Neuro-Ophthalmologic Manifestations of Amyotrophic Lateral Sclerosis
The neuro-ophthalmologic manifestations of amyotrophic lateral sclerosis.
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease affecting both upper and lower motor neurons, resulting in worsening weakness of voluntary muscles. This degeneration of motor neurons results in severe weakness and wasting accompanied by fasciculations of muscles, dysarthria, and dysphagia, and eventually death due to respiratory failure.
The incidence of ALS is 2-3 people per year per 100,000 of the general population over the age of 15 years, and the overall lifetime risk is slightly higher for men than women by a factor between 1.2 and 1.5. The highest prevalence of ALS is in Caucasians, males, and individuals 60 years or older, with the mean age of onset being 62 years.
ALS is a progressive condition caused by the deterioration of the motor neurons in the spinal cord and brain. It involves both upper and lower motor neurons in the cerebral cortex, brainstem nuclei, anterior horn of the spinal cord, and the corticospinal tract.
While there is no unifying theory of ALS pathophysiology, multiple interacting potential pathways such as impairments in RNA and protein processing may play a role in the disease. Impaired processing of proteins such as the SOD1 gene leads to cytosolic aggregation of misfolded proteins and impaired protein degradation in ALS patients. Similarly, errors in RNA processing may be involved in ALS pathophysiology, leading to cytoplasmic inclusion of RNA-binding proteins. ALS is also characterized by cellular abnormalities in addition to immune dysregulation and inflammation which likely play a large role in the disease manifestation. There is a familial form of ALS that is characterized by both loss-of-function and toxic gain-of-function mutations in the gene C9orf72.
Ophthalmologic Symptoms, Signs, and Exam Findings
The initial clinical presentation of ALS can manifest in any body segment and may present as upper motor neuron or lower motor neuron signs. While ocular signs may present at any stage of the illness, extraocular motor neurons in the nuclei of oculomotor, trochlear, and abducens nerves are normally spared until very late in the disease course. Abnormal eye movements, such as square-wave jerks, abnormal cogwheeling during smooth pursuit, and saccade hypometria have been observed in ALS patients. Studies have also found that abnormal smooth pursuits and saccadic dysmetria are more common in ALS patients with bulbar onset compared to those with spinal onset. This is because ALS patients with bulbar involvement commonly have more extensive brainstem pathology compared to those without bulbar involvement. This leads to damage to the brainstem ocular motor network resulting in the ocular symptoms.
Additionally, some studies have demonstrated the involvement of the anterior visual pathway in the disease process of ALS. Some of these findings include intraretinal deposits and structural changes within the visual pathway that point to potential neuronal degeneration. These abnormalities likely correlate to the reduced contrast sensitivity that has been noted in ALS patients. Through the use of optical coherence tomography and histopathologic studies, specific deposits in the inner nuclear layer of the retina were found in ALS patients with the C9orf72 mutation. Another ALS patient with a different clinical presentation developed axonal degeneration in the nerve fiber layer. These varied histophathological findings in ALS patients confirm the heterogeneity of the disease with different genetic and environmental factors resulting in an array of phenotypes and variable clinical manifestations.
ALS is primarily a clinical diagnosis but can be supported by electromyography (EMG). EMG findings in ALS show features of acute and chronic denervation and reinnervation. These findings include fibrillations and positive sharp waves, fasciculations, as well as large amplitude, long duration complex motor unit action potentials. Nerve conduction studies typically demonstrate preserved sensory responses with normal or reduced motor amplitudes. MRI of the brain and spinal cord can also be obtained to rule out other causes.
Differential diagnosis for ALS
Differential diagnoses for ALS include peripheral neuropathy, myasthenia gravis, multifocal motor neuropathy, hyperthyroidism, and subacute combined degeneration.
Traditionally, neuroimaging has been used to rule out other possible diagnoses in the evaluation for suspected ALS. Conventional MRI is normally benign in ALS patients, but increased signal in the corticospinal tracts on T2-weighted images may be seen.
The El Escorial and Awaji criteria for ALS includes progressive upper and lower motor neurons symptoms and signs in one limb or body segment or progressive lower motor neuron symptoms and signs in at least two body segments with the absence of electrophysiologic, neuroimaging, and pathologic evidence of alternate disease processes to explain the disease process.
Classification of ALS
The two primary classifications of ALS are sporadic and familial. Familial ALS occurs in about 5-10% of ALS patients and is usually due to a dominant trait. It can be caused by one of several mutations that are passed along in families. Sporadic ALS comprises the remaining portion of patients and typically occurs during the mid-to-late fifties of a patient’s life while familial ALS occurs during late teens or early adulthood. Sporadic ALS has no known cause but may be due to immune system abnormalities or possible environmental exposures.
The four presentations of ALS are primary lateral sclerosis with sole upper motor neuron involvement, limb-onset ALS with both upper and lower motor neuron involvement, progressive muscular atrophy with pure lower motor neuron involvement, and bulbar-onset ALS with dysarthria and dysphagia presenting first and limb features developing later in the disease course.
Management and Treatment Options
Riluzole, a glutamate release inhibitor, is a disease-modifying therapy for ALS that has shown a survival benefit of approximately 3 months. Edaravone is a free-radical scavenger that is thought to reduce oxidative stress and reduces functional deterioration in ALS patients.
The prognosis for survival in patients with ALS is 2 to 5 years, and the most common cause of death is respiratory failure. Up to 20% of patients live for 5 years after diagnosis, 10% live for 10 years, and 5% live for 20 years or longer. Patients with older age at symptoms onset, bulbar-onset ALS, and early dysfunction of the respiratory muscles have a lower survival risk. ALS patients with a younger age of symptoms onset, limb-onset ALS, and longer time to diagnosis are associated with longer survival.
ALS is a multisystem disorder caused by the deterioration of the upper and lower motor neurons in the spinal cord and brain and may present albeit uncommonly with ocular alterations at different stages of the disease. Many of these abnormalities have especially been observed in ALS patients with bulbar involvement. Multidisciplinary assessments in ophthalmologic evaluations are important to address the ocular impairments that may present during the disease process as this may assist in maintaining a better quality of life in ALS patients. Some of the ocular abnormalities seen in patients could potentially serve as clinical markers to evaluate upper brainstem or cerebral neurodegeneration in ALS. Diagnosis is based on the clinical picture and can be supported by EMG studies. Riluzole is the most commonly used disease-modifying treatment and can extend patients’ survival.
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