The potential for vigabatrin-induced intramyelinic edema in humans.

PURPOSE: Vigabatrin (Sabril, Hoechst Marion Roussel) is an antiepilepsy drug (AED) presently marketed in 64 countries for the treatment of partial and secondarily generalized seizures. Vigabatrin (VGB) is marketed in a subset of these countries for the treatment of infantile spasms. Clinical experience in humans has shown that VGB provides effective seizure control with a wide margin of safety. However, animal toxicity studies raised concern when prolonged administration of VGB was shown to induce intramyelinic edema (IME) in some laboratory animal species. METHODS: Animal and human data were reviewed with respect to the potential for VGB-induced IME. Surveillance of patients receiving VGB in clinical trials or by prescription has been conducted for >15 years to identify patients developing clinical abnormalities that might be IME related. RESULTS: The histologic lesions of VGB-induced IME in animals are reliably reproduced and correlate with changes in multimodality evoked potentials (EPs) and magnetic resonance imaging (MRI). Numerous studies of the effects of VGB on EP and MRI in epilepsy patients have demonstrated no clear-cut IME-related changes in these modalities. Additionally, autopsy and surgical brain samples from VGB-treated patients have been scrutinized for potential IME histopathology. In an estimated 350,000 patient-years of VGB exposure (approximately 175,000 patients exposed for 2 years at an average dose of 2 g/day), no definite case of VGB-induced IME has been identified. CONCLUSIONS: Comprehensive review of a variety of sources of data failed to identify any definite case of IME in humans treated with VGB.

ON-pathway dysfunction in a patient with acquired unilateral night blindness.

PURPOSE: To investigate possible functional correlates of an apparent ON-pathway defect observed in the cone electroretinogram of a patient with acquired unilateral night blindness. METHOD: Visual evoked potentials were recorded to the onset of a grid pattern consisting of either incremental or decremental squares. Saccadic eye movements were measured to luminance increments and decrements presented 5 degrees from fixation. The patient's results were compared with normative data. RESULTS: Visual evoked potential latencies were prolonged to incremental stimulation of the patient's affected left eye but were within normal limits for the other three conditions (increments and decrements, right eye; decrements, left eye). A similar pattern of asymmetry between latencies to incremental and decremental stimulation of the affected eye was observed for saccadic eye movements. CONCLUSIONS: The observed predominant delay in response to luminance increments supports the hypothesis of an ON-pathway dysfunction in this patient with acquired unilateral night blindness.

The peripheral flicker effect: desensitization of the luminance pathway by static and modulated light.

Previous studies have shown that luminance flicker, presented peripheral to a foveal test target, increases thresholds for target detection: the peripheral flicker (PF) effect. These studies have also shown that thresholds are elevated more for luminance targets, relative to chromatic targets. In the present study we examined the specificity of the PF effect on the luminance mechanism and assessed the contribution of modulated stray-light to the test field, as well as longer range spatial interactions. We found that the presence of a foveal luminance pedestal, as well as PF, caused a notch to appear in the spectral sensitivity function around 570 nm. This result confirms the hypothesis that the PF effect decreases the sensitivity of the luminance pathway. To assess the contribution of stray-light to the PF effect, we modulated a luminance pedestal without the presence of PF in order to simulate the stray-light effect in isolation. A decrease in sensitivity for wavelengths around 570 nm occurred with modulated stray-light, suggesting that modulated stray-light contributes substantially to this effect. We then minimized the modulated stray-light by phase-reversing a checkerboard pattern in the periphery. A significant, though smaller, threshold elevation to mid-spectrum stimuli was obtained, suggesting that long range spatial effects are also active in the PF effect. We conclude that the PF effect causes a desensitization of foveal luminance pathways via local and more long range spatial interactions. Our results are consistent with previous data which suggest that the PF effect is due to selective adaptation of cells in the magnocellular pathway (M-cells). Our data imply that local network adaptation may be a property of the magnocellular pathway.

Hemianopic anosognosia.

In a prospective study of 32 consecutive patients with homonymous visual field defects due to ischemic infarcts we found hemianopic anosognosia (HAN), defined as the unawareness of visual loss in the homonymous hemifield (or hemiquadrant), in 20 patients (62%). HAN, although occurring predominantly in right-side lesions in 16 of 26 patients (62%) was also present in four of six patients (or 67%) with left-side lesions. This group of patients has been presented in a prior report on positive spontaneous visual phenomena. HAN was associated with somatic anosognosia in nine patients and hemineglect in 17 patients. Dissociation between somatic and hemianopic anosognosia, as well as between hemineglect and HAN, was present in several patients, indicating that these phenomena may be independent of each other. Eight patients had pure homonymous hemianopia; that is, hemianopia without cognitive, motor, or somatosensory deficits. Four of these patients (Group A) had awareness of the visual deficit, whereas three patients (Group B) had HAN. Patients in these two groups had similar anatomic lesions. Patients with phosphenes, photopsias, or visual hallucinations were usually aware of their visual field loss. We suggest that HAN is most often related to failure of discovery of the deficits, occasionally to severe visual hemineglect, sometimes to generalized cognitive impairment, or to a combination of these factors. We further conclude (1) there is no specific cortical area for conscious visual perception; (2) visual awareness is processed by a distributed network including multiple visual cortices, parietal and frontal lobes, the pulvinar, and lateral geniculate bodies (lesions localized at various nodes or centers in the network may produce similar phenomena); and (3) both hemispheres are involved in visual processing and conscious awareness.

Positive spontaneous visual phenomena limited to the hemianopic field in lesions of central visual pathways.

We prospectively studied 32 patients with ischemic infarction of the retrochiasmal visual pathways. Positive spontaneous visual phenomena (PSVP) in the blind hemifield were present in 13 patients (41%). The PSVP were subdivided into phosphenes, photopsias, visual hallucinations, palinopsia, and agitated delirium with hemianopia. PSVP were never associated with auditory or other sensory positive phenomena, except in patients with agitated delirium. Patients with photopsias, phosphenes, palinopsia, and visual hallucinations had similar lesions in MRI/CT, suggesting no anatomic area unique for these four phenomena. However, there was a significant difference in the severity of associated neurologic deficits between hemianopic patients with and without PSVP. Larger lesions destroying anteriorly located visual association areas precluded the development of PSVP, which may be related to release from inhibitory input of visual regions bordering the damaged area. Patients with the syndrome of agitated delirium and hemianopia had specific lesions involving the mesial aspect of the occipital lobe, the parahippocampal gyrus, and hippocampus.

Dipole-modeling of the visual evoked P300.

We collected visual event-related potentials (ERPs) from 6 normal subjects using an "oddball" paradigm. Subjects were required to count the occurrences of matching shapes presented in the left and right visual field. Shapes matched on 20% of trials. ERPs were recorded from 20 or 43 electrodes distributed over the scalp. A multiple spatio-temporal equivalent dipole (ED) model was used to fit the early sensory and P300 component. A latency window to analyze the P300 was determined using the global field power statistic. The spatial topography of the P300 over this window was characterized by a midline positivity that decreased in amplitude with spatial distance from the peak. After sensory components were fit, the source of P300 could be accounted for by 1 or 2 EDs, which were usually located near medial temporal areas. This result is at odds with evidence from depth recordings during the oddball paradigm, showing that multiple regions of the brain are active during this interval.

Cortical blindness and residual vision: is the "second" visual system in humans capable of more than rudimentary visual perception?

We studied 12 patients with static cortical blindness to evaluate residual vision after destruction of area 17 and to assess the visual capacity of the subcortical "second" visual system in humans. In each case, the cause was bilateral infarction of the occipital lobes. Five patients had total blindness, and four had residual rudimentary vision (RRV), characterized by homonymous areas of light perception in the peripheral field and ability to detect moving objects. Only three patients had the ability to read; two of these had spared macular vision, and the other had spared left homonymous hemimaculae and spared temporal crescent. Neuroimaging and visual evoked potentials (VEPs) correlated with the extent of the visual dysfunction. Total destruction of area 17 bilaterally was associated with total permanent visual loss. The larger the amount of spared visual cortex, the better the vision. Positron emission tomography (PET) or single photon emission computed tomography (SPECT) demonstrated retained metabolic activity in islands of preserved area 17 in patients with some residual vision. VEPs were present in totally blind individuals. We conclude that, in humans, useful visual function is preserved only when a critical amount of area 17 is spared. The subcortical second system may participate in the generation of VEPs, but is incapable of conscious visual perception.

The effects of age on steady-state pattern electroretinograms and visual evoked potentials.

Steady-state pattern-reversal electroretinograms and visual evoked potentials were simultaneously recorded in two groups of young and elderly normal volunteers. The young group consisted of 23 subjects (13 women and 10 men) aged 18 to 28 years, and the elderly group consisted of 24 subjects (11 women and 13 men) aged 58 to 77 years. Stimuli were square-wave gratings ranging in spatial frequency from 0.5 to 6 c/deg and phase reversed at a frequency of 4 Hz. Pattern-reversal electroretinograms and visual evoked potentials consisted of a prominent second and a smaller fourth harmonic response. Spatial frequency-amplitude functions of the pattern-reversal electroretinogram second and fourth harmonics were similar for the young and elderly groups. The mean fourth harmonic phase was significantly shifted in elderly subjects compared with young subjects for all spatial frequencies tested. Spatial frequency tuning was observed for amplitude and phase functions of the visual evoked potential second and fourth harmonic responses for both age groups. Age had a significant effect on phase for spatial frequencies above 1.5 c/deg. Amplitude of the fourth harmonic was significantly lower for the elderly group at 1.5-4 c/deg. Phase was significantly different between groups for spatial frequencies below 3 c/deg. Our results suggest that aging influences both retinal and central visual pathways. Aging differentially affected the visual evoked potential second and fourth harmonic responses, suggesting different neuronal origins for these components.

Topographic mapping of electrophysiologic measures in patients with homonymous hemianopia.

We analyzed electroencephalographic (EEG) activity and spatial distribution of the pattern-reversal visual evoked potential (PVEP) in 20 patients with unilateral lesions in the retrochiasmal visual pathways. Focal abnormalities that were consistent with lesion location were present in the topographically analyzed EEG or VEP of 85% of the patients, compared with a 70% detection rate for conventional analysis techniques. Quantitative analysis of spectrally analyzed EEG revealed focal abnormality in 7 patients whose conventional EEG was interpreted as either normal or diffusely slow. However, focal paroxysmal spikes present in the EEG of 1 patient were missed by EEG mapping, and a false localization of quantitative EEG abnormality contralateral to the lesion occurred in 1 patient. Topographic analysis of the PVEP was no more sensitive to retrochiasmatic lesions than conventional analysis of 2 lateral occipital electrodes. We conclude that topographic mapping is a valid technique in the detection of localized cerebral lesions.

Saccadic latency as a measure of afferent visual conduction.

Latency to initiate a saccadic eye movement to a visual target, and visual evoked potential, were measured in seven patients with resolved unilateral optic neuritis. Saccades were delayed when the target was presented to the clinically involved eye, but were normal when the contralateral eye was tested. With binocular target presentation, saccades were symmetric between eyes and normal in latency. In two patients with pituitary adenoma and low-grade bitemporal field defects, saccades were delayed when targets were presented in the temporal field, but were within normal limits when presented in the nasal field. These results cannot be attributed to lesions in the motor pathways. It is concluded that saccadic latency to visual targets is a valid measure of afferent conduction. If the robust delays found in this study prove to have test-retest reliability, saccadic latency may provide a measure of afferent function which is sensitive to the demyelination that preceeds neuronal degeneration and sensitivity loss in patients suspected of having optic neuropathy.

Pattern electroretinogram threshold does not show contrast adaptation.

Pattern electroretinogram (PERG) thresholds were examined using a swept contrast stimulus method. Stimulus contrast was either continuously changed (swept) from high to low (descending sweep), or from low to high (ascending sweep). Visual evoked potential (VEP) contrast threshold was higher when measured using descending sweeps than when using ascending sweeps. This VEP threshold difference has been attributed to cortical adaptation. Although previous work has reported changes in the PERG amplitude as a function of pre-exposure, we have found no analogous effect on the PERG threshold.

Psychophysical and electroretinographic findings in X-linked juvenile retinoschisis.

We compared psychophysical and electroretinographic test results of four patients with X-linked juvenile retinoschisis who had clinically apparent lesions isolated to the foveal area. The b-wave of the flash electroretinogram was selectively reduced, while the a-wave was within the normal range. Oscillatory potentials generated by either the rod or cone systems were markedly reduced. Absolute thresholds outside the fovea were either normal or only moderately elevated, indicating that the sensory neural pathways were, by and large, operating with limited dysfunction. Therefore, the oscillatory potentials do not directly reflect, to any appreciable extent, the function of bipolar or ganglion cells. Finally, a sequence of pathologic events is proposed for X-linked juvenile retinoschisis that initiates with Müller cell dysfunction.