Amyotrophic Lateral Sclerosis

ALS has an incidence of 1.4/100,000. It typically begins in the sixth to seventh decade of life. Men are affected somewhat more than women, with a ratio of 1.6 : 1. An important and distinctive feature of ALS is the selectivity of degeneration of both the UMNs and LMNs, with relative sparing of other neurons in most cases. Although our understanding of ALS is ever expanding, the pathogenic mechanisms underlying the disease remain surprisingly undefined. The identification of numerous pathogenic gene mutations in association with familial ALS (fALS) has been an important factor contributing to progress within the field. There is remarkable clinical similarity between sporadic ALS and the numerous forms of fALS, suggesting that ALS may be a common disease pathway related to numerous upstream causes. One of the most important recent discoveries was the identification of a hexanucleotide repeat expansion in the chromosome 9 open reading frame 72 ( C9ORF72 ) gene in a large proportion of patients with sporadic and fALS. This finding compels consideration of a pathogenesis related to that of other repeat diseases, such as myotonic dystrophy type 1. In a manner similar to myotonic dystrophy type 1, accumulation of transcribed repeats may bind and sequester RNA-binding proteins and lead to abnormal RNA metabolism and processing. This could be one possible mechanistic explanation for motor neuron loss and a potential target for therapy. Despite the relative selectivity of ALS for degeneration of both UMNs and LMNs, degeneration does occur in other cell types and evidence is mounting that non–cell-autonomous factors, such as astrocyte toxic gain of function, may have a contributory role in the development of motor neuron loss in both sporadic and familial forms.

ALS by definition involves both the upper and lower neurons, but some variants may be restricted to only UMNs or LMNs, or certain body regions. Such variants include primary lateral sclerosis (PLS) and progressive muscular atrophy (PMA) where neuron loss is restricted to the UMNs or LMNs, respectively ( Figure 40-1 ). Similarly, there are regional variants including progressive bulbar palsy affecting the cranial nerve nuclei of the bulbar musculature, brachial amyotrophic diplegia (BAD) affecting the upper limbs in a proximal predominant manner, and leg amyotrophic diplegia (LAD) predominantly affecting the distal lower limbs. Restriction to certain motor neuron pools or regions is often associated with a different prognosis. Importantly, in many, if not most, cases there is subsequent progression to generalized involvement of both UMNs and LMNs typical of classic ALS. The relationship between ALS and other variants is not entirely clear, but there is strong evidence that these disorders are at a minimum tightly related. Phenotypic variability between genetically defined cases of fALS related to single mutations suggests that variants of ALS may be merely different faces of the same underlying pathogenic process.

Spectrum of amyotrophic lateral sclerosis ( ALS ) and ALS variants. Progressive muscular atrophy ( PMA ) is associated with lower motor neuron ( LMN ) features of hypotonic muscle weakness, atrophy, fasciculations, flaccid dysarthria, and absent or reduced reflexes. Primary lateral sclerosis ( PLS ) is associated with weakness with incoordination or slowness of movements, brisk reflexes, spasticity, pathologic reflexes, and spastic dysarthria. ALS has features of both upper motor neuron ( UMN ) and LMN loss. PMA can be further divided into disorders that are restricted to certain regions including progressive bulbar palsy ( PBP ) affecting the bulbar muscles, brachial amyotrophic diplegia ( BAD ) affecting the upper limbs, and leg amyotrophic diplegia ( LAD ) affecting the lower limbs.

(Figure design: courtesy Chad Myers.)

Although the true pathologic relationship between ALS and ALS variants remains debatable, the distinction between these variants is helpful for the clinician. All restricted variants, with the unfortunate exception of progressive bulbar palsy (PBP), have a better prognosis than more typical ALS. Patients with PLS, PMA, and PBP are not usually candidates for clinical trials as a result of lack of ALS diagnostic criteria because of absence of either UMN or LMN involvement. Thus, despite their similarities, it is still helpful to the clinician and the patient to cautiously use one of these labels if appropriate.

Primary Lateral Sclerosis

PLS is a disorder associated with progressive spasticity and weakness of limb and bulbar muscles related to degeneration of UMNs. It is rare and typically seen in the fifth decade. Similar to other sporadic MNDs, the etiology is not known. PLS is defined as having little or no LMN involvement clinically or by electromyography (EMG). In spite of this, most patients with PLS eventually have fasciculations and cramps, some evidence of LMN on examination or EMG, and pathologic evidence of LMN involvement. Although there are clear similarities with ALS, PLS progresses much more slowly than ALS—studies show an average life span of between 8 and 15 years after diagnosis. Thus, although it may not be entirely clear that ALS and PLS are different diseases, because of the different clinical features and prognosis, as Charcot wrote, “the clinical description deserves to exist alone.”

Most patients with PLS have unilateral leg spasticity, later involving the other leg approximately 1 to 2 years after, then progressing to the upper limbs 3 to 4 years later, and eventually showing pseudobulbar involvement 1 to 2 years later. Mills syndrome, a hemiplegic variant of PLS originally described in 1900, is associated with a unilateral presentation of UMN signs in the upper and lower limbs. The primary findings on examination and the cause of disability in PLS are spasticity and clumsiness rather than weakness, consistent with a UMN syndrome. Eventually, bulbar dysfunction is seen in nearly all patients. Unlike ALS, symptoms of bladder dysfunction are common late in the disease.

The diagnosis of PLS is established clinically, but testing can be helpful to exclude other possible diagnoses. Evaluation with magnetic resonance imaging (MRI) should be performed primarily to exclude central nervous system disorders, such as multiple sclerosis; however, cortical atrophy and increased T2 signal intensity of the pyramidal tracts are often seen. Transcranial magnetic stimulation (TMS) may be the confirmatory test, with nearly all patients showing severe abnormalities or absent potentials, but TMS is not widely available. By definition, electrodiagnostic studies should not show significant LMN loss but minor changes can be seen. The differential diagnosis for PLS includes other central nervous system disorders; ALS and hereditary spastic paraparesis are two important conditions. Consideration should be given to genetic analysis for hereditary spastic paraparesis, particularly in patients with relatively symmetrical lower limb involvement. Electrodiagnostic studies should be performed to exclude LMN involvement and should be carried out on all patients. There is no disease-modifying treatment for PLS, and no studies have shown efficacy of riluzole. Symptomatic treatment is similar to that of ALS for spasticity, pseudobulbar affect, and sialorrhea.

Progressive Muscular Atrophy

PMA is an MND causing progressive weakness and muscular atrophy attributable to LMN degeneration. It is thus the LMN analogue of PLS. By definition, patients with PMA have no clinical evidence of UMN dysfunction at onset, but importantly as many as 70% of patients with PMA will eventually demonstrate signs of UMN degeneration. PMA is a rare disease that usually affects older men. Techniques such as TMS and MRI spectroscopy can show subtle corticospinal tract involvement in over 50% of patients with PMA, and in one autopsy series nearly every patient showed ubiquitinated inclusions in LMNs, a pathognomonic sign of ALS. It remains controversial whether PMA represents a disease separate from ALS. Nevertheless, the general approach to PMA is similar to ALS, but because of the different presentation, treatment, and prognosis it should be considered as a related but possibly distinct group of disorders.

Patients show atrophy and weakness, beginning in the hands in nearly 50% of cases, less commonly in the lower limbs, shoulder girdle, and rarely bulbar musculature. Fasciculations are usually evident on examination. Reflexes are reduced or absent, and features of UMN dysfunction are absent. Similar to ALS, EMG abnormalities consist of fibrillation potentials, positive sharp waves, fasciculation potentials, large motor unit action potentials, and normal to decreased motor unit action potential recruitment. The differential diagnosis includes LMN-predominant ALS, other MNDs, and multifocal motor neuropathy (MMN). MMN is particularly important to exclude because this is a relatively treatable disorder with immunomodulatory treatment, such as immunoglobulin therapy.

PMA has not been shown to respond to riluzole. Treatment is supportive and similar to ALS without the complicating issues resulting from UMN involvement, such as spasticity and pseudobulbar affect. Prognosis is better than ALS, with a 5-year survival rate of over 50%, with patients living an average of 1 year longer than with ALS. Older age, lower forced vital capacity (FVC), lower ALS-functional rating scale score, and widespread involvement are poor prognosticators.

Regional Amyotrophic Lateral Sclerosis Variants

The typical onset and progression of ALS is that of focal onset and subsequent regional spread over time. Importantly, it is not uncommon for patients to not recognize mild or even moderate motor deficits, and at presentation disease may be more widespread on examination than acknowledged by the patient. During the natural course of ALS, most patients will develop generalized disease, but certain variants of ALS may remain restricted to certain regions or populations of motor neurons. Some of these variant syndromes include PBP, BAD, and LAD. PBP is an ALS variant with exclusively bulbar symptoms. As mentioned, some patients may develop significant limb involvement and be characterized as bulbar-onset ALS, but this is a less common transition (7.5%) than in PLS or PMA. It comprises almost 10% of all MNDs, primarily affecting women. The age of onset is significantly older than ALS and has a poorer prognosis. BAD is an LMN syndrome closely related to ALS that has been defined differently by various groups. Patients typically have proximal prominent upper limb weakness that starts unilaterally and spreads to the contralateral limb. Distal upper limb muscles are relatively spared and usually finger extensor muscles are more severely affected compared with finger flexors. Muscles of the bulbar, thoracic, and lumbar regions may remain unaffected for a decade or more, although in some cases there is more rapid progression. LAD is a lower limb correlate of BAD, but weakness tends to start in an asymmetrical, distal-predominant manner with subsequent spread to the contralateral lower limb. Similar to BAD, LAD may have delayed progression to other spinal regions and therefore improved prognosis. Interestingly, patients with genetically defined ALS may have clinical features of these variant syndromes, further supporting a close relationship between ALS and ALS variants.

Familial Amyotrophic Lateral Sclerosis

There has been dramatic progress in the ALS field with regard to genetic understanding of the disease. There are a rapidly increasing number of causative genes identified that are related to a phenotype of ALS. Superoxide dismutase 1 ( SOD1 ) mutations were the first to be identified as a causative etiology of fALS. Mutations in SOD1 represent approximately 10% of fALS and are seen in approximately 1% of sporadic ALS. Even within the spectrum of SOD1 -related ALS there is considerable phenotypic variability. For instance, the D90A mutation of SOD1 portends an indolent course with ventilatory failure often occurring 10 years after onset, whereas A4V mutation is typically associated with rapid decline and death within a year of onset. Since the identification of SOD1 mutations over 20 years ago, there have been numerous other ALS-related genes identified. More recently, a genome-wide association study in Finland demonstrated a peak on the short arm of chromosome 9. This finding was vital for subsequent identification of a hexanucleotide repeat expansion in the C9ORF72 gene, which are now known to be responsible for approximately 40% of fALS and approximately 5% of sporadic ALS. There are currently over 20 gene mutations associated with the clinical syndrome of fALS, and because of rapid advances in genetic technology, the molecular understanding of sporadic ALS and fALS is constantly expanding. Continued identification of causative genes will help further the understanding of pathogenesis, guide determination of prognosis, and help design future therapeutic strategies. Currently, studies are under way that are targeting genetic mutations in patients with fALS related to SOD1 mutations using antisense oligonucleotide therapy to knock-down expression of the SOD1 gene.

Amyotrophic Lateral Sclerosis-Plus Syndromes

Although ALS is usually associated with isolated motor deficits, involvement outside of the motor system can occur. By definition, ALS-Plus syndromes meet clinical and electrodiagnostic criteria for ALS, but also have associated nonmotor neuron features that may include parkinsonism, frontotemporal dementia, ocular motility abnormalities, extrapyramidal signs, autonomic dysfunction, or sensory loss. Certain forms of fALS have been associated with development of nonmotor features. For instance, patients with TAR DNA-binding protein ( TARDBP ) gene mutations, known to cause fALS, have been reported with clinical features of parkinsonism. Both frontotemporal dementia and fALS are seen in isolation and combination in patients and families with C9ORF72 gene mutations. The association of nonmotor features in some patients with sporadic and fALS strongly suggests that ALS is a multi­system disease with predilection for UMN and LMN involvement.

Spinal Muscular Atrophy

Spinal muscular atrophy includes a group of genotypically and phenotypically diverse disorders associated with features of LMN loss. The most common form, proximal SMA (also called SMN-related SMA, 5q-SMA, or simply SMA) is an autosomal recessive LMN disorder with a frequency of 1/11,000 births. Carrier frequency is approximately 1/50. Importantly, proximal SMA is the most common genetic cause of death in infants. There is a spectrum of disease associated with SMA with regard to onset of disease and severity. Proximal SMA can be classified into five subtypes of disease ( Figure 40-2 ). The most severe form, type 0, has onset of very severe weakness before birth often with joint contractures resulting from diminished intrauterine movement (not shown in Figure 40-2 ). Type 1 is the most common form of the disease representing 60% to 70% of patients with SMA and is associated with onset before 6 months of age and inability to sit independently. Approximately 95% of patients with type 1 die by the age of 2 years without ventilatory and nutrition support. Onset in patients with type 2 is between 6 and 18 months, and the ability to sit upright independently is achieved but ambulation is not. Patients with type 3 have an onset after 18 months of age and are able to walk independently. Type 4 is the mildest form, with onset in adulthood and relatively mild proximal limb weakness.

Subtypes of proximal spinal muscular atrophy (SMA) related to SMN1 deletion. A, SMA type 1, the most common form, has onset before 6 months of age and the ability to sit upright is never achieved. B, SMA type 2 has onset between 6 and 18 months and the ability to sit independently, but not stand, is achieved. SMA type 3 is associated with onset after 18 months and patients are able to stand or walk at least temporarily. C, SMA type 4 is the mildest subtype with onset after 30 years of age. Type 0 with onset before birth is not shown.

SMA is related to homozygous deletion or mutation of the survival motor neuron 1 ( SMN1 ) gene. In approximately 95% of cases, patients have a homozygous deletion of the SMN1 gene, but the remaining 5% of patients will be compound heterozygotes with deletion of one SMN1 allele and a missense mutation of the other SMN1 allele. Importantly, a second closely related gene, SMN2 , is retained in varying copy numbers within the population. Both the SMN1 and SMN2 genes make SMN protein, but because of the effects of a single nucleotide C-T transition in exon 7, the SMN2 gene predominantly produces a shortened, unstable isoform of SMN that does not function normally and is rapidly degraded. Therefore, when there is loss of both alleles of the SMN1 gene by deletion or mutation, there remains some reduced amounts of SMN protein from the SMN2 gene. Consequently, SMA is not related to absent SMN protein, but rather reduced levels. The mechanism of how motor neuron dysfunction is related to reduced SMN levels remains unknown. The most likely cause is related to the loss of the action of SMN protein to assemble of Sm proteins onto small nuclear ribonucleic acids (snRNAs) and therefore disruption of normal RNA splicing. Because there are varying copy numbers of the SMN2 gene in the general population, this leads to variable levels of full-length SMN protein production. In cross-sectional studies, the copy number correlates inversely with severity of SMA. In general, SMA type 1 is associated with two copies of SMN2. It is important to note that SMN2 copy number cannot precisely predict severity in an individual patient.

The clinical presentation of SMA is that of proximal predominant weakness and hypotonia. Reflexes may be absent or reduced in the setting of milder weakness, therefore mimicking a muscle disease. Sensory examination is typically normal. Most cases of SMA, approximately 60% to 70%, will have onset of weakness and hypotonia after birth but before 6 months of age and will not gain the ability to sit independently, therefore falling within the classification of type 1 disease. Other characteristic clinical features may include a fine tremor, often called polyminimyoclonus, and tongue fasciculations. The diagnosis of proximal SMA should be suspected in any infant developing hypotonia and weakness. The most efficient strategy for diagnosis is gene testing for homozygous deletion of the SMN1 gene, which is seen in 95% of patients. In the other 5%, patients may be compound heterozygotes with a single deletion and a missense mutation. In such cases, dosage testing for a single SMN1 deletion and sequencing of the remaining SMN1 gene is required to confirm the diagnosis of SMA. Other testing strategies include electrodiagnosis and muscle biopsy, but following availability of molecular diagnosis such strategies are reserved for atypical cases or SMN not related to SMN1 gene loss.

Electrodiagnostic testing, at one time a critical tool in the evaluation of suspected 5q-SMA, is less commonly necessary during the workup since the availability of genetic testing. Electrodiagnosis shows variable features of motor loss consistent with loss of motor neuron function in correlation with clinical severity and age. Sensory involvement is usually lacking, but exceptional cases have been reported with an association sensory neuropathy or sensory ganglionopathy. Although electrodiagnosis is not usually a necessary part of the evaluation for most cases of SMA, it is still important in atypical cases and non–5q-related SMA.

Other gene mutations have been associated with a clinical pattern of proximal SMA. Autosomal recessive disorders include IGHMP2 , causing SMA with respiratory distress (SMARD), and Gle1 , causing severe lethal congenital contracture syndrome 1 resulting from fetal loss of motor neurons. Autosomal-dominant proximal SMA has been associated with mutations in VAPB, TRPV4, LMNA , and recently BICD2 . X-linked recessive SMA is associated with Ube1 mutations causing X-linked SMA. Some forms of SMA are associated with a distal predominant patter of weakness, and therefore have been described with the term distal SMA ( Figure 40-3 ). Importantly, there is significant phenotypic and genotypic overlap between distal SMA and other hereditary neuropathies (i.e., Charcot-Marie-Tooth disease); therefore, distal hereditary motor neuropathy (dHMN) is more frequently used. An ever-expanding number of genes have been found to be mutated in association with dHMN, including GARS, DCTN1, HSPB8, HSPB1, BSCL2, SETX, HSPB3, DYNC1H1, REEP1 , and SLC5A7. Distal SMA or dHMN have clinical features of distal weakness and atrophy with reduced to absent reflexes. Sensory function, by definition is preserved, but some patients will have features of sensory loss closely mimicking axonal forms of Charcot-Marie-Tooth disease. A more rare form of SMA called scapuloperoneal SMA or Davidenkow syndrome is associated with features of motor neuron and axonal loss in a periscapular and distal leg distribution, mimicking the pattern of facioscapulohumeral muscular dystrophy ( Figure 40-4 ). This syndrome has been linked to chromosome 12q24.1-q24.31. Chronic or adult-onset hexosaminidase deficiency, sometimes called late-onset Tay-Sachs disease, can cause a clinical syndrome of motor neuron loss similar to that of proximal SMA, sometimes associated with atypical features of cerebellar degeneration, dystonia, and psychosis.

Distal predominant limb muscle atrophy in a patient with distal hereditary motor neuropathy mimicking that of Charcot-Marie-Tooth disease.

A patient with the unusual pattern of periscapular and distal leg muscle atrophy associated with the scapuloperoneal form of spinal muscular atrophy (Davidenkow syndrome) with striking similarity to that seen in facioscapulohumeral muscular dystrophy.

There are no effective therapies for any form of SMA, but supportive care can effectively reduce disease impact and burden. Type 0 is associated with disease onset before birth. The natural history of the remaining subtypes of 5q-SMA, although not fully defined, typically follows three main clinical phases. During the presymptomatic phase, before onset of motor neuron loss, function is relatively preserved even in infants with severe or type 1 SMA. There is rapid onset of weakness at disease onset, which progresses for a period of time, and thereafter patients often have a plateau in the rate of strength loss. Standards of care are established and can alter the natural history in patients with 5q-SMA. Such treatments are designed to address the primary and secondary effects of muscle weakness and include management of pulmonary complications, nutritional and gastrointestinal support, rehabilitative interventions, and end-of-life care. Restrictive lung disease is a major issue that should be aggressively managed similar to other MNDs. During the progressive phase of the disease ventilatory muscle strength may fall rapidly, whereas there is stability thereafter. Importantly, although motor neuron loss does stabilize, strength and vital capacity can often decrease during periods of growth. Pulmonary disease is the main source of mortality and includes complications of muscle weakness leading to impaired ventilation and secretion management or secondary complications, such as pneumonia related to aspiration. Establishing a therapeutic relationship with an experienced pulmonary specialist familiar with the management of SMA is critical and should occur at the time of initial diagnosis to anticipate future needs and prevent complications. Pulmonary complications are related to severity of disease, and thus more severe disease burden requires closer monitoring and more frequent intervention. Determining the appropriate mechanism of ventilator support should be a combination of what is best for the patient and the wishes of the patient and family.

Scoliosis is common in SMA, and progression of scoliosis and the associated impact on pulmonary function is less severe in patients with SMA type 3 compared with type 2. A corset brace has been shown to be unable to halt scoliosis progression but may help provide seating stability and delay surgical need. Surgical treatment is well established in nonambulatory patients with progressive scoliosis at age 10 to 12 years. Bulbar weakness is common in severe forms of SMA predisposing to inadequate nutritional intake. Therefore, nutritional support is an important aspect of supportive care. The goals of nutritional support include adequate nutritional intake, avoiding undernutritional or overnutritional supplementation, and the reduction of the risk of aspiration pneumonia.

X-Linked Spinobulbar Muscular Atrophy (Kennedy Disease)

KD (or X-linked spinobulbar muscular atrophy) is an X-linked recessive disorder that leads to progressive limb and bulbar weakness, testicular atrophy, gynecomastia, muscle cramps, and fasciculations. KD is related to an expanded cytosine-adenine-guanine (CAG) trinucleotide repeat in the q arm of the X chromosome within the first exon of the androgen receptor gene. Healthy individuals have 10 to 36 repeats in this region, whereas patients with KD have 40 to 62 repeats. Usually female carriers are unaffected, but some investigations have suggested subclinical features in manifesting female carriers, including mainly muscle cramps and tremor, and electrodiagnostic or muscle biopsy evaluation may show features of denervation. Early stages of the disease are associated with symptoms of muscle cramps, fasciculations, and tremor as the only manifestation, whereas progressive muscle loss and weakness are evident later. KD typically has an onset of more overt symptoms by the fourth or fifth decade. KD is a slowly progressive disorder, and therefore life span is not usually dramatically reduced. As a result of bulbar involvement, aspiration pneumonia can be a concern later in the disease course.

Clinical examination demonstrates proximal predominant and bulbar muscular weakness and atrophy, but distal involvement and asymmetry can occur. This variability can sometimes complicate the clinical evaluation and more closely mimic the presentation of ALS. Reflexes are absent or reduced. Features of mild asymptomatic sensory loss are usually present. There may be features of androgen insensitivity such as gynecomastia and reduced fertility. Patients with KD often have prominent bulbar involvement with profound atrophy and perioral fasciculations ( Figure 40-5 ).

Typical features of atrophy seen in bulbar and tongue muscles in a patient with Kennedy disease.

Genetic testing for CAG repeats in the androgen receptor gene is diagnostic of KD, but because of a significant overlap with other MNDs, electrodiagnostic testing is often obtained. EMG shows features of active and chronic denervation with fibrillation potentials, fasciculations, and enlarged motor unit action potentials with decreased recruitment in a generalized distribution. Facial muscle investigation usually shows features of fasciculations and myokymia, as well as fibrillations and neurogenic motor unit action potential changes. The nerve conduction studies may show reduced compound muscle action potential amplitudes and relatively preserved conduction velocities. A distinctive feature of KD is a superimposed sensory neuronopathy. Importantly, this neuropathy is non–length-dependent in distribution, which is in contrast to typical neuropathy that may be occasionally seen incidentally in patients with ALS. The electrodiagnostic findings of non–length-dependent sensory neuropathy is consistent with the fact that KD is associated with both sensory and motor neuronopathy, but the features of LMN involvement in KD are more clinically evident and relevant. Creatine kinase (CK) is moderately elevated in the majority of patients with KD, and on average is approximately 5 times normal but can range up to 15 times normal.

There is no curative treatment for KD. Mouse models of KD have shown improvement with treatment with androgen receptor antagonists. Supportive treatment is similar to ALS without the need to treat complications of UMN dysfunction, such as spasticity and pseudobulbar affect. Respiratory and secretion management is particularly important given the high incidence of bulbar dysfunction.

Poliomyelitis and Postpolio Syndrome

Poliomyelitis is an MND caused by viral infection of the central nervous system resulting in loss of anterior horn cells and cranial nerve nuclei. Poliomyelitis results from infections with the poliovirus, a human enterovirus of the Picornaviridae family. Other enteroviruses and flaviviruses such as West Nile virus are also associated with poliomyelitis, but the poliovirus is the most widespread and well-known cause. There are three serotypes of the poliovirus, and immunity is not conferred between serotypes as a result of differing capsid proteins and antigenicity. There has been a dramatic reduction in the annual number of cases of polio as a result of the development of vaccination strategies in the 1950s, and in 1988 the World Health Assembly formulated plans for worldwide efforts to eradicate polio. These efforts have led to a dramatic reduction from over 300,000 cases worldwide to only 223 cases being reported in 2012, culminating in India and 10 other Asian countries declared polio-free in 2014. A continued possibility of resurgent disease remains as a result of persistent cases.

Following exposure via the fecal-oral route, the poliovirus has a variable incubation period of a few days to over a month. During this period the virus replicates in the gastrointestinal tract. Infection can subsequently lead to a continuum of severity from asymptomatic infection to severe paralysis and death. Before the availability of vaccination, polio represented the most common cause of acute flaccid paralysis. In addition to wild-type poliovirus infection, vaccine-derived poliovirus can very rarely cause paralytic disease and spread to nonimmunized individuals. Poliovirus infection may be associated with headache, fever, stiffness, and pain but is often asymptomatic. Less than 5% of infections result in irreversible paralysis, and in these affected individuals mortality can be as high as 10% related to features of autonomic dysfunction, circulatory collapse, and ventilatory muscle failure.

Symptoms of asymmetrical flaccid paralysis and subsequent atrophy are typically more common in limb muscles but may also affect bulbar muscles. It is rare that transverse myelitis associated with features of autonomic, sensory, and sphincter dysfunction can occur. The clinical presentation of poliomyelitis can be closely mirrored by other disorders of the spinal cord, muscle, and nerve. Therefore, the approach to diagnosis should be directed toward the differential associated with acute flaccid paralysis. Electrodiagnostic testing shows features of asymmetrical or multifocal denervation. Cerebrospinal fluid analysis demonstrates elevated protein levels but in contrast to acute immune-mediated, such as Guillain-Barré syndrome, there is evidence of pleocytosis. MRI can show features of increased T2 signal intensity in the region of the ventral horn of the spinal cord. Molecular testing with polymerase chain reaction can confirm viral serotype and can determine whether the infection is vaccine-derived or is a wild-type strain. Management of acute poliomyelitis is supportive and is similar to other disorders of flaccid paralysis.

Following paralytic poliomyelitis, the surviving motor neurons can compensate and through collateral reinnervation expand their territories to provide some functional recovery. This phase usually maximizes within 2 years of disease, and thereafter motor system function stabilizes. For yet-to-be determined reasons, approximately 50% of patients with poliomyelitis develop late features of declining motor function, usually 30 or more years after onset. Onset may be gradual or abrupt. Thorough evaluation is critical to exclude other disorders that may contribute to decline in function, and treatment is designed to maximize and maintain function. Therapeutic rehabilitation typically includes strategies to allow for energy conservation with both modification of the environment and the delivery of appropriate equipment needs similar to other disorders of the motor neuron.

Hirayama Disease

Hirayama disease (HD) is a relatively benign disorder associated with muscle weakness and atrophy of the distal upper limb muscles. Several names have been used to describe HD including monomelic amyotrophy, distal muscular atrophy of the distal upper extremity, and oblique amyotrophy. HD was first described in 1959 by Hirayama. The pathogenesis of HD has been attributed to this anterior displacement of the dural wall causing impaired microcirculation of the lower cervical spinal cord and loss of motor neurons. The disorder primarily affects males during the teenage years or early twenties, and the onset of weakness is insidious and slowly progressive. The natural history of the disease is associated with progression for 5 years or less. Involvement may be unilateral or bilateral, but is usually more prominent in one limb ( Figure 40-6 ). Interestingly, preponderance for right side involvement has been noted. The phenomenon of worsening weakness with exposure to cold, termed cold paresis, has been frequently described in patients with HD. Features including upper motor neuron signs, cranial nerve abnormalities, or incontinence of bowel or bladder are not seen, and sensory disturbance is usually absent or minimal.

Asymmetrical left hand and forearm muscle atrophy in a patient with Hirayama disease.

Electrodiagnostic assessment demonstrates active and chronic denervation in muscles innervated by the C7-T1 myotomes with features of fibrillation potentials and enlarged motor unit action potentials with decreased recruitment. Fasciculations are not apparent on clinical or electrodiagnostic examination. MRI with neck flexion is used to assess for forward displacement of the posterior dural sac.

As a result of insidious onset and slow progression and the overall uncommon nature of the disorder, there is typically a significant delay in recognition of HD. Although HD is an overall benign and self-limited disorder, early diagnosis is critical to avoid delay in treatment and avoid unnecessary loss of upper limb function. Treatment may include using a cervical collar to limit neck flexion, and in patients with continued progression despite conservative management cervical spine surgery for decompression and stabilization may be indicated. Early treatment can demonstrate significant efficacy, supportive of a structural origin rather than a true degenerative process.

Paraneoplastic

Paraneoplastic degeneration of the UMNs and LMNs has been uncommonly reported as a cause of MNDs. In most cases reported, the link between MNDs and paraneoplastic degeneration is purely that of coincidental association. In some cases, an etiologic link has been suspected based on a temporal relationship between the onset of MNDs and cancer, the presence of autoantibodies, and response to immunomodulation with treatments such as intravenous immunoglobulin or corticosteroids. The causative relationship between cancer and the development of motor neuron degeneration is thought to be unlikely in most cases of cancer and MNDs. Some authors have even suggested that paraneoplastic processes could unmask fALS or increase penetrance underlying fALS-related gene mutations. One of the best-defined paraneoplastic syndromes associated with MNDs is an anti-Hu syndrome. The spectrum of anti-Hu–related paraneoplastic disorders include sensory neuronopathy, cerebellar ataxia, limbic encephalitis, overlapping syndromes of multifocal involvement, and a syndrome of motor neuron or motor axonal loss often with sensory involvement. The presence of an anti-Hu MND-like phenotype is infrequent at less than 5%. Anti-Hu antibodies are not thought to be pathogenic but appear to be a marker of autoimmunity against Hu antigens. Treatment includes management of the underlying neoplasm and in some cases immunomodulation.

Nonpoliomyelitis Infections

Infections, other than poliomyelitis, have been more rarely implicated in the pathogenesis of MNDs. Of these infections, the rare association of human immunodeficiency virus (HIV) infection with MNDs is well established. Isolated UMN or LMN involvement may be seen with HIV infection, but patients predominantly have mixed UMN and LMN features. The disease may present at varying stages of HIV infection. A clinical pattern of progressive motor neuron degeneration over weeks rather than months and pathologic features of vacuolar myelopathy and inflammation suggest an immune pathogenesis distinct from ALS. Recognition of this syndrome is important because at least 50% of cases will respond with adequate antiretroviral therapy, further supporting a link to HIV infection and pathogenesis. Other infectious agents that have been suggested as possible etiologies of MNDs including Lyme disease ( Borrelia burgdorferi ), Herpes zoster, Creutzfeldt-Jakob disease, and human T-lymphotropic virus type 1 (HTLV-1) are more controversial. HTLV-1 infections are typically associated with a UMN-predominant syndrome of myelopathy called tropical spastic paraparesis or HTLV-1 association myelopathy (HAM). This disorder is distinct from MNDs as a result of the presence of symmetrical lower limb involvement, sensory loss, and bowel and bladder changes. HAM occurs in approximately 1% to 3% of individuals infected with HTLV-1. HTLV-1 infection is endemic in certain areas and therefore serologic evidence of previous infection should not be used to prove a causative relationship. Herpes zoster can result in segmental weakness and atrophy, with features that overlap with MNDs. It is not usually considered an isolated disorder of the motor neuron but affects the root, plexus, nerve, brain, and rarely the spinal cord.

Electrical Injury

There are sparse reports of electrical injury preceding syndromes of motor neuron loss. The clinical features of such disorders are associated with variable delay of days to years following electrical injury and the epicenter of motor neuron degeneration loss occurs at the site of the electrical entry or exit in 90% of cases. Myelopathic features can also be present in some cases including sensory symptoms, pain, and bowel and bladder dysfunction.

Hereditary Bulbar Syndromes

Brown–Vialetto–Van Laere syndrome 1 (BVLS1) and Fazio-Londe syndrome are two closely related and extremely rare childhood syndromes caused by autosomal recessive mutations in the solute carrier family 52 (riboflavin transporter), member 1, 2, and 3 ( SLC52A1 , SLC52A2 , and SLC52A3 ) genes, which encode riboflavin transport proteins. BVLS1 and Fazio-Londe syndrome both cause progressive motor neuron loss with prominent bulbar and respiratory involvement. Usually, BVLS1 is distinguished from Fazio-Londe syndrome as a result of the universal presence of hearing loss, but the two syndromes are now usually considered synonymous. Onset of both syndromes typically occurs in the first 2 decades of life. The pathogenesis of both syndromes is related to riboflavin deficiency; treatment therefore includes high-dose riboflavin supplementation.