Modeling Uhthoff's phenomenon in MS patients with internuclear ophthalmoparesis.

OBJECTIVE: The goal of this investigation was to demonstrate that internuclear ophthalmoparesis (INO) can be utilized to model the effects of body temperature-induced changes on the fidelity of axonal conduction in multiple sclerosis (Uhthoff's phenomenon). METHODS: Ocular motor function was measured using infrared oculography at 10-minute intervals in patients with multiple sclerosis (MS) with INO (MS-INO; n = 8), patients with MS without INO (MS-CON; n = 8), and matched healthy controls (CON; n = 8) at normothermic baseline, during whole-body heating (increase in core temperature 0.8 degrees C as measured by an ingestible temperature probe and transabdominal telemetry), and after whole-body cooling. The versional disconjugacy index (velocity-VDI), the ratio of abducting/adducting eye movements for velocity, was calculated to assess changes in interocular disconjugacy. The first pass amplitude (FPA), the position of the adducting eye when the abducting eye achieves a centrifugal fixation target, was also computed. RESULTS: Velocity-VDI and FPA in MS-INO patients was elevated (p < 0.001) following whole body heating with respect to baseline measures, confirming a compromise in axonal electrical impulse transmission properties. Velocity-VDI and FPA in MS-INO patients was then restored to baseline values following whole-body cooling, confirming the reversible and stereotyped nature of this characteristic feature of demyelination. CONCLUSIONS: We have developed a neurophysiologic model for objectively understanding temperature-related reversible changes in axonal conduction in multiple sclerosis. Our observations corroborate the hypothesis that changes in core body temperature (heating and cooling) are associated with stereotypic decay and restoration in axonal conduction mechanisms.

Accuracy of clinical detection of INO in MS: corroboration with quantitative infrared oculography.

The authors compared the accuracy of clinical detection (by 279 physician observers) of internuclear ophthalmoparesis (INO) with that of quantitative infrared oculography. For the patients with mild adduction slowing, INO was not identified by 71%. Intermediate dysconjugacy was not detected by 25% of the evaluators. In the most severe cases, INO was not identified by only 6%. Oculographic techniques significantly enhance the precision of INO detection compared to the clinical exam.

Benign paroxysmal positioning vertigo in multiple sclerosis: diagnosis, pathophysiology and therapeutic techniques.

OBJECTIVE: To report on the most common causes of vertigo in patients with multiple sclerosis (MS) and emphasize appropriate diagnostic techniques and treatment interventions. BACKGROUND: True vertigo is estimated to occur in about 20% of MS patients. Lesions within the vestibular nuclei and in the root entry zone of cranial nerve VIII represent the most common locations where demyelinating activity can provoke vertigo in patients with MS. However, other causes of vertigo should be explored in MS patients in order to avoid unnecessary treatment with corticosteroids and vestibular suppressants. Recently, we reviewed our four-year experience with new onset vertigo in our university-based MS population and found that benign paroxysmal positioning vertigo (BPPV) to be the most common cause. All patients diagnosed with BPPV were treated successfully with particle repositioning maneuvers. The remaining patients were treated with conventional therapies appropriate for the specific diagnosis. CONCLUSIONS: Empiric treatments with corticosteroids and/or vestibular suppressants should not be employed until all MS patients undergo a careful bedside examination, which includes diagnostic positional and, if indicated, particle repositioning maneuvers. Here we emphasize the pathophysiology of BPPV and illustrate the proper techniques for the diagnostic and therapeutic maneuvers.

Quantitative oculographic characterisation of internuclear ophthalmoparesis in multiple sclerosis: the versional dysconjugacy index Z score.

BACKGROUND: There is a poor correlation between multiple sclerosis disease activity, as measured by magnetic resonance imaging, and clinical disability. OBJECTIVE: To establish oculographic criteria for the diagnosis and severity of internuclear ophthalmoparesis (INO), so that future studies can link the severity of ocular dysconjugacy with neuroradiological abnormalities within the dorsomedial brain stem tegmentum. METHODS: The study involved 58 patients with multiple sclerosis and chronic INO and 40 normal subjects. Two dimensional infrared oculography was used to derive the versional dysconjugacy index (VDI)-the ratio of abducting to adducting eye movements for peak velocity and acceleration. Diagnostic criteria for the diagnosis and severity of INO were derived using a Z score and histogram analysis, which allowed comparisons of the VDI from multiple sclerosis patients and from a control population. RESULTS: For a given saccade, the VDI was typically higher for acceleration v velocity, whereas the Z scores for velocity measures were always higher than values derived from comparable acceleration VDI measures; this was related to the greater variability of acceleration measures. Thus velocity was a more reliable measure from which to determine Z scores and thereby the criteria for INO and its level of severity. The mean (SD) value of the VDI velocity derived from 40 control subjects was 0.922 (0.072). The highest VDI for velocity from a normal control subject was 1.09, which was 2.33 SD above the normal control mean VDI. We therefore chose 2 SD beyond this value (that is, a Z score of 4.33) as the minimum criterion for the oculographic confirmation of INO. Of patients thought to have unilateral INO on clinical grounds, 70% (16/23) were found to have bilateral INO on oculographic assessment. CONCLUSIONS: INO can be confirmed and characterised by level of severity using Z score analysis of quantitative oculography. Such assessments may be useful for linking the level of severity of a specific clinical disability with neuroradiological measures of brain tissue pathology in multiple sclerosis.

MRI characteristics of the MLF in MS patients with chronic internuclear ophthalmoparesis.

OBJECTIVE: The authors imaged the medial longitudinal fasciculus (MLF) in 58 patients with MS and chronic internuclear ophthalmoparesis (INO) to determine which MRI technique best shows the characteristic lesion associated with this ocular motor syndrome. METHODS: Using quantitative infrared oculography, the authors determined the ratios of abduction to adduction for velocity and acceleration, to confirm the presence of INO and to determine the severity of MLF dysfunction in 58 patients with MS and INO. Conventional MRI techniques, including proton density imaging (PDI), T2-weighted imaging, and fluid-attenuated inversion recovery (FLAIR) imaging, were used to ascertain which technique best shows MLF lesions within the brainstem tegmentum. T1-weighted imaging was performed to determine the frequency of brainstem tegmentum hypointensities. RESULTS: All patients studied had evidence of an MLF lesion hyperintensity on PDI, whereas T2-weighted imaging and FLAIR imaging showed these lesions in 88% and 48% of patients, respectively. With PDI, dorsomedial tegmentum lesions were seen in the pons in 93% of patients and in the midbrain of 66% of patients. Lesions were observed at both locations in 59% of patients. One patient had an MLF lesion with a corresponding T1 hypointensity. CONCLUSIONS: PDI best shows the MLF lesion in patients with MS and INO.

Ocular contrapulsion in multiple sclerosis: clinical features and pathophysiological mechanisms.

The objective was to describe in multiple sclerosis, a cerebellar eye movement syndrome that resulted from an acute episode of inflammatory demyelination. Contrapulsion is an ocular motor disturbance characterised by a triad of (1) hypermetric saccadic eye movements in a direction opposite from a precisely localised lesion within a specific white matter pathway, the uncinate fasciculus, at the level of the superior cerebellar peduncle (SCP); (2) hypometric saccades towards the side of the lesion; (3) oblique saccades directed away from the side of the lesion on attempted vertical saccades. Infrared oculography was used to demonstrate the characteristic features of contrapulsion in two patients with multiple sclerosis. Brain MRI showed lesions within the region of the uncinate fasciculus and superior cerebellar peduncle in both patients. Eye movement recordings showed saccadic hypermetria away from the side of the lesion and saccadic hypometria towards the side of the lesion. The hypometria decomposed into a series of stepwise movements as the eye approached the target. Oblique saccades directed away from the side of the lesion were seen on attempted vertical saccades. In conclusion, ocular contrapulsion can be seen in patients with multiple sclerosis and results from a lesion in the region of the SCP, involving the uncinate fasciculus.

Experimental tests of a neural-network model for ocular oscillations caused by disease of central myelin.

Spontaneous sinusoidal oscillations of the eyes are a feature of disorders affecting central myelin, including multiple sclerosis. The mechanism responsible for these oscillations (pendular nystagmus) is unknown. We tested the hypothesis that pendular nystagmus is due to instability of the neural integrator, a network of neurons that normally guarantees steady gaze by mathematically integrating premotor signals. It was possible to make a model of the neural integrator unstable, and abnormal feedback then produced sustained oscillations so that it simulated pendular nystagmus. One prediction of the model is that a large premotor signal, such as is required to generate a rapid (saccadic) eye movement, will transiently suppress the activity of some neurons in the network, and that this will "reset" the oscillations, i.e., produce a phase shift; larger saccades will produce greater phase shifts. Alternatively, if the source of pendular nystagmus is outside the neural integrator (i.e., is present on velocity inputs to the stable integrator), then it may not be possible to reset the oscillations with a saccadic eye movement. We compared the phase relationships of pendular nystagmus prior to and following saccades in six patients with multiple sclerosis (MS). All patients showed phase shifts (median 64 degrees) of their ocular oscillations following large (more than 10 degrees) saccades; smaller saccades (less than 5 degrees) caused smaller phase shifts (median 17 degrees). Our findings suggest that, in MS, pendular nystagmus arises from an instability in the feedback control of the neural integrator for eye movements, which depends on a distributed network of neurons in the brainstem and cerebellum.

Adaptation of the phase of the human linear vestibulo-ocular reflex (LVOR) and effects on the oculomotor neural integrator.

The phase of the translational linear VOR (LVOR) can be adaptively modified by exposure to a visual-vestibular mismatch. We extend here our earlier work on LVOR phase adaptation, and discuss the role of the oculomotor neural integrator. Ten subjects were oscillated laterally at 0.5 Hz, 0.3 g peak acceleration, while sitting upright on a linear sled. LVOR was assessed before and after adaptation with subjects tracking the remembered location of a target at 1 m in the dark. Phase and gain were measured by fitting sine waves to the desaccaded eye movements, and comparing sled and eye position. To adapt LVOR phase, the subject viewed a computer-generated stereoscopic visual display, at a virtual distance of 1 m, that moved so as to require either a phase lead or a phase lag of 53 deg. Adaptation lasted 20 min, during which subjects were oscillated at 0.5 Hz/0.3 g. Four of five subjects produced an adaptive change in the lag condition (range 4-45 deg), and each of five produced a change in the lead condition (range 19-56 deg), as requested. Changes in drift on eccentric gaze suggest that the oculomotor velocity-to-position integrator may be involved in the phase changes.

A versatile stereoscopic visual display system for vestibular and oculomotor research.

Testing of the vestibular system requires a vestibular stimulus (motion) and/or a visual stimulus. We have developed a versatile, low cost, stereoscopic visual display system, using "virtual reality" (VR) technology. The display system can produce images for each eye that correspond to targets at any virtual distance relative to the subject, and so require the appropriate ocular vergence. We elicited smooth pursuit, "stare" optokinetic nystagmus (OKN) and after-nystagmus (OKAN), vergence for targets at various distances, and short-term adaptation of the vestibulo-ocular reflex (VOR), using both conventional methods and the stereoscopic display. Pursuit, OKN, and OKAN were comparable with both methods. When used with a vestibular stimulus, VR induced appropriate adaptive changes of the phase and gain of the angular VOR. In addition, using the VR display system and a human linear acceleration sled, we adapted the phase of the linear VOR. The VR-based stimulus system not only offers an alternative to more cumbersome means of stimulating the visual system in vestibular experiments, it also can produce visual stimuli that would otherwise be impractical or impossible. Our techniques provide images without the latencies encountered in most VR systems. Its inherent versatility allows it to be useful in several different types of experiments, and because it is software driven it can be quickly adapted to provide a new stimulus. These two factors allow VR to provide considerable savings in time and money, as well as flexibility in developing experimental paradigms.

Context-specific short-term adaptation of the phase of the vestibulo-ocular reflex.

The phase of the angular vestibulo-ocular reflex (VOR) is subject to adaptive control. We had previously found that adapting the phase of the VOR also produced changes in drift on eccentric gaze-holding, implying a change in the time constant of the velocity-to-position neural integrator. Here we attempted to dissociate changes in gaze-holding drift from changes in the phase of the VOR. In normal human subjects, for 2 h, we alternated 5 min of VOR phase adaptation (sinusoids, 0.2 Hz) with 5 min of making saccades in the light with the head stationary. Afterwards, changes in VOR phase were the same (32% of requested) as those obtained with 1 h of phase adaptation alone, but changes in drift following saccades were much smaller than those found after phase adaptation alone (0.8 degrees/s compared with 5 degrees/s). When measuring drift after VOR steps, however, the changes were closer to those found after phase adaptation alone (3.8 degrees/s). To test the relationship between gaze-holding drift after VOR steps and adaptive changes in VOR phase, we alternated sinusoidal VOR phase adaptation with normal VOR steps in the light. In this paradigm, the adaptive change in VOR phase was about the same as with phase-adaptation alone (35%), but there was now little drift after saccades (1.9 degrees/s) or after VOR steps (0.7 degrees/s). We conclude that the state of the velocity-to-position neural integrator can be altered selectively and rapidly depending upon the task required. Such context-specific adaptation is advantageous, because it allows adjustment of the phase of the VOR without degrading the ability to hold eccentric fixation.

Validity of Listing's law during fixations, saccades, smooth pursuit eye movements, and blinks.

In its original formulation, Listing's law referred only to eye positions during steady fixation. In recent years, however, several studies have suggested that Listing's law can be extended to the movements of the eyes, including during saccades and smooth pursuit. A major problem in deciding whether or not Listing's law is obeyed during eye movements is the influence of any spontaneous fluctuations in torsional eye position. To try to settle this question, the three-dimensional position of the eyes (around the three axes: horizontal, vertical, and torsional) was recorded with dual search coils in five normal subjects during fixations, 20 degrees saccades, blinks, and 20 degrees pursuit movements with a 20 degrees/s stimulus velocity. Eye movements across a wide range of horizontal positions were measured at different elevations of gaze during 11 min. Variability (as reflected in the standard deviation of torsional eye position) was used as a measure of the validity of Listing's law. After linear detrending single trials, each lasting 21.5 s, to remove the effects of drift over minutes, the reduction in the standard deviation of torsional position in tertiary eye positions was 54% assuming a planar and 58% assuming a second-order curved Listing's surface. We attributed this long-term fluctuation of the torsional signal to slippage of the coil on the eye. The remaining variability was mainly due to short-term fluctuation of eye torsion over seconds. The impact of hysteresis, associated with consecutive centrifugal-centripetal horizontal movements, on the variability of torsional eye position appeared negligible. Peak increases in the standard deviation from the fixation baseline after fitting individual Listing's planes for each trial were 348% during blinks, 141% during saccades, and 72% during pursuit movements (median value of five subjects). In conclusion, Listing's law during blinks, saccades, and pursuit is less valid than during fixations, which raises doubts about the existence of an internal "Listing's law operator" for eye movements. Possibly, central eye velocity commands do not comply with Listing's law.

Short-term adaptation of the phase of the vestibulo-ocular reflex (VOR) in normal human subjects.

We investigated the effects of short-term vestibulo-ocular reflex (VOR) adaptation on the gain and phase of the VOR, and on eccentric gaze-holding in darkness, in five normal human subjects. For 1 h, subjects sat in a chair that rotated sinusoidally at 0.2 Hz while surrounded by a visual stimulus (optokinetic drum). The drum was rotated relative to the chair, to require a VOR with either a phase lead or lag of 45 deg (with respect to a compensatory phase of zero) with no change in gain, or a gain of 1.7 or 0.5 with no change in phase. Immediately before and after each training session, VOR gain and phase were measured in the dark with 0.2 Hz sinusoidal rotation. Gaze-holding was evaluated following 20 deg eccentric saccades in darkness. Adaptation paradigms that called only for a phase lead produced an adapted VOR with 33% of the required amount of phase change, a 20% decrease in VOR gain, and an increased centripetal drift after eccentric saccades made in darkness. Adaptation paradigms that called for a phase lag produced an adapted VOR with 29% of the required amount of phase change, no significant change in VOR gain, and a centrifugal drift after eccentric saccades. Adaptation paradigms requiring a gain of 1.7 produced a 15% increase in VOR gain with small increases in phase and in centripetal drift. Adaptation paradigms requiring a gain of 0.5 produced a 31% decrease in VOR gain with a 6 deg phase lag and a centrifugal drift. The changes in drift and phase were well correlated across all adaptation paradigms; the changes in phase and gain were not. We attribute the effects on phase and gaze-holding to changes in the time constant of the velocity-to-position ocular motor neural integrator. Phase leads and the corresponding centripetal drift are due to a leaky integrator, and phase lags and the corresponding centrifugal drift are due to an unstable integrator. These results imply that in the short-term adaptation paradigm used here, the control of drift and VOR phase are tightly coupled through the neural integrator, whereas VOR gain is controlled by another mechanism.

Short-term vestibulo-ocular reflex adaptation in humans. II. Error signals.

We oscillated humans sinusoidally at 0.2 Hz for 1 h, using various combinations of rotations of the head and visual surround to elicit short-term adaptation of the gain of the vestibulo-ocular reflex (VOR). Before and after each period of training, the gain of the VOR was measured in darkness, in response to a position step of head rotation. A small foveal target served as well as a full-field stimulus at driving VOR adaptation. Oscillation of the visual surround alone produced a substantial increase in the VOR gain. When the visual scene was rotated in phase with the head but with a larger amplitude to produce a reversal of the VOR, the VOR gain increased if the movement of the visual scene was much greater than that of the head, otherwise the gain decreased. We interpreted these results with a model of VOR adaptation that uses as its "error signal" the combination of motion of images on the retina (retinal slip) and any additional slow-phase eye velocity, beyond that generated by the VOR through the vestibular nuclei, necessary to prevent such retinal slip during head rotation. The slow phase velocity generated by the VOR is derived from "inferred head rotation", a signal based on the discharge of neurons in the vestibular nuclei that receive both labyrinthine and visual (optokinetic) inputs. The amplitude and sign of the ratio of the "error signal" to "inferred head velocity" determined the amplitude and the direction (increase or decrease) of VOR gain adaptation.

Acceptance of hepatitis B vaccine among hospital workers: a follow-up.

We reported earlier on 1,500 hospital employees whose desire for hepatitis B vaccine was assessed. We followed 229 of these subjects to measure the effect of a voluntary educational intervention on desire for vaccine. Acceptance of vaccine declined in 37 per cent of subjects and increased in 13 per cent. One of the extraneous influences on demand for vaccine may have been high-profile media coverage of the AIDS (acquired immune deficiency syndrome) epidemic.

Acceptance of hepatitis B vaccine among hospital workers.

Data on sociodemographic status, health beliefs, knowledge of hepatitis B, experience with prior vaccinations, health locus of control, and desire to receive hepatitis B vaccine were assessed in 1,500 hospital employees. Twenty per cent of the variance of the decision to accept vaccine could be explained; beliefs about the safety and efficacy of vaccine influenced acceptance most. Beliefs concerning the likelihood of contracting hepatitis B and the chance of becoming severely ill were less important determinants of vaccine acceptance. Additional factors studied, including knowledge, experience with vaccinations, and sociodemographic status, were important independent determinants of health beliefs. We conclude that the beliefs of health care providers, particularly regarding the safety and efficacy of hepatitis B vaccine, have a major impact on their decision to accept or reject vaccine. Health education interventions may be most effective when addressing beliefs about vaccine safety and efficacy.

Hospitalization on the high-risk maternity unit. A pilot study.

Women hospitalized for high-risk pregnancy appear to be at high risk for adverse reactions to hospitalization. Nine pregnant women remaining in hospital for 1 week or more were studied prospectively with a semistructured questionnaire, standard self-administered measures, and staff rating. Six women presented serious problems of compliance or psychic functioning. Women who suffered these adverse reactions tended to be poor, unemployed, younger, less educated, Catholic, unmarried, and to have children at home, when compared to the three women not experiencing difficulty. Women subsequently manifesting problems were significantly likelier on admission to appear as "cases" on the SCL-90-R and to have higher scores on the POMS. On the basis of pilot results, hospitalization for high-risk pregnancy appears to be a particularly stressful event. Women most at risk for problems can probably be identified prospectively.

When doctors listen: counseling patterns of nonpsychiatrist physicians.

Recent work has shown that nonpsychiatrist physicians are surprisingly active in the mental health arena. Using the two most recent National Ambulatory Medical Care Surveys (1980-1981), the authors analyzed the provision of counseling services by general medical physicians in more detail. Office visits involving counseling were a third again as long as the average office visit (20 minutes versus 15) and involved notably more diagnostic and therapeutic services. Although patients who received counseling services from nonpsychiatrist physicians were generally not mentally ill, about one in eight did have a psychiatric diagnosis and might have been better served in the mental health sector.

The hidden mental health network. Treatment of mental illness by nonpsychiatrist physicians.

Building on a previous study, this report explores in more detail one aspect of the "de facto mental health services system," the treatment of mental disorders by nonpsychiatrist physicians in office-based practice. Data from the 1980 and 1981 National Ambulatory Medical Care surveys indicate that almost one half of all office visits to a physician resulting in a mental disorder diagnosis are to nonpsychiatrists, mostly in primary care. Nonpsychiatrists' mentally ill patients tend to be less seriously ill than patients of psychiatrists, and are more likely to come in with physical problems. They are also significantly more likely to be female, to be nonwhite, and to be elderly. Physicians treating these patients appear to be providing a different product than psychiatrists are, spending less time with patients, but using a wider range of diagnostic and therapeutic services during each office visit.