CHAPTER 39: AMYOTROPHIC LATERAL SCLEROSIS AND OTHER MOTOR NEURON DISEASES

Amyotrophic lateral sclerosis (ALS) is the most common form of progressive motor neuron disease. It is a prime example of a neurodegenerative disease and is arguably the most devastating of the neurodegenerative disorders.

PATHOLOGY

The pathologic hallmark of motor neuron degenerative disorders is death of lower motor neurons (consisting of anterior horn cells in the spinal cord and their brainstem homologues innervating bulbar muscles) and upper, or corticospinal, motor neurons (originating in layer five of the motor cortex and descending via the pyramidal tract to synapse with lower motor neurons, either directly or indirectly via interneurons) (Chap. 14). Although at its onset ALS may involve selective loss of function of only upper or lower motor neurons, it ultimately causes progressive loss of both categories of motor neurons. Indeed, in the absence of clear involvement of both motor neuron types, the diagnosis of ALS is questionable. In a subset of cases, ALS arises concurrently with frontotemporal dementia (Chap. 35); in these instances, there is degeneration of frontotemporal cortical neurons and corresponding cortical atrophy.

Other motor neuron diseases involve only particular subsets of motor neurons (Tables 39-1 and 39-2). Thus, in bulbar palsy and spinal muscular atrophy (SMA; also called progressive muscular atrophy), the lower motor neurons of brainstem and spinal cord, respectively, are most severely involved. By contrast, pseudobulbar palsy, primary lateral sclerosis (PLS), and familial spastic paraplegia (FSP) affect only upper motor neurons innervating the brainstem and spinal cord.

In each of these diseases, the affected motor neurons undergo shrinkage, often with accumulation of the pigmented lipid (lipofuscin) that normally develops in these cells with advancing age. In ALS, the motor neuron cytoskeleton is typically affected early in the illness. Focal enlargements are frequent in proximal motor axons; ultrastructurally, these “spheroids” are composed of accumulations of neurofilaments and other proteins. Commonly in both sporadic and familial ALS, the affected neurons demonstrate ubiquitin-positive aggregates, typically associated with the protein TDP43 (see below). Also seen is proliferation of astroglia and microglia, the inevitable accompaniment of all degenerative processes in the central nervous system (CNS).

The death of the peripheral motor neurons in the brainstem and spinal cord leads to denervation and consequent atrophy of the corresponding muscle fibers. Histochemical and electrophysiologic evidence indicates that in the early phases of the illness denervated muscle can be reinnervated by sprouting of nearby distal motor nerve terminals, although reinnervation in this disease is considerably less extensive than in most other disorders affecting motor neurons (e.g., poliomyelitis, peripheral neuropathy). As denervation progresses, muscle atrophy is readily recognized in muscle biopsies and on clinical examination. This is the basis for the term amyotrophy. The loss of cortical motor neurons results in thinning of the corticospinal tracts that travel via the internal capsule (Fig. 39-1) and brainstem to the lateral and anterior white matter columns of the spinal cord. The loss of fibers in the lateral columns and resulting fibrillary gliosis impart a particular firmness (lateral sclerosis). A remarkable feature of the disease is the selectivity of neuronal cell death. By light microscopy, the entire sensory apparatus, the regulatory mechanisms for the control and coordination of movement, remains intact. Except in cases of frontotemporal dementia, the components of the brain required for cognitive processing are also preserved. However, immunostaining indicates that neurons bearing ubiquitin, a marker for degeneration, are also detected in nonmotor systems. Moreover, studies of glucose metabolism in the illness also indicate that there is neuronal dysfunction outside of the motor system. Within the motor system, there is some selectivity of involvement. Thus, motor neurons required for ocular motility remain unaffected, as do the parasympathetic neurons in the sacral spinal cord (the nucleus of Onufrowicz, or Onuf) that innervate the sphincters of the bowel and bladder.

CLINICAL MANIFESTATIONS

The manifestations of ALS are somewhat variable depending on whether corticospinal neurons or lower motor neurons in the brainstem and spinal cord are more prominently involved. With lower motor neuron dysfunction and early denervation, typically the first evidence of the disease is insidiously developing asymmetric weakness, usually first evident distally in one of the limbs. A detailed history often discloses recent development of cramping with volitional movements, typically in the early hours of the morning (e.g., while stretching in bed). Weakness caused by denervation is associated with progressive wasting and atrophy of muscles and, particularly early in the illness, spontaneous twitching of motor units, or fasciculations. In the hands, a preponderance of extensor over flexor weakness is common. When the initial denervation involves bulbar rather than limb muscles, the problem at onset is difficulty with chewing, swallowing, and movements of the face and tongue. Early involvement of the muscles of respiration may lead to death before the disease is far advanced elsewhere. With prominent corticospinal involvement, there is hyperactivity of the muscle-stretch reflexes (tendon jerks) and, often, spastic resistance to passive movements of the affected limbs. Patients with significant reflex hyperactivity complain of muscle stiffness often out of proportion to weakness. Degeneration of the corticobulbar projections innervating the brainstem results in dysarthria and exaggeration of the motor expressions of emotion. The latter leads to involuntary excess in weeping or laughing (pseudobulbar affect).

Virtually any muscle group may be the first to show signs of disease, but, as time passes, more and more muscles become involved until ultimately the disorder takes on a symmetric distribution in all regions. It is characteristic of ALS that, regardless of whether the initial disease involves upper or lower motor neurons, both will eventually be implicated. Even in the late stages of the illness, sensory, bowel and bladder, and cognitive functions are preserved. Even when there is severe brainstem disease, ocular motility is spared until the very late stages of the illness. As noted, in some cases (particularly those that are familial), ALS develops concurrently with frontotemporal dementia, characterized by early behavioral abnormalities with prominent behavioral features indicative of frontal lobe dysfunction.

A committee of the World Federation of Neurology has established diagnostic guidelines for ALS. Essential for the diagnosis is simultaneous upper and lower motor neuron involvement with progressive weakness and the exclusion of all alternative diagnoses. The disorder is ranked as “definite” ALS when three or four of the following are involved: bulbar, cervical, thoracic, and lumbosacral motor neurons. When two sites are involved, the diagnosis is “probable,” and when only one site is implicated, the diagnosis is “possible.” An exception is made for those who have progressive upper and lower motor neuron signs at only one site and a mutation in the gene encoding superoxide dismutase (SOD1; see below).

EPIDEMIOLOGY

The illness is relentlessly progressive, leading to death from respiratory paralysis; the median survival is from 3–5 years. There are very rare reports of stabilization or even regression of ALS. In most societies, there is an incidence of 1–3 per 100,000 and a prevalence of 3–5 per 100,000. It is striking that about 1 in 1000 adult deaths in North America and Western Europe (and probably elsewhere) are due to ALS; this finding predicts that some 300,000 individuals now alive in the United States will die of ALS. Several endemic foci of higher prevalence exist in the western Pacific (e.g., in specific regions of Guam or Papua New Guinea). In the United States and Europe, males are somewhat more frequently affected than females. Epidemiologic studies have incriminated risk factors for this disease including exposure to pesticides and insecticides, smoking, and, in one report, service in the military. Although ALS is overwhelmingly a sporadic disorder, some 5–10% of cases are inherited as an autosomal dominant trait.

FAMILIAL ALS

Several forms of selective motor neuron disease are inheritable (Table 39-3). Familial ALS (FALS) involves both corticospinal and lower motor neurons. Apart from its inheritance as an autosomal dominant trait, it is clinically indistinguishable from sporadic ALS. Genetic studies have identified mutations in multiple genes, including those encoding the protein C9orf 72 (open reading frame 72 on chromosome 9), cytosolic enzyme SOD1 (superoxide dismutase), the RNA binding proteins TDP43 (encoded by the TAR DNA binding protein gene), and FUS/TLS (fused in sarcoma/translocated in liposarcoma), as the most common causes of FALS. Mutations in C9orf72 account for ~45–50% of FALS and perhaps 4–5% of sporadic ALS cases. Mutations in SOD1 explain another 20% of cases of FALS, whereas TDP43 and FUS/TLS each represent about 5% of familial cases. It has recently been reported that ~1–2% of cases are caused by mutations in genes encoding the proteins optineuron and profilin-1 as well.

Rare mutations in other genes are also clearly implicated in ALS-like diseases. Thus, a familial, dominantly inherited motor disorder that in some individuals closely mimics the ALS phenotype arises from mutations in a gene that encodes a vesicle-binding protein. A predominantly lower motor neuron disease with early hoarseness due to laryngeal dysfunction has been ascribed to mutations in the gene encoding the cellular accessory motor protein dynactin. Mutations in senataxin, a helicase, cause an early adult-onset, slowly evolving ALS variant. Kennedy’s syndrome is an X-linked, adult-onset disorder that may mimic ALS, as described below.

Genetic analyses are also beginning to illuminate the pathogenesis of some childhood-onset motor neuron diseases. For example, a slowly disabling degenerative, predominantly upper motor neuron disease that starts in the first decade is caused by mutations in a gene that expresses a novel signaling molecule with properties of a guanine-exchange factor, termed alsin.

DIFFERENTIAL DIAGNOSIS

Because ALS is currently untreatable, it is imperative that potentially remediable causes of motor neuron dysfunction be excluded (Table 39-1). This is particularly true in cases that are atypical by virtue of (1) restriction to either upper or lower motor neurons, (2) involvement of neurons other than motor neurons, and (3) evidence of motor neuronal conduction block on electrophysiologic testing. Compression of the cervical spinal cord or cervicomedullary junction from tumors in the cervical regions or at the foramen magnum or from cervical spondylosis with osteophytes projecting into the vertebral canal can produce weakness, wasting, and fasciculations in the upper limbs and spasticity in the legs, closely resembling ALS. The absence of cranial nerve involvement may be helpful in differentiation, although some foramen magnum lesions may compress the twelfth cranial (hypoglossal) nerve, with resulting paralysis of the tongue. Absence of pain or of sensory changes, normal bowel and bladder function, normal roentgenographic studies of the spine, and normal cerebrospinal fluid (CSF) all favor ALS. Where doubt exists, magnetic resonance imaging (MRI) scans and contrast myelography should be performed to visualize the cervical spinal cord.

Another important entity in the differential diagnosis of ALS is multifocal motor neuropathy with conduction block (MMCB), discussed below. A diffuse, lower motor axonal neuropathy mimicking ALS sometimes evolves in association with hematopoietic disorders such as lymphoma or multiple myeloma. In this clinical setting, the presence of an M-component in serum should prompt consideration of a bone marrow biopsy. Lyme disease may also cause an axonal, lower motor neuropathy, although typically with intense proximal limb pain and a CSF pleocytosis.

Other treatable disorders that occasionally mimic ALS are chronic lead poisoning and thyrotoxicosis. These disorders may be suggested by the patient’s social or occupational history or by unusual clinical features. When the family history is positive, disorders involving the genes encoding C9orf72, cytosolic SOD1, TDP43, FUS/TLS, and adult hexosaminidase A or α-glucosidase deficiency must be excluded. These are readily identified by appropriate laboratory tests. Benign fasciculations are occasionally a source of concern because on inspection they resemble the fascicular twitchings that accompany motor neuron degeneration. The absence of weakness, atrophy, or denervation phenomena on electrophysiologic examination usually excludes ALS or other serious neurologic disease. Patients who have recovered from poliomyelitis may experience a delayed deterioration of motor neurons that presents clinically with progressive weakness, atrophy, and fasciculations. Its cause is unknown, but it is thought to reflect sublethal prior injury to motor neurons by poliovirus.

Rarely, ALS develops concurrently with features indicative of more widespread neurodegeneration. Thus, one infrequently encounters otherwise typical ALS patients with a parkinsonian movement disorder or frontotemporal dementia, particularly in instances of C9orf72 mutations, which strongly suggests that the simultaneous occurrence of two disorders is a direct consequence of the gene mutation. As another example, prominent amyotrophy has been described as a dominantly inherited disorder in individuals with bizarre behavior and a movement disorder suggestive of parkinsonism; many such cases have now been ascribed to mutations that alter the expression of tau protein in brain (Chap. 35). In other cases, ALS develops simultaneously with a striking frontotemporal dementia. An ALS-like disorder has also been described in some individuals with chronic traumatic encephalopathy, associated with deposition of TDP43 and neurofibrillary tangles in motor neurons.

PATHOGENESIS

The cause of sporadic ALS is not well defined. Several mechanisms that impair motor neuron viability have been elucidated in mice and rats induced to develop motor neuron disease by SOD1 transgenes with ALS-associated mutations. One may loosely group the genetic causes of ALS into three categories. In one group, the primarily problem is inherent instability of the mutant proteins, with subsequent perturbations in protein degradation (SOD1, ubiquilin-1 and -2, p62). In the second, most rapidly growing category, the causative mutant genes perturb RNA processing, transport, and metabolism (C9orf73, TDP43, FUS). In the case of C9orf72, the molecular pathology is an expansion of an intronic hexanucleotide repeat (-GGGGCC-) beyond an upper normal of 30 repeats to hundreds or more repeats. As observed in other intronic repeat disorders such as myotonic dystrophy (Chap. 56) and spinocerebellar atrophy type 8 (Chap. 37), data suggest that the expanded intronic repeats generate expanded RNA repeats that form intranuclear foci and confer toxicity by sequestering transcription factors or by undergoing noncanonical protein translation across all possible reading frames of the expanded RNA tracts. TDP43 and FUS are multifunctional proteins that bind RNA and DNA and shuttle between the nucleus and the cytoplasm, playing multiple roles in the control of cell proliferation, DNA repair and transcription, and gene translation, both in the cytoplasm and locally in dendritic spines in response to electrical activity. How mutations in FUS/TLS provoke motor neuron cell death is not clear, although this may represent loss of function of FUS/TLS in the nucleus or an acquired, toxic function of the mutant proteins in the cytosol. In the third group of ALS genes, the primary problem is defective axonal cytoskeleton and transport (dynactin, profilin-1). It is striking that variants in other genes (e.g., EphA4) influence survival in ALS but not ALS susceptibility. Beyond the upstream, primary defects, it is also evident that the ultimate neuronal cell death process is complex involving multiple cellular processes that accelerate cell death. These include but are not limited to excitotoxicity, impairment of axonal transport, oxidative stress, activation of endoplasmic reticulum stress and the unfolded protein response, and mitochondrial dysfunction.

Multiple recent studies have convincingly demonstrated that nonneuronal cells importantly influence the disease course, at least in ALS transgenic mice. A striking additional finding in neurodegenerative disorders is that miscreant proteins arising from gene defects in familial forms of these diseases are often implicated in sporadic forms of the same disorder. For example, germline mutations in the genes encoding β-amyloid and α-synuclein cause familial forms of Alzheimer’s and Parkinson’s diseases, and posttranslational, noninherited abnormalities in these proteins are also central to sporadic Alzheimer’s and Parkinson’s diseases. Analogously, recent reports propose that nonheritable, posttranslational modifications in SOD1 are pathogenic in sporadic ALS.

TREATMENT

SELECTED LOWER MOTOR NEURON DISORDERS

In these motor neuron diseases, the peripheral motor neurons are affected without evidence of involvement of the corticospinal motor system (Tables 39-1, 39-2, and 39-3).

X-linked spinobulbar muscular atrophy (Kennedy’s disease)

This is an X-linked lower motor neuron disorder in which progressive weakness and wasting of limb and bulbar muscles begins in males in mid-adult life and is conjoined with androgen insensitivity manifested by gynecomastia and reduced fertility. In addition to gynecomastia, which may be subtle, two findings distinguishing this disorder from ALS are the absence of signs of pyramidal tract disease (spasticity) and the presence of a subtle sensory neuropathy in some patients. The underlying molecular defect is an expanded trinucleotide repeat (-CAG-) in the first exon of the androgen receptor gene on the X chromosome. DNA testing is available. An inverse correlation appears to exist between the number of -CAG- repeats and the age of onset of the disease.

Adult Tay-Sachs disease

Several reports have described adult-onset, predominantly lower motor neuropathies arising from deficiency of the enzyme β-hexosaminidase (hex A). These tend to be distinguishable from ALS because they are very slowly progressive; dysarthria and radiographically evident cerebellar atrophy may be prominent. In rare cases, spasticity may also be present, although it is generally absent.

Spinal muscular atrophy

The SMAs are a family of selective lower motor neuron diseases of early onset. Despite some phenotypic variability (largely in age of onset), the defect in the majority of families with SMA maps to a locus on chromosome 5 encoding a putative motor neuron survival protein (SMN, for survival motor neuron) that is important in the formation and trafficking of RNA complexes across the nuclear membrane. Neuropathologically these disorders are characterized by extensive loss of large motor neurons; muscle biopsy reveals evidence of denervation atrophy. Several clinical forms exist.

Infantile SMA (SMA I, Werdnig-Hoffmann disease) has the earliest onset and most rapidly fatal course. In some instances it is apparent even before birth, as indicated by decreased fetal movements late in the third trimester. Though alert, afflicted infants are weak and floppy (hypotonic) and lack muscle stretch reflexes. Death generally ensues within the first year of life. Chronic childhood SMA (SMA II) begins later in childhood and evolves with a more slowly progressive course. Juvenile SMA (SMA III, Kugelberg-Welander disease) manifests during late childhood and runs a slow, indolent course. Unlike most denervating diseases, in this chronic disorder, weakness is greatest in the proximal muscles; indeed, the pattern of clinical weakness can suggest a primary myopathy such as limb-girdle dystrophy. Electrophysiologic and muscle biopsy evidence of denervation distinguish SMA III from the myopathic syndromes. There is no primary therapy for SMA, although remarkable recent experimental data indicate that it may be possible to deliver the missing SMN gene to motor neurons using intravenously or intrathecally delivered adeno-associated viruses (e.g., AAV9) immediately after birth.

Multifocal motor neuropathy with conduction block

In this disorder lower motor neuron function is regionally and chronically disrupted by remarkably focal blocks in conduction. Many cases have elevated serum titers of mono- and polyclonal antibodies to ganglioside GM1; it is hypothesized that the antibodies produce selective, focal, paranodal demyelination of motor neurons. MMCB is not typically associated with corticospinal signs. In contrast with ALS, MMCB may respond dramatically to therapy such as IV immunoglobulin or chemotherapy; thus, it is imperative that MMCB be excluded when considering a diagnosis of ALS.

Other forms of lower motor neuron disease

In individual families, other syndromes characterized by selective lower motor neuron dysfunction in an SMA-like pattern have been described. There are rare X-linked and autosomal dominant forms of apparent SMA. There is an ALS variant of juvenile onset, the Fazio-Londe syndrome, that involves mainly the musculature innervated by the brainstem. A component of lower motor neuron dysfunction is also found in degenerative disorders such as Machado-Joseph disease and the related olivopontocerebellar degenerations (Chap. 37).

SELECTED DISORDERS OF THE UPPER MOTOR NEURON

Primary lateral sclerosis

This exceedingly rare disorder arises sporadically in adults in mid to late life. Clinically PLS is characterized by progressive spastic weakness of the limbs, preceded or followed by spastic dysarthria and dysphagia, indicating combined involvement of the corticospinal and corticobulbar tracts. Fasciculations, amyotrophy, and sensory changes are absent; neither electromyography nor muscle biopsy shows denervation. On neuropathologic examination, there is selective loss of the large pyramidal cells in the precentral gyrus and degeneration of the corticospinal and corticobulbar projections. The peripheral motor neurons and other neuronal systems are spared. The course of PLS is variable; although long-term survival is documented, the course may be as aggressive as in ALS, with ~3-year survival from onset to death. Early in its course, PLS raises the question of multiple sclerosis or other demyelinating diseases such as adrenoleukodystrophy as diagnostic considerations (Chap. 45). A myelopathy suggestive of PLS is infrequently seen with infection with the retrovirus human T cell lymphotropic virus 1 (HTLV-1) (Chap. 43). The clinical course and laboratory testing will distinguish these possibilities.

Familial spastic paraplegia

In its pure form, FSP is usually transmitted as an autosomal trait; most adult-onset cases are dominantly inherited. Symptoms usually begin in the third or fourth decade, presenting as progressive spastic weakness beginning in the distal lower extremities; however, there are variants with onset so early that the differential diagnosis includes cerebral palsy. FSP typically has a long survival, presumably because respiratory function is spared. Late in the illness, there may be urinary urgency and incontinence and sometimes fecal incontinence; sexual function tends to be preserved.

In pure forms of FSP, the spastic leg weakness is often accompanied by posterior column (vibration and position) abnormalities and disturbance of bowel and bladder function. Some family members may have spasticity without clinical symptoms.

By contrast, particularly when recessively inherited, FSP may have complex or complicated forms in which altered corticospinal and dorsal column function is accompanied by significant involvement of other regions of the nervous system, including amyotrophy, mental retardation, optic atrophy, and sensory neuropathy.

Neuropathologically, in FSP, there is degeneration of the corticospinal tracts, which appear nearly normal in the brainstem but show increasing atrophy at more caudal levels in the spinal cord; in effect, the pathologic picture is of a dying-back or distal axonopathy of long neuronal fibers within the CNS.

Defects at numerous loci underlie both dominantly and recessively inherited forms of FSP (Table 39-3). More than 30 FSP genes have now been identified. The gene most commonly implicated in dominantly inherited FSP is spastin, which encodes a microtubule interacting protein. The most common childhood-onset dominant form arises from mutations in the atlastin gene. A kinesin heavy-chain protein implicated in microtubule motor function was found to be defective in a family with dominantly inherited FSP of variable-onset age.

An infantile-onset form of X-linked, recessive FSP arises from mutations in the gene for myelin proteolipid protein. This is an example of rather striking allelic variation, as most other mutations in the same gene cause not FSP but Pelizaeus-Merzbacher disease, a widespread disorder of CNS myelin. Another recessive variant is caused by defects in the paraplegin gene. Paraplegin has homology to metalloproteases that are important in mitochondrial function in yeast.

WEBSITES

Several websites provide valuable information on ALS including those offered by the Muscular Dystrophy Association (www.mdausa.org), the Amyotrophic Lateral Sclerosis Association (www.alsa.org), and the World Federation of Neurology and the Neuromuscular Unit at Washington University in St. Louis (www.neuro.wustl.edu).