Monitoring of optic nerve function in Neurofibromatosis 2 children with optic nerve sheath meningiomas using multifocal visual evoked potentials.

Monitoring optic nerve sheath meningiomas (ONSM) in Neurofibromatosis type 2 (NF2) patients remains difficult. Other ocular manifestations of NF2 may obscure ophthalmic assessment of optic nerve function in these patients. Serial magnetic resonance imaging (MRI) used to assess the optic nerve is not without limitations, being expensive and often requiring general anaesthetic in children, with associated risks. This study was undertaken to describe the use of multifocal visual evoked potentials (multifocal VEP, mfVEP) in the regular monitoring of NF2 patients with ONSM. This study involved three NF2 patients with ONSM who undertook mfVEP testing at an academic ophthalmic centre. Same day mfVEP and routine ophthalmic testing were undertaken. Topographical function of the optic nerve was assessed, utilising tools such as asymmetry deviation and accumap severity index. Results were assessed alongside MRI and visual acuity (VA). From the three patients, five eyes had ONSMs, of which two caused unilateral blindness. The remaining three affected eyes had initial VAs 6/6, 6/24, and 6/18. Over follow up, ranging from 5 to 12 years, all tumours progressed, and VA declined for all patients. Multifocal VEP detected optic nerve functional loss corresponding with visual decline. This case series suggests mfVEP is effective in the objective topographic monitoring of optic nerve function in NF2 patients with ONSM. Due also to its safety in a paediatric population, the test may be considered in the routine monitoring of these patients, to be used to assist regular ophthalmic review and MRI scans.

Progression of retinal ganglion cell loss in multiple sclerosis is associated with new lesions in the optic radiations.

BACKGROUND AND PURPOSE: The mechanism of retinal ganglion cell and retinal nerve fiber layer loss in multiple sclerosis (MS) remains unknown. This study aimed to investigate the association between temporal retinal nerve fiber layer (tRNFL) thinning and disease activity in the brain determined by T2 lesions on magnetic resonance imaging (MRI). METHODS: Fifty-five consecutive patients with relapsing-remitting MS and 25 controls were enrolled. All patients underwent annual optical coherence tomography and high-resolution MRI scans for tRNFL thickness and brain lesion volume analysis, respectively. RESULTS: Significant tRNFL thickness reduction was observed over the 3-year follow-up period at a relatively constant rate (1.02 µm/year). Thinning of tRNFL fibers was more prominent in younger patients (P = 0.01). The tRNFL loss was associated with new MRI lesions in the optic radiations (ORs). There was significantly greater tRNFL thinning in patients with new lesional activity in the ORs compared with patients with new lesions outside the ORs (P = 0.009). CONCLUSIONS: This study supports the notion that retrograde transneuronal degeneration caused by OR lesions might play a role in progressive retinal nerve fiber layer loss. In addition, the results of the study also indicate that the disease-related neurodegenerative changes in the retina start much earlier than the clinical diagnosis of MS.

Exploring the methods of data analysis in multifocal visual evoked potentials.

PURPOSE: The multifocal visual evoked potential (mfVEP) provides a topographical assessment of visual function, which has already shown potential for use in patients with glaucoma and multiple sclerosis. However, the variability in mfVEP measurements has limited its broader application. The purpose of this study was to compare several methods of data analysis to decrease mfVEP variability. METHODS: Twenty-three normal subjects underwent mfVEP testing. Monocular and interocular asymmetry data were analyzed. Coefficients of variability in amplitude were examined using peak-to-peak, root mean square (RMS), signal-to-noise ratio (SNR) and logSNR techniques. Coefficients of variability in latency were examined using second peak and cross-correlation methods. RESULTS: LogSNR and peak-to-peak methods had significantly lower intra-subject variability when compared with RMS and SNR methods. LogSNR had the lowest inter-subject amplitude variability when compared with peak-to-peak, RMS and SNR. Average latency asymmetry values for the cross-correlation analysis were 1.7 ms (CI 95 % 1.2-2.3 ms) and for the second peak analysis 2.5 ms (CI 95 % 1.7-3.3 ms). A significant difference was found between cross-correlation and second peak analysis for both intra-subject variability (p < 0.001) and inter-subject variability (p < 0.001). CONCLUSIONS: For a comparison of amplitude data between groups of patients, the logSNR or SNR methods are preferred because of the smaller inter-subject variability. LogSNR or peak-to-peak methods have lower intra-subject variability, so are recommended for comparing an individual mfVEP to previous published normative data. This study establishes that the choice of mfVEP data analysis method can be used to decrease variability of the mfVEP results.

Software for analysing multifocal visual evoked potential signal latency progression.

BACKGROUND: This paper describes a new non-commercial software application (mfVEP(2)) developed to process multifocal visual-evoked-potential (mfVEP) signals in latency (monocular and interocular) progression studies. METHOD: The software performs analysis by cross-correlating signals from the same patients. The criteria applied by the software include best channels, signal window, cross-correlation limits and signal-to-noise ratio (SNR). Software features include signal display comparing different tests and groups of sectors (quadrants, rings and hemispheres). RESULTS: The software's performance and capabilities are demonstrated on the results obtained from a patient with acute optic neuritis who underwent 9 follow-up mfVEP tests. Numerical values and graphics are presented and discussed for this case. CONCLUSIONS: The authors present a software application used to study progression in mfVEP signals. It is also useful in research projects designed to improve mfVEP techniques. This software makes it easier for users to manage the signals and allows them to choose various ways of selecting signals and representing results.

Quality control for retinal OCT in multiple sclerosis: validation of the OSCAR-IB criteria.

BACKGROUND: Retinal optical coherence tomography (OCT) permits quantification of retinal layer atrophy relevant to assessment of neurodegeneration in multiple sclerosis (MS). Measurement artefacts may limit the use of OCT to MS research. OBJECTIVE: An expert task force convened with the aim to provide guidance on the use of validated quality control (QC) criteria for the use of OCT in MS research and clinical trials. METHODS: A prospective multi-centre (n = 13) study. Peripapillary ring scan QC rating of an OCT training set (n = 50) was followed by a test set (n = 50). Inter-rater agreement was calculated using kappa statistics. Results were discussed at a round table after the assessment had taken place. RESULTS: The inter-rater QC agreement was substantial (kappa = 0.7). Disagreement was found highest for judging signal strength (kappa = 0.40). Future steps to resolve these issues were discussed. CONCLUSION: Substantial agreement for QC assessment was achieved with aid of the OSCAR-IB criteria. The task force has developed a website for free online training and QC certification. The criteria may prove useful for future research and trials in MS using OCT as a secondary outcome measure in a multi-centre setting.

Relationship between chronic demyelination of the optic nerve and short term axonal loss.

BACKGROUND: Axonal loss is a major determinant of disability in multiple sclerosis (MS). While acute inflammatory demyelination is a principal cause of axonal transection and subsequent axonal degeneration in acute disease, the nature of chronic axonal loss is less well understood. In the current study, the relationship between degree of chronic demyelination and axonal degeneration was investigated using optic neuritis (ON) as a model. METHOD: 25 patients with a first episode of unilateral ON, good recovery of visual function and concurrent brain or spinal cord MRI lesions were enrolled. Axonal loss was assessed using change in retinal nerve fibre layer (RNFL) thickness between 1 and 3 years after ON. Optic nerve conduction was evaluated using latency of multifocal visual evoked potentials (mfVEP). The level of mfVEP latency delay at 12 and 36 months was considered indicative of the degree of permanent demyelination. Data from 25 age and gender matched normal controls were used for comparison. RESULTS: RNFL thickness was significantly reduced in ON eyes at 12 months compared with controls but remained unchanged in fellow eyes. Average RNFL thickness demonstrated a small but significant reduction between 12 and 36 months for both ON and fellow eyes. Change in RNFL thickness between 12 and 36 months, however, did not correlate with the degree of mfVEP latency delay. CONCLUSION: The results, therefore, show no association between the degree of permanent optic nerve demyelination (as measured by latency delay) and progressive axonal degeneration, at least in the early stages of the disease. The fact that fellow eyes demonstrated a similar degree of progressive axonal loss supports this suggestion.

Magnetisation transfer ratio in optic neuritis is associated with axonal loss, but not with demyelination.

BACKGROUND: Pathophysiological basis of Magnetisation Transfer Ratio (MTR) reduction in multiple sclerosis still remains a matter of controversy. Optic nerve represents an ideal model to study the consequences of axonal loss and demyelination on MTR since effects of disease on the optic nerve are clinically apparent and potentially quantifiable by objective means. By measuring the latency of multifocal visual evoked potentials (mfVEP) (measure of optic nerve conduction) and Retinal Nerve Fiber Layer (RNFL) thickness (measure of axonal damage) we investigated the effect of neurodegeneration and demyelination on MTR after an episode of optic neuritis (ON). METHODS: 23 patients with a single unilateral episode of ON and 10 healthy volunteers were enrolled. Orbital MRI including MTR protocol, Optical Coherence Tomography and Multifocal VEP were performed at post-acute stage of ON. RESULTS: Average MTR of affected eye was significantly reduced as compared to the fellow eye and normal controls. There was a highly significant correlation between MTR and measures of axonal loss (RNFL thickness and mfVEP amplitude), which was independent on the level of demyelination. While latency delay also correlated significantly with MTR, correlation became non-significant when adjusted for the degree of axonal loss. There was a significant reduction of MTR in a group of patients with extensive axonal damage, while MTR remained normal in a group of patients with extensive demyelination, but little or no axonal loss. CONCLUSION: Results of this study indicate that reduction of optic nerve MTR after an episode of ON has a strong association with the degree of axonal damage, but not with demyelination.

Fellow eye changes in optic neuritis correlate with the risk of multiple sclerosis.

BACKGROUND: Recent studies demonstrate early diffuse central nervous system (CNS) inflammation in patients with multiple sclerosis (MS). The clinically unaffected (fellow) eye of patients with unilateral optic neuritis (ON) may reflect the status of normal-appearing white matter in the CNS, which can be assessed electrophysiologically. OBJECTIVE: To study the relationship between electrophysiological parameters in the fellow eye of ON patients, and risk of conversion to MS. METHODS: Forty-eight consecutive patients with acute unilateral ON were examined 12 months after ON of which 14 had MS, 19 remained high risk (HR) for MS, and 15 had low risk (LR) for MS according to McDonald's criteria. Twenty-five age-matched controls were also tested. Amplitude and latency of multifocal visual evoked potential (mfVEP) in the fellow eyes of patients at 12 months were analyzed and compared with controls. RESULTS: Average mfVEP amplitude was 240 +/- 35, 232 +/- 36, 181 +/- 38, and 169 +/- 48 nV for controls, LR, HR, and MS groups respectively. Average mfVEP latency for controls, LR, HR, and MS patients was 139.7 +/- 5.5, 141.7 +/- 3.6, 145.9 +/- 8.9, and 152.0 +/- 9.9 ms respectively. CONCLUSIONS: The magnitude of latency prolongation and amplitude decline 12 months after the initial episode was proportional to the risk of MS. The prognostic significance of these changes as predictors of subsequent MS should be investigated longitudinally.

Comparison of objective diagnostic tests in glaucoma: Heidelberg retinal tomography and multifocal visual evoked potentials.

PURPOSE: To compare sensitivity and specificity of functional and structural changes in glaucoma using two objective tests: the multifocal visual evoked potential (m-VEP) and Heidelberg retinal tomography II (HRT). PATIENTS AND METHODS: 41 glaucoma patients and 25 normal individuals participated in the study. One eye per individual was included in the study. Individuals were evaluated with Humphrey visual field (HVF) perimetry, m-VEP, and HRT. Moorfield regression analysis findings of HRT were compared with presence of scotoma on m-VEP. Linear regression analysis of quantitative variables, such as HVF mean deviation (MD), m-VEP discriminant score (Accumap Severity Index) and, global HRT parameters was also performed. RESULTS: m-VEP sensitivity and specificity were 93% and 96% respectively. HRT sensitivity and specificity were 79% and 92% respectively. The area under the receiver operating characteristic curve (ROC) for m-VEP was 0.96 and for HRT varied from 0.79 to 0.86 depending on the parameters used. Linear correlation between MD and Accumap Severity Index score was -77%, while that between HRT global parameters, Accumap Severity Index and MD were at best around 50%. Topographic comparison of the presence of scotoma on HVF and m-VEP in different areas of the visual field showed good agreement. Comparison of optic nerve head structural abnormality with corresponding areas of field defects on HVF and m-VEP showed poor to moderate agreement. CONCLUSION: The objective test of optic nerve function (m-VEP) and structure (HRT) can detect glaucomatous damage, with limited correlation. The 2 functional tests, HVF and m-VEP correlate better with each other than with HRT. It remains important to look for both functional and structural changes in order to detect all glaucoma cases.

Objective perimetry using the multifocal visual evoked potential in central visual pathway lesions.

AIMS: To examine the ability of the multifocal pattern visual evoked potential (mVEP) to detect field loss in neurological lesions affecting the visual pathway from the chiasm to the cortex. METHOD: The mVEPs recorded in the clinic were retrospectively reviewed for any cases involving central neurological lesions. Recordings had been performed with the AccuMap V1.3 objective perimeter, which used an array of four bipolar occipital electrodes to provide four differently oriented channels for simultaneous recording. 19 patients with hemianopias were identified. Of these there were 10 homonymous hemianopias with hemifield type loss, two bitemporal hemianopias, and seven homonymous hemianopias with quadrantanopic distribution. A comparison with subjective field results and CT/MRI findings was done to determine the relation between the two methods of visual field mapping and any relation with the anatomical location of the lesion and the mVEP results. RESULTS: In all hemianopic type cases (12) the defect was demonstrated on the mVEP and showed good correspondence in location of the scotoma (nine homonymous and two bitemporal). The topographic distribution was similar but not identical to subjective testing. Of the seven quadrantanopic type hemianopias, only four were found to have corresponding mVEP losses in the same areas. In the three cases where the mVEP was normal, the type of quadrantanopia had features consistent with an extra-striate lesion being very congruous, complete, and respecting the horizontal meridian. CONCLUSIONS: The mVEP can detect field loss from cortical lesions, but not in some cases of homonymous quadrantanopia, where the lesion may have been in the extra-striate cortex. This supports the concept that the mVEP is generated in V1 striate cortex and that it may be able to distinguish striate from extra-striate lesions. It implies caution should be used when interpreting "functional" loss using the mVEP if the visual field pattern is quadrantic.

Intertest variability of mfVEP amplitude: reducing its effect on the interpretation of sequential tests.

PURPOSE: The multi-focal visual evoked potential (mfVEP) has been recently introduced as an alternative to subjective perimetry in detecting visual field defects. This study examines the source of variability in the mfVEP amplitude, and determines the relationship of this variability to the strength of the signal itself across the visual field. It also investigates possible means to reduce the effects of this variability on between-test interpretation to allow for easier detection of progression. METHODS: 85 normal subjects participated in the study. The mfVEP was recorded using Accumap (ObjectiVision Pty Ltd, Sydney, Australia). Each subject was tested twice with an interval between visits of 3-4 weeks. Comparison between tests was performed using coefficient of variability (CV). Variability was also analysed using scaling and clustering procedures. RESULTS: In the majority of the retinal areas CV fell within 15-20%. Variability increased with eccentricity, but there was no age dependency. There was a significant reduction of variability (by 15.8 +/- 6%, Student's t-test p<0.0001) when a scaling procedure was applied and this was consistent at all eccentricities. A clustering procedure reduced variability on average by a further 18.5 +/- 4.5% (Student's t-test p<0.0001). This result was also consistent at all eccentricities. CONCLUSION: Between test comparisons of raw mfVEP traces is limited by a variability of at least 15%. While this variability required the amplitude of the individual VEP signal to change by 30-40% in order to detect progression, scaling and clustering procedures were able to reduce the required change to 20-25%, thus making an interpretation of consecutive test results more clinically viable.

Multifocal VEP in children: its maturation and clinical application.

AIM: To study the maturation of multifocal visual evoked potentials (multifocal VEP) in normal children between the ages of 5 and 16 years and to apply the results clinically in selected cases to the diagnosis of optic pathway diseases. METHOD: 70 normal children were recruited from the community and multifocal VEP (Accumap ObjectiVision, Sydney, Australia) was recorded. The waveform of the evoked responses, the latency and amplitude were analysed. Using these data, an age matched comparison was made with three children with advanced optic nerve disease; two had optic nerve glioma and one had congenital glaucoma. RESULTS: The full field amplitude did not correlate with age and varied greatly within each age group (coefficient of variability 28%). When scaled with respect to the background electroencephalogram the intra-age group variability decreased to 15% and a sigmoid relation was found between amplitude and age. The scaled amplitude remained largely unchanged till 11 years, between 11 and 13 years there was a rapid increase (40%), and remained stable thereafter. This relation was seen at all eccentricities tested. The latency decreased gradually with age and plateaued at 13 years. In the three children with vision abnormalities this test was able to detect scotomas consistent with their condition. CONCLUSION: Multifocal VEP perimetry shows an age related maturation in the visual pathway, characterised by distinctive timeframe of development for amplitude and latency. It can be performed by children as young as 5 years of age and holds promise as a diagnostic test capable of documenting children's visual fields objectively, even before they are able to perform subjective field tests.

Electroencephalogram-based scaling of multifocal visual evoked potentials: effect on intersubject amplitude variability.

PURPOSE: The interindividual variability of the visual evoked potential (VEP) has been recognized as a problem for interpretation of clinical results. This study examines whether VEP variability can be reduced by scaling responses according to underlying electroencephalogram (EEG) activity. METHODS: A multifocal objective perimeter provided different random check patterns to each of 58 points extending out to 32 degrees nasally. A multichannel VEP was recorded (bipolar occipital cross electrodes, 7 min/eye). One hundred normal subjects (age 58.9 +/- 10.7 years) were tested. The amplitude and inter-eye asymmetry coefficient for each point of the field was calculated. VEP signals were then normalized according to underlying EEG activity recorded using Fourier transform to quantify EEG levels. High alpha-rhythm and electrocardiogram contamination were removed before scaling. RESULTS: High intersubject variability was present in the multifocal VEP, with amplitude in women on average 33% larger than in men. The variability for all left eyes was 42.2% +/- 3.9%, for right eyes 41.7% +/- 4.4% (coefficient of variability [CV]). There was a strong correlation between EEG activity and the amplitude of the VEP (left eye, r = 0.83; P < 0.001; right eye, r = 0.82; P < 0.001). When this was used to normalize VEP results, the CVs dropped to 24.6% +/- 3.1% (P < 0.0001) and 24.0% +/- 3.2% (P < 0.0001), respectively. The gender difference was effectively removed. CONCLUSIONS: Using underlying EEG amplitudes to normalize an individual's VEP substantially reduces intersubject variability, including differences between men and women. This renders the use of a normal database more reliable when applying the multifocal VEP in the clinical detection of visual field changes.

Objective perimetry in glaucoma.

PURPOSE: Objective perimetry in glaucoma is described using the multifocal pattern visually evoked potential (VEP). A multichannel recording technique was used to improve signal detection in healthy volunteers and assess its ability to detect glaucoma and early changes in patients with suspected glaucoma. DESIGN: Prospective, case-control study. PARTICIPANTS: Thirty healthy volunteers, 30 patients with suspected glaucoma, and 30 patients with glaucomatous visual field defects were tested. METHOD: The VEP was recorded using cortically scaled, multifocal, pseudorandomly alternated pattern stimuli with the VERIS system (Electro-Diagnostic Imaging, Inc., San Francisco, CA). An array of four bipolar occipital electrodes provided four differently oriented channels for simultaneous recording. Signals were compared for different locations within the field up to 26 degrees of eccentricity. Healthy volunteers, patients with suspected glaucoma, and glaucoma patients with established visual field defects were tested, and results were compared with Humphrey visual fields (Humphrey Systems, Dublin, CA) performed on the same day. For reproducibility, five healthy volunteers were each tested on four separate days. The patients with suspected glaucoma and the established glaucoma patients were analyzed for intereye asymmetry of signals, and these data were compared with the asymmetry values of the healthy volunteers. RESULTS: Multiple recording channels significantly enhanced the recording of signals from parts of the visual field not reliably sampled with a single channel technique in all healthy volunteers, particularly along the horizontal meridian (P: < 0.001). Signal amplitude did not decline with age in healthy volunteers. Recordings showed good reproducibility within individuals. In all 30 glaucoma patients, the Humphrey visual field defects were well demonstrated by the VEP, and topographic location was strongly correlated (r(s) = 0.79). Despite large interindividual variations in amplitude, scotomas were well demonstrated when compared with normal values. In the patients with suspected glaucoma, smaller changes in signal amplitude could be identified in parts of the field still normal on perimetry using intereye asymmetry analysis. CONCLUSIONS: The multifocal, multichannel VEP can objectively detect glaucomatous visual field defects. The nasal step region can be more reliably tested using multiple channels. Asymmetry analysis has the potential to detect early defects. This technique represents a significant step toward the clinical application of objective perimetry in glaucoma.

Objective VEP perimetry in glaucoma: asymmetry analysis to identify early deficits.

PURPOSE: The multifocal visual evoked potential (VEP) shows markedly symmetrical responses between the two eyes of control subjects. Patients with glaucoma and patients considered at high risk for glaucoma were examined to determine if VEP asymmetry could be identified and used for diagnosis and detection of early damage. METHODS: Multifocal pattern VEP recordings were performed using a single channel bipolar occipital electrode position and the Visual Evoked Response Imaging System (VERIS). There were 125 subjects: 24 control subjects, 70 patients with glaucoma, and 31 patients considered at high risk for glaucoma. A between-eye relative asymmetry coefficient (RAC) was determined for each of the 60 test points in the VEP field. The RAC for patients with glaucoma and patients considered at risk for glaucoma were compared with values from control subjects. Correlation between Humphrey thresholds and RAC scores was performed. RESULTS: Patients with glaucoma and patients considered at risk for glaucoma both showed significantly larger mean quadrant RAC values. When point by point analysis was performed, 69 out of 70 scotomas were identified with a cluster of at least 3 points of P < 0.05. For those considered at high risk for glaucoma, 10 out of 31 patients had abnormal areas in the VEP field. There was a strong correlation (r = 0.82) between quadrantic RAC mean values and Humphrey quadrant threshold scores in an asymmetric glaucoma subgroup. Abnormal VEP responses were identified in parts of the visual field that were still normal on perimetry. CONCLUSIONS: Asymmetry analysis correctly identifies patients with glaucomatous field loss and shows abnormalities in many patients considered at high risk for glaucoma who still have normal fields. Asymmetry analysis is able to identify objectively the extent of glaucomatous damage and may be able to detect changes before subjective field loss occurs.

Multifocal pattern electroretinogram does not demonstrate localised field defects in glaucoma.

PURPOSE: To determine if a multifocal PERG could be recorded in normals, and to examine changes in the multifocal PERG in glaucoma patients. To compare the ability of multifocal PERG and multifocal VEP responses in the same individuals to identify localised field defects in glaucoma. METHODS: Using the VERIS Scientific system multifocal PERGs were recorded from 19 sites of the visual field according to pseudo-random binary m-sequence. Twenty normals and 15 glaucoma subjects were tested. Multifocal pattern VEPs were also recorded in the glaucoma cases using a cortically scaled stimulus. RESULTS: The second order kernel of the PERG shows a consistent signal. The overall PERG amplitude decreases with age in normals. In glaucoma the PERG amplitude was reduced across the field, but reductions did not correspond to the area of the scotoma. The VEP showed localised signal reductions in all 15 cases of glaucoma. CONCLUSION: A multifocal PERG can be recorded in normals. However it did not reflect localised ganglion cell losses, whereas the multifocal pattern VEP recorded to a very similar stimulus in the same individual did show losses in the scotoma area.

The diagnostic significance of the multifocal pattern visual evoked potential in glaucoma.

The concept of objective perimetry is an exciting one because it strives to assess glaucoma damage without relying on psychophysical testing. The recent introduction of multifocal stimulus recording has enhanced our ability to examine the human visual field using electrophysiology. A multifocal pattern visual evoked potential can now be recorded, testing up to 60 sites within the central 25 degrees. The test requires only that the subject fixate on a target, while a cortically scaled dartboard pattern stimulus undergoes pseudorandom alternation within each of the test segments. In its present configuration the test requires at least 8 minutes recording time per eye. Modified bipolar electrode positions are required to ensure that adequate signals are detected from all parts of the visual field. In glaucoma patients, pattern visual evoked potential amplitudes have been shown to reflect visual field loss with reduction of signal amplitude in the affected areas. This technique represents the first major step toward objective detection of visual field defects in glaucoma.