Larry A. Abel

Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study

BACKGROUND Niemann-Pick type C disease (NPC) is an inherited neurodegenerative disorder characterised by an intracellular lipid-trafficking defect with secondary accumulation of glycosphingolipids. Miglustat, a small iminosugar, reversibly inhibits glucosylceramide synthase, which catalyses the first committed step of glycosphingolipid synthesis. Miglustat is able to cross the blood-brain barrier, and is thus a potential therapy for neurological diseases. We aimed to establish the effect of miglustat on several markers of NPC severity. METHODS Patients aged 12 years or older who had NPC (n=29) were randomly assigned to receive either miglustat 200 mg three times a day (n=20) or standard care (n=9) for 12 months. 12 children younger than 12 years of age were included in an additional cohort; all received miglustat at a dose adjusted for body surface area. All participants were then treated with miglustat for an additional year in an extension study. The primary endpoint was horizontal saccadic eye movement (HSEM) velocity, based on its correlation with disease progression. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN26761144. FINDINGS At 12 months, HSEM velocity had improved in patients treated with miglustat versus those receiving standard care; results were significant when patients taking benzodiazepines were excluded (p=0.028). Children showed an improvement in HSEM velocity of similar size at 12 months. Improvement in swallowing capacity, stable auditory acuity, and a slower deterioration in ambulatory index were also seen in treated patients older than 12 years. The safety and tolerability of miglustat 200 mg three times a day in study participants was consistent with previous trials in type I Gaucher disease, where half this dose was used. INTERPRETATION Miglustat improves or stabilises several clinically relevant markers of NPC. This is the first agent studied in NPC for which there is both animal and clinical data supporting a disease modifying benefit.

Frequency and velocity of rotational head perturbations during locomotion

SummaryWe used the magnetic search coil technique to record horizontal (yaw) and vertical (pitch) head rotations of 20 normal subjects during (1) walking in place, (2) running in place, (3) vigorous, voluntary, horizontal head rotation and (4) vigorous, voluntary, vertical head rotation. During walking or running, the predominant frequency of pitch rotations was at least twice that of yaw rotations. During running, the median, predominant pitch frequency from all subjects was 3.2 Hz, but significant harmonics were present up to 15-20 Hz in several subjects. Group median maximal head velocity during walking or running did not exceed 90 degrees/ second. During vigorous, voluntary head rotations median frequency for yaw and pitch was similar and did not exceed 2.6 Hz. However, group median maximal head velocity during vigorous voluntary yaw rotation was 780 degrees/second. Thus, (1) during locomotion, the head is stabilized in space incompletely but adequately so that the vestibulo-ocular reflex (VOR) is not saturated, (2) during vigorous, voluntary head rotations, the maximum head velocity exceeds the range where the VOR can stabilize gaze, (3) the frequencies of head rotations that occur during locomotion greatly exceed frequencies conventionally used in the laboratory for testing the VOR.

THE EFFECTS OF AGE ON NORMAL SACCADIC CHARACTERISTICS AND THEIR VARIABILITY

Age effects on human saccadic eye movements were tested with infrared reflectance oculography in 34 subjects. In contrast to a prior report, only a slight non-significant change was observed in saccadic velocity and duration. An increase in saccadic latency comparable to that found in several previous reports was observed, however. All parameters showed considerable intersubject variability for both age groups. Decreased velocities or increased durations outside of these normal, broad ranges should be regarded as pathological for all subjects; they are not physiological effects of the aging process.

Randomized, controlled trial of miglustat in Gaucher's disease type 3.

To evaluate the efficacy and safety of miglustat, concomitant with enzyme replacement therapy (ERT), in patients with Gauchers disease type 3 (GD3).

Long-term miglustat therapy in children with Niemann-Pick disease type C.

Niemann-Pick disease type C is a rare, genetic disease associated with impaired intracellular lipid trafficking and progressive neurological symptoms. Miglustat slowed disease progression in a 12-month randomized trial in juveniles and adults with Niemann-Pick disease type C, and in a parallel, noncontrolled study in affected children. Here, the authors report the open-label extension to the pediatric study. Patients aged 4 to 12 years received open-label miglustat (dose adjusted for body surface area) for an initial 12 months, during a further 12-month extension, and a long-term, continued extension phase. Efficacy assessments included horizontal saccadic eye movement, swallowing, and ambulation. Ten children completed 24 months’ treatment. Horizontal saccadic eye movement, ambulation, and swallowing were stabilized at 24 months. Analysis of key parameters of disease progression showed disease stability in 8 of 10 patients (80%). Miglustat stabilized neurological disease progression in pediatric patients with Niemann-Pick disease type C, with comparable safety and tolerability to that observed in adults and juveniles.

Quantitative assessment of smooth pursuit gain and catch-up saccades in schizophrenia and affective disorders

The smooth pursuit responses to 5 degrees and 20 degrees/sec constant-velocity stimuli were recorded from 23 patients with schizophrenia, 16 affective disorder patients, and 21 normals using low-noise infrared oculography. Pursuit gain, catch-up saccade (CUS) rate and amplitude, and their interrelationships were examined. Gain in the schizophrenic patients was reduced only at 20 degrees/sec, but for both patient groups, CUS rate at 5 degrees/sec was significantly lower than in normals. Using CUS rate at 20 degrees/sec, the patient groups could be distinguished from each other (the rate for schizophrenic patients being highest, and the rate for affectives the lowest) but neither differed significantly from normals. The diagnostic groups did not differ significantly in mean CUS amplitude, although there was a trend for patients to have larger saccades. Gain-CUS rate correlation was strong in normals but reduced or absent in both patient groups. These results indicate that the ocular motor systems of patients with schizophrenia and affective disorders process eye position error abnormally.

Smooth pursuit eye movements in schizophrenics—What constitutes quantitative assessment?

Although a voluminous literature exists on the eye movements of schizophrenic and affective disorder patients, many of the assessments made of smooth pursuit have been qualitative in nature. Most of them have not differentiated between abnormal functioning of the smooth pursuit system and intrusion of inappropriate saccades during a smooth tracking task. Specific identification of the pursuit or saccadic defect is necessary if the origins of the abnormalities are to be understood and related to psychopathology. Analytical techniques, such as the ln(S/N) ratio, although numerical in nature, are still unable to discriminate among pursuit and saccadic defects, as shown by our analysis of simulated tracking. Thus, to understand the effects of psychiatric disorders on the ocular motor system, specific defects must be identified and quantified.

Analog Model for Gaze-Evoked Nystagmus

A relatively simple model of the fast eye movement (saccadic) system has been developed and simulated on an analog computer. The model is capable of producing normal saccadic eye movements and has several provisions which permit the simulation of clinical signs of gaze-evoked nystagmus. According to the model, gaze-evoked nystagmus may result from various abnormalities in the neuronal pool responsible for integration of the pulse of high frequency fiing which initiates each saccade. Simulation of these inferred neuronal deficits produced subtle differences in saccadic behavior as well as gaze-evoked nystagmus. These differences occurred both in the nystagmus-free range of gaze angles and after the nystagmus appeared. The subtlety of the deficits and the sparsity of studies of gaze-evoked nystagmus using modem oculographic recording techniques, probably explains why such saccadic behavior has not been previously noted. If one, or more than one, of these simulated mechanisms is, in fact, an accurate model of the actual physiological deficit, future studies of such patients should reveal the corresponding abnormal saccadic behavior.

Psychosocial impact of amblyopia and its treatment: a multidisciplinary study

Background:  To explore the meaning of amblyopia from both parents’ and children’s perspectives and to seek correlations between the experiential aspects of the condition and its treatment, the clinical characteristics of amblyopia and any apparent psychopathology.

Intermittent downbeat nystagmus and oscillopsia reversed by suboccipital craniectomy

We describe an unusual case of vertical oscillopsia and primary position downbeat nystagmus associated with an adult Arnold-Chiari malformation. A unique aspect of the ocular motor abnormality was the intermittent nature of the nystagmus, which displayed no relationship to head position, emotion, or the Valsalva maneuver. Conventional computed tomography with posterior fossa views was normal, but metrizamide cisternography demonstrated an extramedullary mass originally believed to be a meningioma. There was a dramatic diminution of the visual comdaints and downbeat nvstamus after suboccipital craniectomy for an Arnold-Chiari malformation. Nystagmus characteristics were documented by serial quantitative eye movement recordings.