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Fig. 1. ALS and communication. Progression of ALS may impose severe communication-al problems. Dysarthria and inability to speak can be compensated in some patients with computer devices, such as special keyboards and a mouse

Amyotrophic lateral sclerosis (ALS) causes the loss of both upper and lower Anatomy motor neurons. On autopsy, there is loss of the pyramidal cells of the motor cortex, with atrophy of the brainstem and spinal cord. The corticospinal tracts are degenerated and gliotic. The ventral nerve roots are atrophied, and there is microscopic evidence of muscle denervation and reinnervation.

ALS usually presents with painless and progressive weakness of a focal distribu- Symptoms tion that over time spreads to contiguous muscle groups. As the disease progresses, fasciculations cause muscle cramps and the patient becomes spastic. Spontaneous clonus may also occur. Weakness can lead to head drop, and contractures can lead to hand and foot deformaties.

Bulbar symptoms may be the presenting feature of ALS, but more commonly patients present with trunk and extremity weakness. Dysarthria is common and may be spastic or flaccid, or a combination of both. Dysphagia puts patients at a high risk for choking and aspiration. Spontaneous swallowing is absent, leading to drooling (sialorrhea).

Respiratory weakness is rarely the presenting feature of ALS, but becomes common with disease progression. Patients initially experience exertional dyspnea and sigh frequently when at rest. This continues on to dyspnea at rest, sleep apnea, morning headaches, and the inability to sleep supine.

Typically, mentation, extraocular movements, bowel and bladder functions, and sensation are spared in ALS. Ophthalmoplegia (ocular apraxia) has been reported. Dementia is observed in 1-2% of patients. Nearly one third of ALS patients report urgent and obstructive micturition. Over time, muscles become atrophied and patients complain of fatigue.

Signs As ALS affects both upper and lower motor neurons, most (80%) of patients show both upper and lower motor neuron signs. There is usually a combination of spasticity, hyperreflexia, and progressive muscle weakness and wasting. A small percentage of patients will only show lower motor neuron signs and symptoms. On the other hand, there are rare instances where patients only have upper motor neuron disease. There is currently debate as to whether this condition, called Primary Lateral Sclerosis (PLS), is a separate entity. The diagnostic procedures and treatments for PLS are currently identical to those for ALS.

Pathogenesis Most cases of ALS (at least 80%) are sporadic. A smaller number are attributable to autosomal dominant familial ALS (FALS). The cause of sporadic ALS is currently unknown, although proposed etiologies include glutamate neurotoxicity, abnormal accumulation of neurofilaments, altered neurotrophism, and toxicity from oxygen radicals or environmental sources. The genetic cause of most FALS is unknown, but 20% of FALS cases show a mutation in the protein cytosolic copper-zinc superoxide dismutase (SOD1), found on chromosome 21q. SOD1 detoxifies superoxide anions, which can lead to cell death when they accumulate and oxidize proteins and lipids. FALS, whether caused by SOD1 mutations or not, is indistinguishable clinically from sporadic ALS; thus, there is reason to believe that oxidative damage to neurons is a common mechanism underlying all forms of ALS.

Diagnosis The El Escorial World Federation of Neurology criteria for the diagnosis of ALS

divides the body into four regions: bulbar (face, jaw, tongue, palate, larynx), cervical (neck, arm, hand, diaphragm), thoracic (back, abdomen), and lumbosacral (back, abdomen, leg, and foot). Upper and lower motor signs must be present in the bulbar region and two of the spinal regions, or in all three spinal regions. A patient with signs in two spinal regions is diagnosed with probable ALS. A diagnosis of possible ALS is given in cases where only one region is affected, or if only lower motor neuron signs are present in two regions, or if regions with lower motor neuron signs occur rostrally to regions with upper motor neuron signs.

Genetic testing can be done to determine if a case of FALS is due to an SOD1 mutation.

EMG and nerve conduction studies with repetitive stimulation are used to confirm lower motor neuron degeneration.

Imaging can be used to confirm that anatomy is normal, and exclude other pathology.

Laboratory tests used to exclude other conditions that may resemble ALS include: CBC and routine chemistries, serum VDRL, creatine kinase, thyroid studies, serum protein electrophoresis, serum immunoelectrophoresis, ANA, rheumatoid factor, and sedimentation rate.

Neuroimaging and laboratory tests can be used to rule out the following Differential diagnosis conditions: syringomyelia, syringobulbia, paraneoplastic motor neuronopathy, polyradiculopathy with myelopathy, post-polio syndrome, multifocal motor neuropathy, motor neuron disease with paraproteinemia, hexoseaminidase-A

deficiency, and heavy metal intoxication.

Riluzole (2-amino-6-(trifluormethoxy)benzothiazole) is the only targeted treat- Therapy ment available. Riluzole blocks glutamate release, which may slow disease if glutamate toxicity is contributing to motor neuron loss. Riluzole is given 50 mg twice daily and may cause nausea and asthenia, but is generally tolerated well. Symptomatic treatment may be indicated for spasticity, cramps, excessive drooling, and pseudobulbar symptoms. Physical therapy, braces, and ambulatory supports are helpful. As speech becomes difficult, alternative communication devices are needed (Fig. 1). A severely dysphagic patient may choose to have a gastric feeding tube placed. Bilevel positive airway pressure ventilation is helpful for the respiratory symptoms of patients.

Prognosis for ALS is poor and the progression of the disease is generally Prognosis relentless. The average 5-year survival is 25%. The mean duration of disease from onset of symptoms to death is 27 to 43 months, with median duration of 23-52 months.

Primary lateral sclerosis progresses much more slowly, with a mean duration of 224 months.

Benditt JO, Smith TS, Tonelli MR (2001) Empowering the individual with ALS at the end of References life: disease specific advance care planning. Muscle Nerve 24: 1706-1709

Hand CK, Rouleau GA (2002) Familial amyotrophic lateral sclerosis. Muscle Nerve 25:

135-159

Mitsumoto H, Chad DA, Pioro EP (1998) Amyotrophic lateral sclerosis. FA Davis, Philadelphia

Willson CM, Grace GM, Munoz DG, et al (2001) Cognitive impairment in sporadic ALS. A pathologic continuum underlying a multisystem disorder. Neurology 57: 651-657 De Carvalho M, Swash M (2000) Nerve conduction studies in amyotrophic lateral sclerosis. Muscle Nerve 23: 344-352

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