Visual evoked potential characteristics and early diagnosis of Pelizaeus-Merzbacher disease.

OBJECTIVE: Early diagnosis of Pelizaeus-Merzbacher disease; assessment of disease progression. DESIGN: Pediatric neuro-ophthalmology evaluation of visual function with pattern and luminance visual evoked potentials; behavioral state assessment; electrophysiological diagnostic test; baseline estimates at the age of 11 weeks; 1-year follow-up. SETTING: University hospital electrodiagnostic vision research laboratory. CASE STUDY: X-linked Pelizaeus-Merzbacher disease; leukodystrophy; patient tested at the age of 11 weeks and at the age of 58 weeks for follow-up; five age-matched normal controls. INTERVENTIONS: Physical therapy, medication, evaluation. MAIN OUTCOME: Early diagnosis; diagnostic confirmation; objective monitor of disease progression. RESULTS: Abnormal spatial and temporal vision and abnormal visual pathway maturation; visual evoked potentials of proband with Pelizaeus-Merzbacher disease were grossly abnormal, reflecting myelination disorder. CONCLUSIONS: Visual evoked potential pediatric electrodiagnosis yields reliable measures of visual function and visual system maturation in leukodystrophy.

Visual evoked response asymmetry only in the albino member of a family with congenital nystagmus.

PURPOSE: To examine the purported relationship between visual fiber misrouting and congenital nystagmus (CN) by studying a family containing members with either hereditary CN alone or in conjunction with albinism. METHODS: Eight relatives in three generations of a family with two genetic disorders (congenital nystagmus [CN] and albinism) underwent complete ophthalmologic examination and visual evoked potential (VEP) assessment of visual pathway organization using a luminance flash and checkerboard pattern onset/offset stimulus paradigm. Age-matched controls patients (albino, CN, or normal) corresponding to the three affected family members underwent the same procedure. RESULTS: The standard VEP albino misrouting test did not reveal any signs of abnormality in all family members tested except for the clinically diagnosed 8-month-old albino proband patient. Visual evoked potential assessment from the albino patient evinced contralateral asymmetry characteristic of aberrant temporal retinostriate projections. CONCLUSIONS: Although CN and albinism share some of the same clinical symptoms, these findings indicate that the disorders may be inherited and manifested independently in members of one family. Furthermore, the functional and/or structural factors responsible for CN cannot be readily ascribed to VEP retinal-cortical misprojections recorded in albinism.

VEP projections in congenital nystagmus; VEP asymmetry in albinism: a comparison study.

Visual evoked potential (VEP) asymmetry in which a preponderance of nasal and temporal retina afferents project to the contralateral hemisphere after full-field monocular stimulation is considered specific to albinism. Some reports, however, suggest that patients with congenital nystagmus (CN) share the albino-like visual pathway anomaly. To examine the clinical specificity of albino misrouting, VEP topography was assessed in ten patients with congenital nystagmus and in ten age-matched albino patients. As an additional control, the VEP response profiles from eight albino patients with no nystagmus were also evaluated. The results are definitive; VEP contralateral asymmetry reflecting temporal retinal misprojection is evinced only in albino patients. Furthermore, ocular-motor instabilities in CN cannot be readily attributed to albino-type misrouted retinal-cortical projections.

Selective broad-band spatial frequency loss in contrast sensitivity functions. Comparison with a model based on optical transfer functions.

PURPOSE: Contrast sensitivity functions (CSFs) were measured under various optical conditions in healthy observers together with CSFs from selected patients. Threshold increases across the spatial frequency range were compared with predictions of a theoretical optical model based on modulation transfer functions. METHODS: Contrast thresholds for various spatial frequencies were determined with a computer-automated method of ascending limits in a control group and a group of patients with various visual pathway diseases ranging from retinal disorders, such as diabetic retinopathy, to neural disorders, such as multiple sclerosis. For normal control subjects, simulated contrast sensitivity losses also were effected by manipulating pupil diameter and dioptric blur. Modulation transfer functions of the eye's optics in polychromatic light were calculated. The wave aberration function included standard spherical aberration, coma, and small amounts of irregular aberrations. RESULTS: Experimentally, slight dioptric blur (e.g., 0.4 to 0.75 D) introduced increased CSF thresholds within either a narrow or broad bandwidth. For the latter, decreased CSF sensitivity occurred across a spatial frequency range as broad as 1 log unit, from low spatial frequencies (2 cyc/deg), and for pupil sizes equal to or larger than 3 mm. Predictions based on an optical model are qualitatively and quantitatively in agreement with these findings. Contrast sensitivity losses of the patients were neither specific nor selective to the pathologic condition at hand. Furthermore, various CSF losses optically induced in the control subjects were indistinguishable from nonoptically induced pathologic CSF profiles. CONCLUSIONS: Selective broad-band contrast sensitivity loss may be optically induced by slight refractive error. As a result, selective contrast sensitivity loss at lower and intermediate spatial frequencies concurrent in patients with various pathologic, neuro-ophthalmologic conditions cannot be a priori attributed to neural factors without carefully controlled and well-defined optical variables.

Origin of notches in CSF: optical or neural?

Grating contrast sensitivity was measured across a range of 1 to 32 cycles per degree (c/deg) in normal observers with a computer-automated method of ascending limits. Monocular contrast sensitivity functions (CSF) were obtained for vertical, oblique and horizontal orientations, with or without full refractive correction. Small amounts of astigmatic error resulted in loss of sensitivity at selective spatial frequencies. Coincident with these CSF "notches" was the presence of monocular diplopia induced, in this study, by the condition of astigmatic error. Experimental manipulation of the selective spatial frequency losses was possible by the introduction of slight cylindrical defocus and by changes in grating orientation. Determination of the angular displacement and orientation of the monocular double images allowed prediction of the spatial frequencies which would show reduced sensitivity due to partial cancellation of contrast. The close fit between the predicted and measured sensitivity loss supports the suggestion that refractive error can affect narrowly-tuned notches. These results indicate that before the presence of a notch in the CSF can be attributed to neural abnormality, an optical cause must be eliminated.

Rapid assessment of visual function: an electronic sweep technique for the pattern visual evoked potential.

We have developed an electronic spatial frequency sweep technique for electrophysiological assessment of visual acuity and pattern vision. The technique allows an accurate and reliable measurement of VEPs to a full range of spatial frequencies in just 10 sec. Because the measurements are so rapid, the technique suggests several new improvements in the assessment of visual function. Sweeping spatial frequency linearly and extrapolating the high-frequency region of the VEP spatial-tuning function to zero voltage allows an estimate of acuity which correlates highly with psychophysical estimates of acuity. Variants of the procedure are appropriate for the assessment of refracture error, determination of equality of visual function for the two eyes and of binocular interactions, and for sequential assessment of therapeutic conditions.

Detection and maturation of VEP albino asymmetry: an overview and a longitudinal study from birth to 54 weeks.

The genetic anomaly in albinism prevents adequate melanin metabolism within the fetal eye cup and stalk. This results in severe disruption of pre- and postnatal retinal development and the condition of abnormal temporal retinal projections. The obligate misrouting of retinal-geniculate-cortical projections in albinism can be detected in the topographical representation across the occiput of the visual evoked potential (VEP). Age-dependent misrouting detection methods are described which yield 100% detection rates with zero false positives across the life span. By combining appropriate state-defined neonatal recording procedures with the albino infant VEP test paradigm, the presence of aberrant optic pathway projections was observed in a 5-day-old full-term infant. Maximum asymmetry was observed within a long-latency window of the response which shifted during the postpartum period to shorter latencies. Longitudinal studies show two specific latency regions of significant VEP asymmetry. The first occurs within 40-70 ms after stimulus onset and remains constant across the age range. The second, more robust, cluster of asymmetry occurs within a longer latency window and shows an age-related shift towards shorter latencies. The decreasing latency of this asymmetry is concomitant with normal maturational changes of the evoked response. These results show that VEP misrouting can be extended to reliable albino diagnosis within the neonatal period and to the assessment of visual maturation.

Motoric response inhibition in finger movement and saccadic eye movement: a comparative study.

OBJECTIVE: To study cortical potentials associated with suppression of intended motoric actions. METHODS: Electro-encephalographic activity was recorded in a Go/NoGo reaction time paradigm. Subjects viewed computer-generated pacing stimuli, which provided information concerning the time at which an imperative Go/NoGo signal occurred. A motoric response was required following Go stimuli while motoric response inhibition was required following NoGo stimuli. To examine whether previously reported 'Go/NoGo effects' on event related potential (ERP) components may be generalized across movement modalities, the present experimental paradigm was performed with either finger movement or saccadic eye movement as required motoric response. RESULTS: For both movement modalities, comparable differences in the morphology, amplitude and scalp topography of ERP components were observed between Go trials, with proper movement execution, and NoGo trials, with complete suppression of motoric activity. In addition, for either movement modality a similar 'error related negativity' (ERN) was found for NoGo trials in which motoric activity was present. CONCLUSIONS: The results of the present study suggest that cortical activity underlying the Go/NoGo differences in ERP components represent general cortical processing associated with detection and/or suppression of inappropriate response behaviour, independent of movement modality.

The use of a system analysis approach to electrodiagnostic (ERG and VEP) assessment.

To evaluate the integrity of a biological system and its constituent functional units, a systematic study of input-output relations adopted from engineering has proven appropriate. With such an approach, sequential analysis can be implemented to probe the various parameter extractions along, for example, the visual system. The a priori assumption in this approach is that the visual world is processed along functionally separate pathways yielding distinct percepts such as contrast and motion. This so-called channel approach has proven useful not only to basic vision research but also for clinical application. The present overview shows that on the basis of the ERG or VEP, a type of functional anatomy can be performed with the biological system of interest remaining intact. Finally, it will be demonstrated that electrophysiological output parameters of the visual system can also serve as a non-invasive entry to investigate general systemic disorders.

Global stereopsis in human albinos.

The presence of global stereopsis was examined in 18 clinically diagnosed albinos; four non-albino controls were also tested including two observers with congenital nystagmus. Stereopsis was evaluated with standard clinical stereo tests and with TV generated random dot stereograms. The latter test involved electrophysiological measures of vertical eye movement tracking in response to a stimulus target. For either test procedure, global stereopsis could be demonstrated in a significant number of albinos across varying phenotypes. These results are of interest in view of electrophysiological investigations in albino animal models which indicate a paucity of binocularly driven cortical neurons in visual areas 17, 18 and 19. While stereopsis may be mediated in our albinos via residual appropriately projecting retino-geniculo-cortical fibres, we suggest that inter and intra cortical communication via corpus callosal connections may play a primary role in providing the adequate neural substrate for albino binocularity.

Effects of contrast, orientation and binocularity in the pattern evoked potential.

Monocular and binocular visual evoked potentials were studied as a function of modulation depth (contrast) of a counterphase sinusoidal grating stimulus. A range of spatial and temporal frequencies of stimulation were used. The contrast functions showed many different forms, and were in some cases nonmonotonic. The binocular response usually had a steeper slope than the monocular response. Extrapolating the slope to the zero intercept gave electrophysiological thresholds which did not correspond with psychophysical threshold at any spatial or temporal frequency used. The binocular response was reduced to the monocular level when the orientation difference between the two eyes exceeded about 20 degrees. The data show that the pattern evoked potential is highly specific to many stimulus variables.

Contrast sensitivity function in Graves' ophthalmopathy and dysthyroid optic neuropathy.

Contrast sensitivity function was measured by a computer automated method on 38 eyes with dysthyroid optic neuropathy and 34 eyes with Graves' ophthalmopathy only. The results were compared with 74 healthy control eyes. Disturbances of contrast sensitivity functions were found in both groups when compared with controls. The eyes affected with dysthyroid optic neuropathy showed pronounced loss of contrast sensitivity in the low frequency range, which facilitates differentiation between the two groups.

Electrodiagnosis in paediatric ophthalmogenetics.

In the present overview, practical application of the visual evoked potential (VEP) in paediatric neuro-ophthalmology is described across a wide range of ophthalmogenetic disorders, including albinism, Pelizaeus-Merzbacher disease and spastic paraplegia. The VEP approach is based on a four parameter subdivision of the electrophysiological response which includes, (1) amplitude (microV), (2) latency (ms), (3) waveform (component specificity), and (4) topography (potential distribution across the electrode array). In the case studies presented, evoked potential measures provide clinically useful and even at times invaluable insights concerning the presence, extent and type of visual pathway compromise. The four parameter subdivision along with age matched normative standards provides a sensitive and reliable means to facilitate detection and diagnosis of sensory anomalies in the developing visual system. The non-invasive electrophysiological assessment of visual function and its maturational course also provides early identification of affected family members as well as an objective measure of various treatment regimes which, particularly for the pre-verbal and non-verbal child, is critical for effective patient care.

See-saw nystagmus and congenital nystagmus identified in the non-decussating retinal-fugal fiber syndrome.

PURPOSE: The purpose of the present study was to accurately document the oculomotor misalignments and instabilities associated with the non-decussating retinal-fugal fiber syndrome, a rare inborn, isolated, achiasmatic condition. To date, the achiasmatic syndrome described has thus far been identified in three unrelated females. A comparable achiasmatic condition has also been identified in a canine breed. MATERIALS AND METHODS: The unique, inborn visual pathway malformation in the form of an isolated absence of the optic chiasm was confirmed by metabolic assay, the visual evoked potential (VEP) misrouting paradigm and neuroradiological evaluation, including magnetic resonance imaging (MRI). Horizontal and vertical, left and right eye, oculomotor scleral search coil recordings were measured, in one of the achiasmats, at 15 years of age. Comparable oculomotor recordings were implemented in three controls, including a normal age-matched control, an adult control and an adult with idiopathic congenital nystagmus (CN). In addition to central and eccentric target fixation with binocular and monocular viewing, binocular and monocular pursuit and optokinetic nystagmus (OKN) also were recorded. RESULTS: Following a binocular and monocular fixation paradigm, classic congenital nystagmus (CN) profiles were recorded in the achiasmat in the horizontal planes together with see-saw nystagmus (SSN) in the vertical planes; an alternating esotropia and vertical tropias also were documented. The CN showed interocular conjugacy and waveforms typically exhibited well-defined foveation periods. In general, both achiasmatic horizontal and vertical eye movements as well as corresponding interocular misalignments varied with stimu-lus and recording conditions. Moreover, horizontal eye movements showed sustained interocular conjugacy while vertical eye movements typically showed disconjugacy. Previous oculomotor studies in the achiasmatic canine breed revealed comparable oculomotor instabilities, albeit the latter were reported to present primarily with unyoked eye movements and uniocular saccades. In the present study, in addition to target fixation with binocular and monocular viewing, binocular and monocular pursuit and OKN responses also were recorded. For the achiasmat, high-gain pursuit results, as with eccentric fixation, emphasized a preference for fixation with the adducting eye. Also at eccentric gaze with monocular viewing, the eye under cover showed, relative to the fixating eye, a hypodeviation concomitant with adduction and a hyperdeviation concomitant with abduction. OKN profiles in the achiasmat with stimuli presented under both normal viewing and open-loop, retinal-field locked conditions proved rather complex; however, when an OKN response was identified, reversed OKN tracking was not apparent. CONCLUSIONS: In general, the oculomotor results reported herein demonstrate that the non-decussating retinal-fugal fiber syndrome is an afferent visual pathway disorder associated with vertical and horizontal misalignments concurrent with congenital nystagmus and also with the rarer see-saw nystagmus.

Temporal frequency responsivity shows multiple maturational phases: state-dependent visual evoked potential luminance flicker fusion from birth to 9 months.

Maturation of temporal resolution was investigated in a visual evoked potential study in 77 infants from birth to 9 months of age. Luminance evoked potential measures in response to homogeneous sinusoidal flickering light (1-64 Hz) were recorded under behavioral state-defined conditions. Behavioral state was determined by direct observation and by polygraphic recording of the electroencephalogram (EEG), eye movements (EOG), muscle activity (EMG), heart rate (ECG), and respiration. Temporal-frequency functions of the amplitude of the fundamental response across the temporal-frequency range were recorded during sleep and wakefulness. The highest temporal-frequency response recorded during wakefulness was accepted as a measure for inclusion in a growth function of temporal-frequency responsiveness. The resulting temporal resolution frequency vs. age function showed three separate maturational phases. Maturational phases were defined as (1) an initial slow phase from 1-32 days postnatal during which maturation of temporal vision is unremarkable; (2) an intermediate rapid phase of improvement from age 26 to 170 days; and (3) an overlapping but final slow phase from 151 to at least 270 days during which adult-like flicker resolution is approximated. This study suggests that the multiple maturational phases of the infant's responses to flickering light are due to maturational differences, which correspond with maturation of structural factors of brain function. Finally, across the age span tested, high-frequency responsivity was influenced significantly by the degree of infant arousal.

A practical approach to albino diagnosis. VEP misrouting across the age span.

In addition to the genetic heterogeneity in albinism, widespread clinical heterogeneity frequently impedes albino detection and differential diagnosis. Further, several auxiliary ocular and/or cutaneous manifestations of this inherited error of pigmentary metabolism are neither pre-requisite nor specific to the albino condition. However, one feature that is specific to albinism regardless of genotype or phenotype is a unique pattern of abnormal visual pathway organization. With an appropriate test paradigm, the albino visual pathway can be revealed by the non-invasive recording of the visual evoked potential (VEP) distribution across the occiput which shows contralateral hemispheric asymmetry following full field monocular stimulation. As described in this report, the VEP albino misrouting detection test has been refined to yield extraordinarily high sensitivity and selectivity across the age span from the neonate to the elderly. As the VEP profile undergoes maturational changes, these changes have been taken into account in the development of an albino age-range VEP test recipe which includes the pattern onset paradigm for older albinos and a luminance flash paradigm for the albino infant. The age appropriate optic pathway misrouting test provides reliable albino detection and definitive differential diagnosis. Further, as the albino VEP signature of contralateral asymmetry is also age specific, the VEP misrouting test can be extended to the objective assessment of visual pathway maturation.

Visual training after long term deprivation: a case report.

During evaluation of an optical to tactile conversion device, the Tactile Vision Substitution System (TVSS), a training program was developed to teach blind subjects to perceive visual information via the tactile modality. Tactile training paradigms which compensate for the limited resolution of the skin sense were applied to visual training procedures in a case of visual restoration following long term deprivation. Visual training in the visual restoration case also included electro-oculography biofeedback to facilitate oculomotor control and visual evoked potential evaluation for the objective assessment of visual function. The development of functional vision over an 11 month training period of a young girl who was form deprived form 3 months to 12 years is discussed.