A randomised double-blind, cross-over trial of 4-aminopyridine for downbeat nystagmus—effects on slowphase eye velocity, postural stability, locomotion and symptoms

Claaßen, Jens; Spiegel, Rainer; Kalla, Roger; Faldon, Mary; Kennard, Christopher; Danchaivijitr, Chotipat; Bardins, Stanislavs; Rettinger, N.; Schneider, Erich; Brandt, Thomas; Jahn, Klaus; Teufel, Julian; Strupp, Michael; Bronstein, Adolfo M.

doi:10.1136/jnnp-2012-304736

Cited by 86 publications

(47 citation statements)

References 42 publications

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“…Potassium channel blockers, 3,4-diaminopyridine and 4-aminopyridine, decrease DBN in gravity-dependent head positions by reducing the overactive otolith-ocular reflex and concomitant reduction of oscillopsia [2, 33]. They also improve postural balance [34, 35]. Unlike expected we did not find changes in postural stability with different head positions.…”

Section: Discussionmentioning

confidence: 59%

Postural Ataxia in Cerebellar Downbeat Nystagmus: Its Relation to Visual, Proprioceptive and Vestibular Signals and Cerebellar Atrophy

et al. 2017

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BackgroundThe cerebellum integrates proprioceptive, vestibular and visual signals for postural control. Cerebellar patients with downbeat nystagmus (DBN) complain of unsteadiness of stance and gait as well as blurred vision and oscillopsia.ObjectivesThe aim of this study was to elucidate the differential role of visual input, gaze eccentricity, vestibular and proprioceptive input on the postural stability in a large cohort of cerebellar patients with DBN, in comparison to healthy age-matched control subjects.MethodsOculomotor (nystagmus, smooth pursuit eye movements) and postural (postural sway speed) parameters were recorded and related to each other and volumetric changes of the cerebellum (voxel-based morphometry, SPM).ResultsTwenty-seven patients showed larger postural instability in all experimental conditions. Postural sway increased with nystagmus in the eyes closed condition but not with the eyes open. Romberg’s ratio remained stable and was not different from healthy controls. Postural sway did not change with gaze position or graviceptive input. It increased with attenuated proprioceptive input and on tandem stance in both groups but Romberg’s ratio also did not differ. Cerebellar atrophy (vermal lobule VI, VIII) correlated with the severity of impaired smooth pursuit eye movements of DBN patients.ConclusionsPostural ataxia of cerebellar patients with DBN cannot be explained by impaired visual feedback. Despite oscillopsia visual feedback control on cerebellar postural control seems to be preserved as postural sway was strongest on visual deprivation. The increase in postural ataxia is neither related to modulations of single components characterizing nystagmus nor to deprivation of single sensory (visual, proprioceptive) inputs usually stabilizing stance. Re-weighting of multisensory signals and/or inappropriate cerebellar motor commands might account for this postural ataxia.

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Section: Discussionmentioning

confidence: 59%

Postural Ataxia in Cerebellar Downbeat Nystagmus: Its Relation to Visual, Proprioceptive and Vestibular Signals and Cerebellar Atrophy

et al. 2017

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“…On the basis of this pathological mechanism, a prospective, randomized, placebo-controlled study of the effects of aminopyridines has indicated a significant improvement of symptoms [68], and the observed effects have since been supported by findings from other studies [70, 71]. The strongest effect was observed in patients with cerebellar atrophy [63].…”

Section: Common Forms Of Central Nystagmusmentioning

confidence: 92%

Central ocular motor disorders, including gaze palsy and nystagmus

et al. 2014

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An impairment of eye movements, or nystagmus, is seen in many diseases of the central nervous system, in particular those affecting the brainstem and cerebellum, as well as in those of the vestibular system. The key to diagnosis is a systematic clinical examination of the different types of eye movements, including: eye position, range of eye movements, smooth pursuit, saccades, gaze-holding function and optokinetic nystagmus, as well as testing for the different types of nystagmus (e.g., central fixation nystagmus or peripheral vestibular nystagmus). Depending on the time course of the signs and symptoms, eye movements often indicate a specific underlying cause (e.g., stroke or neurodegenerative or metabolic disorders). A detailed knowledge of the anatomy and physiology of eye movements enables the physician to localize the disturbance to a specific area in the brainstem (midbrain, pons or medulla) or cerebellum (in particular the flocculus). For example, isolated dysfunction of vertical eye movements is due to a midbrain lesion affecting the rostral interstitial nucleus of the medial longitudinal fascicle, with impaired vertical saccades only, the interstitial nucleus of Cajal or the posterior commissure; common causes with an acute onset are an infarction or bleeding in the upper midbrain or in patients with chronic progressive supranuclear palsy (PSP) and Niemann–Pick type C (NP-C). Isolated dysfunction of horizontal saccades is due to a pontine lesion affecting the paramedian pontine reticular formation due, for instance, to brainstem bleeding, glioma or Gaucher disease type 3; an impairment of horizontal and vertical saccades is found in later stages of PSP, NP-C and Gaucher disease type 3. Gaze-evoked nystagmus (GEN) in all directions indicates a cerebellar dysfunction and can have multiple causes such as drugs, in particular antiepileptics, chronic alcohol abuse, neurodegenerative cerebellar disorders or cerebellar ataxias; purely vertical GEN is due to a midbrain lesion, while purely horizontal GEN is due to a pontomedullary lesion. The pathognomonic clinical sign of internuclear ophthalmoplegia is an impaired adduction while testing horizontal saccades on the side of the lesion in the ipsilateral medial longitudinal fascicule. The most common pathological types of central nystagmus are downbeat nystagmus (DBN) and upbeat nystagmus (UBN). DBN is generally due to cerebellar dysfunction affecting the flocculus bilaterally (e.g., due to a neurodegenerative disease). Treatment options exist for a few disorders: miglustat for NP-C and aminopyridines for DBN and UBN. It is therefore particularly important to identify treatable cases with these conditions.

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“…Since the latter is lipid-soluble and crosses the blood–brain barrier more easily [20, 21], 4-AP is preferred. Recently, a randomized double-blind crossover trial of 4-AP in DBN showed a reduction in slow phase velocity of DBN by half and an improvement of visual acuity at a dosage of 5 mg 4-AP four times a day [22]. Further on, 4-AP at a dosage of 10 mg four times a day reduced postural sway and improved motor performance assessed by the timed “get-up-and-go test.” However, there was no subjective improvement, which may be due to the short half-life of the drug.…”

Section: Drug Therapy For Cerebellar Ataxiamentioning

confidence: 99%

Consensus Paper: Management of Degenerative Cerebellar Disorders

et al. 2013

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Treatment of motor symptoms of degenerative cerebellar ataxia remains difficult. Yet there are recent developments that are likely to lead to significant improvements in the future. Most desirable would be a causative treatment of the underlying cerebellar disease. This is currently available only for a very small subset of cerebellar ataxias with known metabolic dysfunction. However, increasing knowledge of the pathophysiology of hereditary ataxia should lead to an increasing number of medically sensible drug trials. In this paper, data from recent drug trials in patients with recessive and dominant cerebellar ataxias will be summarized. There is consensus that up to date, no medication has been proven effective. Aminopyridines and acetazolamide are the only exception, which are beneficial in patients with episodic ataxia type 2. Aminopyridines are also effective in a subset of patients presenting with downbeat nystagmus. As such, all authors agreed that the mainstays of treatment of degenerative cerebellar ataxia are currently physiotherapy, occupational therapy, and speech therapy. For many years, well-controlled rehabilitation studies in patients with cerebellar ataxia were lacking. Data of recently published studies show that coordinative training improves motor function in both adult and juvenile patients with cerebellar degeneration. Given the well-known contribution of the cerebellum to motor learning, possible mechanisms underlying improvement will be outlined. There is consensus that evidence-based guidelines for the physiotherapy of degenerative cerebellar ataxia need to be developed. Future developments in physiotherapeutical interventions will be discussed including application of non-invasive brain stimulation.

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A randomised double-blind, cross-over trial of 4-aminopyridine for downbeat nystagmus—effects on slowphase eye velocity, postural stability, locomotion and symptoms

Cited by 86 publications

References 42 publications

Postural Ataxia in Cerebellar Downbeat Nystagmus: Its Relation to Visual, Proprioceptive and Vestibular Signals and Cerebellar Atrophy

Postural Ataxia in Cerebellar Downbeat Nystagmus: Its Relation to Visual, Proprioceptive and Vestibular Signals and Cerebellar Atrophy

Central ocular motor disorders, including gaze palsy and nystagmus

Consensus Paper: Management of Degenerative Cerebellar Disorders

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