Infectious or Acquired Motor Neuron Diseases

Historical Background

To many physicians in the developed world, poliomyelitis serves as a dramatic example of how basic virologic methods can lead to vaccine development and almost complete eradication of a human viral infection and crippling neuromuscular disease. Today, with a few geographic exceptions, the formidable anxiety and fear that polio once evoked, especially during the late 19th and early 20th centuries, have been relegated to a closed chapter in the history of medicine. Caution, however, should be exercised, because this human viral infection has not yet been eliminated completely, and lack of vigorous surveillance and sustained efforts to immunize susceptible populations around the world could allow the reemergence of devastating epidemic poliomyelitis.

Although endemic, sporadic paralytic poliovirus infections had occurred for centuries, widespread epidemics did not begin to appear until the 19th and early 20th centuries. The shift from sporadic to epidemic infections, somewhat paradoxically, paralleled improvements in public water supplies and sanitation. As a result of these improvements, exposure to poliovirus was delayed from early childhood to late childhood and adolescence. Delayed exposure eventually led to increasingly larger populations of susceptible older children, adolescents, and adults and eventually to the evolution of seasonal epidemics. It was apparent by the late 19th century that clinical disease caused by poliovirus was more severe and more likely to be paralytic and fatal in older people than it was in young children. At the turn of the century, 80% of paralytic cases occurred in children younger than 5 years old whereas, by the 1950s, the majority of paralytic cases were in children 5 to 9 years old. By some estimates, the risk of paralytic disease and death was almost 10 times greater in adolescents and adults than in young children.

By the first half of the 20th century, this trend for older people to become infected, perhaps with a shift in poliovirus neurovirulence, resulted in epidemics of massive proportions, with thousands of cases of paralytic disease occurring annually. Between 1950 and 1955, for example, 25,000 to 50,000 cases of paralytic polio were reported each year in the United States, with about one-third of paralytic disease and more than half the deaths occurring in people older than 15 years.

Throughout the 19th century, the cause of poliomyelitis was not known. However, by 1951 the three immunologically distinct serotypes of poliovirus had been identified, and all three had been shown to cause paralytic disease. Soon thereafter, Salk’s killed-virus vaccine (1954), Sabin’s live-virus oral vaccine (1961), and trivalent oral vaccine (1963) were developed and became widely distributed.

Remarkably, within only 20 years after the introduction of these vaccines, wild-type poliovirus infections were eliminated in the United States, and major reductions, but not total elimination, had been achieved throughout the world. Today, endemic wild poliovirus infections continue to be detected primarily in southern Asia, central and western Africa, and regions of the Middle East. Despite the continued occurrence of natural paralytic poliovirus infections in these geographic regions, global eradication of all human poliovirus infections appears achievable, though continued outbreaks in undeveloped countries with poor vaccine penetrance continues to pose a problem. Continuous surveillance and early detection programs will be necessary in the future to prevent the reemergence and spread of wild poliovirus infections.

Epidemiology

In the past, poliovirus infections, including paralytic poliomyelitis, had worldwide distribution, with a higher prevalence in temperate climates. Endemic infections occurred sporadically throughout the year. Epidemic outbreaks, however, occurred most frequently in the late summer and early fall in temperate climates but could occur at any time of the year in tropical regions.

As with other human enteroviral infections, the principal mechanism of spread is oral ingestion of virus, usually in fecally contaminated food or water. Less commonly, virus is transmitted by oropharyngeal secretions or respiratory droplets. Close contact, overcrowding, poor sanitation, contaminated water supplies, and inadequate hygiene increase the risk of transmission and promote epidemic outbreaks.

Formerly, poliovirus infection was one of the most common human neurologic viral infections. Before 1956, poliovirus caused 25,000 to 50,000 cases of paralytic disease annually in the United States. By 1957, however, only 2 years after the killed-virus vaccine was licensed in the United States, the incidence of poliovirus infections dropped precipitously from 20 to 40 cases per 100,000 population to fewer than 5 cases per 100,000. After the introduction of oral live-virus vaccine in 1961 and trivalent vaccine in 1963, the incidence was reduced further. By 1970, only 32 cases of paralytic disease were reported in the United States. One of the last cases of poliomyelitis caused by wild-type virus in the Western Hemisphere was reported in 1991 from Peru. During the first half of 2000, 678 cases of paralytic polio were identified worldwide, with only 154 being wild-type, natural infections. In the few regions where natural poliovirus infections still occur, campaigns to eliminate the disease are underway but are hampered by geographic isolation, reduced access to vaccines, limited resources, lax containment standards, and sociopolitical turmoil and unrest. In the past 15 to 20 years, with the gradual elimination of natural paralytic disease, live-virus vaccine-induced neurologic disorders and paralysis have emerged as major risks and concerns. Because of this shift in risk, the use of killed-virus vaccines and revised immunization schedules to achieve maximal protection of populations has been advocated.

Recently, on May 5, 2014, the World Health Organization (WHO) declared a global public health emergency because of the spread of polio to at least 10 countries in Africa, Asia, and the Middle East. In Pakistan, because of a reduced immunization rate, the number of cases increased by 60% in 2013. Polio outbreaks have also occurred recently in unstable conflict zones, such as Syria. WHO has recommended immunization for people travelling to or from 10 countries; further, regardless of age, all residents of Pakistan, Syria, and Cameroon should be vaccinated before travelling abroad. For more information, see the related New York Times article.

Virology, Pathogenesis, and Genetics

Poliovirus, echovirus, coxsackievirus, and other related viruses that are now classified numerically make up the genus Enterovirus, which belongs to the family Picornaviridae. Other human pathogens in the Picornaviridae family include rhinovirus and hepatovirus (hepatitis A). The picornaviruses all share structural and compositional features. They are small (27–30 nanometer diameter), nonenveloped, single-stranded RNA virions that have an icosahedral structure. The virion’s RNA core is enclosed by an outer shell (capsid) composed of four major structural proteins, referred to as VP1, VP2, VP3, and VP4. A fifth precursor protein, VP0, is present in trace amounts and undergoes cleavage to form VP2 and VP4 during virus assembly. Neutralization antigenic sites and attachment sites for host cell receptors are created by these proteins and their geometric conformation on the surface of the virion. After site-specific attachment to the host cell occurs, the virion, by mechanisms incompletely understood, penetrates the host cell membrane, uncoats, and releases viral RNA into the cytoplasm. Cytoplasmic viral RNA and viral protein synthesis take over the host cell’s synthetic machinery and cause inhibition of host cell protein and nucleic acid synthesis. This takeover ultimately leads to progressive failure of vital cellular metabolic and regulatory processes, possible activation of apoptotic processes, and cell death.

Poliovirus and other enteroviruses are typically transmitted by ingestion of virus in fecally contaminated food and water. The stability of enteroviruses at low pH environments and their ability to readily replicate at 37°C allow them to survive passage through the human gastrointestinal tract without becoming inactivated or destroyed and to replicate efficiently. Once ingested, poliovirus attaches to specific receptor sites on specific cells on the mucosal surfaces of the oropharynx and intestine. After attachment, the virus passes through the mucosal surface by pinocytotic and endocytotic mechanisms and is transported to local lymphoid tissue, where local replication occurs. After an incubation period, usually 2 to 3 days, virus is disseminated hematogenously throughout the body, with subsequent secondary replication within susceptible nonneural tissues. Four to five days later, a secondary viremia ensues and results in additional spread of the virus throughout the body, including into the central nervous system (CNS).

The precise mechanisms by which poliovirus passes from the bloodstream across the blood-brain barrier into the CNS are not understood completely. Virus may gain direct access to the CNS in regions normally lacking a blood-brain barrier, such as the area postrema. Circulating cytokines and cerebral endothelial injury may also play a role in allowing virus to reach the CNS. In addition to hematogenous spread, experimental and clinical evidence suggests that virus may gain access to the CNS through axonal transport along nerves that innervate the gastrointestinal tract. Regardless of the route of access, once virus is within the CNS, axonal transport is probably the principal mechanism by which virus is disseminated throughout the CNS.

Within the CNS, discrete cell populations that are specifically susceptible to poliovirus infection include anterior horn cells, medullary (bulbar) motor nuclei, brain stem reticular formation neurons, and a few cell populations rostral to the brain stem in the dentate nucleus, thalamus, hypothalamus, and precentral motor cortex. The specific tropism of poliovirus for certain host cells is determined not only by surface proteins on the virus but also by the presence of specific poliovirus receptors expressed on the surface of host cells. These poliovirus receptor proteins are genetically controlled host cell surface proteins belonging to the immunoglobulin superfamily. Once infected, specifically vulnerable neurons undergo progressive cytolytic changes and ultimately cell death.

Host responses to poliovirus infection play an important part in determining the outcome of infection. After virus enters the body and primary replication begins, serotype-specific immunoglobulin M-neutralizing antibodies become detectable in blood within 1 to 3 days, increase to peak titers by 2 to 3 weeks, and then decline to undetectable levels by 2 to 3 months. Serotype-specific immunoglobulin G-neutralizing antibodies are first detectable 7 to 10 days after infection, increase to peak titers by 2 to 3 months, and then persist for years. Immunoglobulin A antibodies are detectable on mucosal surfaces and in blood 2 to 4 weeks after infection. Humoral antibody responses are serotype specific. Antibodies generated against one strain of poliovirus do not provide cross-immunity against the other two strains. Serotype-specific antibodies are responsible for limiting primary and secondary viremias and preventing hematogenous spread of virus to susceptible tissues. In addition, circulating neutralizing immunoglobulin G and mucosal immunoglobulin A antibodies provide prolonged serotype-specific protection against reinfection.

The outcome of poliovirus infections and the diseases they produce are determined not only by viral cytolytic effects and the host’s humoral and cell-mediated immune responses but also by other important host factors. Inherited and acquired immunodeficiency diseases or drug-induced immunosuppression increase the risk of paralytic disease caused by wild-type or vaccine-associated virus. Age is also an important factor, with increasing age being associated with increasing risk of severe disease, including paralysis and death. For reasons that are not well understood, tonsillectomy and pregnancy also increase the risk that poliovirus infection will cause paralytic disease.

Clinical Features

Infection with the poliovirus typically results in one of four major types of clinical conditions ( Box 10.1 ). First and most common is an asymptomatic, subclinical infection. Second is a mildly symptomatic, monophasic, nonspecific illness. These patients experience only low-grade fever, malaise, headache, diarrhea, or other mild constitutional, nonneurologic symptoms that correlate with the occurrence of the primary viremia. Symptoms resolve in a few days, and the patients recover completely. Asymptomatic and mildly symptomatic illness accounts for more than 95% of all cases of poliovirus infections.

The third clinical illness is aseptic meningitis, sometimes referred to as abortive nonparalytic infection. This accounts for about 1 to 2% of all poliovirus infections. This brief illness is characterized by modest fever, malaise, headache, neck and back aches, muscle stiffness, and vomiting. Patients do not develop focal deficits or paralysis, and they recover quickly and completely, usually within 2 to 4 days.

The fourth condition and the one of greatest clinical concern is paralytic poliomyelitis, which fortunately accounts for only 1% or less of all poliovirus infections. Although anterior horn cells throughout the spinal cord and brain stem are at risk, the sites of highest predilection are the lumbar, cervical, and medullary regions. One to two weeks after exposure, the illness begins as a minor, nonspecific illness characterized by fever (101–103°F), malaise, sore throat, and vomiting ( Box 10.2 ). This initial phase of the illness accompanies the primary viremia. The patient may begin to improve for 1 to 3 days, only to relapse acutely into the second phase of the illness, which is characterized by high fever, malaise, headache, nuchal rigidity, back and limb pain, and painful muscle spasms in the back and extremities. There is rapid evolution of generalized flaccid weakness that reaches maximal severity in 1 to 2 days. After a plateau phase of several days, the patient’s generalized symptoms improve, and the patient is left with asymmetrical flaccid paresis or paralysis of the extremities or, less commonly, the bulbar muscles. In epidemics that occurred in the United States during the 1940s and early 1950s, bulbar paralysis accounted for 10% to 15% of cases, and a combined bulbar and spinal distribution accounted for another 15%.

Osler provides detailed accounts of the clinical features of poliomyelitis. He notes, for example, that the most severely affected muscle groups in the lower extremities are the anterior tibialis, leg extensors, and thigh flexors. Hamstrings and gluteal muscles are often relatively spared. Facial muscles are infrequently involved, and extraocular muscles are usually spared. On examination, muscle stretch reflexes are lost in affected limbs, whereas cerebellar and sensory functions remain intact. Patients with bulbospinal involvement of cranial nerves IX and X or involvement of diaphragmatic and thoracic muscles are at risk of apnea, aspiration, and airway obstruction. Autonomic disturbances constitute less common but clinically important and potentially dangerous manifestations of poliomyelitis. Infections involving brain stem reticular formation neurons may cause severe, sometimes fatal, vasomotor instability, irregular respiratory drive with apnea and cyanosis, hypertension, and cardiac arrhythmias. Patients with involvement of lower brain stem nuclei and reticular formation neurons may require prolonged mechanical ventilation. In contrast to the 5% to 10% mortality in spinal forms of the disease, the mortality rate in bulbar polio reaches 25% to 35%.

During the 1940s, comparisons of poliomyelitis in infants younger than 1 year, children, and adults disclosed important clinical and epidemiologic differences. In all age groups, the annual incidence was higher for males than females, except for 25- to 29-year-olds, where females outnumbered males. Poliomyelitis was infrequent in infants younger than 1 year of age, compared with older children and adults. The incidence was less than 5 per 100,000 in infants younger than 6 months old, was approximately 30 per 100,000 by 1 year, peaked in 5- to 9-year-olds at 103 per 100,000, and then decreased to less than 10 per 100,000 by 25 years. When poliovirus infection did occur in children younger than 1 year old, paralytic disease occurred in 100% of those younger than 2 months old and in 85% to 95% of those 3 to 11 months. In the group of patients younger than 1 year old, almost all cases were of the spinal type; bulbar involvement occurred in less than 10%. In contrast, infections in older children resulted in paralytic disease in approximately 50% to 55% of cases, with 15% to 20% of children and up to 36% of adults having bulbar-type paralysis (see Case Example 10.1 ). Early manifestations of poliomyelitis in young infants included fever, nuchal rigidity, and spasms of the back muscles. The case-fatality ratio in infants younger than 1 year with paralytic disease was 8% to 10%, similar to that seen in other age groups. In patients with bulbar-type paralysis, the case fatality was 30% to 35%.

In general, adults with poliomyelitis were noted to have more widespread and severe weakness and paralysis than children had. Adults tended to develop quadriplegia frequently, whereas children usually had paralysis confined to one or two extremities. Bulbar and brain stem involvement, including cranial nerve nuclei III, IV, and VI and reticular formation neurons, was more frequent in adults. Paralysis of respiratory muscles occurred in 40% of adults, in contrast to 10% of children. In some comparison studies, people between the ages of 16 and 50 years had a death rate nine times higher than that observed in children younger than 15 years old. This difference in mortality was accounted for in part by the fact that more adults than children developed bulbar involvement, and most deaths occurred in patients with bulbar-type paralysis.

Differential Diagnosis

The differential diagnosis of acute flaccid weakness is outlined in Box 10.4 . The diagnosis of poliomyelitis is usually based on information derived from a detailed history and thorough neurologic examination (see Box 10.2 ). At the onset of acute flaccid weakness, Guillain-Barré syndrome may be considered, but this can usually be differentiated by its ascending pattern of weakness, sensory involvement, acellular spinal fluid with high protein content, and impaired motor nerve conduction velocities. Additionally, paralytic poliomyelitis is more typically asymmetric in presentation. Acute motor axonal neuropathy is a frequent cause of acute flaccid paralysis in China and other Asian countries, but it differs clinically from poliomyelitis in that the weakness is bilaterally symmetrical and involves bulbar muscles in 40% to 50% of cases. Botulism may produce acute-onset flaccid weakness of the extremities or bulbar musculature, but the associated pupillary abnormalities, extraocular muscle involvement, gastrointestinal symptoms, normal spinal fluid, and abnormal electromyography results and repetitive nerve stimulation studies distinguish it from polio.

Acute transverse myelitis and acute disseminated encephalomyelitis can resemble viral poliomyelitis initially, with acute symmetrical or asymmetrical flaccid paralysis, fever, and back pain. Occasionally, immunizations with poliovirus vaccine have preceded the onset of acute transverse myelitis. The detection of a sensory level and the emergence of sensory deficits indicative of spinothalamic tract and dorsal column involvement separate this disorder from polio on clinical grounds. Myasthenia gravis, neurotoxins, and spinal cord lesions, such as tumors, abscesses, hemorrhages, and vascular malformations, can cause acute flaccid weakness but can be distinguished from poliomyelitis by their associated clinical features, spinal fluid findings, electrophysiologic abnormalities, and neuroimaging abnormalities.

Currently, patients with acute flaccid weakness who have a history of recent travel through regions known to harbor wild poliovirus need to be evaluated for poliomyelitis. Similarly, a history of recent live-virus vaccination or close contact with a recently vaccinated person raises the possibility of vaccine-induced paralytic polio. This is especially important in patients who may have an underlying inherited or acquired immunodeficiency state. Viruses other than poliovirus rarely cause the poliomyelitis syndrome including other enteroviruses, adenoviruses, mumps virus, members of the herpesvirus family, and several alpha- and flavivirus togaviruses ( Box 10.5 ). Virologic and serologic techniques are necessary to isolate, identify, and differentiate these viruses.

Laboratory Evaluation

Therapy

Specific antiviral pharmacotherapy is not available for poliomyelitis. Treatment of acute poliomyelitis, as well as postpolio syndrome, is directed at managing fever, relieving pain, reducing muscle spasms, and providing supportive treatment. Patients with bulbar polio or generalized weakness may need assistance to protect the airway, support breathing, and maintain nutrition. Once the acute illness subsides, physical and occupational therapy help maintain and promote limb and joint mobility and prevent functionally limiting contractures and joint deformities. Later, depending on how much strength and voluntary movement return, various mechanical and prosthetic devices, along with ongoing physical and occupational therapy programs, assist the patient in achieving maximal functional recovery.

Experience during the past 50 years has demonstrated how a well-organized worldwide vaccination program can dramatically and effectively control and almost completely eliminate a serious human viral disease. In the recent past, most poliovirus vaccination programs have relied on live-virus vaccines to effectively provide immunity for large populations. However, with the near elimination of wild-virus infections worldwide, the shift to the use of killed-virus or inactivated vaccines, as advocated by the Centers for Disease Control and Prevention and enforced in the United States since 2000, has eliminated the risk of vaccine-acquired poliomyelitis but continues to provide effective immunity to children and other susceptible populations. Of note, live-virus polio vaccine is still used in many parts of the world.

Prognosis

The long-term outcome of acute poliomyelitis is dependent on the severity and extent of neuronal damage and loss. Some patients, though quite ill during the acute illness, have minimal neuronal loss and show good functional recovery during the ensuing months. Other patients, especially those with bulbar polio or those with involvement of the diaphragm, may experience minimal recovery and require continued respiratory and physical rehabilitation and intensive supportive care. For most patients with paralytic polio involving lower or upper extremities, a modest amount of steady improvement may continue for 6 to 18 months after the acute illness. These patients, however, commonly have permanent functional impairments that affect their gait, posture, extremity use, and growth.

Asthma-related Poliomyelitis Syndrome

In 1974, Hopkins reported on a series of 10 children he had observed from 1968 through 1974 in Melbourne, Australia. Each child had developed a poliomyelitis syndrome in association with acute asthma attacks. Similar cases were reported from around the world during the next few years. The majority of patients were 1 to 12 years old, although patients as old as 73 years have been described. There was no definite sex predilection. Typically, a flaccid paralysis, without any associated sensory disturbance, began 4 to 7 days after the onset of a moderate to severe attack of asthma. Spinal fluid from most patients was abnormal, with mild to moderate lymphocytic pleocytosis, mild protein elevation, or both. Cerebrospinal fluid glucose concentrations were normal.

Detailed electrophysiologic studies carried out in a few of these patients yielded results consistent with motor neuronopathy and denervation in affected muscles. Virologic, serologic, and epidemiologic studies did not uncover any evidence to implicate recent or active, persistent poliovirus infection in these patients. In a few cases, however, these studies provided evidence that infections with adenovirus, other enteroviruses, or members of the herpesvirus family were causally related to the paralytic illness. Whether an underlying, subtle immunodeficiency state related to asthma or asthma treatment rendered these patients susceptible to the development of paralytic disease is unknown.

There is no specific treatment for this paralytic syndrome. Some reports suggest that if herpesviruses are isolated or suspected, acyclovir or other antiviral agents might modify the course of the disease. The prognosis for asthma-related poliomyelitis is poor. Most patients have a moderate to severe permanent flaccid weakness in one or two extremities.