Subcortical volumetric reductions in adult Niemann-Pick disease type C: a cross-sectional study.

BACKGROUND AND PURPOSE: Voxel-based analysis has suggested that deep gray matter rather than cortical regions is initially affected in adult Niemann-Pick type C. We sought to examine a range of deep gray matter structures in adults with NPC and relate these to clinical variables. MATERIALS AND METHODS: Ten adult patients with NPC (18-49 years of age) were compared with 27 age- and sex-matched controls, and subcortical structures were automatically segmented from normalized T1-weighted MR images. Absolute volumes (in cubic millimeters) were generated for a range of deep gray matter structures and were compared between groups and correlated with illness variables. RESULTS: Most structures were smaller in patients with NPC compared with controls. The thalamus, hippocampus, and striatum showed the greatest and most significant reductions, and left hippocampal volume correlated with symptom score and cognition. Vertex analysis of the thalamus, hippocampus, and caudate implicated regions involved in memory, executive function, and motor control. CONCLUSIONS: Thalamic and hippocampal reductions may underpin the memory and executive deficits seen in adult NPC. Volume losses in other subcortical regions may also be involved in the characteristic range of motor, psychiatric, and cognitive deficits seen in the disease.

Saccades in adult Niemann-Pick disease type C reflect frontal, brainstem, and biochemical deficits.

BACKGROUND: The autosomal recessive disorder Niemannn-Pick type C (NPC) presents in adulthood with psychosis or cognitive deficits associated with supranuclear gaze palsies. While saccadic innervation to the extraocular muscles is generated in the brainstem, the frontal lobes play an integral role in the initiation of volitional saccades and the suppression of unwanted reflexive saccades. No study has examined the frontally driven volitional control of saccadic eye movements in NPC. OBJECTIVE: To examine self-paced and antisaccades as well as reflexive saccades in adult patients with NPC, a disorder known to affect brainstem and frontal cortical function. METHODS: Three biochemically confirmed adult patients with NPC were compared with 10 matched controls on horizontal saccadic and antisaccadic measures using an infrared limbus eye tracker. Patients' cholesterol esterification and filipin staining, Mini-Mental State performance, and NPC symptom level were rated. RESULTS: Reflexive saccade latency ranged from shorter to longer than normal, reflexive saccade gain was reduced, asymptotic peak velocity was reduced, fewer self-paced saccades were generated, and increased errors on antisaccades were made by patients compared to controls. Patients with more severe biochemical, cognitive, and symptom deficits performed most poorly on brainstem and frontal ocular motor measures. Paradoxically, less severe illness was associated with an abnormally reduced saccadic latency. CONCLUSIONS: Ocular motor measures provide an index of disease severity in Niemannn-Pick type C (NPC) and may be a useful adjunct for monitoring the illness progress and medication response. Reduced saccadic latency may result from inadequate fixation input from abnormally functioning frontal eye fields in NPC.

Eye movements in Parkinson's disease: before and after pallidotomy.

PURPOSE: To evaluate the effects of unilateral, stereotactic, posteroventral pallidotomy on saccadic eye movements in patients with Parkinson disease (PD). METHODS: Eye movements of 31 patients with moderate to advanced PD were recorded with an infrared system 1 month before and 3 months after pallidotomy. Two kinds of saccade tasks were used: saccade tasks for eliciting visually guided saccades and saccade tasks for eliciting internally mediated saccades (memory-guided, predictive, and anti-saccades). Latency, accuracy, peak velocity, and other parameters of saccades were evaluated. RESULTS: Internally mediated saccades were more impaired in patients with advanced PD compared with those with moderate PD. Pallidotomy did not affect visually guided saccades. After pallidotomy, the peak saccadic velocity of internally mediated saccades decreased. CONCLUSIONS: Hence, although pallidotomy has led to improvements in other motor functions, none were observed in saccadic responses. Rather, several modest decrements, below the level of clinical significance and all in internally mediated saccades, were observed.

Bedside tests of saccades after head injury.

OBJECTIVES: To compare the techniques of bedside and infrared oculographic tests of saccades and to compare the results of both tests in control subjects and in patients with traumatic brain injuries (TBI). MATERIALS AND METHODS: The authors elicited single memory-guided saccades, antisaccades, and self-paced saccades in 19 TBI subjects and 26 age-matched control subjects at the bedside. Taped instructions were used to ensure that the timing and sequence of each stimulus (index finger flexion) were the same in all subjects and as close as possible to those used in both the current and previous laboratory studies. RESULTS: Self-paced saccade rate was significantly decreased in patients with TBI. The increased error rate in single memory-guided saccades and antisaccades was not statistically significant. CONCLUSION: The authors concluded that the bedside saccade tests have limited value in patients with TBI because of the range of results and large overlap of the distributions of these two groups. The number of parameters that can be measured is limited. Bedside saccade tests are easier than infrared oculographic tests because the target remains visible.

Voluntary nystagmus associated with accommodation spasms.

BACKGROUND: Voluntary nystagmus has been recognized as a pendular, rapid, conjugate, primarily horizontal, benign eye movement initiated and maintained by voluntary effort. CASE: A 10-year-old Japanese girl presented with voluntary nystagmus associated with accommodation spasms. Her chief complaints, intermittent blurred vision, headache, and soreness of the eyes, were thought to be related to the voluntary nystagmus and accommodation spasms. FINDINGS: The waveform of the nystagmus appeared pendular, the frequency was 13-15 Hz, and the amplitude was 3-5 degrees. Scanning laser ophthalmoscopic video images clearly demonstrated vertical and torsional components in addition to the horizontal eye movements. Her refraction was unstable, varying between -0.5 diopters (D) and -5.5 D, and the recording of the accommodometer increased to -12.0 D when nystagmus was initiated. CONCLUSIONS: This may be a unique form of voluntary nystagmus that consists of horizontal, vertical, and rotational components associated with accommodation spasms. Observation of this patient continues, without any further treatment or examination.

Influences of chorion type on saccadic eye movements in twins.

PURPOSE: The influence of genetic and prenatal environmental factors on characteristics of saccadic performance were evaluated in young monozygotic (MZ) twins (8-19 years old) of known chorion type. METHODS: Saccadic eye movements were recorded using an infrared system. Saccadic latency, accuracy, and parameters of amplitude-peak velocity exponential equation (main sequence) were quantified. RESULTS: Intraclass correlations of saccadic parameters differed significantly from zero for monochorionic and dichorionic MZ twins. The within-pair mean squares were significantly less, and intraclass correlations were significantly higher in monochorionic than in dichorionic twins for latency and were similar for other saccadic parameters (accuracy, slope of main sequence, and peak velocity for 15 degrees saccades). CONCLUSIONS: These findings confirmed previous reports that saccadic parameters of MZ twins are significantly correlated and indicated that similarity of these parameters seen in MZ twins may be driven both by genetic and by prenatal environmental factors.

Effects of acupuncture on foveation characteristics in congenital nystagmus.

AIMS/BACKGROUND: To examine the effects of acupuncture at the sternocleidomastoid muscles on foveation characteristics in congenital nystagmus. METHODS: Six patients with congenital nystagmus (CN) received a series of treatments consisting of two needles inserted into each sternocleidomastoid, stimulated by tapping gently every 5 minutes, for 20 minutes per session. Their eye movements were recorded using scleral search coils and changes in their CN waveforms analysed at each point in the treatment. Changes in the stability and duration of foveation periods were examined. RESULTS: Four of the six patients showed improved foveation at the commencement of treatment; three maintained this response throughout the treatment period and after the needles were removed. In two, the CN waveform itself was modified. CONCLUSION: This study and others involving afferent stimulation to the neck and face suggest that projections from these areas to the reticular formation and vestibular nucleus may alter the behaviour of the pathophysiological mechanism underlying congenital nystagmus.

Smooth pursuit in twins before and after alcohol ingestion.

PURPOSE: The influence of genetic factors on characteristics of smooth pursuit were evaluated in young adult monozygotic (MZ) and dizygotic (DZ) twins before and after the administration of a single dose of ethanol. METHODS: Sinusoidal pursuit was recorded using a scleral search coil at frequencies of 0.25 and 0.5 Hz before and after alcohol consumption. Pursuit gain, interval between saccades, saccadic accuracy, and saccadic amplitude were quantified. RESULTS: Alcohol consumption reduced pursuit gain and saccadic accuracy and increased the rate and amplitude of saccades. Before and after alcohol consumption, the intraclass correlations for MZ twins (rMZ) were highly significant for pursuit gain, interval between saccades, and saccade amplitude. Corresponding correlations for DZ twins (rDZ) were not significant. Heritability values were similar before and after alcohol ingestion. CONCLUSIONS: The disparity between rMZ and rDZ suggests either multiple gene interactions or common environmental influences for MZ twins, greater than those for DZ twins.

Cerebral control of saccades and neuropsychological test results after head injury.

Abnormalities in the control of saccades have been described in patients with cerebral pathology.(1, 2) We assessed control of visually guided, reflexive and volitional saccades in 16 patients suffering severe traumatic brain injury and 12 controls and related the results to deficits on neuropsychological tests of speed of information processing and goal directed behaviour. All saccadic latencies were prolonged. Suppression of inappropriate saccades was impaired on volitional saccade tests which proved to be more sensitive in identifying impairment of goal directed behaviour than the neuropsychological test results. Patients' self-paced saccade rate was lower than controls' and correlated with performance on several visually mediated neuropsychological test results. Patients' visually guided, reflexive saccades were hypometric; this hypometria correlated with both visual and non-visual neuropsychological test results and with post-traumatic amnesia duration. Hypometria in reflexive saccades may reflect diffuse brain injury. Re-examination after 12 months revealed that the control of volitional saccades improved but there was no improvement in the visually guided reflexive saccade measures. The volitional saccade tests may be useful in documenting both impairment and subsequent recovery.

Saccadic characteristics of monozygotic and dizygotic twins before and after alcohol administration.

PURPOSE: To evaluate the degree of heritability in the latency, accuracy, and peak velocity of reflexive saccades in young adult monozygotic (MZ) and dizygotic (DZ) twins before and after the administration of a single dose of ethanol. METHODS: Saccades were recorded using a scleral search coil before and after alcohol consumption, and data were analyzed offline. Estimates of heritability based in intraclass correlations (ICCs) and using a maximum likelihood estimates of genetic variance were calculated for the saccadic measures made before and after alcohol, as well as for the changes in latency, accuracy, and velocity. RESULTS: Intraclass correlations for MZ twins (rMZ) were highly significant; those for DZ twins (rDZ) were not significantly different from zero. This disparity between rMZ and rDZ suggests either multiple gene interactions or in utero environmental differences in the MZ twins. Alcohol significantly prolonged latency, reduced accuracy, and lowered peak velocity. Although the changes after alcohol were not significant, heritability values increased in all three measures after alcohol administration. CONCLUSIONS: Latency, accuracy, and peak velocity appear to be controlled by multiple genes or to depend on prenatal environmental factors. Even a single low dose of alcohol appeared to enhance heritability measures. Differences seen between ICCs for latency, accuracy, and velocity after alcohol administration suggest that developmental control of the neural mechanisms underlying each measure may vary.

Effects of stimulus velocity and acceleration on smooth pursuit in motor neuron disease.

Sinusoidal smooth pursuit eye movements were evaluated in 11 normals, five moderately and four severely affected motor neuron disease (MND) patients, using two target amplitudes and a range of frequencies. This enabled us to examine separately the effects of peak target velocity and acceleration on pursuit gain. Moderately affected patients showed an acceleration, but not a velocity saturation; severely impaired patients' performance declined with increased velocity. Smooth pursuit eye movements are thus impaired in MND, but the nature of this pursuit deficit is complex and changes with the progression of the disease.

Concordance of smooth pursuit and saccadic measures in normal monozygotic twin pairs.

Although the range of normal ocular motor performance is broad, little is known about the sources of variability. Genetic transmission of eye movement deficits has been described but such possible control of normal function has been little investigated. Characteristics of smooth pursuit and saccades can be examined for the degree of concordance in related individuals. In this pilot study, we studied saccades and pursuit in eight monozygotic (MZ) twin pairs. The statistical analysis of the data used the intraclass correlation of MZ twins (rMZ) to estimate what fraction the covariance of the twin pairs was of the population variance. All saccadic measures showed significant MZ correlations (p < 0.05). Smooth pursuit gains were even more highly correlated (p < 0.001). These results indicate considerable similarity within pairs of twins, particularly for horizontal smooth pursuit, and suggest that larger studies on monozygotic and dizygotic twins would be desirable, to help separate out the relative contributions of environmental and genetic factors.

Voluntary saccadic oscillations, resembling ocular flutter and opsoclonus.

Two human subjects, who had no signs of other neurologic disorders, produced large amplitude, to-and-fro saccadic oscillations. One subject generated these oscillations intentionally. Eye movement recordings by DC electro-oculography and/or magnetic scleral search coil showed that the movements were bursts of conjugate saccades in opposing directions with no intersaccadic intervals. They were multidirectional (horizontal, vertical, or oblique), had amplitudes up to 40 degrees and had linear or curvilinear trajectories. These characteristics are similar to those of ocular flutter and opsoclonus in patients with brainstem and/or cerebellar disorders. Our observations show that fixation instabilities resembling ocular flutter and opsoclonus can be produced voluntarily.

Hereditary congenital nystagmus and gaze-holding failure: the role of the neural integrator.

Congenital nystagmus (CN) may be due to an instability of the neural integrator responsible for gaze holding. This longitudinal study tests that hypothesis, investigates the saccadic instabilities of relatives, and assesses the effects of afferent stimulation on both the CN and the coexisting gaze-holding failure. We recorded four siblings who had CN and gaze-holding failure while fixating in primary position and lateral gaze. In lateral gaze, the CN waveforms were superimposed on the centripetal drift caused by the gaze-holding failure; the drift time constants ranged from 300 to 1,450 msec. CN waveforms lacked extended foveation periods. Saccadic instabilities were present in the father and two clinically unaffected siblings; the mother's eye movements were normal. We conclude that CN in the subjects of this study, and in others with idiopathic CN, is not due to gaze-holding abnormalities, and we speculate that development of the fixation reflexes that produce CN foveation periods requires some minimal foveation interval during which the target image is in the foveal area with low retinal slip velocity and acceleration.

Saccadic intrusions into smooth pursuit in patients with schizophrenia or affective disorder and normal controls.

Two types of saccadic intrusions into smooth pursuit eye tracking, anticipatory saccades (AS), and square wave jerks (SWJ), were measured in 23 patients with schizophrenia, 16 patients with affective disorder, and 21 normal controls. Constant velocity (5 degrees and 20 degrees/sec) predictable targets were employed. High resolution infrared oculography was employed to record eye movements. Although most subjects had at least one SWJ, there were no significant group differences, and the highest individual rates of SWJ were seen in the normal control group. On the other hand, AS were never seen in normals, but were present in 25%-44% of patients with either schizophrenia or affective disorder. Both patient groups had significantly more AS than controls, but the two patient groups were not significantly different.

Abnormalities of smooth pursuit and saccadic control in schizophrenia and affective disorders.

Smooth pursuit abnormalities have been reported in patients with schizophrenia and their first-degree relatives, suggesting that abnormal tracking may serve as a biological marker for schizophrenia. Recent studies in schizophrenic patients have found reduced pursuit gain, low initial acceleration and abnormal gain-corrective saccade interactions. Impaired saccadic initiation has been noted in anti-saccade tasks and in predictive saccade generation, as has saccadic hypometria. While abnormalities have been found in affective disorder patients, studies of their first-degree relatives suggest that abnormalities during pursuit are more closely associated with schizophrenia. Identification of specific defects allows informed speculation about their neural substrates and suggests possible relationships between the ocular motor defects and other cognitive and perceptual abnormalities associated with the major psychiatric disorders.

Catch-up saccade amplitude is related to square wave jerk rate.

Mean catch-up saccade (CUS) amplitude and square wave jerk (SWJ) rate during pursuit were recorded in 20 normal controls, 23 patients with schizophrenia, and 15 patients with affective disorder, using infrared oculography. Target speed during pursuit was 5 degrees/sec. An especially robust correlation was noted in normal controls between SWJ rate during pursuit and mean CUS amplitude (Spearman's rs = 0.87, P less than 0.0001). This correlation also was present in the psychiatric patients (rs = 0.53, P = 0.0006), although it was significantly weaker than in normal controls (P less than 0.02). There were no significant differences between the patient groups regarding the strength of the relationship. Furthermore, similar strong correlations between SWJ rate during fixation and mean CUS amplitude also were found for normals (rs = 0.73, P = .0002) and both patient groups combined (rs = 0.52, P = 0.0009). The results suggest that saccadic intrusions during tracking tax the saccade correcting system, delaying correction for the position error that accumulates when gain is less than 1.0.