Utilization of Visual Acuity Retroilluminated Charts for the Assessment of Afferent Visual System Dysfunction in a Pediatric Neuroimmunology Population.

BACKGROUND: Visual acuity has been a significant outcome measure in clinical trials for patients suffering from neuro-ophthalmological diseases and multiple sclerosis; however, there are limited data on the comparison of various testing strategies in pediatric patients with these disorders. Clinical trials using vision as an outcome could include a variety of tools to assess the acuity, including 2-m and 4-m standardized retroilluminated charts. METHODS: We investigated the difference in Early Treatment Diabetic Retinopathy Study (ETDRS) scores obtained using 2-m and 4-m charts, as well as the impact of optic neuritis, use of vision correction, age, and gender on visual acuity data from 71 patients with pediatric neuroimmunological conditions in a cross-sectional study. RESULTS: We determine that the ETDRS letter scores obtained using 4-m charts are on average 3.43 points less (P = 0.0034) when testing monocular ETDRS letter scores and on average 4.14 points less (P = 0.0008) when testing binocular ETDRS letter scores, relative to that obtained using the 2-m charts. However, we find that when performing monocular testing, optic neuritis in the eye being tested did not result in a statistically significant difference between 2-m and 4-m ETDRS letter scores. CONCLUSIONS: Although visual acuity charts are formatted by the distance, there are significant differences in the number of letters correctly identified between 2-m and 4-m charts. Although the differences may not impact the clinical acuity, research protocols should consider these differences before collapsing data across disparate studies.

Assessment of Pediatric Optic Neuritis Visual Acuity Outcomes at 6 Months.

Importance: Optic neuritis (ON) in children is uncommon. There are limited prospective data for visual acuity (VA) outcomes, associated diseases, and neuroimaging findings. Prospective data from a large sample would be useful for counseling families on treatment decisions and prognosis. Objective: To prospectively study children with a first episode of ON, describe VA after 6 months, and ascertain the network's (Pediatric Eye Disease Investigator Group and Neuro-Ophthalmology Research Disease Investigator Consortium) ability to enroll pediatric patients with ON prospectively. Design, Setting, and Participants: This nonrandomized cohort study was conducted from September 20, 2016, to July 20, 2018, at 23 sites in the United States and Canada in pediatric ophthalmology or neuro-ophthalmology clinics. A total of 44 children (aged 3-15 years) presented with a first episode of ON (visual loss, pain on eye movements, or both) within 2 weeks of symptom onset and at least 1 of the following in the affected eye: a distance high-contrast VA (HCVA) deficit of at least 0.2 logMAR below age-based norms, diminished color vision, abnormal visual field, or optic disc swelling. Exclusion criteria included preexisting ocular abnormalities or a previous episode of ON. Main Outcomes and Measures: Primary outcomes were monocular HCVA and low-contrast VA at 6 months. Secondary outcomes were neuroimaging, associated diagnoses, and antibodies for neuromyelitis optica and myelin oligodendrocyte glycoprotein. Results: A total of 44 children (mean age [SD], 10.2 [3.5] years; 26 boys [59%]; 23 White individuals [52%]; 54 eyes) were enrolled in the study. Sixteen patients (36%) had bilateral ON. Magnetic resonance imaging revealed white matter lesions in 23 children (52%). Of these children, 8 had myelin oligodendrocyte glycoprotein-associated demyelination (18%), 7 had acute disseminated encephalomyelitis (16%), 5 had multiple sclerosis (11%), and 3 had neuromyelitis optica (7%). The baseline mean HCVA was 0.95 logMAR (20/200), which improved by a mean 0.76 logMAR (95% CI, 0.54-0.99; range, -0.70 to 1.80) to 0.12 logMAR (20/25) at 6 months. The baseline mean distance low-contrast VA was 1.49 logMAR (20/640) and improved by a mean 0.72 logMAR (95% CI, 0.54-0.89; range, -0.20 to 1.50) to 0.73 logMAR (20/100) at 6 months. Baseline HCVA was worse in younger participants (aged <10 years) with associated neurologic autoimmune diagnoses, white matter lesions, and in those of non-White race and non-Hispanic ethnicity. The data did not suggest a statistically significant association between baseline factors and improvement in HCVA. Conclusions and Relevance: The study network did not reach its targeted enrollment of 100 pediatric patients with ON over 2 years. This indicates that future treatment trials may need to use different inclusion criteria or plan a longer enrollment period to account for the rarity of the disease. Despite poor VA at presentation, most children had marked improvement by 6 months. Associated neurologic autoimmune diagnoses were common. These findings can be used to counsel families about the disease.

Functional-structural assessment of the optic pathways in patients with optic neuritis.

BACKGROUND: The pattern-reversal visual evoked potential (pVEP) is widely used for the diagnosis of Optic Neuritis (ON), but this method has some limitations. The aim of this study was to examine the added value of multifocal visual evoked potentials (mfVEP) and spectral-domain optical coherence tomography (SD-OCT) in the diagnosis of ON in patients that exhibit a normal pVEP. METHOD: Thirty-three patients with a history of having ON and 30 sex- and age-matched healthy controls (HC) were investigated. We included patients who were suspected of having a first-time ON and in whom pVEP showed normal results. Both eyes of the patients and HC were systematically investigated with SD-OCT, visual acuity, pVEP and mfVEP. The ON-affected eyes of the patients were compared with only one randomly selected eye per person in the HC group. The fellow "non-affected" eye of patients was held as a separate group. Statistical analyses were performed (including t test, Spearman's rank-order correlation test) using SPSS Statistics, Version 24.0. RESULTS: A significant difference was found in OCT mean retinal nerve fibre layer thickness (RNFLt) between patients and HC (p = 0.013) (i.e. 84.24 (± 17.00) µm versus 93.48(± 6.44) µm). An association was detected in patients between mean inter-eye asymmetry of the RNFLt and global (averaged) mfVEP amplitude (r = 0.565, p = 0.002). When analysing mfVEP signals from sectors in the upper hemifield, a significant difference was found in mean mfVEP amplitude between patients and HC (p = 0.005). CONCLUSIONS: Abnormality is potentially measurable (via reduced RNFLt and focal analyses with mfVEP amplitude) in patients suspected of having a first episode of ON where pVEP reports no abnormality. The mfVEP and SD-OCT may together be of value as supplementary tools in diagnosing ON in this patient group.

Assessment of Opicinumab in Acute Optic Neuritis Using Multifocal Visual Evoked Potential.

BACKGROUND: Multifocal visual evoked potential (MF-VEP) assesses a wider visual field than full-field VEP (FF-VEP) and potentially offers a more precise analysis of optic nerve injury and repair following optic neuritis. MF-VEP may offer advantages over FF-VEP as an endpoint in clinical trials of remyelinating therapies. OBJECTIVE: MF-VEP testing was used to study changes in visual pathways in 48% of RENEW [phase II, opicinumab (anti-LINGO-1; BIIB033) vs. placebo after first acute unilateral optic neuritis] participants. METHODS: This exploratory MF-VEP RENEW substudy compared mean outcomes at weeks 24 and 32 among participants in the intent-to-treat (ITT; n = 39; 72% female; mean age: 32.3 years) and per-protocol (PP; n = 31; 71% female; mean age: 32.2 years) populations in affected and fellow eye latency from fellow eye baseline latency and affected and fellow eye amplitude from their own baselines. Treatment differences were evaluated using analysis of covariance (week 24) and a mixed-effect model of repeated measures (week 32). Last observation carried forward was used to impute missing data at week 24. RESULTS: A trend for improvement in affected eye MF-VEP latency with opicinumab versus placebo was seen in the ITT and PP populations at weeks 24 and 32. Both treatment groups in the ITT population experienced partial recovery of amplitude in the affected eye at week 32. Notably, the mean change in fellow eye amplitude at weeks 24 and 32 was - 17.57 and - 31.41 nanovolts (nV) in placebo but only - 0.59 and 1.93 nV in the opicinumab group [differences at weeks 24 and 32: 16.98 nV (p = 0.050) and 33.33 nV (p < 0.01), respectively]. CONCLUSION: Results from this substudy showed advantages of MF-VEP over FF-VEP in multicenter studies of central nervous system reparative therapies and provide novel evidence that fellow eye visual pathway amplitude loss occurs after optic neuritis but can potentially be prevented by opicinumab treatment. REGISTRATION: ClinicalTrials.gov identifier NCT01721161.

Objective assessment of a relative afferent pupillary defect by B-mode ultrasound.

PURPOSE: To evaluate B-mode ultrasound as a novel method for objective and quantitative assessment of a relative afferent pupillary defect (RAPD) in a prospective case-control study. METHODS: Seventeen patients with unilateral optic neuropathy and a clinically detectable RAPD and 17 age and sex matched healthy controls were examined with B-mode ultrasound using an Esaote-Mylab25 system according to current guidelines for orbital insonation. The swinging flashlight test was performed during ultrasound assessment with a standardized light stimulus using a penlight. RESULTS: B-mode ultrasound RAPD examination was doable in approximately 5 minutes only and was well tolerated by all participants. Compared to the unaffected contralateral eyes, eyes with RAPD showed lower absolute constriction amplitude of the pupillary diameter (mean [SD] 0.8 [0.4] vs. 2.1 [0.4] mm; p = 0.009) and a longer pupillary constriction time after ipsilateral light stimulus (mean [SD] 1240 [180] vs. 710 [200] ms; p = 0.008). In eyes affected by RAPD, visual acuity correlated with the absolute constriction amplitude (r = 0.75, p = 0.001). CONCLUSIONS: B-mode ultrasound enables fast, easy and objective quantification of a RAPD and can thus be applied in clinical practice to document a RAPD.

[Appraisal of the formation of afterimages by means of a new computer application in patients with demyelinating optic neuropathies]. / Valoracion de la formacion de postimagenes mediante una nueva aplicacion informatica en pacientes con neuropatias opticas desmielinizantes.

INTRODUCTION: The perception of colour is one of the visual functions affected by optic neuritis. Most of the tests currently available for evaluating dichromatism are based on assessing the hue, but no clinical studies have been conducted to investigate the formation of afterimages on the retina of these patients. AIMS: To evaluate the dichromatism acquired in demyelinating optic neuritis by means of the formation of afterimages on the retina. SUBJECTS AND METHODS: This is an observation-based, cross-sectional, case-control study. The cases are patients with at least one bout of optic neuritis and confirmed multiple sclerosis. A healthy age- and sex-paired control was selected for each case. The main variable is the capacity to see afterimages after saturation of the retinal photoreceptor cells. A specific computer application was developed to evaluate this phenomenon. RESULTS: The sample consisted of 30 cases and 30 controls (63% females; mean age: 33 years; range: 18-48 years). The cases showed less probability of seeing the afterimage (36.6% of the cases, while none of the controls failed to see an afterimage) and, if it was seen, it remained for less time. The ROC curve shows a sensitivity of 86.3% and a specificity of 83.3%. The odds ratio was 5 (95% confidence interval: 2.21-11.3) for the probability of seeing the afterimage in controls versus cases. CONCLUSIONS: Patients with at least one episode of optic neuritis presented a lower capacity to observe afterimages. The test is therefore useful in the assessment and follow-up of functional damage in demyelinating optic neuropathies.

TITLE: Valoracion de la formacion de postimagenes mediante una nueva aplicacion informatica en pacientes con neuropatias opticas desmielinizantes.Introduccion. En las neuritis opticas se afecta, entre otras funciones visuales, la percepcion del color. La mayoria de las pruebas existentes para evaluar discromatopsias se basa en evaluar el matiz, pero no se ha estudiado clinicamente la formacion de postimagenes en la retina en estos pacientes. Objetivo. Evaluar la discromatopsia adquirida en las neuritis opticas desmielinizantes mediante la formacion de postimagenes en la retina. Sujetos y metodos. Estudio observacional, transversal, de casos y controles. Los casos son pacientes con al menos un episodio de neuritis optica y esclerosis multiple confirmada. Se selecciono un control sano por cada caso, emparejado por edad y sexo. La variable principal es la capacidad de ver postimagenes tras saturar los fotorreceptores retinianos. Para evaluar dicho fenomeno se desarrollo una aplicacion informatica especifica. Resultados. La muestra comprende 30 casos y 30 controles (63% mujeres; edad media: 33 años; rango: 18-48 años). Los casos mostraron menor probabilidad de ver la postimagen (el 36,6% de los casos y ningun control no veian postimagen) y, en caso de verla, una menor permanencia de ella. La curva ROC muestra una sensibilidad del 86,3% y una especificidad del 83,3%. La odds ratio era de 5 (intervalo de confianza al 95%: 2,21-11,3) para la probabilidad de ver la postimagen en los controles frente a los casos. Conclusiones. Los pacientes con al menos un episodio de neuritis optica presentan una menor capacidad de observar postimagenes, por lo que la prueba es util para la evaluacion y el seguimiento del daño funcional en neuropatias opticas desmielinizantes.

Multifocal VEP assessment of optic neuritis evolution.

OBJECTIVE: To evaluate multifocal visual evoked potentials (mfVEP) changes in optic neuritis (ON) and fellow eyes during first year after the attack. METHODS: Eighty-seven patients and twenty-five controls were examined. Patients were classified as multiple sclerosis (MS) group, high risk (HR) or low risk (LR) groups for conversion to MS. mfVEP recordings and retinal nerve fiber layer (RNFL) thickness were analyzed. RESULTS: Recovery of amplitude and shortening of latency was fastest within the first 3months. The largest amplitude reduction and longest latency delay of the ON eye were recorded in the MS group. This was accompanied by deterioration of both parameters in fellow eyes (p<0.03). mfVEP remained stable in fellow eyes of the LR group. Inter-eye asymmetry showed similar amount of amplitude reduction and latency delay in all three groups. RNFL thickness strongly correlated with mfVEP amplitude as early as 3 months after ON (R(2)=0.6, p=0.001). CONCLUSION: mfVEP amplitude is an early predictor of post-ON axonal loss. The apparent more severe involvement of ON eyes in the MS subgroup may be due to subclinical inflammation along the visual pathway. SIGNIFICANCE: Severity of amplitude reduction and latency delay after episode of ON is not MS-related. Retro-chiasmal demyelination is a possible factor contributing to amplitude and latency differences between MS and non-MS patients.

The value of clinical electrophysiology in the assessment of the eye and visual system in the era of advanced imaging.

Electrophysiological techniques allow clinical investigations to include a 'dissection' of the visual system. Using suitable electrophysiological techniques, the 'dissection' allows function to be ascribed to the different photoreceptors (rod and cone photoreceptors), retinal layers, retinal location or the visual pathway up to the visual cortex. Combined with advances in genetics, retinal biochemistry, visual fields and ocular imaging, it is now possible to obtain a better understanding of diseases affecting the retina and visual pathways. This paper reviews core electrophysiological principles that can complement other examination techniques, including advanced ocular imaging, and help the interpretation of other clinical data and thus, refine and guide clinical diagnosis.

Color vision versus pattern visual evoked potentials in the assessment of subclinical optic pathway involvement in multiple sclerosis.

BACKGROUND: Optic pathway involvement in multiple sclerosis is frequently the initial sign in the disease process. In most clinical applications, pattern visual evoked potential (PVEP) is used in the assessment of optic pathway involvement. OBJECTIVE: To question the value of PVEP against color vision assessment in the diagnosis of subclinical optic pathway involvement. MATERIALS AND METHODS: This prospective, cross-sectional study included 20 multiple sclerosis patients without a history of optic neuritis, and 20 healthy control subjects. Farnsworth-Munsell (FM) 100-Hue testing and PVEPs to 60-min arc and 15-min arc checks by using Roland-Consult RetiScan® system were performed. P 100 amplitude, P 100 latency in PVEP and total error scores (TES) in FM 100-Hue test were assessed. RESULTS: Expanded Disability Status Scale score and the time from diagnosis were 2.21 ± 2.53 (ranging from 0 to 7) and 4.1 ± 4.4 years. MS group showed significantly delayed P 100 latency for both checks (P < 0.001). Similarly, MS patients had significantly increased total error scores (TES) in FM-100 Hue (P < 0.001). The correlations between TESs and PVEP amplitudes / latencies were insignificant for both checks (P > 0.05 for all). 14 MS patients (70%) had an increased TESs in FM-100 Hue, 11 (55%) MS patients had delayed P 100 latency and 9 (45%) had reduced P 100 amplitude. The areas under the ROC curves were 0.944 for FM-100 Hue test, 0.753 for P 100 latency, and 0.173 for P 100 amplitude. CONCLUSIONS: Color vision testing seems to be more sensitive than PVEP in detecting subclinical visual pathway involvement in MS.

The value of neurophysiological and MRI assessment in demyelinating optic neuritis (DON).

PURPOSE: To study, by neurophysiological means, the possible involvement of the retina, in demyelinating optic neuritis (DON). MATERIAL AND METHODS: Thirty-five patients fulfilling strict criteria of unilateral DON were investigated with a battery of neurophysiological tests and MRI within 3 weeks of the onset of their symptoms. Flash-ERG (F-ERG) in photopic conditions, Flash-VEPs and PR-VEPs were recorded. MRI of the brain and the optic nerve were performed. RESULTS: The amplitude of b-wave of F-ERG in photopic conditions was statistically significantly lower in the affected eye (p < 0.001) compared to normal controls, whereas in the unaffected eye, it was also statistically significantly lower than normal controls (p < 0.01). All patients had statistically significant prolongation of P100 latency in PR-VEPs of the affected eye (p < 0.001) in comparison to normal controls. The P100 wave of the unaffected eye was also delayed (p < 0.01). In MRI, Gd-DTPA enhancement was observed in 7 symptomatic nerves with only minimal enhancement of the optic nerve between optic chiasm and optic canal, whereas 11 patients were presented with intracranial associated plaques. Five of the above patients had optic nerve enhancement and diffused demyelinating findings simultaneously. CONCLUSION: These results are a neurophysiological indication of involvement of the retina in DON, probably of vascular origin.

The role of NMR imaging in the assessment of multiple sclerosis and isolated neurological lesions. A quantitative study.

The form and distribution of MRI abnormalities in 114 patients with clinically definite multiple sclerosis (MS) have been compared with observations on 53 apparently healthy individuals, 129 patients with isolated focal neurological lesions with which MS often presents (51 patients with optic neuritis, 44 with isolated brainstem lesions and 34 with isolated spinal cord syndromes) and 105 patients with disorders which may be confused clinically or radiologically with MS. The latter comprised 55 patients with cerebral vascular disease (including 7 cases of dementia with diffuse white matter disease), 24 with degenerative ataxic disorders, 8 with cerebellar tonsillar ectopia, 7 with sarcoidosis and 11 with a variety of other disorders. Periventricular abnormalities were found in all but 2 patients with MS and discrete white matter lesions in all but 12. Characteristically the periventricular changes in MS were irregular in outline. Periventricular abnormalities which were often milder and of smooth outline were seen in 37/55 patients with cerebral vascular disease, 9/24 with cerebellar degeneration, 5/7 with sarcoidosis and in 2/3 apparently healthy individuals over the age of 60. The appearances in the 7 cases of dementia resembled those with advanced MS. Cerebellar and/or brainstem atrophy characteristic of the cerebellar degenerations, in the absence of white matter abnormalities, was helpful in making the distinction from MS. Congenital anomalies and tumours in the region of the brainstem and foramen magnum were readily shown. More than half the patients with symptoms attributable to isolated focal neurological lesions had additional lesions at presentation. MS cannot be diagnosed in these cases at presentation, but repeat scans after 5 to 20 months in 25 patients with optic neuritis and 10 with clinically isolated brainstem lesions have shown new lesions in 7 (20%). The patients with new lesions fulfil the criteria for clinically probable MS (Poser et al., 1983). Measurements of T1 and T2 in vivo permitted the distinction of acute from chronic brainstem lesions. There were quantitative differences in T1 and T2 between the normal appearing white matter in MS and normal brain. Studies of postmortem brains provided convincing evidence that the MRI abnormalities in MS correspond with plaques. Evidence is adduced to support the view that an important source of the abnormal NMR signals in acute lesions is oedema, and in chronic lesions is gliosis; demyelination per se is unlikely to make an important contribution.

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.

Assessment of unilateral afferent pupillary defects by pupillography.

A pupillographic technique, an adaptation of the swinging light test, is described for the measurement of unilateral afferent pupillary defects. In normal persons it yielded accurate, reproducible estimates of the magnitude of artificial afferent defects made with neutral filters of 1 to 4 log units density. In 15 studies on 8 patients with unilateral optic neuritis and 2 with unilateral compressive lesions the measured afferent pupillary defects correlated closely with both visual acuity and visual threshold deficits. Measurement of the pupillary defect underestimated severe degrees of impairment revealed by visual threshold determination. Discrepancies between pupillary defect and visual acuity were observed in the 2 patients with compressive lesions and in 1 patient who had a central scotoma 4 months after an attack of optic neuritis.

Visual evoked responses in the assessment of field defects in glaucoma.

A technique for producing steady state visual evoked responses (VERs) to pattern reversal stimulation of retinal areas corresponding to discrete field quadrants is described. Patients examined included 10 normal individuals, 11 patients with ocular hypertension, and 21 with glaucomatous field defects (unilateral except in two cases with bilateral defects). The VERs relating to normal homonymous field quadrants were in phase in all three groups, excluding patients with cataracts. The VERs corresponding to quadrants with small field defects showed a phase shift compared with responses from normal homonymous quadrants in all cases, but were not detectable if the defect filled more than three quarters of the quadrant tested in most cases. The method offers a means for the objective assessment of visual fields in patients with unilateral optic nerve lesions, provided that central visual acuity is 20/80 or better