Ocular dysfunctions and toxicities induced by antiepileptic medications: Types,pathogenic mechanisms,and treatment strategies

Introduction: Ocular dysfunctions and toxicities induced by antiepileptic drugs (AEDs) are rarely reviewed and not frequently received attention by treating physicians compared to other adverse effects (e.g. endocrinologic, cognitive and metabolic). However, some are frequent and progressive even in therapeutic concentrations or result in permanent blindness. Although some adverse effects are non-specific, others are related to the specific pharmacodynamics of the drug.

Areas covered: This review was written after detailed search in PubMed, EMBASE, ISI web, SciELO, Scopus, and Cochrane Central Register databases (from 1970 to 2019). It summarized the reported ophthalmologic adverse effects of the currently available AEDs; their risks and possible pathogenic mechanisms. They include ocular motility dysfunctions, retinopathy, maculopathy, glaucoma, myopia, optic neuropathy, and impaired retinal vascular autoregulation. In general, ophthalmo-neuro- or retino-toxic adverse effects of AEDs are classified as type A (dose-dependent), type B (host-dependent or idiosyncratic) or type C which is due to the cumulative effect from long-term use.

Expert opinion: Ocular adverse effects of AEDs are rarely reviewed although some are frequent or may result in permanent blindness. Increasing knowledge of their incidence and improving understanding of their risks and pathogenic mechanisms are crucial for monitoring, prevention, and management of patients’ at risk.     

Rotational occlusion of the vertebral artery at the atlantoaxial joint: is it truly physiological?

We present a patient with vertebrobasilar insufficiency, with vertigo and horizontal nystagmus, induced by turning the head to the right. Angiography demonstrated transient occlusion of the left vertebral artery at the atlantoaxial joint during rotation of the head. The pathogenesis and angiographic findings are discussed.     

Periodic alternating nystagmus and rebound nystagmus in spinocerebellar ataxia type 6.

We report on a family with ataxia type 6 (SCA6) showing peculiar oculomotor symptoms. The proband presented with periodic alternating nystagmus (PAN), and her 2 brothers had rebound nystagmus and gaze-evoked nystagmus. They carried the identical mutation (the number of expanded CAG repeat, 24) in the CACNA1A gene. The intrafamilial variability of oculomotor symptoms may be ascribed to factors other than CAG repeat expansion size in SCA6.     

健康人视动性眼球震颤的研究

用微处理机(单板计算机)实时分析了视动性眼震,提取了10项参数,其中9项参数得出正常值,可作为评定视动性眼震之参考。各项参数间均有相关,整体评定,可提高诊断水平。将平均慢相速度、快相波辐和累积快相波辐、慢相时间等4项参数分别用计算机处理和人工处理,把两种处理结果进行t检验,无显著差异(P值均>0.05)。将计算机与人工计算的眼震频率进行比较,两者符合率达96.7％以上。采用微处理机可显著提高工效。     

头低位模拟失重状态对前庭功能的影响

为研究头低位模拟失重对运动病症状、垂直视动眼震（ＶＯＫＮ）及体液重新分配的影响，在头低位－１０°的模拟失重状态下，采用大视野的垂直视动刺激，观察１８名正常人的运动病症状、ＶＯＫＮ、激素（ＡＶＰ、ＶＩＰ、ＣＯＲＴ、ＡＬＤＯ）的反应特点。结果表明，头低位－１０°状态下的大视野垂直视动刺激可以诱发出明显的运动病症状，头低位－１０°的垂直视动刺激比坐位更容易诱发运动病。坐位状态ＶＯＫＮ慢相速度有明显的方向性不对称，敏感组ＶＯＫＮ方向性不对称有显著差异（Ｐ＜０．０５）。头低位－１０°时ＶＯＫＮ的不对称现象不明显，向下方向运动的ＶＯＫＮ慢相速度显著增加。分析指出，头低位－１０°状态下垂直视动刺激比坐位和秋千刺激的贡献率大。尿中ＣＯＲＴ（皮质醇）在秋千和头低位的垂直视动刺激前后有显著性增加。提示：大视野的垂直视动刺激与头低位－１０°两种刺激的结合可能成为预测空间运动病的方法之一．     

Two Autopsied Cases of Familial Sudanophilic Leukodystrophy

Abstract: Two autopsied female sibling cases of sudanophilic leukodystrophy are reported. Case A and case B were the second and third of seven siblings, and a sister and a brother died from severe progressive neurological disease with similar symptoms. Consanguineous marriages were noted in the family of both cases through the past three generations. Case A gradually developed intellectual deterioration and tetraplegia at the age of 29, progressed to akinetic mutism within one year and thereafter survived for 14 years. Neuropathologically, a severe atrophy and degeneration were noted in the white matter of the whole cerebrum, sparing the subcortical U-fibers. Myelin and axons were severely damaged with peripheral astrocytic gliosis. Case B developed similar clinical symptoms at the age of 20 and survived for 7 years in the state of akinetic mutism. Similar postmortem findings as those of case A were found in the white matter of the cerebrum with formation of sudanophilic breakdown products and with thick fibrillary gliosis. The pyramidal tract was completely degenerated. There was no accumulation of abnormal lipid in the brains of both cases.     

Fast-phase instabilities in normally sighted relatives of congenital nystagmus patients—autosomal dominant and x-chromosome recessive modes of inheritance

Verification of inheritance in congenital nystagmus (CN) is only possible through the identification of more than one affected member in a family, since in a single case there are no accurate clinical differentiations between spontaneous and inherited CN. We performed electronystagmographic examinations (ENG) to search for abnormal involuntary eye movements as a sign of heredity in seemingly unaffected members of CN families.ENG registrations were performed under three test conditions: (1) with the subject fixating a target, (2) with the room lights off and (3) with closed eyes.Fifty normally sighted individuals (group (a) underwent the test procedure to provide a baseline of normality. Five CN families (three dominant, two sex-linked recessive) were tested as group (b). The eye movement recordings were analysed in terms of nystagmus intensity (amplitude x frequency of the involuntary saccade). In every one of the five families, abnormalities in seemingly non-affected members could be demonstrated: in four families, fastphase instabilities, in the fifth family a true (CN) (slowphase instability).All certain gene carriers were diagnosed correctly by the ENG.These findings indicate a method for detecting slightly affected members in dominant pedigrees and female gene carriers in sex-linked mode of transmission.     

Sigma-movement and optokinetic nystagmus elicited by stroboscopically illuminated stereopatterns

Summary Sigma-movement is an apparent movement seen when a stationary periodic visual pattern of the period P_s is illuminated Stroboscopically at the flash frequency f_s and smooth gaze pursuit eye movements are performed across the pattern at an angular velocity V_e = P_s · f_s deg · s^–1. Sigma-movement leads to an optokinetic nystagmus (Sigma OKN) which in turn sustains Sigma-movement perception. (1) Sigma-movement was also seen in an apparent three-dimensional periodic stripe pattern generated by two periodic monocular stimulus patterns with a certain degree of horizontal binocular disparity. (2) Sigma-movement perception and Sigma-OKN were also elicited by a Stroboscopically illuminated, stationary, random dot stereostripe pattern. The periodicity P_s of this pattern is generated on the cyclopean retina (Julesz 1971). The equation described above was also valid. When the time delay t between left eye and right eye flashes was varied, the apparent depth of the random dot stereostripe pattern decreased with increasing t, but the Sigmaeffects were not affected. (3) Sigma-movement illusion and Sigma-pursuit movements can also be induced when real three-dimensional objects composed of periodic components are Stroboscopically illuminated and adequate gaze or eye pursuit movements are induced. Sigma-movement is related to gaze movement and is therefore elicitable by eye, head or body movements. (4) Sigma-movement is presumably caused by the interaction of efference copy signals (generated in a cortical gaze pursuit system) and afferent visual signals. The present data indicate that neuronal mechanisms for this interaction are located — at least in part — at or beyond the level of binocular fusion and stereopsis.Supported by grants of the Deutsche Forschungsgemeinschaft (Gr161)     

Habituation and adaptation of the vestibuloocular reflex: a model of differential control by the vestibulocerebellum

Summary We habituated the dominant time constant of the horizontal vestibuloocular reflex (VOR) of rhesus and cynomolgus monkeys by repeated testing with steps of velocity about a vertical axis and adapted the gain of the VOR by altering visual input with magnifying and reducing lenses. After baseline values were established, the nodulus and ventral uvula of the vestibulocerebellum were ablated in two monkeys, and the effects of nodulouvulectomy and flocculectomy on VOR gain adaptation and habituation were compared. The VOR time constant decreased with repeated testing, rapidly at first and more slowly thereafter. The gain of the VOR was unaffected. Massed trials were more effective than distributed trials in producing habituation. Regardless of the schedule of testing, the VOR time constant never fell below the time constant of the semicircular canals (5 s). This finding indicates that only the slow component of the vestibular response, the component produced by velocity storage, was habituated. In agreement with this, the time constant of optokinetic after-nystagmus (OKAN) was habituated concurrently with the VOR. Average values for VOR habituation were obtained on a per session basis for six animals. The VOR gain was adapted by natural head movements in partially habituated monkeys while they wore ×2.2 magnifying or ×0.5 reducing lenses. Adaptation occurred rapidly and reached about ±30%, similar to values obtained using forced rotation. VOR gain adaptation did not cause additional habituation of the time constant. When the VOR gain was reduced in animals with a long VOR time constant, there were overshoots in eye velocity that peaked at about 6–8 s after the onset or end of constant-velocity rotation. These overshoots occurred at times when the velocity storage integrator would have been maximally activated by semicircular canal input. Since the activity generated in the canals is not altered by visual adaptation, this finding indicates that the gain element that controls rapid changes in eye velocity in the VOR is separate from that which couples afferent input to velocity storage. Nodulouvulectomy caused a prompt and permanent loss of habituation, returning VOR time constants to initial values. VOR gain adaptation, which is lost after flocculectomy, was unaffected by nodulouvulectomy. Flocculectomy did not alter habituation of the VOR or of OKAN. Using a simplified model of the VOR, the decrease in the duration of vestibular nystagmus due to habituation was related to a decrement in the dominant time constant of the velocity storage integrator (1/h ₀). Nodulouvulectomy, which reversed habituation, would be effected by decreasing h ₀, thereby increasing the VOR time constant. Small values of h ₀ would cause velocity storage to approach an ideal integrative process, leading the system to become unstable. By controlling the VOR time constant through habituation, the nodulus and uvula can stabilize the slow component of the VOR. VOR gain adaptation was related to a modification of the direct vestibular path gain g ₁, without altering the coupling to velocity storage g ₀ or its time constant (1/h ₀). The mismatched direct- and indirect-pathway gains simulated the overshoots in the dynamic response to a step in velocity, that were observed experimentally. We conclude that independent distributed elements in the VOR modify its dynamic response, under control of separate parts of the vestibulocerebellum.     

Directional preponderance in human optokinetic nystagmus

Summary In afoveate animals, and in neonatal or cortically deficient foveate animals, monocular optokinetic nystagmus (OKN) is controlled by directly innervated subcortical nuclei and occurs only in response to temporonasal motion. In higher mammals, the subcortical nuclei receive direct inputs predominantly from the nasal hemiretinae and indirect inputs from the visual cortex. These indirect inputs counterbalance the directional asymmetry of the primitive mechanism. These facts lead to the prediction that the velocity of the slow phase of OKN in the normal human adult should be higher for stimuli moving centripetally rather than centrifugally in each monocular and binocular hemified. The predicted patterns of directional preponderance were found in both monocular and binocular hemifields. Directional asymmetries were still present in monocular hemifields when the central retina was occluded and were reduced when the stimulus was confined to a narrow central strip of the visual field. These results are discussed in terms of the contributions of the central and peripheral retina to directional preponderance.This study is part of DCIEM research contract 97711-3-7595/ 8SE83-00221 and was also supported by NSERC grant A0195