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ANTERIOR HORN CELL DISORDERS

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Disorders that predominantly affect the anterior horn cells are characterized clinically by wasting and weakness of the affected muscles without accompanying sensory changes. Electromyography shows changes that are characteristic of chronic partial denervation, with abnormal spontaneous activity in resting muscle and a reduction in the number of motor units under voluntary control; signs of reinnervation may also be present. Motor conduction velocity is usually normal but may be slightly reduced, and sensory conduction studies are normal. Muscle biopsy shows the histologic changes of denervation. Serum CK may be mildly elevated, but it never reaches the extremely high values seen in some muscular dystrophies.

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IDIOPATHIC DISORDERS

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The clinical features and outlook depend in part on the patient’s age at onset. The cause of these disorders is unknown, but some have a genetic basis.

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MOTOR NEURON DISEASE IN CHILDREN
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Three forms of spinal muscular atrophy (SMA-I, II, and III) occur in infants and children, and mutations in the survival of motor neuron 1 (SMN1) gene have been identified in 95% of patients. A nearby gene, coding for neuronal apoptosis inhibitory protein (NAIP), is also affected in 45% of patients with SMA-I and 18% of those with SMA-II and SMA-III. NAIP may modify disease severity. The survival of motor neuron 2 (SMN2) gene, a homolog of SMN1 gene, is also is a disease modifier of spinal muscular atrophy, improving survival. Gene therapy trials are underway, replacing the SMN1 gene or regulating SMN2 expression.

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Infantile Spinal Muscular Atrophy (Werdnig-Hoffmann Disease or SMA-I)
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This autosomal recessive disorder usually manifests itself within the first 3 months of life. The infant is floppy and may have difficulty with sucking, swallowing, or ventilation. Examination reveals impaired swallowing or sucking, atrophy and fasciculation of the tongue, and muscle wasting in the limbs that is sometimes obscured by subcutaneous fat. The tendon reflexes are normal or depressed, and the plantar responses may be absent. There is no sensory deficit. The disorder is rapidly progressive, generally leading to death from respiratory complications by approximately 3 years of age.

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Intermediate Spinal Muscular Atrophy (Chronic Werdnig-Hoffmann Disease or SMA-II)
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This autosomal recessive disorder usually begins clinically in the latter half of the first year of life. The extremities become wasted and weak; bulbar weakness is less common. Progression occurs slowly, ultimately leading to severe disability with kyphoscoliosis and contractures, but the course is more benign than in the infantile variety, and many patients survive into adulthood. Treatment is supportive and directed particularly at the prevention of scoliosis and other deformities.

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Juvenile Spinal Muscular Atrophy (Kugelberg-Welander Disease or SMA-III)
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This disorder develops in childhood or early adolescence, on a sporadic or hereditary (usually autosomal recessive) basis. It particularly affects the proximal limb muscles, with generally little involvement of the bulbar musculature. It follows a gradually progressive course, leading to disability in early adult life. The proximal weakness may lead to a mistaken diagnosis of muscular dystrophy, but serum CK determination, electromyography, and muscle biopsy will differentiate the disorders. There is no effective treatment, but noninvasive ventilatory support has extended survival.

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MOTOR NEURON DISEASE IN ADULTS
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These disorders are characterized by degeneration of anterior horn cells in the spinal cord, motor nuclei of the lower cranial nerves in the brainstem, and corticospinal and corticobulbar pathways.

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Epidemiology
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Motor neuron disease in adults generally begins between the ages of 30 and 60 years and has an annual incidence of approximately 2 per 100,000, with a male predominance, except in familial cases. Occasional familial cases have a juvenile onset. The disorder usually occurs sporadically but may be familial in 5% to 10% of cases.

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Pathogenesis
++ Genetics
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Approximately 90% to 95% of cases are sporadic and of unknown cause; no robust environmental risk factors have emerged. Approximately 20% of familial cases show autosomal dominant inheritance of motor neuron disease (with upper and lower motor neuron signs) related to mutations in the copper/zinc superoxide dismutase (SOD1) gene. Other autosomal dominant forms are associated with mutations in senataxin (SETX), fused in sarcoma (FUS), vesicle-associated membrane protein-associated protein B (VAPB), angiogenin (ANG), TAR DNA-binding protein (TARDP), homolog of S. cerevisiae FIG4 (FIG4), ataxin 2 (ATXN2), profilin 1 (PFN1), or valosin-containing protein (VCP). Autosomal recessive motor neuron disease is linked in some cases to alsin (ALSN), and both dominant and recessive inheritance have been seen with mutations in optineurin (OPTN). An X-linked mutation occurs in ubiquilin 2 (UBQLN2).

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Vascular endothelial growth factor (VEGF) gene polymorphisms may increase the risk of motor neuron disease. Other susceptibility genes include heavy neurofilament subunit (NEFH), peripherin (PRPH), and dynactin (DCTN1).

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A GGGGCC hexanucleotide repeat is present within the non-coding region of the C9ORF72 gene on chromosome 9q21, and accounts for many familial and some sporadic cases, discussed later. C9ORF72 is an RNA-binding protein and provides a new target for therapy.

++ Mechanisms
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The pathophysiologic basis of motor neuron disease is uncertain, but several mechanisms have been proposed, based largely on studies in animal models with SOD1 mutations. Because these are gain-of-function mutations, the mechanisms inferred generally involve a toxic effect of the mutated protein.

++ Cellular Mechanisms
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Although motor neurons are the primary cellular target, studies in which mutant SOD1 is expressed selectively in different cell types indicate that non-neuronal cells also contribute to the pathogenesis of motor neuron disease. Involvement of neurons appears to determine the age at onset and early course of disease, whereas microglia and astrocytes influence the subsequent rate of progression.

++ molecular mechanisms
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Several explanations have been offered for the toxicity of mutant SOD1—and, perhaps, of factors involved in sporadic motor neuron disease. These are not mutually exclusive, as multiple mechanisms might operate in concert, or different mechanisms might underlie different forms of the disease. With SOD1 mutations, an early pathogenetic step is abnormal folding and aggregation of the mutant protein, as in other neurodegenerative proteinopathies (see Chapter 5, Dementia & Amnestic Syndromes). How this leads to disease is disputed.

++ Excitotoxicity
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The principal excitatory neurotransmitter, glutamate, is toxic to neurons when present in excessive amounts. In motor neuron disease, spinal cord astrocytes express reduced levels of the EAAT2 excitatory amino acid (glutamate) transporter, which is the major site through which extracellular glutamate is cleared. This could expose motor neurons to toxic concentrations of glutamate.

++ Endoplasmic Reticulum Stress
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Mutant SOD1 accumulates in the endoplasmic reticulum, where it may interfere with the degradation of misfolded proteins or the synthesis of normal proteins.

++ Proteasome Inhibition
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The proteasome is a large protein complex involved in proteolytic degradation and elimination of abnormal cellular proteins. The production of large amounts of mutant SOD1 may overwhelm the ability of the proteasome to perform its normal function.

++ Mitochondrial Damage
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Mutant SOD1 associates with the outer mitochondrial membrane, which might inhibit the production of ATP or the ability of mitochondria to regulate intracellular calcium levels.

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Secretion of Mutant SOD1

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SOD1 released into the extracellular space may activate microglia, resulting in immune-mediated injury of motor neurons.

++ Increased Production of Superoxide
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Mutant SOD1 may stimulate increased production of toxic superoxide radicals by glial cell NADPH oxidase.

++ Impaired Axonal Transport
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Anterograde and retrograde axonal transport may be disrupted by the accumulation of misfolded SOD1 or other proteins.

++ Microvascular Dysfunction
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Loss of tight junctions between capillary endothelial cells could cause microhemorrhages that allow toxins such as iron to escape into the extravascular compartment and damage motor neurons.

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Classification
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Five varieties of adult-onset motor neuron disease can be distinguished clinically by their predominant distribution (limb or bulbar musculature) and whether deficits are from upper or lower motor neuron involvement (Figure 9-8).

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Figure 9-8.

Adult-onset motor neuron disease syndromes. Upper motor neurons are shown with filled circles and lower motor neurons with open circles for cell bodies. Cerebral cortex is indicated with dark, brainstem white, and spinal cord light shading.

Graphic Jump Location
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  1. Progressive bulbar palsy—Predominant bulbar (brainstem) involvement from lesions affecting the motor nuclei of cranial nerves (ie, lower motor neurons) in the brainstem.

  2. Pseudobulbar palsy—Predominant bulbar involvement due primarily to upper motor neuron disease (ie, to bilateral involvement of corticobulbar pathways). A pseudobulbar palsy can occur in any disorder that causes bilateral corticobulbar disease (eg, vascular dementia or progressive supranuclear palsy), however, and not just in motor neuron disease.

  3. Progressive spinal muscular atrophy—There is primarily a lower motor neuron deficit in the limbs, caused by anterior horn cell degeneration in the spinal cord. Familial forms have been recognized.

  4. Primary lateral sclerosis—A purely upper motor neuron (corticospinal) deficit is found in the limbs.

  5. Amyotrophic lateral sclerosis—A mixed upper and lower motor neuron deficit is present in the limbs. Bulbar involvement of the upper or lower motor neuron type may also occur. Both primary lateral sclerosis and progressive spinal muscular atrophy are considered to be variants of amyotrophic lateral sclerosis because, at autopsy, abnormalities of both upper and lower motor neurons are likely. Cognitive and behavioral changes also occur in some patients.

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Clinical Findings
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  1. Bulbar muscles—In approximately 20% of patients with amyotrophic lateral sclerosis, the initial symptoms are related to weakness of bulbar muscles. Bulbar involvement is somewhat more common in familial cases and is generally characterized by difficulty in swallowing, chewing, coughing, breathing, and speaking (dysarthria). In progressive bulbar palsy, examination may reveal drooping of the palate, a depressed gag reflex, a pool of saliva in the pharynx, a weak cough, and a wasted and fasciculating tongue. The tongue is contracted and spastic in pseudobulbar palsy and cannot be moved rapidly from side to side. The extraocular muscles are not involved.

  2. Limb muscles—Patients may first present with weakness of the upper (approximately 40% of patients) or lower extremity (40%) muscles. Limb involvement is characterized by easy fatigability, weakness, stiffness, twitching, wasting, and muscle cramps, and there may be vague sensory complaints and weight loss.

  3. Other systems—Amyotrophic lateral sclerosis and frontotemporal dementia (see Chapter 5, Dementia & Amnestic Syndrome) overlap clinically, pathologically, and genetically. The GGGGCC hexanucleotide repeat in the non-coding region of the C9orf72 gene on chromosome 9q21 occurs in at least 40% of familial cases of amyotrophic lateral sclerosis cases, 25% of familial cases of frontotemporal dementia, and 5% to 10% of apparently sporadic cases of these disorders. Cognitive and behavioral alterations are common in patients with amyotrophic lateral sclerosis, including personality change, irritability, lack of insight, and deficits in executive function. In other instances, parkinsonian or dysautonomic features may be present. Sensory and sphincteric functions are characteristically spared. The CSF is normal.

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Diagnosis
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Diagnostic criteria for amyotrophic lateral sclerosis have been established by the World Federation of Neurology. Criteria vary depending on the level of certainty of the diagnosis, as shown in Table 9-11. Definitive diagnosis requires the presence of upper and lower motor neuron signs in the bulbar region and at least two other spinal regions (cervical, thoracic, or lumbosacral), or in three spinal regions. Alternative causes of signs and symptoms must be excluded.

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Table Graphic Jump Location
Table 9-11.Clinical Diagnosis of Amyotrophic Lateral Sclerosis: El Escorial Criteria of the World Federation of Neurology.
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Differential Diagnosis
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Other noninfective disorders of anterior horn cells (discussed later) must be excluded: They have different prognostic and therapeutic implications. Multifocal motor neuropathy is also an important consideration; its clinical features and treatment are discussed later in this chapter. Cervical spondylosis can mimic amyotrophic lateral sclerosis when it produces lower motor neuron signs in the arms and upper motor neuron signs in the legs, but can be distinguished by the absence of clinical and electromyographic evidence of lower motor neuron involvement in the legs.

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Treatment
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  1. Riluzole (50 mg orally twice daily) may reduce the mortality rate and slow progression of amyotrophic lateral sclerosis, possibly because it blocks NMDA receptor-mediated glutamatergic transmission in the central nervous system. However, it probably prolongs survival by only about 2 or 3 months. Those most likely to benefit are patients with definite or probable amyotrophic lateral sclerosis who have been symptomatic for less than 5 years, have a vital capacity exceeding 60% of the predicted value, and do not require a tracheostomy. Adverse effects of riluzole include fatigue, dizziness, gastrointestinal symptoms, reduced pulmonary function, and an increase in liver enzymes.

  2. Symptomatic measures may include muscarinic anticholinergic drugs (eg, glycopyrrolate, trihexyphenidyl, amitriptyline, transdermal hyoscine, or atropine) if drooling of saliva is troublesome. Refractory drooling may respond to injection of botulinum toxin into the parotid and other salivary glands. Braces or a walker may improve mobility, and physical therapy may prevent contractures.

  3. Diet—A semiliquid diet or feeding via nasogastric tube may be required for severe dysphagia. Percutaneous endoscopic gastrostomy (PEG) is indicated for dysphagia with accelerated weight loss due to insufficient caloric intake, dehydration, or choking on food. For optimal safety, it should be offered when the patient’s vital capacity is more than 50% of predicted.

  4. Ventilation—Noninvasive or invasive ventilation may be necessary as hypoventilation develops. Palliative care to relieve distress without prolonging life then becomes an important consideration and requires detailed discussion with the patient and family. Such discussions are best initiated early in the course of the disease, with continuing discussion as the disease advances.

  5. Other—Treatment with celecoxib, coenzyme Q-10, creatine, gabapentin, insulin growth factor-1, lamotrigine, lithium, minocycline, topiramate, valproic acid, verapamil, and vitamin E has been studied experimentally in the hope of slowing disease progression, but no benefit was found. Stem cell–based treatments are under investigation.

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Prognosis
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Motor neuron disease is progressive and usually has a fatal outcome within 3 to 5 years, most commonly from respiratory failure. Some familial cases progress more slowly. In general, patients with bulbar involvement have a poorer prognosis than those in whom dysfunction is limited to the extremities. Patients with primarily upper motor neuron involvement (primary lateral sclerosis) often survive longer despite severe quadriparesis and spasticity. Survival and quality of life improve when patients are followed in a specialized multidisciplinary clinic.

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Kiernan  MC, Vucic  S, Cheah  BC,  et al.. Amyotrophic lateral sclerosis. Lancet. 2011;377:942–955.
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Miller  RG, England  JD, Forshew  D  et al.. Practice parameter update: the care of the patient with amyotrophic lateral sclerosis. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2009;73:1218–1226 and 1227-1233
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Swinnen  B, Robberecht  W. The phenotypic variability of amyotrophic lateral sclerosis. Nat Rev Neurol. 2014;10, 661–670.

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OTHER NONINFECTIVE ANTERIOR HORN CELL DISORDERS

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Bulbospinal neuronopathy (Kennedy disease) is a sex-linked recessive disorder associated with an expanded CAG trinucleotide repeat sequence in the androgen receptor (AR) gene. It has a more benign prognosis than the other motor neuron diseases. Its clinical characteristics include tremor (resembling essential tremor), cramps, fasciculations, proximal weakness, and twitching movements of the chin that are precipitated by pursing of the lips. Severity of weakness and earlier disease onset correlate with CAG repeat.

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Juvenile spinal muscular atrophy can occur in patients with hexosaminidase deficiency. Rectal biopsy may be abnormal, and reduced hexosaminidase A is found in serum and leukocytes.

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Patients with monoclonal gammopathy may present with pure motor syndromes. Plasmapheresis and immunosuppressive drug treatment (with dexamethasone and cyclophosphamide) may be beneficial in such cases.

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Anterior horn cell disease may occur as a rare paraneoplastic complication of lymphoma. Both men and women are affected, and the symptoms typically have their onset after the diagnosis of lymphoma has been established. The principal manifestation is weakness, which primarily affects the legs, may be patchy in its distribution, and spares bulbar and respiratory muscles. The reflexes are depressed, and sensory abnormalities are minor or absent. Neurologic deficits usually progress over months, followed by spontaneous improvement and, in some cases, resolution.

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INFECTIVE ANTERIOR HORN CELL DISORDERS

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POLIO VIRUS INFECTION
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Poliomyelitis due to infection with polio virus became rare in developed countries with the introduction of immunization programs. The usual route of infection is fecal-oral, and the incubation period varies between 5 and 35 days.

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Neurologic involvement follows a prodromal phase of fever, myalgia, malaise, and upper respiratory or gastrointestinal symptoms in a small number of cases. This involvement may consist merely of aseptic meningitis but in some instances leads to weakness or paralysis due to involvement of lower motor neurons in the spinal cord and brainstem. Weakness develops over the course of one or a few days, sometimes in association with recrudescence of fever, and is accompanied by myalgia and signs of meningeal irritation. The weakness is asymmetric in distribution and can be focal or unilateral; the bulbar and respiratory muscles may be affected either alone or in association with limb muscles. Tone is reduced in the affected muscles, and tendon reflexes may be lost. There is no sensory deficit.

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CSF pressure is often mildly increased, and spinal fluid analysis characteristically shows a polymorphonuclear or lymphocytic pleocytosis, slightly elevated protein concentration, and normal glucose level. Diagnosis may be confirmed by virus isolation from the stool or nasopharyngeal secretions—and less commonly from the CSF. A rise in viral antibody titer in convalescent-phase serum, compared with serum obtained during the acute phase of the illness, is also diagnostically helpful. A clinically similar disorder is produced by coxsackie virus infection.

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There is no specific treatment. Management is purely supportive, with attention directed particularly to respiratory function. With time, there is often useful recovery of strength even in severely weakened muscles.

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POSTPOLIO SYNDROME
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The postpolio syndrome is characterized by the occurrence some years after the original illness of increasing weakness in previously involved or seemingly uninvolved muscles. Muscle pain and ease of fatigue are common. Slow progression occurs and may lead to increasing restriction of daily activities. The postpolio syndrome probably relates to loss of anterior horn cells with aging from a pool that was depleted by the original infection. There is no specific treatment.

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WEST NILE VIRUS INFECTION
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West Nile virus infection is acquired from infected mosquitos. Its most common manifestation is meningoencephalitis. Acute paralytic poliomyelitis is another manifestation and is characterized by acute, focal or generalized, asymmetric weakness or by a rapidly ascending quadriplegia that may be mistaken for the Guillain-Barré syndrome. Electrodiagnostic studies may be helpful in showing the nature and extent of involvement, distinguishing the disorder from a neuropathy, and guiding prognosis. Examination of the CSF is also helpful; there is a pleocytosis, often with a predominance of neutrophils, and viral-specific IgM antibodies are also found. Treatment is supportive, as in paralytic polio virus infection.

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