Effects of 4-aminopyridine on nystagmus and vestibulo-ocular reflex in ataxia-telangiectasia

Ataxia-telangiectasia (A-T) is a progressive neurodegenerative disorder with prominent eye movement deficits localizing to the cerebellum. We sought to determine if 4-aminopyridine (4-AP), which putatively enhances the precision of Purkinje neurons, could improve the disorders of eye movements and vestibular function in A-T. The influence of 4-AP on disorders of eye movements and vestibular function was studied in four A-T patients. The effects on the cerebellar control of vestibulo-ocular reflex (VOR) was quantitatively assessed by the decay time constant of per- and post-rotational nystagmus during constant velocity en bloc rotations. The length of the VOR time constant determines the fidelity of the vestibular velocity storage, a neural mechanism that increases the bandwidth of VOR under cerebellar control. The VOR time constant was not increased in A-T patients. The latter is explained by the extent of cerebellar lesion as previously described in A-T and other cerebellar disorders. Nevertheless, 4-AP shortened the VOR time constant during horizontal rotations. Severe disinhibition of velocity storage in subjects with putatively profound cerebellar degeneration manifest periodic alternating nystagmus (PAN). Among two A-T subjects who manifested PAN, 4-AP reduced the peak slow phase velocity of the more severely affected individual and abrogated the PAN in the other. Two A-T subjects manifested horizontal and vertical spontaneous nystagmus (SN) in primary gaze, 4-AP reduced its slow phase velocity. We conclude that in subjects with A-T 4-AP has a prominent effect on the ocular motor and vestibular deficits that are ascribed to the loss of cerebellar Purkinje neurons.     

Anti-GAD antibodies and periodic alternating nystagmus

BACKGROUND: Autoantibodies directed against glutamic acid decarboxylase (GAD-Ab) have recently been described in a few patients with progressive cerebellar ataxia, suggesting an autoimmune physiopathologic mechanism. OBJECTIVE: To determine the exact role of GAD-Ab and gamma-aminobutyric acid (GABA)-ergic neurotransmission in the pathogenesis of cerebellar ataxia. DESIGN: Case report. SETTING: University neurological hospital. PATIENT: We report the case of a patient with subacute cerebellar ataxia associated with GAD-Ab showing periodic alternating nystagmus (PAN). INTERVENTION: Baclofen, a GABAergic medication, was given to the patient. MAIN OUTCOME MEASURES: Eye movement recording of spontaneous nystagmus and postrotatory vestibular responses. RESULTS: Baclofen was effective in suppressing PAN and improving postrotatory vestibular responses but not for improving cerebellar ataxia. CONCLUSION: The presence of PAN and the response to baclofen provide a unique opportunity to suggest a direct role of GAD-Ab in cerebellar dysfunction in this patient.     

Pathologic nystagmus and related phenomena. A review

Pathological nystagmus may be spontaneous, positional, or gaze-evoked. Peripheral vestibular nystagmus is usually rotatory, the horizontal component being most prominent. It is - in contrast to a central vestibular nystagmus - strongly inhibited by fixation. Spontaneous congenital nystagmus is also prominent with fixation, but it can usually be distinguished from acquired fixation nystagmus based on its long duration, atypical waveforms and high frequency. Two general types of positional nystagmus can be identified on the basis of nystagmus regularity: static and paroxysmal. The most common variety of positional nystagmus is the so-called benign paroxysmal positional nystagmus, which in the majority of cases occurs as an isolated symptom of unknown cause. Gaze-evoked nystagmus, prominent with fixation, includes dissociated, rebound and gaze-paretic nystagmus forms. Symmetrical gaze-evoked nystagmus is most commonly produced by ingestion of certain drugs. Phenomena related to nystagmus include: amblyopic, voluntary, and convergence-retraction nystagmus, ocular dysmetria, ocular flutter, opsoclonus, ocular bobbing, and ocular myoclonus.     

The effects of the "vestibular sedative" drug, Flunarizine upon the vestibular and oculomotor systems.

The effects of the "vestibular sedative" drug Flunarizine upon the oculomotor functions of pursuit and voluntary saccades and upon the vestibular response (to rotational stimuli) were assessed in twenty volunteer subjects. The study was then extended to three patients with chronic imbalance of central origin who had reported a beneficial symptomatic response to the drug. Three of the volunteer subjects were found to have a directional preponderance (presumed to arise from peripheral dysfunction). In the remaining seventeen normal subjects Flunarizine was found to reduce the amplitudes of fast phases of vestibular nystagmus. The directional preponderance in the other three subjects was redressed through production of fast phases which were of lower and more uniform amplitude. In the patients, in addition to a reduction in fast phase amplitude, there was a reduction or abolition of after nystagmus. In no case was any reduction in slow phase velocity observed. Pursuit and voluntary saccades were unaffected by the drug. It was concluded, on the basis that the fast phases of nystagmus are centrally generated, that Flunarizine has a central action rather than a depressant effect upon the vestibular end organ. In view of known oculomotor physiology and pharmacology it is proposed that vestibular sedatives act by depression of Type II vestibular neurons, and modification of the functional relationships between the vestibular nuclei, the perihypoglossal nuclei and the flocculus of the cerebellum. A trial of vestibular active drug is indicated particularly in patients in whom asymmetry of the vestibular response and/or abnormal after nystagmus is demonstrated.     

Abnormal visual--vestibular interactions in psychosis

Vestibular reactivity and suppression of caloric nystagmus by visual fixation were examined in 40 psychiatric patients (36 schizophrenics and 4 manic-depressives) and 20 normal control subjects. Indices of reactivity commonly considered to reflect vestibular integrity, namely, slow-phase velocity and bilateral symmetry of response, did not discriminate patients from controls. However, response irregularities in the form of dysrhythmia and slower velocity of the nystagmus fast (saccadic) component were present to a significant degree in patients. Visual fixation effectively suppressed caloric nystagmus in normal controls, but not in hospitalized patients. This failure of fixation suppression was most marked in patients showing active symptomatology. These results indicate a central regulatory dysfunction of visual-vestibular interaction in psychiatric patients which varies with intensity of psychotic symptomatology and which does not seem attributable to medication or attentional factors.     

Eye movement related neurons in the cat pontine reticular formation: projection to the flocculus

This study examines projection to the cerebellar flocculus of eye movement-related neurons in the median and paramedian part of the cat pontine tegmentum between the trochlear and the abducens nucleus. They were identified by rhythmic activity related to horizontal vestibular nystagmus induced by sinusoidal rotation. These neurons were classified into several groups by their discharge patterns during nystagmus, using criteria of earlier studies on saccadic eye movements and vestibular nystagmus in the monkey. Electrical stimulation of the ipsilateral flocculus elicited antidromic spike responses in a number of burst-tonic neurons and long-lead and medium-lead burst neurons. These neurons were located in and around the medial longitudinal fasciculus, the nucleus raphe pontis and the nucleus reticularis tegmenti pontis. A few neurons tested were also activated antidromically by stimulation of the contralateral flocculus. In contrast, no pauser neurons were activated from the ipsi-lateral flocculus. It is concluded that eye movement-related neurons in the medial pontine tegmentum, except for pauser neurons, directly project to the flocculus and may convey information about eye movements of visual and vestibular origins to the flocculus.     

Bedside Evaluation of Dizzy Patients

In recent decades there has been marked progress in the imaging and laboratory evaluation of dizzy patients. However, detailed history taking and comprehensive bedside neurotological evaluation remain crucial for a diagnosis of dizziness. Bedside neurotological evaluation should include examinations for ocular alignment, spontaneous and gaze-evoked nystagmus, the vestibulo-ocular reflex, saccades, smooth pursuit, and balance. In patients with acute spontaneous vertigo, negative head impulse test, direction-changing nystagmus, and skew deviation mostly indicate central vestibular disorders. In contrast, patients with unilateral peripheral deafferentation invariably have a positive head impulse test and mixed horizontal-torsional nystagmus beating away from the lesion side. Since suppression by visual fixation is the rule in peripheral nystagmus and is frequent even in central nystagmus, removal of visual fixation using Frenzel glasses is required for the proper evaluation of central as well as peripheral nystagmus. Head-shaking, cranial vibration, hyperventilation, pressure to the external auditory canal, and loud sounds may disclose underlying vestibular dysfunction by inducing nystagmus or modulating the spontaneous nystagmus. In patients with positional vertigo, the diagnosis can be made by determining patterns of the nystagmus induced during various positional maneuvers that include straight head hanging, the Dix-Hallpike maneuver, supine head roll, and head turning and bending while sitting. Abnormal smooth pursuit and saccades, and severe imbalance also indicate central pathologies. Physicians should be familiar with bedside neurotological examinations and be aware of the clinical implications of the findings when evaluating dizzy patients.     

Spontaneous vertical nystagmus

We reviewed the clinical and oculographic features of 106 patients with spontaneous vertical nystagmus evaluated at the UCLA Eye Movement Laboratories over the past 10 years. Downbeat nystagmus typically occurred with lesions involving the caudal midline cerebellum whereas upbeat nystagmus was most often associated with lesions of the central medulla. Since the vestibular systems is the main source of tonic input to the oculomotor neurons and since the up and down vestibulo-ocular pathways separate beginning at the level of the vestibular nuclei asymmetric involvement of these pathways can explain spontaneous vertical nystagmus.     

Fixation suppression of optokinetic nystagmus modulates cortical visual-vestibular interaction

Water activation positron emission tomography and statistical group analysis were used to evaluate differences in activation-deactivation patterns during small-field visual motion stimulation, eliciting rightward optokinetic nystagmus and its fixation suppression in 12 healthy volunteers. Bilateral patterns of activation in the visual cortex, including the motion-sensitive area MT/V5, and deactivations in an assembly of vestibular areas (posterior insula, thalamus, anterior cingulate gyrus) during optokinetic nystagmus was markedly diminished or totally absent during its fixation suppression. This finding agrees with the concept of a reciprocal inhibitory interaction between the visual-optokinetic and the vestibular systems, which takes place at a lower level during fixation suppression, because the potential mismatch between the two sensory inputs, visual and vestibular, is then reduced.     

The site of brainstem lesions causing semicircular canal paresis: an MRI study.

Ten patients with canal paresis of central origin and ten patients with peripheral canal paresis were studied using MRI of the brainstem to identify lesions within the central vestibular pathways. In the central group, the magnitude of the canal paresis was generally lower than in the peripheral group and removal of fixation had little effect on the nystagmic response. In the peripheral group, removal of fixation enhanced the nystagmus and lessened the discrepancy between the two ears. Statistical processing of the MRI showed that in the central group significant spatially coincident lesions occurred within the medial vestibular nucleus, lateral vestibular nucleus and proximal portion of the vestibular fascicle.     

Oculomotor and vestibular findings in autosomal recessive spastic ataxia of Charlevoix-Saguenay.

Electronystagmographic recordings were made of oculomotor and vestibular function in 11 patients with autosomal recessive spastic ataxia of Charlevoix-Saguenay. All had horizontal gaze nystagmus, marked impairment of smooth ocular pursuit and optokinetic nystagmus, and defective fixation suppression of caloric nystagmus. Many had saccadic dysmetria, but saccade velocity was probably unaffected. Abnormalities pointing to brainstem disturbance were sparse. The findings are thought to indicate mainly diffuse cerebellar disease, with particular involvement of vermis and vestibulo-cerebellum.     

Translocation of cortical migraine phosphenes through eye movements and vestibular stimulation]

Self-observations of migraine-phosphenes demonstrate the influence of gaze and vestibular stimuli upon cortical foci in the human are 17. The scintillating phosphenes appearing in one half-field are seen as moving during voluntary gaze shifts: Saccades and pursuit movements translocate the phosphenes besides the fixation point within a stable outer visual surround. Vestibular stimuli cause a shift and deformation of the phosphene towards the slow phase direction of vestibular nystagmus. In contrast to voluntary eye movements the phosphenes do not transgress the midline during vestibular nystagmus and the translocation is much smaller than the sum nystagmus amplitudes elicited by head acceleration.     

Optic nystagmus and vestibular nuclei: Unitary activity of vestibular neurons during nystagmus

The behavior of 102 vestibular neurons during optic nystagmus was investigated in 25 guinea pigs with extracellular microelectrodes. The recorded vestibular neurons were electrophysiologically identified by their orthodromic response to ipsilateral labyrinthine stimulation and by antidromic activation from the medial longitudinal fascicle. Of the 102 recorded units, 92 were modulated by the electrical stimulation of at least one optic nerve. The presence of vestibular neurons sensitive to the direction of nystagmus induced by labyrinthine or optic stimulation was also analyzed.     

Impaired suppression of vestibular nystagmus by fixation in cerebellar and noncerebellar patients

Summary The suppression of vestibular nystagmus (VN) by fixation of a small visual target moving with the observer was tested while subjects seated on a rotatable chair were oscillated at 0.1 Hz and peak accelerations of +-10 to 130°/s². Total amplitudes of nystagmus during movement towards one direction occurring despite intended fixation were compared to slow phases of optokinetic nystagmus (OKN) and smooth pursuit (SP) towards the opposite direction.Supported by the Deutsche Forschungsgemeinschaft, SFB 70 (Hirnforschung und Sinnesphysiologie)     

Alexander's law: its behavior and origin in the human vestibulo-ocular reflex

Alexander's law refers to the phenomenon in which the spontaneous nystagmus of a patient with a vestibular lesion is more intense when the patient looks in the quick-phase than in the slow-phase direction. Alexander's law was investigated in normal subjects as well as patients with vestibular lesions. During sinusoidal rotations of normal subjects, there was no trace of this phenomenon when subjects looked 25 degrees left and right in the dark. The phenomenon of Alexander's law is therefore created centrally and is not due to any mechanical properties of the orbit. During rotation at constant velocity in the dark, normal subjects did weakly demonstrate Alexander's law because of a mild gaze-evoked nystagmus present in normal subjects in the dark. Gaze-evoked nystagmus from a cerebellar lesion involved a pronounced demonstration of Alexander's law during rotatory nystagmus. In patients with a vestibular lesion and a mild spontaneous nystagmus in the dark that obeyed Alexander's law, the nystagmus reversed upon far gaze in the slow-phase direction. We propose that in patients with a vestibular lesion, the phenomenon of Alexander's law is created by the sum of vestibular nystagmus and an abnormally large gaze-evoked nystagmus that is consequent to the vestibular lesion. This conclusion has a number of neurological implications concerning the ways in which the nervous system attempts to compensate for vestibular lesions.     

VESTIBULAR ABERRATIONS IN MULTIPLE SCLEROSIS

82 patients with multiple sclerosis (MS), selected on McAlpine's criteria, were examined by a battery of clinical vestibular tests. Spontaneous nystagmus, positional nystagmus or pathological differential caloric tests were found in 49 (60 per cent) patients. Pathological horizontal optokinetic nystagmus occurred in 47 (57 per cent) patients. In 36 cases, the optokinetic nystagmus was pathological to both sides; in 28 cases combined with a pathological vertical optokinetic nystagmus, which indicates diffuse cerebral lesions. Lesions in the central vestibular system and in the optokinetic pathways are frequently discovered in early or atypical cases of MS by a relevant examination. As it was possible to find subclinical signs of MS by the examination mentioned, it is recommended that patients suspected of suffering from MS be investigated by a vestibular examination, including an examination of the optokinetic nystagmus.     

Electrophysiological correlates of the reversed postoptokinetic nystagmus in the rabbit: Activity of vestibular and floccular neurons

Unit activity changes accompanying the optokinetic nystagmus (OKN) and reversed postoptokinetic nystagmus (RPN) in the rabbit were examined in 180 vestibular and floccular neurons. After initial charging of the RPN generator by 60-min optokinetic stimulation, a sequence of 1-min optokinetic stimulation (OKN) followed by 1-min darkness (RPN) and 1-min illumination of the stationary optokinetic drum (L), was cycled while corresponding unit activity changes were recorded during 3–5 cycles and evaluated with a computer. About 50% of vestibular neurons (type A) increased their activity during OKN and/or decreased it during RPN with respect to the L period, whereas 24% (type B) reacted in a reciprocal manner. The remaining neurons were either unaffected or responded in an atypical way. Most floccular neurons (75%) were activated during ipsilateral optokinetic stimulation, but were not significantly affected by RPN. It is suggested that the neural trace of RPN develops in the vestibular complex and vestibulocerebellum as a part of the process compensating for the effect of continued optokinetic stimulation.     

Assessment of vestibulo-ocular reflexes in congenital nystagmus

The vestibulo-ocular reflex and its suppression by fixation of a target rotating with the subject were tested in 18 subjects with congenital nystagmus using steps of constant velocity rotation and sinusoidal stimuli swept in frequency between 0.01 and 1.0 Hz. Responses to stopping stimuli were abnormal in waveform and of short duration in most subjects tested. This pattern was attributed to masking of the response by spontaneous eye movements and to adaptation. In contrast, during both oscillation in the dark and attempted suppression of the vestibulo-ocular reflex, all subjects had nystagmus that was modulated with the stimulus during all frequencies of stimulation. The phase relationship of the nystagmus to the motion stimulus was the same as in normal subjects. Estimates of the gain of the vestibulo-ocular reflex response were not meaningful because of contamination of the vestibular response by the congenital nystagmus waveforms. Modulation of amplitude and reversal of nystagmus in phase with the vestibular stimulus at all frequencies of oscillation were shown most clearly during attempted suppression of the vestibulo-ocular reflex. This finding is clinically useful because it establishes suppression as a test of the presence of vestibular function in congenital nystagmus.     

Absence of nystagmus during REM sleep in patients with vestibular neuritis

Saccades, including fast phases of nystagmus, disappear during drowsiness and non-rapid eye movement (NREM) sleep, but are present during the alert state and REM sleep. The purpose of this study was to determine whether spontaneous nystagmus is present in patients with vestibular neuritis during REM sleep. Eight patients with spontaneous nystagmus due to vestibular neuritis and eight control patients without any nystagmus underwent at least one night of polysomnography. Fast phases of nystagmus were analyzed. The number of right and left horizontal saccades were counted, first during 3-5 minute samples of the awake state before sleep onset, then during the first REM episode and the last REM episode of nocturnal sleep, and finally during the alert state in the morning after nocturnal sleep. All patients with vestibular neuritis showed significantly more saccades (fast phases) towards the side contralateral to their vestibular lesion in the awake state before and after the polysomnography. This reflects their spontaneous nystagmus. By contrast, during REM sleep the patients with vestibular neuritis showed no preponderance in saccade direction. The eye movement pattern in REM was the same for patients and controls. In conclusion, peripheral vestibular imbalance producing nystagmus in vestibular neuritis in the awake state is not active at the brain stem level during REM sleep.     

Hyperventilation-induced nystagmus in patients with vestibular schwannoma

OBJECTIVE: To analyze the nystagmus evoked by hyperventilation in patients with unilateral vestibular schwannoma and to use this information to predict the effects of hyperventilation on individual ampullary nerves. METHODS: Three-dimensional scleral search coil eye movement recording techniques were used to record the magnitude and time course of eye movements in six patients with unilateral vestibular schwannoma and hyperventilation-induced nystagmus. The presenting complaints in five of these patients were vertigo or dysequilibrium. RESULTS: The eye movement response to hyperventilation was a "recovery" nystagmus with slow-phase components corresponding to excitation of the affected vestibular nerve. Projection of the eye velocity vector into the plane of the semicircular canals revealed that fibers arising from the ampulla of the horizontal canal were most affected by hyperventilation with lesser activation of fibers to the superior canal and smaller, more variable responses from posterior canal fibers. CONCLUSIONS: The three-dimensional characteristics of the nystagmus evoked by hyperventilation in patients with vestibular schwannoma provide insight into the vestibular end organs affected by the tumor and the mechanism responsible for the nystagmus. This finding indicates that hyperventilation resulted in a transient increase in activity from these partially demyelinated axons.