Faculty Bibliography

The oxazolidinone antimicrobial linezolid is effective against gram-positive bacteria. Although maximal recommended therapy is 28 days, treatment durations greater than this are common. Linezolid may cause reversible optic neuropathy and irreversible peripheral neuropathy after months of treatment. Three cases of linezolid-induced optic and peripheral neuropathy are described, and previously reported cases of linezolid-induced optic neuropathy are reviewed. The mechanism of neural toxicity may be impairment of mitochondrial protein synthesis.

BACKGROUND: Eye movements are clinically normal in most patients with motor neuron disorders until late in the disease course. Rare patients are reported to show slow vertical saccades, impaired smooth pursuit, and gaze-evoked nystagmus. We report clinical and oculomotor findings in three patients with motor neuronopathy and downbeat nystagmus, a classic sign of vestibulocerebellar disease. CASE PRESENTATION: All patients had clinical and electrodiagnostic features of anterior horn cell disease. Involvement of finger and wrist extensors predominated, causing finger and wrist drop. Bulbar or respiratory dysfunction did not occur. All three had clinically evident downbeat nystagmus worse on lateral and downgaze, confirmed on eye movement recordings using the magnetic search coil technique in two patients. Additional oculomotor findings included alternating skew deviation and intermittent horizontal saccadic oscillations, in one patient each. One patient had mild cerebellar atrophy, while the other two had no cerebellar or brainstem abnormality on neuroimaging. The disorder is slowly progressive, with survival up to 30 years from the time of onset. CONCLUSION: The combination of motor neuronopathy, characterized by early and prominent wrist and finger extensor weakness, and downbeat nystagmus with or without other cerebellar eye movement abnormalities may represent a novel motor neuron syndrome.

Two patients sharing a novel mutation of the CACNA1A gene for P/Q calcium channels showed significant slowing of adducting saccades compared with normal subjects or patients with cerebellar disease. Internuclear ophthalmoparesis (INO) was clinically evident in one. While these findings might be specific to this mutation, INO in our patients with episodic ataxia type 2 suggested involvement outside the cerebellum, either in the brain-stem internuclear pathway or at the neuromuscular junction.

We conducted a two-year follow-up study of 40 patients with MS in whom we had reported that abnormal eye movements (AEM) were associated with greater general disability. AEM patients (17/40) remained significantly (p < .001) more disabled (median EDSS of 7.0) than those with normal eye movements (median EDSS of 5.0). AEM and great disability were associated with abnormal MRI signals in brainstem or cerebellum, where disease may involve control circuits for eye movements as well as descending motor pathways.

Clinicians conventionally test saccades at the bedside by noting the accuracy, initiation time, and speed of large movements, with the patient's head stationary. Partly for methodological reasons, laboratory analysis of saccades has mainly focused on movements of 20 degrees or less. By measuring the velocity waveform of large saccades, it is possible to examine more closely the way in which brain stem and cerebellum guide the eye to the target. Large saccades made by healthy humans show a positively skewed velocity profile. Slow saccades made by patients with brain-stem disorders show a prolonged plateau of low velocity. Some patients with cerebellar disorders may show increased acceleration and deceleration of saccades. Each of these velocity waveforms can be modeled by changing the parameters that describe medium-lead burst neuron firing. In certain other brain-stem and cerebellar disorders, transient decelerations or premature terminations of saccades occur; such velocity waveforms cannot be modeled solely by changing the parameters that describe burst neuron firing. Instead, it is necessary to postulate dysfunction of the mechanism that normally inhibits pontine omnipause neurons, thereby permitting burst neurons to discharge until the saccade is completed. Analysis of large, abnormal saccades calls for application of novel techniques to identify the beginning and end of the saccadic pulse command.

BACKGROUND: Diplopia is a common complaint in both inpatient and outpatient neurologic practice. Its causes are many, and special historical and examination features are important to localization and accurate diagnosis. REVIEW SUMMARY: This review is divided into 2 sections: the first related to diagnosis and the second to treatment of binocular diplopia. In the diagnostic section, emphasis is placed on identification of historical and examination features that can help to differentiate diplopia caused by dysfunction of cranial nerves versus neuromuscular junction, or orbital extraocular muscle. Techniques available to the neurologist for examining ocular motility and ocular misalignment and focused laboratory testing to evaluate diplopia are discussed in detail. The final section covers the various treatments for binocular diplopia, with recommendations regarding the utility of each treatment for different types of diplopia. CONCLUSIONS: A logical step-by-step approach applied to each patient with diplopia will help prevent misdiagnosis and improve patient care.

Acquired and congenital nystagmus often causes decreased visual acuity as a direct result of the inability to maintain stable foveal vision. In addition, acquired nystagmus causes a disabling subjective sensation of movement of the visual world called oscillopsia. The eye movements themselves do not require treatment if the patient is asymptomatic. However, therapy is necessary if visual disability is present. Treatments based in pharmacologic mechanisms are preferred. There are few controlled treatment trials and therapeutic efficacy generally is sought in a trial and error approach, depending on the type of nystagmus present. Treatment with 3,4-diaminopyridine and 4-aminopyridine recently have been shown to be effective for downbeat nystagmus. Gabapentin, baclofen, and clonazepam also are useful in some patients with downbeat nystagmus. Baclofen is the therapy of choice for periodic alternating nystagmus. Gabapentin often is effective for acquired pendular nystagmus. Clonazepam and valproate also may be effective for acquired pendular nystagmus. Memantine now is available in the United States and is promising in the treatment of pendular nystagmus. Optical devices that negate the negative effects of nystagmus continue to undergo development research. These and other medical, surgical, and optical devices are potentially useful alone or in combination with other therapies.

BACKGROUND: Late-onset Tay-Sachs disease (LOTS) is an adult-onset, autosomal recessive, progressive variant of GM2 gangliosidosis, characterized by involvement of the cerebellum and anterior horn cells. OBJECTIVE: To determine the range of visual and ocular motor abnormalities in LOTS, as a prelude to evaluating the effectiveness of novel therapies. METHODS: Fourteen patients with biochemically confirmed LOTS (8 men; age range 24 to 53 years; disease duration 5 to 30 years) and 10 age-matched control subjects were studied. Snellen visual acuity, contrast sensitivity, color vision, stereopsis, and visual fields were measured, and optic fundi were photographed. Horizontal and vertical eye movements (search coil) were recorded, and saccades, pursuit, vestibulo-ocular reflex (VOR), vergence, and optokinetic (OK) responses were measured. RESULTS: All patients showed normal visual functions and optic fundi. The main eye movement abnormality concerned saccades, which were "multistep," consisting of a series of small saccades and larger movements that showed transient decelerations. Larger saccades ended earlier and more abruptly (greater peak deceleration) in LOTS patients than in control subjects; these changes can be attributed to premature termination of the saccadic pulse. Smooth-pursuit and slow-phase OK gains were reduced, but VOR, vergence, and gaze holding were normal. CONCLUSIONS: Patients with late-onset Tay-Sachs disease (LOTS) show characteristic abnormalities of saccades but normal afferent visual systems. Hypometria, transient decelerations, and premature termination of saccades suggest disruption of a "latch circuit" that normally inhibits pontine omnipause neurons, permitting burst neurons to discharge until the eye movement is completed. These measurable abnormalities of saccades provide a means to evaluate the effects of novel treatments for LOTS.