C. Helmchen

Diagnostic Criteria for Central versus Peripheral Positioning Nystagmus and Vertigo: a Review

Head positioning can lead to pathological nystagmus and vertigo. In most instances the cause is a peripheral vestibular disorder, as in benign paroxysmal positioning vertigo (BPPV). Central lesions can lead to positional nystagmus (central PN) or to paroxysmal positioning nystagmus and vertigo (central PPV). Lesions in central PPV are often found dorsolateral to the fourth ventricle or in the dorsal vermis. This localization, together with other clinical features (associated cerebellar and oculomotor signs), generally allows one to easily distinguish central PPV from BPPV. However, in individual cases this may prove difficult, since the two syndromes share many features. Even if only BPPV as a peripheral lesion is considered, differentiation based on such features as latency, course, and duration of nystagmus during an attack, fatigability, vertigo, vomiting, and time period during which nystagmus bouts occur, may be impossible. Only the direction of nystagmus during an attack can allow differentiation.

Deficits in vertical and torsional eye movements after uni- and bilateral muscimol inactivation of the interstitial nucleus of Cajal of the alert monkey

Abstract The mesencephalic interstitial nucleus of Cajal (iC) is considered the neural integrator for vertical and torsional eye movements and has also been proposed to be involved in saccade generation. The aim of this study was to elucidate the function of iC in neural integration of different types of eye movements and to distinguish eye movement deficits due to iC impairment from that of the immediately adjacent rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF). We addressed the following questions: (1) According to the neural integrator hypothesis, all eye movements including the saccadic system and the vestibulo-ocular reflex (VOR) share a common neural integrator. Do iC lesions impair gaze-holding function for vertical and torsional eye positions and the torsional and vertical VOR gain to a similar degree? (2) What are the dynamic properties of vertical and torsional eye movements deficits after iC lesions, e.g., the specificity of torsional and vertical nystagmus? (3) Is iC involved in saccade generation? We performed 13 uni- and three bilateral iC inactivations by muscimol microinjections in four alert monkeys. Three-dimensional eye movements were studied under head-stationary conditions during vertical and torsional VOR. Under static conditions, unilateral iC injections evoked a shift of Listing’s plane to the contralesional side (up to 20°), which increased (ipsilesional ear down) or decreased (ipsilesional ear up) by additional static vestibular stimulation in the roll plane, i.e., ocular counterroll was preserved. The monkeys showed a spontaneous torsional nystagmus with a profound downbeat component. The fast phases of torsional nystagmus always beat toward the lesion side (ipsilesional). Pronounced gaze-holding deficit for torsional and vertical eye positions (neural integrator failure) was reflected by the reduction of time constants of the exponential decay of the slow phase to 330–370 ms. Whereas the vertical oculomotor range was profoundly decreased (up to 50%) and vertical saccades were reduced in amplitude, saccade velocity remained normal and horizontal eye movements were not affected. Bilateral iC injections reduced the shift of Listing’s plane caused by unilateral injections, i.e., back toward the plane of zero torsion. Torsional nystagmus reversed its direction and ceased, whereas vertical nystagmus persisted. In contrast to unilateral injection, there was additional upbeating nystagmus. Time constants of the position integrator of the gaze-holding system did not differ between unilateral and bilateral injections. The range of stable vertical eye positions and saccade amplitude was smaller when compared with unilateral injections, but the main sequence remained normal. Dynamic vestibular stimulation after unilateral iC injections had virtually no effect on torsional and vertical VOR gain and phase at the same time when time constants already indicated severe integrator failure. Torsional VOR elicited a constant slow-phase velocity offset up to 30° toward the contralesional side, i.e., in the opposite direction to spontaneous torsional nystagmus. Likewise, vertical VOR showed a velocity offset in an upward direction, i.e., opposite to the spontaneous downbeat nystagmus. Contralesional torsional and upward vertical quick phases were missing or severely reduced in amplitude but showed normal velocity. In contrast, bilateral iC injections reduced the gain of the torsional and vertical VOR by 50% and caused a phase lead of 10–20° (eye compared with head velocity). We propose that the slow-phase velocity offset during torsional and vertical VOR reflects a vestibular imbalance. It therefore appears likely that the vertical and torsional nystagmus after iC lesions is not only caused by a neural integrator failure but also by a vestibular imbalance. Unilateral iC injections have clearly differential effects on the VOR and the gaze-holding function. These results are not compatible with a single common neural integrator model, which would predict a much stronger VOR gain reduction and phase advance, as found in our data. Our data support the existence of multiple integrators in iC with parallel processing.

Saccade-related activity in the fastigial oculomotor region of the macaque monkey during spontaneous eye movements in light and darkness

Saccade-related burst neurons were recorded in the caudal part of the fastigial nucleus (fastigial oculomotor region) during spontaneous eye movements and fast phases of optokinetic and vestibular nystagmus in light and darkness from three macaque monkeys. All neurons (n=47) were spontaneously active and exhibited a burst of activity with each saccade and fast phase of nystagmus. Most neurons (n=31) only exhibited a burst of activity, whereas those remaining also exhibited a pause in firing rate before or after the burst. Burst parameters varied considerably for similar saccades. For horizontal saccades all neurons, except for three, had a preferred direction with an earlier onset of burst activity to the contralateral side. For contralateral saccades the burst started on average 17.5 ms before saccade onset, whereas the average lead-time for ipsilateral saccades was only 6.5 ms. Three neurons were classified as isotropic with similar latencies and peak burst activity in all directions. None of the neurons had a preferred direction with an earlier onset of burst activity to the ipsilateral side. Burst duration increased with saccade amplitude, whereas peak burst activity was not correlated with amplitude. There was no relationship between peak burst activity and peak eye velocity. In the dark, neurons generally continued to burst with each saccade and fast phase of nystagmus. Burst for saccades in the dark was compared with burst for saccades of similar amplitude and direction in the light. Saccades in the dark had a longer duration and peak burst activity was reduced on average to 62% (range 36–105%). In three neurons a burst in the dark was no longer clearly distinguishable above the ongoing spontaneous activity. These data suggest that the saccade-related burst neurons in the FOR modify saccadic profiles by directly influencing acceleration and deceleration, respectively, of individual eye movements. This could be achieved by an input to the inhibitory and excitatory burst neurons of the saccadic burst generator in the brainstem. From neuroanatomical studies it is known that FOR neurons project directly to the brainstem regions containing the immediate premotor structures for saccade generation.

Cogan's syndrome: clinical significance of antibodies against the inner ear and cornea.

The aim of this study was to evaluate the pathological significance of antibodies against cornea and inner ear tissue in the development of audiovestibular and ocular symptoms in patients with Cogans syndrome (CS). We analysed the serum of 5 CS patients for binding of IgM and IgG to fresh cryosections of rat labyrinth (semicircular canals, ampulla, utricle, saccule) and cornea by indirect immunofluorescence (IF). The predominant pattern of anti-corneal IgM was staining of the superficial cell layer of the non-keratinizing squamous epithelium. IgM against cornea was found in 3 patients, all of whom had bilateral inflammatory eye signs at the start of the disease. However, IgM was also detected in the chronic stage of the disease when no clinical signs of eye involvement were apparent. The study includes the first follow-up examination of anti-corneal IgM and IgG antibodies during a complete episode of active CS. During the first episode of CS in 1 patient, anti-corneal IgM became detectable 1 week after the onset of interstitial keratitis and 3 weeks after the onset of audiovestibular symptoms. It increased over several weeks and then fell to very low levels. However, at no time was anti-corneal IgG found. In the course of follow-up examinations, the serum of 4 patients intermittently contained low titre IgG antibodies against inner ear labyrinthine tissue, but without any clear correlation with the active stages of CS. In addition, high-resolution MRI (HR-MRI) of the inner ear was performed in the acute and chronic stages of CS to evaluate the activity of CS. In the acute stage, HR-MRI revealed abnormal MRI signals in the vestibule, semicircular canals, vestibular nerve, or cochlea. In the chronic stage, patients showed narrowing or occlusion of semicircular canals and the cochlea on the 3D-CISS images, but no high signal lesions (T1) and no enhancement. Antibodies against cornea or labyrinthine tissue were not consistently detected in CS and the level of organ-specific antibodies did not correlate with the activity of the disease.

Saccade-related Purkinje cell activity in the oculomotor vermis during spontaneous eye movements in light and darkness

Saccade-related Purkinje cells (PCs) were recorded in the oculomotor vermis (lobules VI, VII) during spontaneous eye movements and fast phases of optokinetic and vestibular nystagmus in the light and darkness, from two macaque monkeys. All neurons (n=46) were spontaneously active and exhibited a saccade-related change of activity with all saccades and fast phases of nystagmus. Four types of neurons were found: most neurons (n=31) exhibited a saccade-related burst of activity only (VBN); other units (n=7) showed a burst of activity with a subsequent pause (VBPN); some of the units (n=5) paused in relation to the saccadic eye movement (pause units,VPN); a few PCs (n=3) showed a burst of activity in one direction and a pause of activity in the opposite direction. For all neurons, burst activity varied considerably for similar saccades. There were no activity differences between spontaneous saccades and vestibular or optokinetically elicited fast phases of nystagmus. The activity before, during, and after horizontal saccades was quantitatively analyzed. For 24 burst PCs (VBN, VBPN), the burst started before saccade onset in one horizontal direction (preferred direction), on average by 15.3 ms (range 27-5 ms). For all these neurons, burst activity started later in the opposite (non-preferred) direction, on average 4.9 ms (range 20 to -12 ms, P<0.01) before saccade onset. The preferred direction could be either with ipsilateral (42% of neurons) or contralateral (58%) saccades. Nine burst PCs had similar latencies and burst patterns in both horizontal directions. The onset of burst activity of a minority of PCs (n=5) lagged saccade onset in all directions. The pause for VBPN neurons started after the end of the saccade and reached a minimum of activity some 40–50 ms after saccade completion. For all saccades and quick phases of nystagmus, burst duration increased with saccade duration. Peak burst activity was not correlated with saccade amplitude or peak eye velocity. PCs continued to show saccade-related burst activity in the dark. However, in 59% of the PCs (VBN, VBPN), peak burst activity was significantly reduced in the dark (on average 28%, range 15–36%) when saccades with the same amplitude (but longer duration in the dark) were compared. For VBP neurons, the pause component after the saccade disappeared in the dark. The difference in peak burst activity (light vs darkness) is similar to that seen for saccade-related neurons in the fastigial oculomotor region (FOR, the structure receiving direct input from vermal PCs) and suggests that the oculomotor vermis also might affect saccade acceleration and/or deceleration. The findings indicate that in the oculomotor vermis — in contrast to the FOR — several different types of saccade-related neurons (PCs) are found. However, the vast majority of PCs behave qualitatively similar to FOR neurons with regard to the burst activity pattern and a direction-specific burst activity onset starting well before saccade onset. This latency will allow these neurons to influence the initiation of saccades in the saccadic brainstem generator through multisynaptic pathways. At present, it has to be determined how (saccade-related) PC activity determines FOR activity.

Saccade-related burst neurons with torsional and vertical on-directions in the interstitial nucleus of Cajal of the alert monkey

The interstitial nucleus of Cajal (iC) is known to be the neural integrator for vertical and torsional eye movements. Burst-tonic neurons are thought to be the neural substrate for this function. Until now, the iC has not been specifically considered to play a part in saccade generation. The aim of this study was to characterize saccade-related burst neurons in the iC during torsional and vertical eye movements. Saccade-related burst neurons were recorded in the iC of macaque monkeys during fast phases of torsional and vertical vestibular nystagmus, spontaneous and visually guided eye movements, and in light and darkness. Burst neurons in the iC (n=85) were found intermingled between burst-tonic and tonic neurons. They were not spontaneously active, showed no eye position sensitivity, and responded during saccades and quick phases of nystagmus with a burst of activity whose duration was closely correlated with saccade amplitude and hence saccade duration (correlation coefficients up to 0.9). Latency in the on-direction was, on average, 10.4 ms (range 5–23 ms); it decreased with different saccade directions and became negative in the off-direction. In a horizontal-vertical coordinate system, on-direction of the majority of neurons was either upward (n=52) or downward (n=33). There was no horizontal on-direction. Burst neurons of different vertical on-directions were found intermingled throughout the iC. In the vertical-torsional plane, on-direction always showed an ipsiversive torsional component, i.e., a clockwise (positive) torsion for neurons in the right iC and a counterclockwise (negative) torsional component when recorded in the left iC. The findings indicate that saccade-related burst neurons in the iC control coordinate axes for vertical and torsional quick eye rotations. As in the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF), burst neurons in the iC encode vertical saccades with an ipsitorsional direction with similar burst characteristics. It is suggested that iC burst neurons play a part in the local feedback loop of the reciprocal iC-riMLF projections.

The localizing value of nystagmus in brainstem disorders

As causes for conjugate jerk nystagmus at the midposition of the eye. vestibular imbalance, a neural integrator deficit, smooth pursuit imbalance and a saccade generator deficit have been considered. The authors investigated anatomically brainstem lesions of patients with downbeat, upbeat, torsional and horizontal nystagmus. Although relatively common, downbeat nystagmus is only rarely seen with brainstem lesions. In these instances it is localized in midline medullary structures. Upbeat nystagmus is more often caused by a discrete brainstem lesion in the medulla, which can be as far caudal as the cranio-cervical junction. Lesions have also been found at the pontine level. In the mesencephalon, torsional nystagmus occurs with lesions to the interstitial nucleus of Cajal and the rostral interstitial nucleus of the MLF. In addition torsional nystagmus is seen after vestibular nuclei and lateral medullary lesions. Both lesion sites are also found with horizontal nystagmus.Although in some instances pathophys...

Unilateral muscimol inactivations of the interstitial nucleus of Cajal in the alert rhesus monkey do not elicit seesaw nystagmus

Seesaw-nystagmus (SSN) is a unique form of nystagmus with disconjugate vertical and conjugate torsional eye movements. Although rare, this disorder serves as a model for neuronal binocular control of the alignment of vertical-torsional eye movements of both eyes. The pathomechanism of SSN, however, is unclear. Studies in patients have suggested that the jerk SSN is associated with a midbrain lesion, i.e. a lesion of the interstitial nucleus of Cajal (iC), a center of integration of vertical and torsional eye movements. To test this hypothesis, we examined three dimensional binocular eye movements after reversible local inactivations of the iC and its immediate vicinity in the midbrain of the alert monkey. Inactivations were induced by muscimol microinjections. Eye movements were recorded with binocular scleral search coils. Isolated inactivations of neither the iC nor its immediate vicinity in the midbrain (including the adjacent rostral interstitial nucleus of the medial longitudinal fascicle, riMLF) elicited a disconjugate vertical/torsional nystagmus (SSN). However, there was a direction-specific right/left asymmetry in which a larger vertical amplitude was associated with the contralesional eye and a larger torsional amplitude with the ipsilesional eye, indicating a vestibular imbalance. We conclude that, first, iC lesions do not elicit SSN and, second, that apart from the gaze holding deficit a vestibular imbalance contributes to the vertical/torsional nystagmus after iC lesions.

Centripetal nystagmus in a case of Creutzfeldt-Jacob disease

Acquired forms of gaze-holding nystagmus usually produce centrifugal nystagmus. The authors report about a 63-year-old-patient with a rapidly deteriorating syndrome of cerebellar signs, dementia and myoclonus suggesting Creutzfeldt-Jakob disease (CJD), who developed the unusual sign of bilateral horizontal and vertical centripetal nystagmus with sustained eccentric fixation early in the disease. To our knowledge, this is the first report of centripetal nystagmus in CJD.

Is Saccadic Lateropulsion in Wallenberg’s Syndrome Caused by a Cerebellar or a Brain-Stem Lesion?

One of the common features of Wallenberg’s lateral medullary syndrome is the tendency to fall towards the side of the lesion, called lateropulsion [4]. Less well known, however, is ocular lateropulsion [9], i.e., a tonic drift of the eyes to the ipsilateral side, compatible with the direction of the body lateropulsion. Also, there is a directional preponderance of saccades to the side of the lesion [1, 10] affecting quick phases of vestibular and optokinetic nystagmus [9]. Thus, saccades to the contralateral side of the lesion, i.e., against the ocular bias, are hypometric, whereas ipsilateral saccades are hypermetric. Other oculomotor signs include cogwheel smooth-pursuit eye movements directed against the lateropulsive bias, i.e., to the contralateral side [1], and the ocular tilt reaction with skew deviation [6].