science revisited

The underlying pathomechanism of sporadic ALS remains elusive. A complex interplay of genetic and environmental factors is likely involved in the etiology of motor neuron degeneration.

Some risk factors implicated in the development of ALS include age, diet, physical activity, heavy metal and pesticides exposure, cigarette smoking, trauma, electrical injury, geographical residence, being a Gulf war veteran, and others. The exact relationship among these factors and ALS are unknown.

Of patients with familial ALS 20% are due to mutations in the superoxide dismutase gene (SOD1), implicating a dysfunction of oxidative stress response. Another 10% are due to mutations in the fused sarcoma gene (FUS) and transactive response DNA-binding protein gene (TARDBP) encoding TDP43 protein, implicating abnormalities in RNA processing. Abnormal FUS and TDP43 protein aggregates are found in the brain and spinal cord tissues of sporadic ALS and non-SOD1 familial ALS, whereas abnormal SOD1 protein aggregates are found only in SOD1 familial ALS cases. Other genes involved in ALS include alsin, senataxin, VAMP-associated protein gene, VAPB, angiogenin, and optineurin.

Several abnormalities of cellular mechanisms are implicated in ALS including protein and neurofilament aggregation, axonal transportation, glutamate excitotoxicty, mitochondrial dysfunction, glial cell pathology, and inflammatory dysfunction.

Diagnosis of ALS

ALS is a clinical diagnosis. A detailed history and physical examination are therefore paramount for an accurate diagnosis. Progressive weakness that starts asymmetrically is the clinical basis for suspecting ALS. On physical examination, the physician should detect signs of LMN degeneration, such as muscle atrophy and fasciculations, and signs of UMN dysfunction in the affected limbs, such as clumsiness in fine motor movements and pathological reflexes. These findings must be found along the neuraxis, including the bulbar/cranial, cervical, thoracic, and lumbosacral regions, to achieve a level of diagnostic certainty as defined by the original El Escorial criteria that were set forth by the World Federation of Neurology in 1994.

Nerve conduction study/electromyography (NCS/EMG) testing supplements the clinical and physical evaluation of LMN dysfunction, and excludes other neuromuscular disorders that may mimic ALS; they are used by ALS experts to facilitate early diagnosis of ALS.

NCSs of ALS patients typically show normal sensory nerve responses with borderline normal or low motor nerve responses. Increased distal motor latency or markedly slowed conduction velocity should raise concerns for other conditions. Focal slowing or proximal conduction block should prompt further investigation for multifocal motor neuropathy with conduction block, which can be treated with intravenous immunoglobulin.

EMG is performed to determine the characteristics and the extent of LMN dysfunction. For the diagnosis of ALS, at least two of four regions (bulbar/cranial, cervical, thoracic, and lumbar) have to show evidence of active and chronic denervation, as defined in the Airlie House criteria and the recently modified Awaji electrodiagnostic guidelines.

Routine laboratory tests, including complete blood count, chemistry (including calcium, magnesium, and phosphorus), liver function tests, erythrocyte sedimentation rate, serum VDRL (Venereal Disease Reference Laboratory) test, creatine kinase, thyroid function test, and parathyroid hormones should be obtained to exclude other conditions. Serum protein electrophoresis with immunofixation is obtained to exclude paraproteinemia. Chest radiograph and age-appropriate cancer prescreening should also be performed to exclude the rare paraneoplastic syndrome affecting predominantly the motor neurons. Neuroimaging with magnetic resonance imaging (MRI) studies is essential to exclude structural lesions or treatable conditions, such as cervical spinal spondylosis, myelopathy, cerebral or brain-stem tumors, chronic vasculopathy, or leukodystrophy, as the cause of UMN signs in presumed ALS cases. If a male patient has an LMN syndrome, gynecomastia, sensory neuropathy, and chin twitching, genetic testing for Kennedy’s disease (spinobulbar muscular atrophy) would be appropriate.

Table 31.1 lists the various forms of ALS and their mimickers. However, diagnosis of ALS at an early stage remains challenging. A high incidence of cervical spondylosis and nerve entrapment in the elderly population can make it difficult to assign the symptoms to ALS; sometimes only time and progression can affirm the diagnosis.