Hypothetical membrane mechanisms in essential tremor

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Pharmacotherapy of vestibular and ocular motor disorders, including nystagmus

We review current pharmacological treatments for peripheral and central vestibular disorders, and ocular motor disorders that impair vision, especially pathological nystagmus. The prerequisites for successful pharmacotherapy of vertigo, dizziness, and abnormal eye movements are the “4 D’s”: correct diagnosis, correct drug, appropriate dosage, and sufficient duration. There are seven groups of drugs (the “7 A’s”) that can be used: antiemetics; anti-inflammatory, anti-Ménière’s, and anti-migrainous medications; anti-depressants, anti-convulsants, and aminopyridines. A recovery from acute vestibular neuritis can be promoted by treatment with oral corticosteroids. Betahistine may reduce the frequency of attacks of Ménière’s disease. The aminopyridines constitute a novel treatment approach for downbeat and upbeat nystagmus, as well as episodic ataxia type 2 (EA 2); these drugs may restore normal “pacemaker” activity to the Purkinje cells that govern vestibular and cerebellar nuclei. A limited number of trials indicate that baclofen improves periodic alternating nystagmus, and that gabapentin and memantine improve acquired pendular and infantile (congenital) nystagmus. Preliminary reports suggest suppression of square-wave saccadic intrusions by memantine, and ocular flutter by beta-blockers. Thus, although progress has been made in the treatment of vestibular neuritis, some forms of pathological nystagmus, and EA 2, controlled, masked trials are still needed to evaluate treatments for many vestibular and ocular motor disorders, including betahistine for Ménière’s disease, oxcarbazepine for vestibular paroxysmia, or metoprolol for vestibular migraine

Effects of visual blur on microsaccades during visual exploration

Microsaccades shift the image on the fovea and counteract visual fading. They also serve as an optimal sampling strategy while viewing complex visual scenes. Microsaccade production relies on the amount of retinal error or acuity demand of a visual task. The goal of this study was to assess the effects of blur induced by uncorrected refractive error on visual search. Eye movements were recorded in fourteen healthy subjects with uncorrected and corrected refractive error while they performed a) visual fixation b) blank-scene viewing c) visual search (spot the difference) tasks. Microsaccades, saccades, correctly identified differences and reaction times were analyzed. The frequency of microsaccades and correctly identified differences were lower in the uncorrected refractive error during visual search. No similar change in microsaccades was seen during blank-scene viewing and gaze holding tasks. These findings suggest that visual blur, hence the precision of an image on the fovea, has an important role in calibrating the amplitude of microsaccades during visual scanning

Purkinje Cells in Posterior Cerebellar Vermis Encode Motion in an Inertial Reference Frame

SummaryThe ability to orient and navigate through the terrestrial environment represents a computational challenge common to all vertebrates. It arises because motion sensors in the inner ear, the otolith organs, and the semicircular canals transduce self-motion in an egocentric reference frame. As a result, vestibular afferent information reaching the brain is inappropriate for coding our own motion and orientation relative to the outside world. Here we show that cerebellar cortical neuron activity in vermal lobules 9 and 10 reflects the critical computations of transforming head-centered vestibular afferent information into earth-referenced self-motion and spatial orientation signals. Unlike vestibular and deep cerebellar nuclei neurons, where a mixture of responses was observed, Purkinje cells represent a homogeneous population that encodes inertial motion. They carry the earth-horizontal component of a spatially transformed and temporally integrated rotation signal from the semicircular canals, which is critical for computing head attitude, thus isolating inertial linear accelerations during navigation

Medical and Paramedical Care of Patients With Cerebellar Ataxia During the COVID-19 Outbreak: Seven Practical Recommendations of the COVID 19 Cerebellum Task Force

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), the cause of the current pandemic coronavirus disease 2019 (COVID-19), primarily targets the respiratory system. Some patients also experience neurological signs and symptoms ranging from anosmia, ageusia, headache, nausea, and vomiting to confusion, encephalitis, and stroke. Approximately 36% of those with severe COVID-19 experience neurological complications. The virus may enter the central nervous system through the olfactory nerve in the nasal cavity and damage neurons in the brainstem nuclei involved in the regulation of respiration. Patients with cerebellar ataxia (CA) are particularly vulnerable to severe outcome if they contract COVID-19 because of the complexity of their disease, the presence of comorbidities, and their use of immunosuppressive therapies. Most CA patients burdened by progressive neurologic deficits have substantially impaired mobility and other essential functions, for which they rely heavily on ambulatory services, including rehabilitation and psychosocial care. Cessation of these interventions because of isolation restrictions places the CA patient population at risk of further deterioration. This international panel of ataxia experts provides recommendations for neurologists caring for patients with CA, emphasizing a pro-active approach designed to maintain their autonomy and well-being: continue long-term medications, promote rehabilitation efforts, utilize the technology of virtual visits for regular contact with healthcare providers, and pay attention to emotional and psychosocial health. Neurologists should play an active role in decision-making in those CA cases requiring escalation to intensive care and resuscitation. Multi-disciplinary collaboration between care teams is always important, and never more so than in the context of the current pandemic

Oculopalatal tremor explained by a model of inferior olivary hypertrophy and cerebellar plasticity

The inferior olivary nuclei clearly play a role in creating oculopalatal tremor, but the exact mechanism is unknown. Oculopalatal tremor develops some time after a lesion in the brain that interrupts inhibition of the inferior olive by the deep cerebellar nuclei. Over time the inferior olive gradually becomes hypertrophic and its neurons enlarge developing abnormal soma-somatic gap junctions. However, results from several experimental studies have confounded the issue because they seem inconsistent with a role for the inferior olive in oculopalatal tremor, or because they ascribe the tremor to other brain areas. Here we look at 3D binocular eye movements in 15 oculopalatal tremor patients and compare their behaviour to the output of our recent mathematical model of oculopalatal tremor. This model has two mechanisms that interact to create oculopalatal tremor: an oscillator in the inferior olive and a modulator in the cerebellum. Here we show that this dual mechanism model can reproduce the basic features of oculopalatal tremor and plausibly refute the confounding experimental results. Oscillations in all patients and simulations were aperiodic, with a complicated frequency spectrum showing dominant components from 1 to 3 Hz. The model’s synchronized inferior olive output was too small to induce noticeable ocular oscillations, requiring amplification by the cerebellar cortex. Simulations show that reducing the influence of the cerebellar cortex on the oculomotor pathway reduces the amplitude of ocular tremor, makes it more periodic and pulse-like, but leaves its frequency unchanged. Reducing the coupling among cells in the inferior olive decreases the oscillation’s amplitude until they stop (at ∼20% of full coupling strength), but does not change their frequency. The dual-mechanism model accounts for many of the properties of oculopalatal tremor. Simulations suggest that drug therapies designed to reduce electrotonic coupling within the inferior olive or reduce the disinhibition of the cerebellar cortex on the deep cerebellar nuclei could treat oculopalatal tremor. We conclude that oculopalatal tremor oscillations originate in the hypertrophic inferior olive and are amplified by learning in the cerebellum

Tremor in cervical dystonia

Background: Cervical dystonia (CD) is the most common form of focal dystonia encountered in the clinic. Approximately one-third of CD patients have co-existing tremor in the head and hands. Assessment of tremor as regular or irregular in context of its oscillation trajectory, frequency, and amplitude is a major clinical challenge and can confound the diagnosis of CD. The misdiagnosis may lead to therapeutic failures, poor quality of life, and poor utilization of medical and financial resources.Methods: We analyzed the largest cohort of CD patients (n = 3117) available to date, collected from 37 movement disorder centers in North America, Europe, and Asia. We used machine learning to determine what clinical features from clinician reports predicted the presence of tremor as well as its regular or irregular appearance.Results: Out of 3,117 CD patients, 1,367 had neck tremor. The neck tremor was interpreted as irregular in 1,022, regular in 345, and mixed (both irregular and regular) in 442. A feature importance analysis determined that greater severity of CD, longer disease duration, and older age, in descending order, predicted the presence of neck tremor. The probability of neck tremor was reduced if the dystonia affected other body parts in addition to the neck. We also found a significantly heightened risk for developing neck tremor in women. An additional feature importance analysis indicated that increased severity of dystonia affecting other body parts, severity of CD, and prolonged disease duration was associated with a lower likelihood of regular neck tremor while increased age predicted a higher likelihood.Conclusion: Machine learning recognized the most relevant clinical features that can predict concurrent neck tremor and its irregularity in a large multi-center dystonia cohort. These results may facilitate a more accurate description of neck tremor and improved care path in CD

Novel Eye Movement Disorders in Whipple’s Disease—Staircase Horizontal Saccades, Gaze-Evoked Nystagmus, and Esotropia

Whipple’s disease, a rare systemic infectious disorder, is complicated by the involvement of the central nervous system in about 5% of cases. Oscillations of the eyes and the jaw, called oculo-masticatory myorhythmia, are pathognomonic of the central nervous system involvement but are often absent. Typical manifestations of the central nervous system Whipple’s disease are cognitive impairment, parkinsonism mimicking progressive supranuclear palsy with vertical saccade slowing, and up-gaze range limitation. We describe a unique patient with the central nervous system Whipple’s disease who had typical features, including parkinsonism, cognitive impairment, and up-gaze limitation; but also had diplopia, esotropia with mild horizontal (abduction more than adduction) limitation, and vertigo. The patient also had gaze-evoked nystagmus and staircase horizontal saccades. Latter were thought to be due to mal-programmed small saccades followed by a series of corrective saccades. The saccades were disconjugate due to the concurrent strabismus. Also, we noted disconjugacy in the slow phase of gaze-evoked nystagmus. The disconjugacy of the slow phase of gaze-evoked nystagmus was larger during monocular viewing condition. We propose that interaction of the strabismic drifts of the covered eyes and the nystagmus drift, putatively at the final common pathway might lead to such disconjugacy