Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases

Epidemiology

ALS is a neurodegenerative disorder that causes progressive injury and cell death of lower motor neurons in the brain stem and spinal cord, as well as upper motor neurons in the motor cortex. ALS has an incidence of about 2 per 100,000 and a prevalence of 6 to 8 per 100,000. The global incidence is fairly uniform, with the exception of a few high-incidence foci such as the Western Pacific island of Guam. The disease affects predominantly middle-aged and elderly individuals, with a mean age at onset of 55 to 60 years, although younger individuals can also be affected. Increasing age, male sex (male/female ratio ≈ 1.6 : 1), and genetic susceptibility are the only proven risk factors, although strenuous physical exercise, head trauma, and lead exposure may also be potential environmental risk factors ^, Approximately 90% of cases of ALS occur sporadically, but 5 to 10% are familial, usually with an autosomal dominant mode of inheritance.

Pathobiology

The process of neuronal degeneration in ALS is complex, and more than 40 ALS susceptibility genes have been identified. GGGGCC hexanucleotide intronic expansions in the chromosome 9 C9ORF72 gene are the most common genetic cause of ALS identified to date, accounting for up to 40 to 50% of familial ALS cases and 7 to 10% of sporadic ALS. Accumulating evidence suggests that defective RNA processing likely plays a key role in the pathogenesis of C9ORF72 ALS as well as other genetic subtypes. The pathobiology of C9-ALS is not yet completely understood, but the sequestration of RNA binding proteins by RNA foci and altered nucleocytoplasmic transport that allows the expansion RNA to translate into dipeptide repeat proteins in the cytoplasm are clearly of key importance.

The subtype of disease caused by SOD1 mutations accounts for 20% of familial ALS cases and 2% of ALS cases overall. Mutant SOD1 appears to transmit templated propagation in a prion-like ( Chapter 378 ) fashion, with these aggregates then triggering a complex interplay of multiple pathogenic processes, including oxidative stress, protein aggregation, mitochondrial dysfunction, excitotoxicity, and impaired axonal transport. Non-neuronal cells in the vicinity of motor neurons may contribute importantly to neuronal injury. Genetically engineered mouse models of SOD1 -related ALS have shown that normal astrocytes can protect motor neurons expressing mutant SOD1 and that removing the expression of mutant SOD1 from microglia or astrocytes slows the progression of disease in these murine models. Astrocytes expressing mutant SOD1 exert toxic effects on neighboring motor neurons through as yet undefined mechanisms.

Familial motor neuron disease has been linked to mutations involving alsin, senataxin, angiogenin, VAPB , dynactin, TARDBP, TBK1, FUS/TLS , and multiple other genes. Intermediate-length polyQ expansions (27-33Q) in ataxin 2 are found as a risk factor for ALS in approximately 5% of patients. Associations have been reported with alterations in at least eight other genes in cases that appear sporadic. Large combined genome-wide association studies suggest that rare genetic variants underpin 15 to 20% of cases of sporadic ALS.

Clinical Manifestations

ALS is characterized by a combination of upper and lower motor neuron degeneration. Lower motor neuron degeneration causes weakness, atrophy, and fasciculation of the limb and bulbar musculature. Features of upper motor neuron dysfunction include the incongruous presence of active or brisk tendon reflexes in a wasted limb, increased muscle tone, and sometimes the presence of the Babinski sign. Upper motor neuron bulbar disease causes pseudobulbar palsy, with emotional lability, a brisk jaw jerk, slowing of repetitive tongue movements, and strained effortful speech. Fatigue and weight loss are also common symptoms. At end-stage disease, most patients will have features of upper and lower motor neuron dysfunction affecting all four limbs and the bulbar musculature.

In approximately 75% of patients, the disease starts distally, focally, and asymmetrically in an upper or lower limb ( Video 387-1 ), followed by progressive spread of pathology in an anatomically logical progression to contiguous groups of motor neurons. Affected individuals may notice weakness, wasting or clumsiness of one hand, or unilateral footdrop. Muscle cramps may precede other clinical features, and fasciculations are most noticeable in the large proximal limb muscles. In the upper limbs, the thenar and intrinsic hand muscles tend to be severely affected, whereas the triceps and finger flexors are relatively spared until late in the disease. In the lower limbs, the pattern of weakness is often in a pyramidal distribution (flexors weaker than extensors), with early weakness of hip flexion and ankle dorsiflexion and severe involvement of the distal muscles.

Bulbar symptoms, which are the initial feature in approximately 25% of patients, are especially common in elderly women with ALS ( Video 387-2 ). The first problem is usually slurring of speech, initially apparent only when the individual is tired. Patients often have a mixed spastic/flaccid dysarthria in which speech develops a tight strangled quality because of the upper motor neuron component, with a superimposed nasal quality as a result of the flaccid lower motor neuron weakness of the palate and nasopharynx. In patients with bulbar disease, examination often reveals weakness of the facial muscles; a spastic, weak, wasted, and fasciculating tongue; and a brisk jaw jerk. Dysphagia, initially more pronounced for liquids than for solids, usually follows the dysarthria within a few weeks or months ( Video 387-3 ). Complications include weight loss and prolonged and arduous meal times with frequent episodes of coughing, drooling of saliva, and aspiration pneumonia.

Respiratory muscle weakness is rarely the initial feature of ALS. More commonly, respiratory muscle weakness develops insidiously and causes dyspnea and orthopnea. Diaphragmatic weakness may be apparent from the paradoxical movement of the abdominal wall during inspiration and a marked decline in forced vital capacity in the supine position. Symptoms of nocturnal carbon dioxide retention may develop, including interrupted sleep, morning headaches, anorexia, and daytime somnolence.

Neck muscle weakness, which is common later in the course of the disease, causes difficulty holding the head upright (dropped head syndrome). Eye movements tend to be spared even in advanced disease, thereby permitting limited communication by movements of the eyes. Similarly, the strength of the pelvic floor muscles is relatively preserved, so patients with ALS usually remain continent throughout the course of the disease.

Overt features of frontotemporal dementia ( Chapter 371 ), with progressive deterioration in personality and behavior, will develop in approximately 5% of patients with ALS. Cognitive dysfunction may precede, follow, or coincide with the features of motor dysfunction. Up to 50% of ALS patients without overt dementia may show more subtle features of frontal lobe dysfunction. The C9ORF72-ALS variant causes both ALS and/or frontotemporal dementia ( Chapter 371 ), and patients with this subtype of ALS are more likely to have cognitive disturbances as well as a family history of dementia or psychosis.

About 5 to 10% of ALS patients have the progressive muscular atrophy variant, with clinical features reflecting only degeneration of lower motor neuron groups in the spinal cord. In primary lateral sclerosis, patients have pure upper motor neuron degeneration. Although severe spastic spinobulbar paresis ultimately develops in these patients, the duration of survival is commonly 10 to 15 years after the onset of symptoms. The progressive bulbar palsy variant usually progresses to involve the limbs, although limb signs may not be present initially.

Several ALS variants follow a more segmental pattern than is typical in ALS. Up to 10% of patients with ALS have flail arm syndrome, which is more common in men and is associated with a longer median survival than seen in those with typical ALS. A similar focal manifestation in the lower limbs, flail leg syndrome, is another recognized segmental variant.

Diagnosis

The diagnosis of ALS is essentially clinical, and there currently is no specific diagnostic test. Nevertheless, biomarkers of motor neuron injury, including elevated levels of neurofilament light and phosphorylated neurofilament heavy in cerebrospinal fluid (CSF), and plasma have promise for the future.

Diagnosis requires evidence of lower motor neuron degeneration by clinical, electrophysiologic ( Chapter 366 ), or neuropathologic examination; upper motor neuron degeneration by clinical examination; and progressive spread of symptoms or signs within a region or to other regions, as determined by the history or examination. The diagnosis also requires the absence of other disease processes as determined by electrophysiologic testing, neuroimaging, and blood tests. Generally accepted criteria ( Table 387-2 ) classify patients as having definite, probable, or possible ALS. However, a number of other conditions may mimic ALS ( Table 387-3 ), and about 8% of patients in whom ALS is initially diagnosed have other lower motor neuron syndromes, such as multifocal motor neuropathy with conduction block, Kennedy disease, or mixed spinal cord and nerve root compression ( Chapter 369 ). Conversely, 10 to 15% of patients in whom ALS is ultimately diagnosed may first undergo inappropriate surgery for presumed spinal cord or root compression abnormalities.

Blood tests that may be helpful in distinguishing ALS from mimic syndromes (see Table 387-3 ) include a complete blood count and serum calcium level, thyroid function tests, parathyroid hormone, serum protein electrophoresis, Venereal Disease Research Laboratory test, creatine kinase level, inflammatory markers (erythrocyte sedimentation rate and C-reactive protein), and levels of anti-GM1 ganglioside and anti–myelin-associated glycoprotein (MAG) antibodies. Further testing, which is guided by the patient’s clinical findings, might include acetylcholine receptor antibody; mutation screening in patients with familial disease, suspected Kennedy disease, or spinal muscular atrophy (SMA); heavy metal screening; urinary porphyrins; serum hexosaminidase A and B levels; Borrelia titers; and testing for human immunodeficiency virus.

Typical features of ALS on electromyography (EMG) include evidence of active denervation (i.e., positive sharp waves, fibrillation, and fasciculation potentials) and chronic denervation, as evidenced by large motor unit potentials that cannot be explained by a single nerve, root, or plexus lesion. Neuroimaging of the brain and spinal cord is usually needed to exclude structural pathology.

Baseline respiratory function tests should be performed on all patients. Muscle biopsy is indicated only in atypical cases when diagnostic uncertainty persists.

In the current era of emerging trials of genetic therapy, a case can be made for offering genetic panel screening to patients with both sporadic and familial ALS.