The previous three chapters discussed motor neuron diseases (MNDs) that are inherited or degenerative in etiology. This chapter will focus on the less common (of this era), largely acquired motor neuron syndromes including the acute and delayed effects of poliomyelitis and other neurotropic viral infections. In addition, other less common causes of lower motor neuron (LMN) disease such as the potential association with malignancy and radiation exposure will be discussed.

Technically, poliomyelitis implies inflammation of spinal cord grey matter regardless of cause resulting in a phenotype of acute flaccid paralysis (AFP). In this chapter, in order to avoid confusion, we will refer to poliomyelitis as the myelopathy associated with infection with the three strains of the poliovirus, distinguishing it from other infectious myelopathies that may also be dominated by LMN weakness. Other infectious myelopathies or myeloradiculopathies with signs and symptoms of notable sensory or long-tract involvement will not be addressed.

Poliomyelitis dates to antiquity. Endemic polio continues to occur in countries where vaccination programs and public health measures are suboptimal. In these cultures, individuals are likely to be exposed early in life. Cases occur more randomly than in epidemic disease and paralytic disease tends to be less severe in this population typically affected at an earlier age. Epidemic polio is a disorder of considerable historical interest. Epidemics tended to occur in the summer and early fall when people were more likely to be in contact with common water sources and each other. Individuals were typically exposed at an older age frequently resulting in more severe disease.

The Salk vaccine, a killed injectable product, became available in 1955. In the early 1960s, the live, attenuated oral vaccine (Sabin) was introduced providing two notable advantages, ease of delivery and long-term immunity. The disadvantage, however, was the potential for infection in vaccinated individuals, or those coming in contact with the vaccinated individuals who were themselves inadequately immunized. People in the latter category most at risk were those who had emigrated from countries without adequate vaccination programs, those whose religious or cultural beliefs opposed vaccination, or those whose immunity had lapsed from the exclusive use of the Salk vaccine. Since 2000, no cases of AFP from the polio virus have been reported in the United States coincident with withdrawal of Sabin vaccine usage.¹

Although poliomyelitis is a disease of largely historical interest in the United States as a public health menace, it continues to have relevance on a number of levels. It is one of the earliest and best models of selective neuronal vulnerability from environmental cause. The development and distribution of effective polio vaccines represents one of the most notable triumphs of translational medicine in the 20th century. The relevance of poliomyelitis persists as well in that survivors of the paralytic polio epidemics of the late 1940s and early 1950s continue to populate neurology clinics.¹

CLINICAL FEATURES

Poliomyelitis may occur as a monophasic or biphasic disease. The initial symptoms (“minor illness”) are nonspecific, lasting 1–2 days. The symptoms are predominantly constitutional or gastrointestinal in nature consisting of some combination of fever, malaise, pharyngitis, headache, nausea, vomiting, and/or abdominal cramping. In the majority of individuals who are infected, the illness is self-limited and ends at this point. In individuals who fall victim to the “major illness”, symptoms may occur immediately or after a delay of up to 10 days. The major illness is defined by any central nervous system (CNS) involvement including aseptic meningitis, encephalitis, or any paralytic component affecting bulbar, trunk, ventilatory, or limb musculature. Stiff neck, back pain, and fever are prominent.

Encephalitis occurs with or without a paralytic component in less than 5% of cases.² The manifestations may include tremulousness, obtundation, agitation, autonomic dysfunction (hypertension, hypotension, tachycardia, arrhythmias, excessive sweating), and/or upper motor neuron signs.

Although poliomyelitis is best known for its paralytic manifestations, weakness develops in 2% or less of infected individuals. The paresis typically evolves over the course of a few days. In individuals destined to develop paralytic disease, prominent myalgias, cramping, and fasciculations precede paralysis by 48 hours or less. The paresis is typically asymmetric and is confined to the limbs and trunk in half of the cases (Fig. 9-1). There is preferential involvement of the lower extremities and proximal muscles but these tendencies are relative and of limited value in the evaluation of an individual case. About 10–15% of cases have weakness limited to bulbar muscles; the majority of these occur in children. A similar percentage is afflicted with both spinal and bulbar weakness. The most frequently affected cranial nerves are the 7th, 9th, and 10th.² In adults, bulbar weakness is invariably accompanied by limb weakness. Ventilatory failure is more common in this latter group. Affected limbs are paretic if not plegic with deep tendon reflexes diminished or absent. As in virtually all disorders with a predilection for anterior horn cells, the 3rd, 4th, and 6th cranial nerves are inexplicably spared. Sensory signs and symptoms are atypical although poliomyelitis may rarely result in a transverse myelitis phenotype.^3,4

The natural history of AFP from the polio virus is variable, dependent in large part on the severity and extent of the initial illness. Less than 10% of individuals will die from the acute illness, typically due to the complications of ventilatory failure or immobility. Those who survive typically regain strength. Patients with mild weakness typically regain most, if not all, of their strength presumably due to the effectiveness of reinnervation through collateral sprouting of unaffected, neighboring neurons or through recovery of reversibly injured anterior horn cells.⁵ The majority of this recovery takes place over the course of the first 3–6 months and plateaus by 2 years. Patients with severe initial weakness typically are left with residual atrophy and weakness. A chronic persistent form of poliomyelitis can occur in children who are immunosuppressed and have received modified live vaccination. It typically begins a few months after vaccination and is invariably lethal.^6,7

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

Differential diagnostic considerations for AFP are listed in Table 9-1. Other nonpolio enterovirus species and neurotropic viral agents are also capable of producing paralytic disease (Table 9-2).^8–10 The most common culprits are enterovirus 71 and the flaviviruses, including Japanese encephalitis, dengue, tick-borne encephalitis, and West Nile virus (WNV).^10,11 With the decline in poliomyelitis, Japanese encephalitis and WNV appear to be the most common causes of infectious AFP in southeast Asia and North America respectively.¹¹ “Dumb” rabies may present uncommonly as a paralytic illness.¹²

This list is not exhaustive and other viral agents that are more typically associated with encephalitis may occasionally produce an AFP phenotype. Agents such as herpes simplex virus type-2, varicella zoster virus, cytomegalovirus, Epstein–Barr virus, and Coxsackie A & B viruses may produce weakness but typically affect other aspects of the spinal cord in addition to the anterior horns producing concomitant sensory involvement. Paresis caused by nonpolio agents is typically less severe than that produced by polio viruses, though West Nile infection is a notable exception.¹²

Other notable infectious agents have less certain associations with MND phenotypes. HIV-infected patients have been uncommonly reported with different MND phenotypes resembling amyotrophic lateral sclerosis (ALS) including the bibrachial amyotrophic diplegia form of progressive muscular atrophy, but the significance of these associations remains unclear.¹³ The pace of progression would be unlikely to be as acute as with poliomyelitis. Importantly, MND is an unlikely phenotypic presentation of Lyme disease.¹⁴

The differential diagnosis of AFP includes other disorders that present with acute weakness occurring in either a regional or generalized pattern, particularly in the absence of sensory symptoms. Of these, the Guillain–Barré syndrome (GBS) is the most common and notable. Porphyria may produce an acute generalized neuropathy. Disorders of neuromuscular transmission need to be considered, particularly botulism in consideration of its acuity. Severe hypokalemia (<2 mEq/L), hyperkalemia (>7 mEq/L), and hypophosphatemia (<1 mEq/L) are potential causes of acute generalized weakness. In the appropriate context, and in view of their acuity, tick paralysis, intoxication from marine toxins, reptile and insect envenomations, and vasculitic neuropathy need to be considered. In many but not all cases, sensory signs and symptoms will serve as distinguishing features from poliomyelitis and other causes of AFP.

LABORATORY FEATURES

The evaluation of the patient with AFP ideally begins with magnetic resonance (MR) imaging of the relevant aspects of the neuraxis. The findings in poliomyelitis are indistinguishable from other viral myelopathies.^15,16 Hyperintense T2 signal abnormalities which may extend longitudinally over a number of segments are centered in the ventral horns on axial images. Additional findings may include T1 signal abnormalities indicated of hemorrhagic necrosis, short-lived enhancement with gadolinium, and cord expansion due to swelling. Routine blood work has a very limited role in the evaluation of a suspected polio patient. Like all anterior horn cell diseases, mild elevations of serum creatine kinase (CK) values are common.

The value of electrodiagnosis in cases of AFP is largely to identify a motor neuron pattern and to distinguish it from an acute neuropathy pattern. As the most common differential diagnostic consideration is GBS, it is particularly important to look for demyelinating features such as prolonged distal and F wave/H reflex latencies [in the setting of normal compound muscle action potential (CMAP) amplitudes], waveform dispersion, and conduction block, none of which would not be expected in anterior horn cell diseases. Although interpretation of sensory nerve conduction study results may be difficult in the first week of an illness, reduction in sensory nerve action potential (SNAP) amplitudes is not expected in polio but would be the norm in GBS and other neuropathies. The acute motor axonal neuropathy variant of GBS is a notable exception to this rule.

The electrodiagnostic (EDX) findings in poliomyelitis would include reduced CMAP amplitudes in weak muscles, reduced recruitment of initially normal-appearing motor unit potentials, and within 3 weeks, evidence of ongoing denervation in the form of positive waves and fibrillation potentials occurring in a multifocal, segmental distribution including the paraspinal musculature. The EDX features of postpolio muscular atrophy will be addressed in the postpolio section.

Examination of the cerebrospinal fluid (CSF) is integral to the diagnosis and differential diagnosis of poliomyelitis although may be initially negative in 10% of cases. Within 2 weeks of onset, however, a pleocytosis develops. Initially, there may be a neutrophilic predominance, but 50–200 lymphocytes/mm³ represent the typical pattern. These cells typically dissipate within 2 weeks. There is a gradual increase in the CSF protein level to a peak of 300 mg/dl or less, which then resolves within 2 months. This pattern is similar with all of the viral agents that may produce a poliomyelitis syndrome. Hypoglycorracchia would be a rare finding.

CSF viral cultures are rarely positive in poliomyelitis. Currently, the gold standard for viral identification in the CNS is the polymerase chain reaction (PCR) for DNA viruses and reverse transcription PCR for RNA viruses.¹⁰ CSF antibody levels may be helpful, as the presence of IgM antibodies that cannot cross the blood–brain barrier implies production within the CNS. A four-fold rise in serum antibody levels comparing chronic to acute serum or viral culture obtained from stool or throat provide diagnostic confirmation but are of limited value in acute diagnosis. The virus will be shed from the saliva for weeks and from the stool for months following infection aiding diagnosis in cases where the patient is not seen acutely. Unfortunately, identification of a specific viral agent remains elusive in the majority of AFP cases.

HISTOPATHOLOGY

The original pathologic studies of the CNS in acute poliomyelitis were made by Bodian, at times within days of disease onset.⁵ The earliest pathologic changes were in motor neurons consisting of dissolution of the cytoplasmic Nissl substance (chromatolysis) occurring in the absence of inflammation. Although neuronal loss appeared independent of inflammation suggesting an apoptotic mechanism of cell death, the presence of inflammation in the anterior horn or neuronophagia was described as a poor prognostic indicator.

The macroscopic spinal cord pathology can include pial inflammation, vascular dilatation, and petechial hemorrhages.¹⁷ In addition to the anterior horn cells, particularly of the cervical and lumbar regions, poliomyelitis may affect neurons of the intermediate, intermediolateral, and posterior horns of the spinal cord; the dorsal root ganglia; the precentral motor cortex; hypothalamus; thalamus; cerebellar roof nuclei and vermis; nucleus ambiguous; nuclei of the facial, hypoglossal, vestibular, and trigeminal nerves; as well as the reticular formation of the brainstem.⁵ Other than for hyperplasia of lymphatic tissues, the pathology of poliomyelitis is largely confined to the CNS.¹⁸

PATHOGENESIS

There are three known serotypes of the poliovirus. Type 1 is most frequently associated with paralytic disease. Poliomyelitis is typically contracted through fecal–oral transmission, infection often initiated within families by infants not adequately toilet trained. The incubation period is typically 6–20 days. The virus replicates in the oropharyngeal and intestinal mucosa, amplifies in lymphatic tissue, and typically goes through two viremic phases, the second of which may result in CNS disease. The exact mechanism of CNS invasion is unclear but either a disrupted blood–brain barrier or entry through neuromuscular junctions with retrograde axonal transport has been suggested. This provides a potential explanation for why AFP is more common and severe in older individuals whose fast axonal transport mechanisms are better established.¹⁹

Susceptibility to poliomyelitis is conferred by the presence of the poliovirus receptor (PVR) or CV155 that allows viral entry into motor neurons.²⁰ CV155 is a protein belonging to an immunoglobulin-like class of proteins known as nectins that promote cell surface adhesion. The PVR normally exists only in primates but transgenic mice expressing this gene are disease susceptible and have provided an animal model that has offered valuable insights into disease pathogenesis. For example, the CV155 protein expresses itself embryologically in transgenic mouse neurons destined to become anterior horn cells suggesting a potential mechanism for the selective vulnerability of motor neurons. Genetic susceptibility to paralytic polio (PP) has been suspected but never proven.

TREATMENT

The best current treatment for poliomyelitis is prevention. The peak incidence of AFP from the polio virus occurred in the United States in 1952 with more than 20,000 new victims. Subsequent to the introduction of vaccine programs, the annual incidence fell to approximately 10 cases a year, the majority of which were felt to be vaccine-related. Since the moratorium on the modified-live virus (Sabin) vaccine in 2000, no new cases in the United States have occurred.

There are no known antiviral agents effective against the polio virus. Strategies to alter the structure of the PVR to prevent viral access to motor neurons has been theoretically proposed. We are aware of anecdotal reports of intravenous immune globulin (IVIG) being utilized in AFP due to WNV and in postpolio syndrome (PPS) but not in acute poliomyelitis.^21,22

The treatments for polio and other causes of AFP remain largely symptomatic. Acute care measures include monitoring of, and if needed, support for hypoventilation and dysautonomia. Prevention of pressure injury to skin and nerve is of great importance as is attention to adequate nutrition particularly in patients with bulbar disease. Treatment of the sequelae of polio involves consideration of durable equipment needs and orthopedic procedures and is addressed in Chapter 5.

The WNV has been recognized as a human pathogen since 1937. The first documented cases in humans in the United States were in 1999. WNV has supplanted poliovirus as the most common viral cause of AFP in adults in this country. It is a mosquito-borne pathogen belonging to the Flavivirus family, all members of which have been reported to cause an AFP syndrome.

CLINICAL FEATURES

Like poliomyelitis, most individuals who are infected remain asymptomatic or develop minimal symptoms. A minor, flu-like illness develops in approximately 20% of patients. Those who become symptomatic do so suddenly with combination of fever, malaise, anorexia, nausea, emesis, diarrhea, headache, photosensitivity, neck pain and stiffness, myalgia, rash, and/or lymphadenopathy.^23,24

Meningoencephalitis and/or AFP develops in approximately 1 out of 150 infected individuals. Meningoencephalitis is the more common phenotype. Most, but not all, patients with AFP have concomitant meningeal or encephalitic signs and symptoms. There is at least a suggestion that the elderly and immunocompromised, particularly those with T cell deficiencies, are most at risk.^24,25

The clinical spectrum of meningoencephalitis is quite broad and may include high fever, nuchal rigidity, seizures, and cognitive impairment including confusion, memory loss, and aphasia. Movement disorders are a common feature of WNV encephalitis and may have either hyperkinetic manifestations such as tremor or myoclonus or a hypokinetic syndrome with Parkinsonism. Stiff-person syndrome has been reported.²⁶ In addition, patients with WNV infection are more prone to develop systemic manifestations than poliomyelitis. Chorioretinitis is reported to occur in 75% of patients with meningoencephalitis. Hepatitis, pancreatitis, rhabdomyolysis, and myocarditis may occur.²⁴

AFP as a consequence of WNV infection is a well-established concept.^{23,25,27–32} Like polio, the phenotype is that of an acute onset of asymmetric flaccid weakness which usually develops over a 3- to 8-day period.²³ Unlike polio, older individuals appear to be at the greatest risk with the mean age of affected individuals being 55 years. The facial nerve is affected frequently which could prompt confusion with GBS or Lyme polyradiculopathy. Ventilatory muscle involvement with the need for mechanical breathing support occurs. As in AFP secondary to poliomyelitis, the outcome is variable with residual deficits being commonplace. Fatality rates in patients with WNV meningoencephalitis average 9% and are reported to be as high as 14%, invariably affecting those greater than 50 years of age.^24,33 It is estimated that only a third of individuals affected with meningoencephalitis will be fully recovered 1 year after their illness.²⁴

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

The diagnosis of West Nile should be considered in any case of AFP of acute to subacute onset, particularly if associated with features of meningitis and/or encephalitis. The majority of cases will be seasonal and related to periods of mosquito activity. Nonetheless, the diversity of transmission mechanisms described below, that are not seasonally dependent, allow for potential WNV infection in patients at risk at any time of year. The differential diagnosis of AFP secondary to WNV is identical to that described in the poliomyelitis section.

LABORATORY FEATURES

Imaging has a supportive role in diagnosis. High-resolution MR imaging of the spine may demonstrate increased signal in the ventral horns or ventral roots in West Nile patients with AFP.^25,34,35 Leptomeningeal, ventral root, and cauda equina enhancement, as well as increased signal in the basal ganglia, mesial temporal lobes, brainstem, cerebellum, and thalami have been described with MR imaging in patients with WNV infection.^33,36–38

The earliest reports of WNV patients with AFP, based on EDX data, suggested polyneuropathy as the likely cause of patient weakness. This is no longer felt to be the case. Subsequent reports of AFP associated with WNV infection describe an EDX pattern identical to poliomyelitis.²⁵ Sensory nerve conductions are normal. CMAP amplitudes are normal or reduced without demyelinating features. Needle examination reveals evidence of reduced recruitment of normal-appearing motor unit action potentials (MUAPs) if done acutely. Within 1–3 weeks, fibrillation potentials and positive waves develop in a generalized pattern that includes clinically unaffected as well as clinically weak muscles.²⁵

Routine laboratory studies have limited utility in suspected WNV infection. Like poliomyelitis, patients with AFP secondary to WNV infection can be anticipated to have modest elevations of serum CK levels. The CSF examination in cases of meningoencephalitis and/or AFP should include enzyme-linked immunosorbent assays for IgM and IgG antibodies for the WNV. WNV reverse transcriptase PCR and viral culture should be utilized as well due to their specificity. Unfortunately, both suffer from inadequate diagnostic sensitivity and cannot be relied upon to exclude the diagnosis. The preliminary CSF results typically include a pleocytosis of between 5 and 500 cells/mm³ in 96% of cases. Initially, there may be a sizeable proportion of neutrophils, but transition to lymphocytic predominance occurs. CSF protein levels are normal in 7% of cases, elevated to <100 mg/dl in 63% of cases, and elevated to >100 mg/dl in 26% of all meningoencephalitis cases but in 47% of cases with a predominantly encephalitic phenotype.³⁹

The Centers for Disease Control and Prevention provide diagnostic criteria for both probable and confirmed meningoencephalitis due to WNV which presumably extrapolate to an AFP syndrome as well. A probable diagnosis requires the appropriate clinical syndrome, occurring at the appropriate time of year associated with a singular serum determination of IgM antibodies to WNV detected by antibody capture enzyme-linked immunosorbent assay. A definite diagnosis requires the identical clinical context with more complex serologic confirmation provided through one of four potential testing methods. These options include either a four-fold increase in serum antibody concentration (usually over a 4-week interval), isolation of WNV antigen or genomic sequences usually through reverse transcription PCR, detection of virus-specific IgM antibodies in CSF, or serum IgG antibodies in addition to IgM.^24,36,40 These testing paradigms are not mutually exclusive and can be used in a complementary fashion. One unfortunate issue related to WNV serologic testing is the recognition that the latency between infection and seroconversion may be up to 8 days.⁴¹

HISTOPATHOLOGY

The histopathology of WNV meningoencephalitis is characterized by perivascular and leptomeningeal chronic inflammation, the formation of microglial nodules, neuronal necrosis within gray matter, and neuronophagia with a predilection for the temporal lobes, basal ganglia, and brainstem. In individuals with AFP, similar findings are noted in the spinal cord, particularly in the lumbar region. The predominant inflammatory cells are CD3+ T lymphocytes and CD68+ macrophages.^33,36,42