Search

Objective: Downbeat nystagmus (DBN) is the most frequent form of acquired persisting fixation nystagmus with different symptoms such as unsteadiness of gait, postural instability, and blurred vision with reduced visual acuity (VA) and oscillopsia. However, different symptomatic therapeutic principles are required, such as 3,4-diaminopyridine and 4-aminopyridine, that effectively suppress DBN. Chlorzoxazone (CHZ) is a nonselective activator of small conductance calcium-activated potassium (SK) channels that modifies the activity of cerebellar Purkinje cells. We evaluated the effects of this agent on DBN in an observational proof-of-concept pilot study. Methods: Ten patients received CHZ 500 mg 3 times a day for 1 or 2 weeks. Slow-phase velocity of DBN, VA, postural sway, and the drug's side effects were evaluated. Recordings were conducted at baseline, 90 minutes after first administration, and after 1 or 2 weeks. Results: Mean slow-phase velocity significantly decreased from a baseline of 2.74°/s ± 2.00 to 2.29°/s ± 2.12 (mean ± SD) 90 minutes after first administration and to 2.04°/s ± 2.24 (p < 0.001; post hoc both p = 0.024) after long-term treatment. VA significantly increased and postural sway in posturography showed a tendency to decrease on medication. Fifty percent of patients did not report any side effects. The most common reported side effect was abdominal discomfort and dizziness. Conclusions: The treatment with the SK-channel activator CHZ is a potentially new therapeutic agent for the symptomatic treatment of DBN. Classification of evidence: This study provides Class IV evidence that CHZ 500 mg 3 times a day may improve eye movements and visual fixation in patients with DBN.

Objective: The therapeutic effects of 4-aminopyridine (4AP) were investigated in a randomized, double-blind, crossover trial in 10 subjects with familial episodic ataxia with nystagmus. Methods: After randomization, placebo or 4AP (5 mg 3 times daily) was administered for 2 3-month-long treatment periods separated by a 1-month-long washout period. The primary outcome measure was the number of ataxia attacks per month; the secondary outcome measures were the attack duration and patient-reported quality of life (Vestibular Disorders Activities of Daily Living Scale [VDADL]). Nonparametric tests and a random-effects model were used for statistical analysis. Results: The diagnosis of episodic ataxia type 2 (EA2) was genetically confirmed in 7 subjects. Patients receiving placebo had a median monthly attack frequency of 6.50, whereas patients taking 4AP had a frequency of 1.65 ( p = 0.03). Median monthly attack duration decreased from 13.65 hours with placebo to 4.45 hours with 4AP ( p = 0.08). The VDADL score decreased from 6.00 to 1.50 ( p = 0.02). 4AP was well-tolerated. Conclusions: This controlled trial on EA2 and familial episodic ataxia with nystagmus demonstrated that 4AP decreases attack frequency and improves quality of life. Level of evidence: This crossover study provides Class II evidence that 4AP decreases attack frequency and improves the patient-reported quality of life in patients with episodic ataxia and related familial ataxias.

Background: In a recent study, the authors found that blinks in healthy volunteers always triggered ocular torsion quick phases during dynamic roll movements of the head. On the basis of this observation, they hypothesized that blinks in patients with a vestibular tone imbalance would also trigger torsional quick phases. Methods: Using video-oculography with a fixation target, the authors recorded the ocular torsion position of the left eye of 37 participants while they made voluntary blinks once every 6 to 10 seconds. The participants were recruited from four groups: two age groups of healthy volunteers with a mean ± SD age of 32 ± 4 (n = 9) and 65 ± 11 y (n = 9); patients with a unilateral vestibular disorder in an acute state (n = 12, 53 ± 17 y); and those in a persisting state in which spontaneous nystagmus had already faded (n = 9, 65 ± 13 y). Results: In the control groups of healthy volunteers, blinks triggered no or only small quick phases on the order of 0.1 deg. In both patient groups blinks always triggered quick phases with significantly higher amplitudes of 1.85 ± 1.02 deg and were followed by exponentially decaying slow-phases with time constants on the order of 1 to 2 seconds. Patients in the persisting state clearly differed from patients in the acute state in that their torsional spontaneous nystagmus had already vanished due to vestibular compensation. But surprisingly, these two groups did not show a large difference in terms of the effect of blinks on ocular torsion. The authors always observed torsional quick phases with the upper pole of the eye beating away from the side of the lesion. Conclusions: Blinks are able to trigger torsional quick phases in patients with both acute and persisting vestibular disorders. The side of the impairment can be determined from the direction in which the eye is rotated after a blink. Thus, ocular torsion recordings during blinks can be used as a simple clinical test for a vestibular tone imbalance, particularly during a persisting failure in which spontaneous nystagmus has resolved and can therefore no longer be used for diagnosis.

Background: Neurologic disorders in which the etiology and pathogenesis are not yet understood are termed idiopathic. Downbeat nystagmus (DBN) is a frequent eye movement disorder that clinically manifests with oscillopsia and postural instability. Forty percent of patients with DBN are classified as having idiopathic DBN, because no underlying pathology can be demonstrated by conventional MRI or laboratory tests. Methods: We evaluated gray matter brain volumes of 11 patients with idiopathic DBN and compared them to those of healthy controls using voxel-based morphometry. In a second, functional MRI experiment, patients and controls performed downward smooth pursuit eye movements (DOWN), which were then compared with straight-ahead fixation of a stationary target (MID). Results: Small areas of localized gray matter atrophy were detected in the lateral cerebellar hemispheres (lobule VI) and ocular motor vermis of patients with idiopathic DBN, but not in the flocculus and paraflocculus. The functional imaging data, however, revealed reduced activation in the parafloccular lobule and in the ponto-medullary brainstem of the patients when they performed smooth pursuit eye movements downwards. Conclusions: The applied specialized imaging and data analysis techniques disclosed pathologies in an idiopathic eye movement disorder. The focal atrophy found in the vermal and lateral cerebellar regions in downbeat nystagmus (DBN) may lead to deficits in smooth pursuit eye movement initiation, which in turn causes hypofunction of the parafloccular lobe, associated with DBN. Our data are in line with experiments in primates showing that ablation of the floccular and parafloccular lobes disrupts smooth pursuit and causes DBN.

The authors evaluated floccular activity with fMRI during the performance of vertical smooth pursuit eye movements in four patients with downbeat nystagmus (DBN) due to cerebellar degeneration and in 16 healthy controls. Region of interest analysis revealed a significantly diminished activation of both floccular lobes during downward but not upward pursuit in DBN. These imaging data support the view that a functional deficiency of the flocculi in downward pursuit causes DBN.

Patients with episodic ataxia type 2 (EA2) can often be successfully treated with acetazolamide. The authors report three patients with EA2 (two with proven mutations in the CACNA1A gene) whose attacks were prevented with the potassium channel blocker 4-aminopyridine (4-AP; 5 mg tid). Attacks recurred after treatment was stopped; subsequent treatment alleviated the symptoms (mean follow-up time 6 months). These effects might be due to an improvement of the impaired functioning of Purkinje cells.

Downbeat nystagmus (DBN), the most frequent form of acquired persisting fixation nystagmus, is hypothesized to occur when physiologic, inhibitory cerebellar input to the vestibular nuclei is inhibited. Bilateral cerebellar lesions affecting the vestibulocerebellum or bilateral paramedian brainstem lesions could induce such inhibition.1 GABAergic, glutaminergic, or cholinergic drugs have been used to manage DBN with moderate success.2 3,4-Diaminopyridine (3,4-DAP) was shown recently to effectively suppress DBN.3 In animal experiments, the related 4-aminopyridine (4-AP) increased the excitability of Purkinje cells (PCs).4 Both agents seem to influence DBN by increasing the physiologic, inhibitory influence of the vestibulocerebellum on the vestibular nuclei.3 4-AP penetrates the blood–brain barrier better than 3,4-DAP but has not yet been tested for management of ocular motor disorders. To evaluate how aminopyridines affect DBN and to test whether 4-AP is also effective, we measured DBN, smooth pursuit, gaze holding, and the gain of the vestibular ocular reflex (VOR) with the search coil technique in one patient. A 65-year-old pharmacist had blurred vision for 7 years that increased during lateral gaze. Neurologic examination was normal, except for DBN during fixation, impaired smooth pursuit, and postural imbalance. DBN increased during lateral and downward gaze and convergence. Brain MRI and blood chemistry (including vitamin B12 and Mg2+ …

{#article-title-2} “A randomized trial of 4-aminopyridine in EA2 and related familial episodic ataxias”1 follows this group's preliminary report on how 4-aminopyridine (4-AP) is one of few compounds that effectively blocks attacks in EA2 patients.1,2 The authors convincingly demonstrate that 4-AP reduces the frequency of attacks, but it would be interesting to know if it modified the severity or duration of the attacks. A …