Effects of intravenous opioids on eye movements in humans: possible mechanisms.

Oculomotor symptoms such as downbeat nystagmus can be due to side effects of drugs. We investigated the clinical effects as well as the eye movement symptoms after intravenous administration of opiates (pethidine and fentanyl). Eye movements were recorded with the magnetic search coil technique. All four normal subjects showed a transient disturbance of eye fixation with downbeat nystagmus, a range of saccadic intrusions and oscillations, including square wave jerks and saccadic pulses, lasting from 10 to 15 minutes. The gain of sinusoidal VOR and smooth pursuit was moderately decreased; in particular the vertical pursuit showed an upward velocity offset. On the basis of the clinical findings and of recent diprenorphine PET findings in humans, which detected opiod binding sites in the cerebellum and the known inhibitory action of opiates, we hypothesized that a cerebellar dysfunction occurs after opiate administration which could possibly be mediated by inhibition of the parallel fiber activation of the Purkinje cells. Furthermore, opiate binding sites in the vestibular nuclei could be responsible for the vertical vestibular tonus imbalance involved in the pathophysiolgy of downbeat nystagmus.

[Valproic acid in prophylaxis of bipolar disorder. A case of valproate-induced encephalopathy]. / Valproinsäure als Phasenprophylaktikum. Ein Fall von Valproat-Enzephalopathie.

A 28-year-old patient with a 5-year history of bipolar disorder developed signs of encephalopathy 2 weeks after the addition of valproic acid to his treatment regimen of doxepine, risperidone, and biperidene. The clinical signs were drowsiness, ataxic gait, asterixis, and a generalized epileptic seizure. Discontinuation of valproic acid gradually resulted in complete remission of these symptoms. Valproate encephalopathy has been described mainly in patients receiving anticonvulsant polytherapy. This complication might become more prevalent in psychiatric pharmacotherapy due to the increasing use of valproic acid.

Intermittent claudication due to ischaemia of the lumbosacral plexus.

The distinct clinical syndrome of exercise induced ischaemia of the lumbosacral plexus is not a widely known cause for intermittent claudication. Eight patients with the mentioned syndrome were investigated clinically, neurophysiologically, and with imaging techniques. The clinical examination showed a typical exercise induced sequence of symptoms: pain, paraesthesia, and sensory and motor deficits. The underlying vascular conditions were high grade stenoses or occlusions of the arteries supplying the lumbosacral plexus. Spinal stenosis could be excluded in all cases. Five patients received successful interventional radiological therapy. The syndrome can be diagnosed clinically and successful therapy is possible by interventional radiology.

Trigeminal neuralgia triggered by auditory stimuli in multiple sclerosis.

OBJECTIVES: To describe a patient with a demyelinating brainstem lesion who developed right-sided trigeminal neuralgia triggered by auditory stimuli and to discuss the pathophysiological mechanisms underlying this unusual phenomenon. DESIGN: Case report. SETTING: Referral center. PATIENT: A 27-year-old man who presented with clinical signs of a brainstem lesion developed right-sided trigeminal neuralgia triggered by auditory stimuli to the right ear. Magnetic resonance imaging and electrophysiological studies demonstrated a demyelinating lesion in the pons affecting the right lateral lemniscus and the right trigeminal pathway. This phenomenon completely subsided within 4 days. After a relapse, the diagnosis of clinically definite multiple sclerosis was made. CONCLUSION: Lateral spread of impulse activity within the demyelinating pontine lesion is the likely explanation for the unusual phenomenon of trigeminal neuralgia triggered by auditory stimuli.

Properties of horizontal saccades accompanied by blinks.

Using the magnetic search coil technique to record eye and lid movements, we investigated the effect of voluntary blinks on horizontal saccades in five normal human subjects. The main goal of the study was to determine whether changes in the dynamics of saccades with blinks could be accounted for by a superposition of the eye movements induced by blinks as subjects fixated a stationary target and saccadic movements made without a blink. First, subjects made voluntary blinks as they fixed on stationary targets located straight ahead or 20 degrees to the right or left. They then made saccades between two continuously visible targets 20 or 40 degrees apart, while either attempting not to blink, or voluntarily blinking, with each saccade. During fixation of a target located straight ahead, blinks induced brief downward and nasalward deflections of eye position. When subjects looked at targets located at right or left 20 degrees, similar initial movements were made by four of the subjects, but the amplitude of the adducted eye was reduced by 65% and was followed by a larger temporalward movement. Blinks caused substantial changes in the dynamic properties of saccades. For 20 degrees saccades made with blinks, peak velocity and peak acceleration were decreased by approximately 20% in all subjects compared with saccades made without blinks. Blinks caused the duration of 20 degrees saccades to increase, on average, by 36%. On the other hand, blinks had only small effects on the gain of saccades. Blinks had little influence on the relative velocities of centrifugal versus centripetal saccades, and abducting versus adducting saccades. Three of five subjects showed a significantly increased incidence of dynamic overshoot in saccades accompanied by blinks, especially for 20 degrees movements. Taken with other evidence, this finding suggests that saccadic omnipause neurons are inhibited by blinks, which have longer duration than the saccades that company them. In conclusion, the changes in dynamic properties of saccades brought about by blinks cannot be accounted for simply by a summation of gaze perturbations produced by blinks during fixation and saccadic eye movements made without blinks. Our findings, especially the appearance of dynamic overshoots, suggest that blinks affect the central programming of saccades. These effects of blinks need to be taken into account during studies of the dynamic properties of saccades.

A double-blind controlled study of gabapentin and baclofen as treatment for acquired nystagmus.

We conducted a double-blind crossover trial comparing gabapentin (up to 900 mg/day) to baclofen (up to 30 mg/day) as therapy for acquired nystagmus in 21 patients. We measured visual acuity and the nystagmus before, and at the end of, 2 weeks on each medication. For a group of 15 patients with acquired pendular nystagmus (APN), visual acuity improved significantly with gabapentin, but not with baclofen. Gabapentin significantly reduced APN median eye speed in all three planes, but baclofen did so only in the vertical plane. In 10 patients with APN, the reduction of nystagmus with gabapentin was substantial and 8 of these elected to continue taking the drug. In 6 patients with downbeat or torsional downbeat nystagmus, changes in median slow-phase eye speed were less consistent with both drugs, either increasing or decreasing, and being dependent on viewing conditions. Only 1 patient showed consistent reduction of median eye speed, and this was achieved by either drug. Our findings suggest that gabapentin may be an effective treatment for many patients with APN and that occasional patients with downbeat nystagmus will respond to gabapentin or baclofen.

Torsional eye movements in patients with skew deviation and spasmodic torticollis: responses to static and dynamic head roll.

We measured torsional eye movements induced by sinusoidal rotation or static tilt, of the head in roll while viewing a far or near target in 4 patients with skew deviation due to brainstem lesions, 4 patients with spasmodic torticollis (ST), 2 patients with unilateral eighth nerve section (VIIIS), and 10 normal subjects. Torsional nystagmus was present in all 4 patients with skew deviation. In subjects and patients, responses to both sinusoidal and static roll were larger while viewing the far target, consistent with factors dictated by geometry. Response gains to sinusoidal roll were abnormal in 3 patients with skew (increased in one, decreased in two), abnormal in 3 with ST (increased in 1, decreased in 2), and in abnormal both VIIIS patients (decreased). Greater abnormalities were evident in 3 skew patients while rolling away from the side of their brainstem lesions and in both VIIIS patients while rolling toward their lesioned ears. There were similar but less pronounced changes during static head roll. We conclude that patients with skew, ST, and VIIIS may all have abnormal ocular counter-rolling that is more evident during dynamic testing while viewing a far target. Such abnormalities endure because of the limited influence exerted by vision on torsional eye movements.

Evidence for independent feedback control of horizontal and vertical saccades from Niemann-Pick type C disease.

We measured the eye movements of three sisters with Niemann-Pick type C disease who had a selective defect of vertical saccades, which were slow and hypometric. Horizontal saccades, and horizontal and vertical pursuit and vestibular eye movements were similar to control subjects. The initial movement of oblique saccades was mainly horizontal and most of the vertical component occurred after the horizontal component ended; this resulted in strongly curved trajectories. After completion of the horizontal component of an oblique saccade, the eyes oscillated horizontally at 10-20 Hz until the vertical component ended. These findings are best explained by models that incorporate separate feedback loops for horizontal and vertical burst neurons, and in which the disease selectively affects vertical burst neurons.

Transforming sensory perceptions into motor commands: evidence from programming of eye movements.

The visual stimulus for a saccadic eye movement is encoded in place-coded maps in cerebral cortex and the dorsal superior colliculus. In contrast, the motor command for the saccade is encoded by the temporal discharge properties of ocular motoneurons and premotor burst neurons in the brain-stem reticular formation. Thus, there is need for a spatial-temporal transformation of neural signals, and recent findings suggest that the superior colliculus might contribute to this process. The ventral, output layers of the superior colliculus encode the metric of the desired saccade in polar coordinates. However, premotor neurons in the pontine and mesencephalic reticular formation are organized to generate horizontal and vertical saccades, respectively. Studies of oblique saccades in patients with slow vertical components--due to Niemann-Pick type C disease--support the interpretation that the saccadic command from the reticular formation is encoded in Cartesian coordinates. Currently, saccades are thought to be generated under local, brain-stem feedback control in which current eye displacement is continuously subtracted from desired eye displacement to compute motor error--the remaining movement required for the eye to acquire the target. If the superior colliculus is positioned in the feedback loop, then there is a need for transformation of premotor signals back into a place-coded version of motor error. Recent studies suggest that, during the saccade, this might be achieved by a wave of activity spreading rostrally, which traverses the collicular map in a direction corresponding to progressively smaller movements and finally activates a group of neurons concerned with fixation. These new hypotheses are ripe for testing by basic and clinical studies. By confronting the issue of what signal transformations are required to program visually guided saccades, new experimental approaches have emerged. Such computational approaches offer insights into how the brain controls behavior not just by measuring stimulus and response, but by asking what "currency" is being used by interacting populations of neurons at any stage in the process.

Saccades to remembered targets: the effects of smooth pursuit and illusory stimulus motion.

1. Measurements were made in four normal human subjects of the accuracy of saccades to remembered locations of targets that were flashed on a 20 x 30 deg random dot display that was either stationary or moving horizontally and sinusoidally at +/-9 deg at 0.3 Hz. During the interval between the target flash and the memory-guided saccade, the "memory period" (1.4 s), subjects either fixated a stationary spot or pursued a spot moving vertically sinusoidally at +/-9 deg at 0.3 Hz. 2. When saccades were made toward the location of targets previously flashed on a stationary background as subjects fixated the stationary spot, median saccadic error was 0.93 deg horizontally and 1.1 deg vertically. These errors were greater than for saccades to visible targets, which had median values of 0.59 deg horizontally and 0.60 deg vertically. 3. When targets were flashed as subjects smoothly pursued a spot that moved vertically across the stationary background, median saccadic error was 1.1 deg horizontally and 1.2 deg vertically, thus being of similar accuracy to when targets were flashed during fixation. In addition, the vertical component of the memory-guided saccade was much more closely correlated with the "spatial error" than with the "retinal error"; this indicated that, when programming the saccade, the brain had taken into account eye movements that occurred during the memory period. 4. When saccades were made to targets flashed during attempted fixation of a stationary spot on a horizontally moving background, a condition that produces a weak Duncker-type illusion of horizontal movement of the primary target, median saccadic error increased horizontally to 3.2 deg but was 1.1 deg vertically. 5. When targets were flashed as subjects smoothly pursued a spot that moved vertically on the horizontally moving background, a condition that induces a strong illusion of diagonal target motion, median saccadic error was 4.0 deg horizontally and 1.5 deg vertically; thus the horizontal error was greater than under any other experimental condition. 6. In most trials, the initial saccade to the remembered target was followed by additional saccades while the subject was still in darkness. These secondary saccades, which were executed in the absence of visual feedback, brought the eye closer to the target location. During paradigms involving horizontal background movement, these corrections were more prominent horizontally than vertically. 7. Further measurements were made in two subjects to determine whether inaccuracy of memory-guided saccades, in the horizontal plane, was due to mislocalization at the time that the target flashed, misrepresentation of the trajectory of the pursuit eye movement during the memory period, or both. 8. The magnitude of the saccadic error, both with and without corrections made in darkness, was mislocalized by approximately 30% of the displacement of the background at the time that the target flashed. The magnitude of the saccadic error also was influenced by net movement of the background during the memory period, corresponding to approximately 25% of net background movement for the initial saccade and approximately 13% for the final eye position achieved in darkness. 9. We formulated simple linear models to test specific hypotheses about which combinations of signals best describe the observed saccadic amplitudes. We tested the possibilities that the brain made an accurate memory of target location and a reliable representation of the eye movement during the memory period, or that one or both of these was corrupted by the illusory visual stimulus. Our data were best accounted for by a model in which both the working memory of target location and the internal representation of the horizontal eye movements were corrupted by the illusory visual stimulus. We conclude that extraretinal signals played only a minor role, in comparison with visual estimates of the direction of gaze, in planning eye movements to remembered targ

Quantitative measurements of eye movements in a patient with Tullio phenomenon.

The Tullio phenomenon consists of vestibular symptoms on exposure to high-intensity acoustic stimuli, reflecting pathological stimulation of semicircular canals or otoliths. We report a patient with posttraumatic Tullio phenomenon to illustrate how precise measurement of eye movements during auditory stimulation, using the magnetic search coil technique, may characterize movements that are not clinically apparent or easily measured by other means. Such measurements in patients with surgically verified lesions may further elucidate the mechanisms responsible for this phenomenon.

Comparison of horizontal, vertical and diagonal smooth pursuit eye movements in normal human subjects.

We compared horizontal and vertical smooth pursuit eye movements in five healthy human subjects. When maintenance of pursuit was tested using predictable waveforms (sinusoidal or triangular target motion), the gain of horizontal pursuit was greater, in all subjects, than that of vertical pursuit; this was also the case for the horizontal and vertical components of diagonal and circular tracking. When initiation of pursuit was tested, four subjects tended to show larger eye accelerations for vertical as opposed to horizontal pursuit; this trend became a consistent finding during diagonal tracking. These findings support the view that different mechanisms govern the onset of smooth pursuit, and its subsequent maintenance when the target moves in a predictable waveform. Since the properties of these two aspects of pursuit differ for horizontal and vertical movements, our findings also point to separate control of horizontal and vertical pursuit.

A pilot study of gabapentin as treatment for acquired nystagmus.

The effects of the anticonvulsant gabapentin were measured on vision and eve movements in three patients with acquired pendular nystagmus. In two patients, the nystagmus was associated with multiple sclerosis and, in the other, it followed brainstem stroke. A single oral 600 mg dose of gabapentin produced improvement of vision due to changes in ocular oscillations in all three patients. The effect was sustained after five weeks of treatment in two patients who elected to continue taking gabapentin 900-1500 mg/day. The results of this pilot study suggest that a controlled trial of gabapentin should be conducted to evaluate its role in the treatment of acquired forms of nystagmus.

Dysfunction of pontine omnipause neurons causes impaired fixation: macrosaccadic oscillations with a unilateral pontine lesion.

Macrosaccadic oscillations of eyes (MSO) are regarded as a form of saccadic dysmetria secondary to cerebellar dysfunction. They are usually conjugate, horizontal, and symmetric in both directions of gaze. Using magnetic search coils, we studied a patient with MSO that developed five years following head injury and involved synchronously horizontal, vertical, and torsional planes. The MSO were characterized by directional pre-ponderance and were associated with ipsilateral pontine lesion. We propose a disturbance of fixation mechanisms due to unilateral disinhibition of saccadic burst neurons in three planes. This could arise from either primary or secondary dysfunction of omnipause neurons due to impaired input from the contralateral superior colliculus. The delayed onset is suggestive of denervation supersensitivity as the underlying pathophysiology.

Dynamic properties of horizontal and vertical eye movements in parkinsonian syndromes.

We studied dynamic properties of horizontal, vertical, and oblique eye movements in 23 patients with the following parkinsonian syndromes: idiopathic parkinsonism (PD), multiple system atrophy (MSA), pure akinesia (PA), progressive supranuclear palsy (PSP), and cortical-basal ganglionic degeneration (CBGD). Compared with age-matched controls, only PSP patients showed slowing of saccades. Patients in all groups showed saccadic hypometria that was most marked vertically. The trajectories of saccades made to diagonal target jumps were deviated toward the horizontal plane, due to the vertical hypometria; this was most marked in PA and PSP groups. Saccade latency was only increased in the CBGD group. Sinusoidal smooth pursuit did not differentiate between controls and patients; however, with step-ramp stimuli, pursuit eye acceleration was impaired in all patient groups compared with controls. The vestibulo-ocular reflex, with or without visual enhancement, was similar in patients and controls. These findings indicate that (1) in parkinsonian syndromes apart from PSP, the saccade-generating brainstem burst neurons are probably spared, but the signals that they receive, specifying the size and direction of saccades, are flawed; and (2) measurements of the gain and trajectory of oblique saccades, and initiation of smooth pursuit, may aid in diagnosing these different types of parkinsonism.