Keywords
Poliomyelitis, vaccine associated poliomyelitis, post-polio syndrome, Hopkins syndrome, rabies, tetanus
Infantile Poliomyelitis
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.
Major syndromes
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Asymptomatic infection
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Mild symptomatic transient illness
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Aseptic meningitis (abortive nonparalytic infection)
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Paralytic poliomyelitis
Uncommon syndromes
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Encephalitis
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Acute cerebellar ataxia
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Acute transverse myelitis
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Guillain-Barré syndrome
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%.
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Fever, meningeal signs, muscle pain
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Muscle spasms precede paralysis
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Generalized weakness (fever present) followed by asymmetrical flaccid paralysis
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Normal sensory functions
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Spinal fluid abnormalities
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Increased white cell count (20–200 cells)
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Increased protein (50–100 mg/dL)
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Normal glucose
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Cultures usually negative
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Throat swab and stool cultures positive
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Electromyographic and nerve conduction velocity studies
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Early: diminished recruitment pattern
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Subacute: fibrillations, positive waves
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Late: motor units very high amplitude, long duration, diminished members, increased firing rate
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Motor conduction-decreased compound action potential amplitudes: normal sensory conduction parameters
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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%.
A 7-year-old boy was admitted to the hospital with complaints of fever, headache, and vomiting for the previous week and stiffness and spasms of the neck and back muscles for the previous 2 days. Examination confirmed nuchal rigidity and tenderness and spasms of muscles of the back and hips. On admission, Brudzinski’s and Kernig’s signs were present, and muscle stretch reflexes at the knees and ankles were hyperactive. As a result of weakness of abdominal and truncal muscles, the child could not go from a supine position to sitting without assistance and could not sit erect without support. His speech, swallowing, and other bulbar functions were normal. Spinal fluid protein concentration was 20 mg/dL, and glucose concentration was 59 mg/dL. In the cerebrospinal fluid, there were 78 white cells/mm 3 , predominantly lymphocytes. The clinical diagnosis of poliomyelitis was made, and the patient was treated with supportive measures. During the next 3 months, the patient’s strength improved, and there were no residual functional deficits.
Approximately 1 year later, this boy again developed fever, headache, vomiting, and neck pain. Within the first 2 to 3 days of illness, he also developed inability to swallow without nasal regurgitation, nasal speech, inability to cough, and double vision. Examination revealed tenderness and spasms of the muscles of the neck and upper back and prominent nuchal rigidity. His tongue protruded to the left, and there was paralysis of soft palate elevation. Cough reflex was absent. Spinal fluid contained 32 lymphocytes/mm 3 . Protein and glucose concentrations were normal. Bulbospinal poliomyelitis was diagnosed, and the patient was treated with supportive and rehabilitative measures. Gradually, this boy improved with prolonged convalescent care.
This child, originally seen in 1946 and reported in 1948, illustrates many common features, as well as some rare clinical features, of acute poliomyelitis during epidemics in the 1940s. Each acute illness experienced by this patient was initially characterized by the common triad of fever, nuchal rigidity, and muscle spasms of the back and neck. In the initial illness, muscular weakness was most severe in the lower back and proximal lower extremity muscles. Although this boy initially displayed hyperreflexia, most patients eventually lose muscle stretch reflexes in the paralytic extremities. The second episode illustrates the development and progression of bulbar polio with prominent early deficits in chewing, swallowing, and coughing. Extraocular muscle weakness was uncommon in children but was not unusual in older adolescents and adults. Patients with bulbar involvement were at risk of developing vocal cord and diaphragmatic weakness, autonomic instability, and respiratory failure. Intubation and tracheostomies were required to provide mechanical ventilatory support.
This youngster was particularly unusual in developing recurrent paralytic disease. By 1948, almost 40 cases of recurrent polio were reported. Statistically, the risk of recurrent polio was estimated to be about 1 recurrence per 1000 cases of paralytic disease. The immunity that developed during illness with one strain did not seem to provide protection against disease caused by other strains. A few years later, laboratory techniques were developed demonstrating the absence of cross-immunity among the three strains of poliovirus and confirming these earlier clinical observations.
Comment
Today, cases of wild-type and vaccine-induced poliomyelitis continue to occur in a few areas of the world. Occasionally such cases are seen in the United States in patients who have traveled from those regions. The clinical symptoms, signs, and course followed by contemporary patients are the same as those experienced by patients during the first half of the 20th century and illustrated by the case example. Until eradication of all human poliovirus infections has been achieved, clinicians worldwide need to continue to include viral poliomyelitis in the differential diagnosis of acute-onset flaccid weakness accompanied by fever, headache, nuchal rigidity, and muscle spasms of the back. Today, patients suspected of having poliomyelitis should undergo a thorough evaluation using virologic and immunologic diagnostic techniques capable of isolating and typing the infective agent and quantifying the patient’s immunologic responses. Unfortunately, our ability to treat patients has progressed little during the past 50 years. General measures to assist breathing, detect and correct autonomic dysfunction, protect the airway, relieve pain, reduce muscle spasms, and provide rehabilitation continue to be the main treatment modalities available to patients with viral poliomyelitis.
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.
Postpolio Syndrome
An unusual late manifestation of polio has been observed in adults who had paralytic poliomyelitis 15 to 20 years or more after the acute illness. It is characterized by a gradual or, in rare cases, a sudden onset of progressive and persistent new muscle weakness, decreased muscle endurance, fatigue, pain, and atrophy in the same muscle groups that appeared to be involved in the acute infection or in muscle groups not clinically involved originally. This slowly progressive anterior horn cell degenerative disorder may continue for long periods and in a few patients may lead to new, severe functional impairments and incapacitation. Since there are no specific diagnostic tests for postpolio syndrome (PPS), diagnosis is based on exclusion of other possible causes for the new symptoms. Several diagnostic criteria for PPS have been proposed but that recommended at the March of Dimes International Conference on PPS in 2000 is the most plausible ( Box 10.3 ).
- 1.
Prior paralytic poliomyelitis with evidence of motor neuron loss, as confirmed by history of the acute paralytic illness, signs of residual weakness and atrophy of muscles on neurologic examination, and signs of denervation on electromyography (EMG).
- 2.
A period of partial or complete functional recovery after acute paralytic poliomyelitis, followed by an interval (usually 15 years or more) of stable neurologic function.
- 3.
Gradual or sudden onset of progressive and persistent new muscle weakness or abnormal muscle fatigability (decreased endurance), with or without generalized fatigue, muscle atrophy, or muscle and joint pain. (Sudden onset may follow a period of inactivity, trauma, or surgery.) Less commonly, symptoms attributed to PPS include new problems with breathing or swallowing.
- 4.
Symptoms persist for at least 1 year.
- 5.
Exclusion of other neurologic, medical, and orthopedic problems as causes of symptoms.
The total number of polio survivors is estimated to be about 20 million by the World Health Organization. The prevalence of PPS has been reported to range from 15% to 80% of all people with previous paralytic poliomyelitis depending on the criteria applied and population studied. Given the large numbers of survivors of the 1940 and early 1950s poliomyelitis epidemics when vaccination programs were launched, this frequency of new weakness makes PPS the most prevalent motor neuron disease in North America.
The pathogenesis of PPS is still unclear. It may be related in part to the loss of terminal axonal sprouts in pathologically large motor units. Over time previously damaged anterior horn cells may be unable to metabolically support and maintain the increased number of axon sprouts that developed during recovery after the initial acute infection. Degeneration and loss of these sprouts lead secondarily to muscle necrosis and progressive weakness. Although results of previous virologic and immunologic studies failed to show evidence for active viral replication or viral reactivation in this syndrome, results of recent investigations using polymerase chain reaction techniques have suggested that the development of postpolio syndrome may be related to persistence of mutated poliovirus in the CNS.
In addition to paralytic disease and the other three major clinical outcomes of poliovirus infection, other less common neurologic disorders can result. Poliovirus encephalitis has been described and is similar clinically to other viral encephalitides in causing lethargy, confusion, disorientation, focal and lateralized neurologic deficits, and occasionally seizures. Acute cerebellar ataxia, acute transverse myelitis, and Guillain-Barré syndrome have all been reported with or following natural poliovirus infections and after use of oral live-virus vaccines.
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.
Neuronopathies/Neuropathies
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Viral poliomyelitis syndrome (see Box 10.5 )
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Parainfectious disorders
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Guillain-Barré syndrome
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Acute motor axonal neuropathy
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Plexopathies
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Isolated mononeuropathies
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Myoneural junction disorders
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Myasthenia gravis
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Botulism
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Biologic toxins and venoms
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Chemical neurotoxins
Myopathy
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Polymyositis
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Glycogen storage
Spinal cord or brain stem lesions
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Tumors
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Abscesses
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Vascular lesions
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Infarcts
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Hemorrhages
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Arteriovenous malformations
Trauma
Asthma-associated poliomyelitis syndrome
Postpolio syndrome
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.
Enteroviruses
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Poliovirus serotypes 1, 2, 3
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Coxsackievirus
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Group A (A7, A10)
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Group B (B3, B5)
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Echovirus types 2, 6, 9
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Other human enterovirus types 70, 71
Adenovirus
Mumps virus
Herpesvirus
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Herpes simplex virus type 1
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Varicella-zoster virus
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Epstein-Barr virus
Togaviruses
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Alphaviruses
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Eastern equine encephalitis virus
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Western equine encephalitis virus
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Venezuelan equine viruses
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Laboratory Evaluation
Blood, Cerebrospinal Fluid, and Urine Studies
During the acute, nonspecific early stages of infection, no specific or diagnostically helpful changes occur in the blood chemistries or urinalysis. In paralytic cases, the spinal fluid pressure may be normal or mildly elevated. Pleocytosis, normal or modestly increased protein concentration, and normal glucose concentration characterize the spinal fluid formula. The spinal fluid cell count usually ranges from 10 to 200 leukocytes/mm 3 but occasionally reaches or exceeds 500 cells. In the first few days of illness, neutrophils predominate in the cerebrospinal fluid, but as the disease evolves, lymphocytes become predominant. The protein concentration typically ranges from 50 to 100 mg/dL, though normal or very high levels are occasionally encountered.
Poliovirus is cultured from the cerebrospinal fluid in less than 1% of cases. In contrast, this virus is frequently recovered from throat swabs and fecal specimens. Once isolated in culture, viruses are specifically identified and typed using type-specific neutralizing antibodies. Monoclonal antibodies, polymerase chain reaction techniques, and restriction fragment length polymorphism analysis are also used to detect the presence of poliovirus and determine whether the virus is vaccine derived or wild type. Of the three poliovirus serotypes, types 1 and 3 are most frequently associated with epidemic poliomyelitis, but all three serotypes can cause paralytic disease.
Other diagnostically useful laboratory procedures include detection and titration of virus-specific neutralizing and complement-fixing antibodies in the patient’s blood. These antibodies are serotype specific and do not provide cross-immunity among the three serotypes of poliovirus. Evidence of poliovirus infection includes detection of antipoliovirus serotype-specific immunoglobulin M and immunoglobulin A neutralizing antibodies and the demonstration of a fourfold or greater rise in immunoglobulin G serotype-specific neutralizing antibodies over a 2- to 4-week interval. The use of polymerase chain reaction techniques capable of detecting small amounts of viral nucleic acid in human tissues and fluids provides a rapid, specific, and sensitive method for the early diagnosis of poliovirus and other enteroviruses.
Electromyography
In the early stage of paralytic disease, electromyography and nerve conduction velocity studies demonstrate increased numbers of polyphasic potentials and a generalized reduction in the motor unit recruitment pattern. In later stages, fibrillation and fasciculation potentials develop in affected muscle groups. With recovery, reinnervation produces motor unit potentials that are prolonged and eventually of profoundly increased amplitude (10–20 mV). Nerve conduction velocities are normal at the beginning of the illness, but compound muscle action potentials may be quite small and polyphasic. Throughout the course of the illness, sensory nerve action potentials usually remain normal.
Pathology
During the early stages of acute disease, there is extensive hyperemia, vessel engorgement, and perivascular lymphocytic infiltration in the meninges of the spinal cord. These changes are most intense and extensive in the meninges along the anterolateral aspect of the spinal cord. In the spinal cord parenchyma, most notably in the lumbar region, perivascular lymphocytic infiltration may be associated with multifocal sites of hemorrhagic necrosis. In very early stages, the inflammatory infiltrate may contain many polymorphonuclear leukocytes, whereas in later stages, the infiltrates contain a mixture of lymphocytes, plasma cells, and macrophages. As the lesions advance, microglia proliferate, and regions of hemorrhagic necrosis evolve into small cystic lesions. Chromatolytic and other intracellular degenerative changes affect anterior horn neurons. Rarely, Cowdry type B intranuclear inclusion bodies may be seen. Neuronophagia, neuronal cell loss, and gliosis lead to atrophy of the anterior horn and corresponding anterior spinal root in the late, chronic phases of the disease. The involvement, however, is asymmetrical between the two sides of the cord and is quite variable from level to level rostrocaudally. Pathologic changes are usually most prominent in the lumbar region of the spinal cord, though identical features may be present in variable degrees in the cervical cord, thoracic cord, or brain stem motor nuclei and reticular formation. The sacral spinal cord is usually minimally involved or spared.
In addition to the spinal cord, other regions of the CNS may contain foci of perivascular and parenchymal inflammation and neuronal degeneration. These sites include the brain stem reticular formation, dentate nucleus, globus pallidus, thalamus, hypothalamus, and precentral motor cortex. Other cortical regions and the meninges over the cortical hemispheres show little or no involvement.
Pathologic changes in affected muscle groups are secondary and nonspecific, typical of a disease affecting primarily motor neurons. Early in the course, there may be isolated angulated fibers, myofiber degeneration, and necrosis. Subsequently, type grouping and grouped atrophy develop. In paralytic muscle, fatty, fibrous connective tissue may completely replace muscle tissue. Severe motor neuron loss and secondary muscle atrophy markedly impair growth of the affected extremities.
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.
Poliomyelitis in Patients with Immunodeficiency
The clinical illness in these patients differs significantly from that which develops in otherwise normal, immunocompetent individuals. In immunodeficient patients, vaccine-associated poliovirus infection causes a chronic, slowly progressive neurologic disease with asymmetrical flaccid paralysis. The distribution of paralysis is similar to that seen in typical cases of poliomyelitis but evolves slowly over several weeks or months. Occasionally, tremors, myoclonus, and seizures are observed in some patients, indicating more widespread encephalitic disease. Evidence suggests that virus may persist in both the gastrointestinal tract and the CNS and be excreted in feces for months or years. During this period of persistent infection and chronic excretion, virus may mutate or revert to more neurovirulent forms. The pathologic lesions in the CNS of immunodeficient patients are similar in type and distribution to those found in typical cases but are more numerous, extensive, and severe.
Because of the risk of vaccine-associated poliomyelitis, immunodeficient patients should not receive live-virus vaccines and should be separated for at least 3 weeks from people who have recently been immunized with live-virus vaccines. Killed-virus vaccines eliminate the risk of vaccine-induced poliomyelitis and are preferred for immunodeficient patients who have not received poliomyelitis immunization.
Vaccine-Associated Poliomyelitis
Historical Background
Development of Poliovirus Vaccines
The first clinical description of poliomyelitis was provided in the 1840s, and poliovirus was discovered to be the etiologic agent of poliomyelitis in 1908.
In the late 1930s, the first human trials of poliovirus-infected central nervous system tissue vaccines were attempted, although these studies did not incorporate measures of safety and efficacy. Additionally, some cases of paralytic poliomyelitis resulted from use of the vaccine. Several advancements in the late 1940s and early 1950s facilitated the development of the modern vaccines. In 1949, Enders demonstrated that poliovirus could be grown in cultures of human embryonic tissues (including brain). That same year, Bodian reported the existence of three distinct antigenic types of poliovirus.
In the 1950s, Salk took pathogenic, wild-type poliovirus strains grown in primary monkey kidney cell cultures and rendered them noninfectious by treatment with formaldehyde. The inactivated viruses retained their immunogenicity. Large-scale national field trials commenced in 1954, with more than 1.8 million children involved. Overall, protection rates were high, as measured by effective coverage for the various viral serotypes. Unfortunately, during the vaccine campaign, 260 cases of paralytic poliomyelitis developed in vaccine recipients. Analysis identified defective vaccine lots originating from a single manufacturer, Cutter Laboratories. In these preparations, there was incomplete formaldehyde inactivation. New safety requirements and another filtration step during vaccine preparation were added, and no further cases of vaccine-associated paralytic poliomyelitis (VAPP) have occurred with inactivated poliovirus vaccine (IPV). IPV was licensed in the United States in 1955, and until 1961, it was the only poliovirus vaccine used in the USA.
In the late 1950s, Sabin developed an oral poliovirus vaccine (OPV) consisting of live attenuated strains selected by numerous passages of wild-type polioviruses in monkey tissues, both in vivo and in vitro . Repeated passages produced populations of viruses with diminished neurovirulence in monkeys, and eventually purified clones of all three serotypes were obtained. Oral administration produced a natural gut infection, leading to resistance to reinfection. Once a child has completed a primary series (three doses of OPV), greater than 95% of recipients have long-lasting immunity to all three viral serotypes. Between 1959 and 1962, several large-scale studies ensued, particularly in the Soviet Union, Mexico, and the United States, with demonstration of efficacy and high levels of coverage. In 1959 to 1960, over 100 million people in Eastern Europe received OPV, with almost complete elimination of poliomyelitis (a drop from 10.6 to 0.43 cases per 100,000 by 1963). In 1960, Sabin demonstrated the safety and high seroconversion rate of a single type of each OPV given in sequence, and in 1961, 700,000 children in the United States received OPV safely, with reduced epidemics as a result. OPV was licensed in 1961. Starting in 1965, trivalent OPV became the preferred vaccine (over IPV) in the United States, because it was easy to administer, was low in cost, conferred long-lasting immunity, and produced bowel immunity, which interrupted the cycle of community transmission.
Development of a third vaccine, an enhanced immunogenic IPV (eIPV), began in the 1970s. In 1978, van Wezel described a technique for making a more immunogenic vaccine, and subsequent use demonstrated a high seroconversion rate to all three serotypes ; after three doses of eIPV, 99 to 100% of recipients developed immunity to all three serotypes at 6 months. Numerous clinical trials in several countries, including Sweden, Finland, Africa, the United States, and Canada, demonstrated high seroconversion rates. The eIPV was licensed in 1987. More recent trials in the United States, using a sequential eIPV-OPV schedule (1 to 3 doses of eIPV followed by 1 to 2 doses of OPV), have demonstrated high levels of immunity ; safety and efficacy data have been provided.
Impact of Poliovirus Vaccines
IPV-only strategies are employed successfully in numerous countries, including Sweden, Finland, Iceland, and the Netherlands. Sweden eliminated wild-type poliovirus infection by 1962, with the exception of a single outbreak in members of an unvaccinated religious group. Similarly, Finland eliminated wild-type poliovirus infection with the exception of an isolated outbreak in 1984, attributed to a single poorly immunogenic lot of vaccine. The Netherlands also achieved successful control with an IPV-only protocol, apart from two outbreaks, one in 1978 (110 cases) and a second in 1992 (71 cases); both outbreaks were confined to members of a religious sect that refused vaccination.
In the United States, mass community vaccination programs and mandatory school immunization requirements greatly affected the incidence of poliomyelitis. From 1950 to 1955, there was an average of 16,000 new cases of poliomyelitis reported annually in the United States, with the peak occurring in 1952, when there were over 20,000 cases. By 1957, the annual figures had declined to 2499, by the mid-1960s to less than 100 cases, and from 1980 to 1991 only 8 to 9 cases had been reported yearly ; the latter cases were all VAPP, as are discussed later ( Figure 10.1 ).
The last outbreaks occurring in the United States appeared in 1972 and 1979. In 1972, 11 of 128 students in a Connecticut Christian Scientist school contracted poliomyelitis; 10 of the 11 had never received poliomyelitis immunization. In 1979, 13 Amish developed poliomyelitis; again, the victims had never received poliovirus vaccine. The last case of indigenously acquired wild-type poliomyelitis infection in the United States occurred in 1979 ; the last to appear in the Western Hemisphere was recorded in Peru in August 1991. In 1994, an international commission certified that wild-type poliovirus transmission was now interrupted in the Western Hemisphere. Concomitantly, the global eradication initiative of the World Health Organization (WHO) has resulted in an 80% reduction in the incidence of reported poliomyelitis cases worldwide since 1988. By 1996, 81% of the infants in the world had been appropriately vaccinated. In 1997, there were only 5160 cases reported to WHO, and in 1998, all countries with endemic poliomyelitis staged “immunization day” campaigns to provide additional OPV to children. But the existence of occasional outbreaks in the world, as witnessed in the Netherlands, Africa, and the Middle East as well as the persistence of some unvaccinated or inadequately vaccinated groups, will require that vaccination programs continue world wide in order to prevent outbreaks induced by accidental reintroduction of a wild-type poliovirus strain. The recent outbreaks in Pakistan, Syria, Cameroon, and other countries were discussed in the previous section.
Epidemiology of Vaccine-Associated Paralytic Poliomyelitis
Because OPV contains live attenuated viruses, spontaneous reversion to a more virulent state can cause a vaccinated child, or a close contact of a vaccinated child, to contract paralytic poliomyelitis. The temporal association of a case of paralytic poliomyelitis with administration of the OPV vaccine, or the recovery of a “vaccine-related” poliovirus from the victim’s stool, has typically identified these cases. National surveillance is largely coordinated by the Centers for Disease Control and Prevention (CDC) in the United States. However, a National Vaccine Injury Compensation Program (NVICP) was established by Congress in 1986, to help assist individuals suffering adverse reactions to vaccines. Some cases (average 1.4 cases per year ) have been reported only to the NVICP, and not to the CDC. In general, the CDC risk estimates of VAPP are not altered by inclusion of previously unidentified VAPP cases (reported to the NVICP only ).
The earliest vaccine-associated cases occurred with the poliovirus-infected central nervous system tissue vaccines in the 1930s and the Cutter Laboratories IPV incident in the 1950s. The earliest OPV-associated cases appeared in 1962. At a meeting of the OPV Advisory Committee in Washington in 1962, 11 cases of paralytic poliomyelitis following administration of monovalent OPV vaccine were reviewed: it was felt that sufficient evidence existed to conclude that these cases were vaccine-related. Through 1964, 123 cases of VAPP had been reported, with a calculated risk of 0.4 per 1 million doses of monovalent type 3 OPV, and 0.17 per 1 million doses of monovalent type 1 OPV.
Several large epidemiologic studies reviewed the US experience with VAPP between 1961 and 1984. There were 229 cases of VAPP reported between 1961 and 1984. From 1961 to 1964, most VAPP cases resulted from monovalent type 1 or type 3 OPV, while from 1965 to 1972 more than half the cases were associated with trivalent OPV. When an interim analysis in 1964 disclosed that many VAPP recipients were older than 14 years of age, vaccination guidelines were revised to exclude the routine vaccination of persons older than 18. After 1965, only 2 of 16 recipient cases were older than 14.
From 1973 to 1984, 138 cases of paralytic poliomyelitis were reported in the United States, and of these, 105 (76%) were cases of VAPP. Of the 105, 85 occurred in immunocompetent individuals: 35 in recipients of OPV, and 50 in contacts of OPV recipients. Fourteen cases occurred in immunodeficient individuals, and six victims were not recipients and had no close contacts (presumed “community” contact). Ninety-four percent of recipient cases, 82% of contact cases, and 36% of immunodeficiency cases were associated with the first dose of OPV. The interval between vaccination and illness onset for the three groups was 4 to 34 days (median 20 days) for recipients, 11 to 58 days (median 35 days) for contacts, and 12 days to 8 months (median 41 days) in immunodeficient victims. The calculated risk at that time was 1 per 2.6 million doses overall, or 1 per 520,000 first doses and 1 per 12.3 million subsequent doses.
From 1980 to 1994, 133 cases of paralytic poliomyelitis were reported to the CDC, with 125 representing cases of VAPP; six cases were imported, and two were declared indeterminate. Forty-nine (39%) occurred in healthy recipients (91% within the first year of life), 40 (32%) in healthy close contacts of OPV recipients, 30 (24%) in immunodeficient recipients (23) and contacts (7), and 6 in “community” contacts (nonrecipients with no close contacts, but in whom vaccine virus was recovered from stool). Ninety-seven cases (78%) were associated with the first dose of OPV. The overall risk was calculated at 1 per 750,000 children receiving the first OPV dose, with a 1 per 2.4 million dose risk overall. This estimated risk was similar to earlier estimates, indicating that the overall risk of VAPP in the United States was relatively unchanged from 1965 to 1994. In general, 8 to 9 cases of VAPP are reported annually in the United States (see Figure 10.1 ), though possibly some underreporting exists.
Immunodeficiency significantly increases the risk of VAPP in infants 3200- to 6800-fold. Most cases occur either among individuals with disorders of humoral immunity, or those with B-lymphocyte disorders that inhibit immune globulin synthesis, such as agammaglobulinemia, hypogammaglobulinemia, and combined immune deficiency. Other cases are described in association with thymic abnormalities, human immunodeficiency virus (HIV) infection, prednisone treatment, and cancer treated with chlorambucil/prednisone.
Epidemiologic studies are also available from other countries. In Latin America, from 1989 to 1991, the overall risk of VAPP was 1 per 1.5 to 2.2 million doses of OPV, compared with 1 per 1.4 million doses in England and Wales (1985 to 1991).
As vaccine policy in the United States has evolved in recent years, there has been increased usage of IPV over OPV, with a resultant decline in the number of VAPP cases. From January 1997 to December 1998, only four cases of VAPP were reported, all following the first or second dose of an all-OPV regimen. Three cases occurred in recipients, one in a contact.
Laboratory Techniques
Since 1979, the CDC has characterized viral isolates (as wild-type or vaccine-derived) by molecular methods such as oligonucleotide fingerprinting and RNA sequencing. Not only do these techniques allow for the differentiation of wild-type and vaccine strains but they can also demonstrate genetic homologies between polioviruses in different geographic areas, permitting a surveillance team to trace an outbreak.
In the evaluation of a patient with suspected poliomyelitis, the CDC recommends obtaining at least two stool and two throat swab specimens, 24 hours apart, as early in the course of the illness as possible (ideally within the first 14 days). The stool has the greatest yield, followed by the throat; virus is rarely detected in the cerebrospinal fluid (CSF). The specimens should be cultured for enteroviruses, followed by serotyping. In addition, an acute-phase serologic specimen should be secured as soon as possible, followed by a convalescent specimen obtained 3 weeks later; each should be tested for neutralizing antibodies to each of the three serotypes of poliovirus, with a fourfold rise in titer indicating infection.
Viral Attenuation and Reversion to Virulence
A number of mutations in the Sabin OPV strains attenuate the viruses during vaccine preparation, rendering them nonpathogenic. Mutations at numerous locations in the viral genome impede the ability of Sabin strains to replicate and spread in the nervous system. As Sabin OPV strains replicate in the gut, some strains revert (mutate) back toward wild type, and changes in the nucleotide sequences can lead to increased neurovirulence of the poliovirus vaccine strains. Such neurovirulent-mutated progeny of vaccine virus are capable of producing paralytic disease in recipients and contacts, and neurovirulent vaccine strains have been found in the stool of vaccinees (and the central nervous system of patients with VAPP).
The various poliovirus vaccine serotypes are unstable to varying degrees. Type 1 is more likely to cause paralytic poliomyelitis in nonimmunized individuals, and types 2 and 3 are more often isolated in immunized groups; poliovirus types 2 and 3 are the most frequent serotypes isolated from VAPP cases (88% of cases). Furthermore, VAPP appears to be primarily associated with type 3 vaccine virus in immunocompetent individuals (see Case Example 10.2 ), and type 2 vaccine virus is more commonly associated with contact cases and immunodeficient individuals. In actuality, VAPP is probably caused by a variety of alterations of the attenuated viral genomes, including reverse mutations at key locations, genetic recombination (vaccine/vaccine and vaccine/nonvaccine), and host factors.
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