Evaluación funcional del nervio óptico en pacientes con esclerosis múltiple mediante los potenciales evocados visuales multifocales

Abstract

INTRODUCTION:Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. The etiology is unknown. Environmental, genetic and infectious factors have been proposed but none of them have been demonstrated to be the cause of the disease. The diagnosis is made by McDonald Criteria by clinical, radiological (RM) and bioquimical markers. The course of the disease has a great variability, and can affect to the total central nervous system. The most common course of the disease is the relapssing‐remitting form. The disability is measured by the Expanded Disability Status Scale of EDSS Kurtke (EDSS). Optic neuritis (ON) is an inflammatory optic neuropathy and is the presenting symptom of multiple sclerosis (MS) in around 20% of patients affected by MS. ON occurs in more than 50% of patients with MS at some point during the disease course In the Optic Neuritis Treatment Trial (ONTT) 38% of the patients who experienced an episode of ON developed MS within 10 years. After an acute attack of ON, visual acuity (VA) typically recover to near normal levels. Optical coherence tomography (OCT) is a relatively recent optical imaging technique that measures cross‐sectional retinal nerve fiber layer (RNFL) thickness with high resolution and good reproducibility. Reduced retinal nervous fiber layer thickness (RNFL) has been demonstrated by optical coherence tomography (OCT) in patients with MS‐ON and MS‐no‐ON eyes. OCT is a promising new tool for measuring structural damage of optic nerve in the retina, evaluating atrophy in the RNFL, but not in the complete optic nerve. The visual evoked potential (VEP), has been found to reveal optic nerve conduction delays (demyelinitating damage) and small amplitudes (axonal damage) in patients with MS‐ON and MS‐no‐ON. However, the clinical usefulness of the full VEP (fVEP) is limited by the fact that it is greatly dominated by the macular region . For this reason, local defects can be missed. Recent studies have argued that the multifocal Visual Evoked Potentials (mfVEP) should be superior to the fVEP in detecting local damage to the optic nerve, with a high sensibility and specificity. Multifocal visual evoked potentials (mfVEP) provide a method to diagnose optic pathway conditions by assessing the VEP not as a single global response, but as responses from multiple individual segments of the visual field. This allows for objective information on topographic visual field deficits (amplitude) to be combined with information on the speed of conduction along the visual pathways (latency). Several recent studies have demonstrated the sensitivity of the mfVEP technique in identifying defects following recovery from an episode of ON. However, to date, little information is available regarding the effect of optic nerve dysfunction in MS by mean of the mfVEP. The aim of the present study was to analyse the axonal and demyelinating damage in MS‐ON and MS‐no‐ON eyes, to assess the ability of the mfVEP for detecting axonal damage in MS and to detect early subclinical changes in the optic nerve in MS‐no‐ON eyes. We wanted to evaluate the relationship between abnormalities detected by the mfVEP compared with those detected by static achromatic automated perimetry (SAPP), optical coherence tomography (OCT) and clinical examination by EDSS and visual acuity by Snellen test. PATIENTS AND METHODS: Twenty eight patients with multiple sclerosis and optic neuritis were recruited for this prospective, observational, case‐control study. All patients had suffered at least one optic neuritis episode passed six months (after acute phase). Exclusion criteria were the age before 18 years and after 55 years, acute ON (before 6 months), ON of unknown origin and psyquiatric, neurological, systemic or ophthalmologic pathology. Neurological exploration by EDSS scale, measurement of the Visual Acuity by Snellen test, Optical coherence tomography (OCT) (OCT‐3,Zeiss Instruments) and mfPEV (Veris system, EDI) are made in all patients simultaneous. The study was performed at baseline and at 6 months to validate the first results. Control group age‐matched subjects with normal ophthalmic examination results, normal visual field, OCT and mfVEP with no history of optic neuritis were included. The study protocol was approved by the Institutional Review Boards of Alcalá University affiliated Hospitals. All participants provided informed consent. The design of the study protocol adhered to the tenets of the Declaration of Helsinki for biomedical research. Multifocal visual‐evoked potential recordings and analysis: MfVEP recordings were obtained using VERIS software (Electro‐Diagnostic Imaging, San Mateo, California, USA). The stimulus was a scaled dartboard with a diameter of 44.5º, contained 60 sectors, each with 16 checks alternating, 8 white (luminance 200 cd/m2) and 8 black (luminance < 3 cd/m2) with a Michelson contrast of 99%. The sectors were cortically scaled with eccentricity to stimulate approximately equal areas of the visual cortex. The dartboard pattern reversed according to a pseudorandom m‐sequence at a frame rate of 75 Hz. Three recording channels were connected to gold cup electrodes (Astro‐Med Inc., West Warwick, RI, USA). For the midline channel, electrodes were placed 4 cm above the inion (active), at the inion (reference) and on the forehead (ground). For the other two active channels, the same ground and reference electrodes were used but the active electrode was placed 1 cm up and 4 cm lateral to the inion on either side. By subtracting different combinations of pairs of channels, three additional derived channels were obtained resulting effectively in six channels representing the six possible pairs of the four electrodes. The channel providing the best recording for each sector was selected during the analysis as Best channel response. The signals were amplified, band‐pass filtered from 3 to 100 Hz and sampled at 1200 Hz. Each patient completed two monocular recordings per eye and the time recording was about 8 minutes. SAP was performed using Humphrey visual field Strategy SITA 24‐2 (Humphrey Instruments, Dublin, California). To allow a comparison of the visual‐field sensitivity to the mfVEP responses, estimates of sensitivity for each sector of the multifocal stimulus were obtained from the visual field values (total deviation). These estimates and all analyses were obtained with programs written in MATLAB (MATLAB software; The Mathworks, Natick, Massachusetts, USA). A normative database was used for analyses. Amplitudes of the responses were calculated by obtaining root mean square (RMS) of the amplitude for each mfVEP response over time intervals from 45 to 150 ms. Signal‐to‐noise ratios were calculated for each response by dividing the RMS of the signal window by the average of the 60 RMS values of the noise only window. Each of these values vas compared to values for normative group subjects 148 and monocular probability plot were derived. Interocular amplitude differences for each patient were also calculated by taking the logarithm of the interocular ratio at each location140 and interocular probability plot were derived. The amplitude probability plot are a colour code with saturated red squares (left eye), saturated blue squared (right eye), depicting a difference significant at a P value <0,05 and desaturated colours at a P value <0,01. Black squares indicate no significant differences and grey squares indicate a signal too small to be compared. Monocular and interocular latencies were measured as the temporal shift producing the best cross correlation value between the corresponding responses of the patient’s eye and a template based on control eyes (monocular analysis) or between the corresponding responses from two eyes (interocular analysis) using the cross‐correlation function in MATLAB. The signal‐to‐noise ratio is <1,7. An eye was defined as abnormal when met the abnormal cluster criteria. An abnormal cluster had two o more contiguous points at P<0,05, or three or more contiguous points at P>0,01 with at least one point at P<0,05. Statistical analysis: Differences in proportions were evaluated by the chi‐square test. Difference in the means between groups were calculated using the Student’s t‐test or by the Mann‐Whitney U‐test. Differences of means for paired groups were calculated using the Student’s t‐test for paired samples or by the Wilcoxon T‐test. The association between two quantitative variables was evaluated by Pearson’s or Spearman’s correlations coefficients. P values below 0,05 were considered statistically significant. The SPSS version 15 (SPSS Inc, Chicago, IL, USA) were used. CONCLUSIONS: 1. Visual Acuity and EDSS scale have been correlated with mfVEP amplitudes, total average, sector thickness nerve fibber layer and macular volume of the retina in OCT. Number of episodes of optic neuritis have been correlated with latencies of mfVEP. Time since first event has been correlated with total average thickness layer of the retina in OCT and amplitudes in mfVEP. These clinical parameters could be useful in clinical practice to indicate the severity of optic nerve lesion in multiple sclerosis. 2. All parameters obtained in Perimetry (Humphrey visual field) correlated with EDSS scale. Media deviation (DM) of SAPP correlated with Visual Acuity. DM and GHT correlated with total, temporal, foveal thickness nerve fibber layer and macular volume of the retina in OCT and only with global amplitudes in mfVEP. These results indicate that defects detected by Perimetry are correlated with OCT and mfVEP . But perimetry visual field defects have less sensitivity than mfVEP and have a great variability by subjectivity. 3. Our study have demonstrate reduction of total average, sector, foveal thickness nerve fibber layer and macular volume of the retina in OCT in MS‐ON and MS‐no‐ON eyes. The OCT is a useful and non invasive tool to determine the severity of damage of optic nerve in patients with multiple sclerosis in post‐acute phase and to detect subclinical axonal damage in eyes without clinical optic neuritis. 4. Significant correlation exists between total average, temporal, foveal thickness nerve fibber layer and macular volume of the retina in OCT and EDSS. Total average, temporal, nasal, superior thickness nerve fibber layer of the retina are correlated with time since first event of multiple sclerosis. These results are the same described in literature. These parameters of OCT could be objective and structural markers of axonal damage in optic nerve and of progression of the disease. 5. Seventy‐three per cent of the eyes without optic neuritis (MS‐no‐ON eyes) showed significant alterations in amplitudes and thirty one in latencies in mfVEP probability analysis. mfVEP is and objective , non‐invasive technique that provides the detection of demyelinating and axonal lesions in the whole visual field, in MS‐ON and MS‐no‐ON eyes. This technique can detect local or peripheric lesions of the visual field. Our study demonstrates subclinical axonal lesion in MS‐no‐ON eyes, so these results confirm than the mfVEP can detect subclinical axonal damage. The interocular mfVEP amplitudes and latencies probability analysis showed a higher diagnostic sensitivity than the monocular mfVEP probability analysis. 6. Significant correlation exists between mfVEP amplitudes, Visual acuity, EDSS scale and time since first event of multiple sclerosis. Significant correlation exists between latencies of the mfVEP and the number of optic neuritis. Significant correlation exists between amplitudes of mfVEP and total average, temporal thickness nerve fibber layer of the retina. Correlation existis between temporal thichness nerve fibber layer of the retina. The ability of the mfVEP to detect subclinical demyelination and axonal damage could be important for the diagnosis of MS and subsequent monitoring of treatment and disease progression, with a good correlation with EDSS and Visual Acuity. Six months later there were no statistics differences between the main results in perimetry, OCT and mfVEP. This result shows a good repeatability of these techniques.