance imaging. A definitive diagnosis is based on pathologic findings of widespread deposition of polyglucosan bodies in the central and peripheral nervous systems ( Figure 28–2 ). Sural nerve biopsy shows multiple intra-axonal polyglucosan bodies, which together with the appropriate clinical manifestations can confirm the diagnosis of adult polyglucosan body disease.
Other Atypical Motor Neuron Disorders
Monomelic Amyotrophy
Monomelic amyotrophy is a rare restricted form of motor neuron disease. Most cases are sporadic, although a familial form has been reported. The male-to-female ratio is 5:1, with the majority of patients presenting between 18 and 22 years old. Although first reported in Japan and India, the disease has been described in young adults from all parts of the world. Many different names have been used for this condition, including monomelic atrophy, juvenile muscular atrophy of a unilateral upper extremity, benign focal amyotrophy, Sobue disease, Hirayama’s disease and juvenile segmental muscular atrophy.
Patients typically present with the insidious onset of unilateral weakness and atrophy of the hand muscles that often progresses to the forearm. In some cases, the syndrome is bilateral but often asymmetrical. Of note, the brachioradialis muscle is usually spared. The syndrome affects C7–C8–T1 muscles with sparing of the C5–6 muscles. In most cases, no particular precipitating infection or trauma is identified . The weakness tends to progress slowly over 1 to 3 years and then stabilizes. In some patients, there is an aggravation of weakness when exposed to cold, a phenomenon known as cold paresis. Deep tendon reflexes are usually normal, and upper motor neuron signs are absent. Sensation in the affected extremity is preserved, except for a rare and mild sensory abnormality over the dorsum of the hand.
The etiology of monomelic amyotrophy is unknown. Postulated mechanisms include low-grade venous ischemia of the spinal cord, especially the anterior horn cells, which lie in the watershed area, possibly precipitated by trauma to the arm or neck, or by recurrent neck flexion and extension.
The diagnosis is often made with the classic clinical presentation of distal hand weakness and atrophy, usually in a young male. Laboratory investigations including blood chemistries and CSF analysis are normal, with the exception of the serum CK, which may be slightly elevated. On EDX testing, motor nerve conduction studies may be normal or may reveal asymmetrically low median or ulnar CMAP amplitudes in the affected hand. Slightly prolonged distal motor latencies or slightly slowed conduction velocities may occur, depending on the degree of axonal loss. The SNAPs are always preserved.
Recall that one of the patterns that may occur in typical sporadic ALS is the “split-hand syndrome,” wherein the first dorsal interosseous (FDI) and abductor pollicis brevis (APB) are more affected than the abductor digiti minimi (ADM) (see Chapter 27 ). In monomelic amyotrophy, the reverse pattern is more often noted: the ADM is much weaker and more wasted than the APB. The correlate of this clinical observation is a distinctive pattern on routine ulnar and median motor nerve conductions: an ADM/APB CMAP amplitude ratio of <0.6, which strongly suggests the diagnosis of monomelic atrophy rather than ALS. First described by Lyu et al., this ratio is calculated simply by measuring the amplitudes of the CMAPs of the ADM and the APB, during routine ulnar and median motor conduction studies. An ADM/APB CMAP amplitude ratio of <0.6 is considered abnormal. Conversely, in cases wherein the ADM/APB CMAP amplitude ratio was >4.5 or when the median motor response was absent and the ulnar motor response recording the ADM was present, this pattern only occurred in ALS. Of course, these conclusions are predicated on the understanding that there is no additional lesion affecting the median and/or ulnar nerves, especially median neuropathy at the wrist or ulnar neuropathy at the elbow. In cases in which the diagnoses of monomelic amyotrophy and ALS are being considered in a patient, paying attention to this ratio may be helpful.
On needle EMG, fibrillation potentials are not prominent; they are found in slightly less than half of patients. MUAPs are large and prolonged in duration, and recruitment is invariably reduced. Low-amplitude, short-duration MUAPs, which represent early reinnervated motor unit potentials, occur in approximately 20% of patients. Often, similar EDX abnormalities are detected, to a much lesser degree, in the clinically unaffected contralateral limb. Radiologic findings on computed tomographic myelogram or magnetic resonance imaging may show segmental atrophy of the spinal cord at the level of the involved myotomes, especially in the lower cervical and upper thoracic spinal cord. The course in monomelic amyotrophy is generally benign.
Motor Neuron Disease Associated with Electrical Injury
There are rare case reports of adults and children who develop a delayed upper and lower motor neuron syndrome after exposure to an electrical injury or lightning. Electrical injuries usually occur from high-voltage lines, household circuits, or lightning. Transient neurologic deficits immediately after an electrical shock are well described and usually recover after hours to several days. In more severe electrical injuries, spinal cord damage may occur, resulting in a non-progressive syndrome that includes either lower or upper motor neuron damage, which often correlates with the level of the entrance and exit sites of the electrical current. Patients with non-progressive syndromes may recover partially or completely.
In contrast, a progressive motor neuron syndrome may develop at variable time periods after the electrical injury. Weakness begins near the site of the trauma and progresses in an ALS-like fashion to the contralateral limb. Bulbar weakness and upper motor neuron signs develop later on. Sensory symptoms can occur in the region of the electrical injury. The clinical course in the progressive motor neuron syndrome associated with electrical injury is similar to the progression seen in typical ALS, with death typically occurring within 3 years after the initial presentation. Whether there is truly a causal relationship between the electrical injury and the progressive motor neuron syndrome remains unknown.
The underlying mechanism of the electrical injury and its relationship to spinal cord damage, particularly to the anterior horn cells, are unclear. Autopsy findings in one patient with motor neuron disease after an electrical injury revealed the classic changes found in ALS, including loss of anterior horn cells and motor neurons in the hypoglossal nuclei, and degeneration of the corticospinal tract. There was no evidence of vascular cord injury or mechanical distortion of the spinal cord. Thus, the relationship between electrical injuries and ALS remains tenuous at best.
Delayed Radiation-Induced Motor Neuron Syndrome
Progressive pure lower motor neuron syndromes have been described in patients as a delayed response of radiation therapy, with typical total doses in the range from 5000 to 6000 rads. The clinical syndrome is characterized by progressive weakness, usually of the lower extremities, with marked atrophy and fasciculations, which develops months to years after radiation therapy. Deep tendon reflexes are depressed or absent in the affected limbs. Sphincter function and sensation are spared, and upper motor neuron signs are absent. Interestingly, the lower extremities are preferentially involved, although radiation may involve the entire neuraxis. The weakness generally stabilizes after several months, although weakness continues to progress over years in some patients. A delayed lower motor neuron bulbar palsy, consisting of dysarthria, dysphagia, and in some cases neck weakness, has been reported following radiation to the head and neck for various cancers ( Figure 28–3 ).
The diagnosis is based on a history of lower motor neuron weakness primarily in the lower extremities, months to years following radiation exposure. CSF usually is normal, although there may be a mild elevation of CSF protein. On EDX studies, nerve conduction studies show low CMAPs in the lower extremities, with intact SNAPs. On EMG, prominent fibrillation potentials are often present in the lower extremities. Of course, if the weakness and wasting involves bulbofacial and neck muscles, these findings are seen in the bulbofacial and neck muscles. Myokymic discharges may be seen in affected muscles and are an important marker suggesting radiation-induced injury ( Figure 28–4 ). EDX testing of the upper extremities is normal in most cases, depending on the site of radiation. The clinical course is slowly progressive and usually confined to the region of the spinal cord exposed to the original radiation. Most patients stabilize after several months and usually survive for 15 to 20 years after the initial presentation, although the weakness can be severe and debilitating.
The pathogenesis of delayed radiation-induced injury is not well defined. Some evidence suggests that the disease process in the lower extremities involves damage to the lumbosacral anterior nerve roots, whereas other evidence suggests that the pathology is in the anterior horn cells. Based on purported mechanisms involved in delayed radiation-induced encephalopathy, it is likely that a combination of factors is involved in postradiation-induced motor neuron syndrome. These include direct radiation-induced damage to neurons and ischemic changes secondary to radiation-induced damage to vascular endothelial cells.
Paraneoplastic Motor Neuron Disease
Paraneoplastic disorders occur as a remote effect of cancer. Whether motor neuron disease occurs as a paraneoplastic syndrome is controversial. Since several initial reports of a paraneoplastic motor neuron syndrome, many have questioned whether the association of cancer and motor neuron disease is simply a coincidence of two relatively common diseases, or if there is a true etiologic relationship between the two conditions. Several epidemiologic studies have failed to find an increased incidence of cancer in patients with ALS compared with the general population, although several small studies have reported a co-occurrence of cancer and motor neuron disease that appears to be higher than the incidence expected in the general population.
One of the strongest cases for a paraneoplastic motor neuron disease occurs in association with lymphoma, wherein a clinical syndrome characterized by subacute progressive, painless lower motor neuron weakness with minimal or absent sensory symptoms has been reported. The progression of neurologic symptoms varies. In some patients the progression is slow; some even show clinical improvement or normalization of neurologic deficits, which appear to be independent of the course of the cancer. In other patients, the disease is progressive, with accompanying upper motor neuron signs and a clinical course similar to typical ALS.
Electrophysiologic Evaluation
Nerve Conduction Studies
The nerve conduction study protocol for a suspected atypical motor neuron disorder is the same as that for ALS (see Chapter 27 ). At a minimum, routine motor and sensory conduction studies along with late responses should be performed in a symptomatic upper and lower extremity before proceeding to the needle EMG study. The most important reason to perform motor nerve conduction studies is to look for the following:
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Unequivocal evidence of demyelination along motor nerves, especially conduction block, at non-entrapment sites. Demyelination is not present in ALS, and its presence strongly supports an alternative, treatable diagnosis, usually multifocal motor neuropathy with conduction block ( Figure 28–5 ).
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Abnormalities on sensory nerve conduction studies. Sensory nerve conduction studies are always normal in ALS unless the patient has a superimposed disorder (e.g., polyneuropathy or entrapment neuropathies). The presence of abnormal sensory conduction studies should always seriously question the diagnosis of ALS. Abnormal sensory conduction studies are often seen in Kennedy’s disease and adult polyglucosan body disease. In addition, some cases of West Nile encephalitis and demyelinating motor neuropathy with conduction block may rarely display sensory conduction abnormalities.
Electromyographic Approach
Akin to the nerve conduction studies, the EMG evaluation of patients with suspected atypical motor neuron disorders is similar to that of ALS. An extensive study is indicated, often of all four limbs, the paraspinal muscles, and the bulbar muscles. Certain types of spontaneous discharges take on additional meaning in patients with suspected atypical motor neuron disorders. CRDs are unusual in ALS and imply a much more chronic condition. Prominent CRDs are reported most often in very chronic motor neuron disorders, especially late-onset Tay–Sachs disease, adult-onset spinal muscular atrophy, and some cases of old poliomyelitis. The presence of myokymic discharges should always raise the possibility of prior radiation-induced injury. In addition, myokymic discharges are sometimes seen in acquired demyelinating neuropathies. Lastly, prominent facial fasciculation potentials or grouped discharges with activation should raise the possibility of Kennedy’s disease.
Almost all motor neuron disorders are slowly progressive. Thus, MUAPs should be large, long, and polyphasic with decreased recruitment. The pattern of acute or subacute neuropathic loss (active denervation, with decreased recruitment of normal configuration MUAPs) is not seen in ALS. This pattern implies either an acute/subacute motor neuron disease, such as acute poliomyelitis or West Nile encephalitis/myelitis, or demyelination with conduction block and some secondary axonal loss.
Case 28–1
History and Physical Examination
A 49-year-old man was referred for progressive weakness and fatigue. Over the past 6 months, he had complained of more difficulty walking and noted increased weakness in the left leg. He had a history of paralytic poliomyelitis at age 5 years. He recalled being hospitalized for 2 weeks at that time and developing weakness of both legs, left more than right. The upper extremities and bulbofacial and respiratory muscles were not affected. Within 1 year following the poliomyelitis, he had regained full function of his legs. During high school and college, he had participated regularly in athletics without difficulty.
On examination, the left leg was slightly shorter and smaller than the right. Neurologic examination revealed normal mental status and cranial nerves. In the upper extremities, muscle bulk, tone, and strength were normal. In the lower extremities, there was slight weakness of all movements around the ankle, especially on the left. In addition, there was mild weakness of hip extension and abduction bilaterally. Reflexes were absent in the lower extremities and hypoactive in the upper extremities. Sensory examination was normal to all modalities.