28 Atypical Motor Neuron Disorders

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).

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.

FIGURE 28–1 West Nile virus.

The vector for the West Nile virus is the common mosquito. Although rare, an increasing number of cases of poliomyelitis have been associated with this virus, either alone or in association with encephalitis.

(Courtesy of US Geological Survey.)

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.

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