Amyotrophic lateral sclerosis By Summer B Gibson MD (Dr. Gibson of University of Utah owns stock in Recursion Pharmaceuticals.) Originally released June 21, 1996; last updated May 9, 2017; expires May 9, 2020 Introduction This article includes discussion of amyotrophic lateral sclerosis, Charcot disease, Lou Gehrig disease, motor neuron disease, Aran-Duchenne disease, Duchenne-Aran disease, familial amyotrophic lateral sclerosis, flaccid bulbar palsy, PLS, primary lateral sclerosis, progressive bulbar palsy, progressive crural palsy, progressive muscular atrophy, and spastic bulbar palsy. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations. Overview Amyotrophic lateral sclerosis is a devastating neurodegenerative disease characterized by progressive muscle weakness without notable sensory loss. There are now 2 U.S. Food and Drug Administration–approved medications that have demonstrated modest effects on slowing disease progression: riluzole, approved in 1995, and edaravone, approved in 2017. In this article, the author reviews clinical manifestations, risk factors, symptomatic management, and clinical trials and provides updates on recent genetic discoveries. Historical note and terminology Aran believed this syndrome was a muscular disease and was the first to use the term “progressive muscular atrophy” (Aran 1850). Cruveilhier first noticed the atrophy of the anterior spinal roots and thought progressive muscular atrophy was a myelopathic disorder (Cruveilhier 1853). Charcot and Joffroy proposed the term “amyotrophic lateral sclerosis” when they noticed the involvement of the corticospinal tract (Charcot and Joffroy 1969). Brain used the term “motor neuron disease” to emphasize the connections between progressive muscular atrophy, amyotrophic lateral sclerosis, and progressive bulbar palsy (Brain 1962). The term “motor neuron disease” also highlights the variety of involvement of upper and lower motor neurons. Rowland suggested using the plural form, “motor neuron diseases,” to describe all of the diseases of the anterior horn cells and the motor system, including spinal muscular atrophies (Rowland 1982). Spinal muscular atrophies are clinically and pathologically distinct from amyotrophic lateral sclerosis. Clinical manifestations Presentation and course Amyotrophic lateral sclerosis is characterized by asymmetric progressive weakness without notable sensory symptoms or loss. Common presenting signs correspond to selective involvement of particular motor systems (Table 1). Presenting symptoms can be bulbar, cervical, thoracic, or lumbosacral. The time course can vary from rapid progression, with patients becoming ventilator-dependent in a few months, to slow progression, with patients still living independently more than 10 years after diagnosis. Table 1. Clinical Manifestations of Amyotrophic Lateral Sclerosis System involved Symptoms and signs Bulbar • dysarthria • dysphagia • sialorrhea (drooling) • tongue atrophy • tongue fasciculations Upper motor neuron • hyperreflexia • spasticity • Babinski signs • jaw jerk • snout reflexes • spread of reflexes • incoordination • weakness Lower motor neuron • weakness • muscle atrophy • fasciculations Cognitive changes • frontotemporal dysfunction or dementia Bulbar signs and symptoms. Bulbar signs and symptoms include dysarthria, dysphagia, sialorrhea (drooling), tongue atrophy, and tongue fasciculation. They are caused by the involvement of cranial nerve motor nuclei in the medulla, including VII (facial), IX (glossopharyngeal), and XII (hypoglossal). Bulbar signs and symptoms develop during the course of the disease, but they may be a presenting feature, especially in middle-aged women. In older women, as in men, limb involvement is more common. Bulbar involvement leads to difficulty in speaking and swallowing and is often closely correlated with reduced vital capacity. When the medullary lower motor neurons are primarily affected, the condition is called flaccid or paretic bulbar palsy. When upper motor neurons or their descending tracts (corticobulbar) are affected, the condition is called spastic bulbar palsy. A mixed flaccid and spastic bulbar palsy is usually observed. Upper motor neuron signs and symptoms. Upper motor neuron signs and symptoms include hyperreflexia, spasticity, Babinski signs, jaw jerk, snout reflexes, spread of reflexes, incoordination, and weakness. Upper motor neuron weakness is different from lower motor neuron weakness because the former may not be associated with muscle atrophy. Patients may complain of slowness, inability to control the muscles (incoordination), or stiffness, which is due to spasticity. Recognition of upper motor neuron involvement in a patient with severe muscle wasting can be challenging. The muscle may be so weak and atrophied that the tendon reflexes are difficult to elicit. However, elicitable tendon reflex in a wasted muscle probably signifies the co-existence of an upper motor neuron lesion. Yet upper motor neuron signs may disappear as the lower motor neuron weakness progresses. Lower motor neuron signs and symptoms. These include weakness, muscle atrophy, and fasciculations; they may be focal, multifocal, or diffuse. Focal onset of weakness may be misinterpreted as a focal disease process such as cervical or lumbosacral radiculopathy or nerve entrapment. The absence of sensory findings and the presence of hyperactive reflexes and fasciculations argue against entrapment neuropathy or radiculopathy. However, it should be emphasized that some patients may have superimposed entrapment neuropathies or radiculopathies. MRI of the cervical or lumbosacral spine and electrodiagnostic tests are useful diagnostic tools for these patients. Fasciculations are common and often abundant and widespread, but patients rarely present with fasciculations as an isolated symptom. Rather, they usually seek medical attention because of weakness and may be not aware of fasciculations. It should be noted that fasciculations are not diagnostic as they may result from any lesion of the lower motor neurons.{embed="pagecomponents/media_embed" entry_id="8897"} “Benign fasciculations,” which are intermittent, focal, and aggravated by stress, exercise, or lack of sleep, may occur in normal subjects without associated weakness. When fasciculations occur with weakness or upper motor neuron signs, consider the possibility of amyotrophic lateral sclerosis. Because many disorders may cause lower motor neuron signs, it is important to perform a detailed physical examination and electrodiagnostic test to search for evidence of other more benign processes, such as radiculopathies, plexopathies, entrapment neuropathies, or myopathy. Cognitive changes. A significant number of patients with amyotrophic lateral sclerosis have cognitive impairment, particularly frontotemporal dementia. Lomen-Hoerth and colleagues examined the relationship between amyotrophic lateral sclerosis and frontotemporal dementia (Lomen-Hoerth et al 2002; Lomen-Hoerth et al 2003). They studied 100 patients with amyotrophic lateral sclerosis using the mini mental status state examination (MMSE) and word generation (Lomen-Hoerth et al 2003). Thirty-one patients had abnormal word generation; 50% of patients with bulbar onset disease had an abnormal score whereas approximately 25% of patients with limb onset disease had an abnormal score. No patient had an abnormal score on the MMSE. Of the 44 patients who agreed to undergo more extensive testing, 18 had results consistent with probable or definite frontotemporal dementia, and 5 patients had possible frontotemporal dementia (Lomen-Hoerth et al 2003). In another study, they performed a detailed neuromuscular examination, nerve conduction studies and EMG in 36 patients with frontotemporal dementia (Lomen- Hoerth et al 2002). According to the El Escorial criteria, 5 patients had definite amyotrophic lateral sclerosis, and 1 patient had neurogenic changes limited to a single limb. Hosler and colleagues have also reported families in whom some members developed amyotrophic lateral sclerosis, others frontotemporal dementia, and still others amyotrophic lateral sclerosis–frontotemporal dementia (Hosler et al 2000). Important negatives. Sensory symptoms, memory loss, bladder and bowel dysfunction, ocular palsy, and decubiti are rare. Clinically, amyotrophic lateral sclerosis is usually a pure motor neuron syndrome, and motor neurons that innervate extraocular muscles, the bladder, and anal sphincter muscles are typically unaffected. Although patients generally have no sensory abnormalities in routine neurologic examinations, detailed quantitative measurements show that 18% of patients have abnormally elevated vibratory thresholds, suggestive of subclinical involvement of some sensory neurons (Mulder et al 1983) and up to 20% of patients have abnormal sensory nerve conduction studies in at least 1 nerve (Pugdahl et al 2007). Memory loss may be evident in about 5% of patients. Moreover, memory loss is a part of the amyotrophic lateral sclerosis-parkinsonism-dementia complex in the Western Pacific (Hirano et al 1961). Clinically, approximately 38% of these patients develop parkinsonism and dementia. Extraocular muscles are typically spared, but the velocity of saccade or smooth pursuit movements may be abnormal due to extrapyramidal or supranuclear dysfunction (Gizzi et al 1992). Bladder and bowel function in patients is generally thought to be normal because the motor neurons in the Onufrowicz nucleus that