By Marcello Cherchi, MD PhD
For patients
Amyotrophic lateral sclerosis (ALS) comes on slowly, and causes weakness in the face, arms and legs, and problems with breathing and swallowing. Less commonly, patients have problems with thinking or with their eye movements. Your doctor may order nerve-muscle tests to make sure the diagnosis is correct. ALS is usually treated by a neuromuscular specialist.
For clinicians
Overview
Amyotrophic lateral sclerosis (ALS) results from progressive cellular death of upper and lower motor neurons, and presents with asymmetric, painless, progressive weakness involving some combination of face, arm and leg, with eventual involvement of respiratory and swallowing function. Electromyographic findings supportive of the diagnosis include a patern of acute and chronic denervation and reinnervation. Most cases of ALS are sporadic; a smaller proportion occur in familiar patterns. While the motoric features usually dominate the clinical picture, more recent research has also characterized cognitive deficits. A smaller proportion of ALS patients also exhibit ocular motor abnormalities, though these can sometimes only be detected on instrumented ocular motor testing, and play no significant role in diagnosis or prognosis. Two disease-modifying agents (riluzole, edaravone) have received FDA approval, and prolong survival by several months.
Introduction
The first complete description of amyotrophic lateral sclerosis (ALS) is usually credited to Jean-Martin Charcot (Charcot 1874). The presenting core clinical features are asymmetric, painless, progressive weakness of some combination of face, arm and leg, with the eventual development of deficits in respiration and deglutition. These symptoms result from progressive death of upper and lower motor neurons. Most cases occur sporadically and the cause is unknown; cases occurring in familial patterns have implicated a range of genes. The disease is more common in males, and in Caucasians. While the clinical picture is usually dominated by motoric findings, more recent research has additionally characterized cognitive deficits. Ocular motor abnormalities have also been documented, but are less common, and do not have significant diagnostic or prognostic value for ALS.
Epidemiology
ALS is somewhat more common in males, and more common among Caucasians. The reported incidence varies from 2.7 – 7.4 cases per 100,000 person-years.
Genetics
Most cases of ALS appear to occur spontaneously. A smaller proportion of cases occur in familial patterns, and a large number of genetic loci have been implicated.
Pathophysiological mechanism of disease
In the sporadically occurring cases of ALS, the underlying etiology (in other words, the mechanism of motor neuron cell death) is unknown.
As far as ocular motor abnormalities are concerned, different findings localize to different neuroanatomical pathways, involving both nuclear and supranuclear structures (Mizuno 1986), for example:
- The deficits in smooth pursuit may be due to ALS involvement of the frontal lobes, and specifically the frontal eye fields (Donaghy et al. 2011).
- Increased amplitude of saccadic intrusions is thought to be due to involvement of frontal-collicular pathways (Donaghy et al. 2011).
- The increased error rate and latency in antisaccades is thought to localize to the dorsolateral prefrontal cortex and frontal eye fields (Donaghy et al. 2011).
- Balaratnam and colleagues (Balaratnam et al. 2010) hypothesize that the emergence of ocular flutter may be the result of “initial loss of brainstem inhibitory neurons result[ing] in disinhibition of burst interneurons,” and the subsequent disappearance results because “burst interneurons also became affected by the disease process.”
Clinical presentation
The core clinical features of ALS are asymmetric, painless, progressive weakness of some combination of face, arm and leg. Some patients initially come to attention due to respiratory problems.
Physical examination
General neurological examination reveals weakness with upper and lower motor neuron signs involving some combination of the face, arms and legs.
Ocular motor examination
Some ocular motor abnormalities may be observable on face-to-face examination, but many are sufficiently subtle that they may only be detectable on instrumented ocular motor testing (Sharma et al. 2011).
Testing: vestibular
Instrumented ocular motor testing of patients with ALS have documented a number of findings, including:
- Adventitial ocular motor events:
- Square wave jerks (Kang et al. 2018)
- Increased amplitude of saccadic intrusions (Donaghy et al. 2011)
- Ocular flutter (Balaratnam et al. 2010)
- Gaze paresis:
- Global ophthalmoplegia (Cohen and Caroscio 1983)
- Paresis of horizontal gaze and upgaze (Kushner et al. 1984)
- Gaze-evoked abnormalities:
- “Gaze evoked rotatory nystagmus” (Kushner et al. 1984)
- Saccades:
- Saccadic dysmetria (Kang et al. 2018)
- Reduced saccadic velocity (Ohki et al. 1994)
- Deficits in generating voluntary saccades (Cohen and Caroscio 1983)
- Deficits (increased latency) in memory-guided saccades (Donaghy et al. 2011)
- Deficits (increased error rate and increased latency) in anti-saccades (Donaghy et al. 2011)
- Mixed deficits in saccades (Mizuno 1986)
- Smooth pursuit:
- Saccadic breakdown of smooth pursuit (Jacobs et al. 1981; Kang et al. 2018)
- Deficits in smooth pursuit (Cohen and Caroscio 1983; Mizuno 1986; Ohki et al. 1994)
- Optokinetic nystagmus:
- Deficits in optokinetic nystagmus (Jacobs et al. 1981; Mizuno 1986; Ohki et al. 1994)
- Vergence abnormalities:
- Convergence insufficiency (Cohen and Caroscio 1983)
- Dysconjugate gaze (Jacobs et al. 1981)
- Other abnormalities:
- Head shaking positional nystagmus (Kang et al. 2018)
- Deficits in visual suppression (Ohki et al. 1994)
Some of these are more common in ALS patients with other bulbar (i.e., brainstem) findings (Kang et al. 2018; Ohki et al. 1994).
Testing: other
Electromyography and nerve conduction velocities (EMG/NCV) shows a pattern of acute and chronic denervation and reinnervation.
Imaging
Standard MRI of the brain and spine is often normal in ALS, though T2/FLAIR abnormalities may be identified in the corticospinal tracts.
Histopathology
ALS is characterized by cellular death of upper and lower motor neurons.
Differential diagnosis
None of the ocular motor findings discussed earlier are specific or sensitive for ALS, so while interesting, they are not particularly diagnostically useful.
Treatment
Treatment of ALS is undertaken by neuromuscular specialists. As of this writing the two FDA-approved disease modifying agents, riluzole and edaravone, prolong survival by several months. Care is otherwise supportive.
Prognosis
ALS is uniformly fatal.
References
Balaratnam MS, Leschziner GD, Seemungal BM, Bronstein AM, Guiloff RJ (2010) Amyotrophic lateral sclerosis and ocular flutter. Amyotroph Lateral Scler 11: 331-4. doi: 10.3109/17482960902875133
Charcot JM (1874) De la sclérose latérale amyotrophique. Prog Med 2: 341-453.
Cohen B, Caroscio J (1983) Eye movements in amyotrophic lateral sclerosis. J Neural Transm Suppl 19: 305-15.
Donaghy C, Thurtell MJ, Pioro EP, Gibson JM, Leigh RJ (2011) Eye movements in amyotrophic lateral sclerosis and its mimics: a review with illustrative cases. J Neurol Neurosurg Psychiatry 82: 110-6. doi: 10.1136/jnnp.2010.212407
Jacobs L, Bozian D, Heffner RR, Jr., Barron SA (1981) An eye movement disorder in amyotrophic lateral sclerosis. Neurology 31: 1282-7. doi: 10.1212/wnl.31.10.1282
Kang BH, Kim JI, Lim YM, Kim KK (2018) Abnormal Oculomotor Functions in Amyotrophic Lateral Sclerosis. J Clin Neurol 14: 464-471. doi: 10.3988/jcn.2018.14.4.464
Kushner MJ, Parrish M, Burke A, Behrens M, Hays AP, Frame B, Rowland LP (1984) Nystagmus in motor neuron disease: clinicopathological study of two cases. Ann Neurol 16: 71-7. doi: 10.1002/ana.410160114
Mizuno M (1986) Neurotological findings in amyotrophic lateral sclerosis. Auris Nasus Larynx 13 Suppl 2: S139-46. doi: 10.1016/s0385-8146(86)80067-0
Ohki M, Kanayama R, Nakamura T, Okuyama T, Kimura Y, Koike Y (1994) Ocular abnormalities in amyotrophic lateral sclerosis. Acta Otolaryngol Suppl 511: 138-42. doi: 10.3109/00016489409128318
Sharma R, Hicks S, Berna CM, Kennard C, Talbot K, Turner MR (2011) Oculomotor dysfunction in amyotrophic lateral sclerosis: a comprehensive review. Arch Neurol 68: 857-61. doi: 10.1001/archneurol.2011.130
