Raymond Garrick

Axonal loss and myelin in early ON loss in postacute optic neuritis

To investigate the relation between retinal nerve fiber layer (RNFL) thickness and latency and amplitude of multifocal visual‐evoked potentials (mfVEPs) in the postacute stage of optic neuritis in patients with early or possible multiple sclerosis.

Axonal loss of retinal neurons in multiple sclerosis associated with optic radiation lesions

Objective: To investigate the potential links between thinning of retinal ganglion cell axons in eyes of patients with multiple sclerosis (MS) without past optic neuritis (ON) and MS-related inflammatory damage of the posterior visual pathway. Methods: Temporal retinal nerve fiber layer (tRNFL) thickness was analyzed in eyes with no history of ON (NON) from 53 patients with relapsing-remitting MS. Fifty normal age- and sex-matched controls were examined with optical coherence tomography. Low-contrast visual acuity charts were used for functional assessment of vision. The optic tract (OT) and optic radiation (OR) were identified using probabilistic tractography, and volume of T2 fluid-attenuated inversion recovery lesions and diffusion tensor imaging (DTI) indices were measured within both structures. Cross-sectional diameter of the OT was also calculated. Results: tRNFL thickness was significantly reduced in NON eyes and was associated with reduced low-contrast visual acuity. Lesions within the OR were detected in the majority of patients. There was a significant correlation between thinning of the tRNFL and OR lesion volume (adjusted for non-OR lesion volume, age, sex, and disease duration). tRNFL thickness also correlated with OR DTI indices. No OT lesions were identified in any of the patients and no relationship between retinal nerve fiber layer loss and potential markers of OT lesions was found. Conclusion: The results demonstrate a strong tract-specific association between loss of tRNFL fibers and MS-related inflammation within OR.

Evoked potential changes in clinically definite multiple sclerosis: a two year follow up study.

Visual, spinal and somatosensory evoked potentials were performed on 56 patients with clinically definite multiple sclerosis at the beginning and end of a 2 1/2 year follow-up period. At the initial examination one or both visual evoked potentials were abnormal in all but nine patients (84%), five of whom had abnormalities of either spinal or somatosensory evoked responses; that is, one or more abnormal results were obtained from 52 of 56 (91%) patients. At the final examination there were abnormalities of one or more evoked potentials in 55 of the 56 (98%) patients. There was an increase in latency of the components of the evoked responses over the period; reduction in latency in individual patients was exceptional. The change in these electrophysiological measurements correlated with the increase in clinical disability of the group of patients over the period of study.

Interrelationship of Optical Coherence Tomography and Multifocal Visual-Evoked Potentials after Optic Neuritis

PURPOSE Acute optic neuritis (ON) is often followed by recovery of visual function. Although this recovery is mainly attributable to resolution of the acute inflammation, the redistribution of ion channels along the demyelinated membrane, and subsequent remyelination, part of it may be the result of neural plasticity. In the present study, the interrelationship was examined between structural (retinal nerve fiber layer [RNFL] thickness) and functional (amplitude of multifocal visual evoked potentials [mfVEPs]) measures of the integrity of the visual pathway in the postacute stage of ON, to determine whether there was any evidence of ongoing neural reorganization. METHODS Twenty-five subjects with acute unilateral ON underwent serial RNFL thickness measurement and mfVEP recording. The inter-eye asymmetry of both measures was analyzed. In the period between 6 and 12 months, the subjects were considered free of optic disc edema, and that period was used to analyze the structure-function relationship. Twenty control subjects were also examined. RESULTS There were significant but opposite changes in RNFL thickness and mfVEP amplitude. The average asymmetry of RNFL thickness between affected and fellow eyes increased from 17.5 +/- 11.5 to 21.1 +/- 12.8 microm (P = 0.0003), indicating progressive axonal loss, whereas mfVEP amplitude asymmetry decreased from 46.6 +/- 32.4 to 38.3 +/- 31.1 nV (P = 0.0015), indicating continuous functional recovery. In comparison to the 6-month results, the mfVEP amplitude in the ON eye improved by 17.8%, whereas RNFL thickness decreased by 20.8%. The result remained unchanged regardless of the degree of optic nerve remyelination. CONCLUSIONS The finding of structural-functional discrepancy at the postinflammatory stage may support the concept that neural plasticity contributes to functional recovery after acute ON.

Axonal loss in non–optic neuritis eyes of patients with multiple sclerosis linked to delayed visual evoked potential

Objective: Recent studies demonstrate significant thinning of the retinal nerve fiber layer (RNFL) in multiple sclerosis (MS) non–optic neuritis (MS-NON) eyes. However, the pathologic basis of this reduction is not clear. The aim of the current study was to investigate the relationship of the RNFL thickness in MS-NON eyes with latency delay of the multifocal visual evoked potential (mfVEP), a surrogate marker of the visual pathway demyelination. Methods: Total and temporal RNFL thickness and latency of the mfVEP in 45 MS-NON eyes of 45 patients with relapsing-remitting MS and 25 eyes of age- and gender-matched controls were measured and analyzed. Results: There was significant reduction of total and temporal RNFL thickness (p = 0.015 and p = 0.006, respectively) and significant latency delay (p < 0.0001) in MS-NON eyes. Both total and temporal RNFL thickness were associated with latency of the mfVEP (r2 = 0.43, p < 0.0001 and r2 = 0.36, p = 0.001, respectively). MS-NON eyes with normal latency (n = 26) showed no significant reduction of RNFL thickness compared with controls (p = 0.44 and p = 0.1 for total and temporal RNFL, respectively), whereas eyes with delayed latency (n = 19) demonstrated significantly thinner RNFL (p = 0.001 and p = 0.0005). MS-NON eyes with delayed latency also had significantly thinner RNFL compared with those with normal latencies (p = 0.013 and p = 0.02). In patients with no previous optic neuritis in either eye, delayed latency and reduced RNFL were bilateral whenever present. Conclusions: The study demonstrated significant association between RNFL loss and a latency delay of the mfVEP in MS-NON eyes.

Transsynaptic Retinal Degeneration in Optic Neuropathies: Optical Coherence Tomography Study

PURPOSE Recently demonstrated neuronal loss in the inner nuclear layer of the retina in multiple sclerosis (MS) and glaucoma raises the question of a primary (possibly immune-mediated) or secondary (transsynaptic) mechanism of retinal damage in these diseases. In the present study we used optical coherence tomography to investigate retrograde retinal transsynaptic degeneration in patients with long-standing and severe loss of ganglion cells due to optic neuropathy. METHODS Fifteen eyes of glaucoma patients with visual field defect limited to upper hemifield and 15 eyes of MS patients with previous episode of optic neuritis (ON) and extensive loss of ganglion cells were imaged using spectral-domain optical coherence tomography and compared with two groups of age-matched controls. Combined retinal ganglion cell layer/inner plexiform layer (GCL/IPL) thickness and inner nuclear layer (INL) thickness were analyzed. RESULTS In the glaucoma group there was a significant (P = 0.0005) reduction of GCL/IPL thickness in the lower (affected) retina compared with normal controls; however INL thickness was not statistically reduced (P = 0.49). In the MS group reduction of GCL/IPL thickness in both hemifields of ON eyes was also significant (P = 0.0001 and P < 0.0001 for inferior and superior retina respectively). However, similar to the glaucomatous eyes, there was no significant reduction of INL thickness in both hemifields (P = 0.25 and P = 0.45). CONCLUSIONS This study demonstrates no significant loss of INL thickness in parts of the retina with long-standing and severe loss of retinal ganglion cells.

TRANSFER FACTOR IN TREATMENT OF MULTIPLE SCLEROSIS

A 2-year prospective double-blind trial of the treatment of multiple sclerosis patients with the leucocyte extract, transfer factor (TF), obtained from leucocytes of relatives living with the patient, was conducted. 60 patients with definite MS, of whom 58 completed the trial, were divided into two equal groups, one of which received TF and the other placebo. The groups were evenly balanced with respect to sex ratios, disability, duration of disease, ratio of moderate to severe cases, and HLA phenotype. Neurological, electrophysiological, and immunological assessments were done at the start of the trial and every 6 months thereafter. The results indicated that (1) TF retarded but did not reverse progression of the disease; (2) a significant difference between treatment and placebo groups was not apparent with 18 months after the start of the trial; and (3) treatment was effective only in those patients with mild to moderate disease activity.

Relationship between Optical Coherence Tomography and Electrophysiology of the Visual Pathway in Non-Optic Neuritis Eyes of Multiple Sclerosis Patients

Purpose Loss of retinal ganglion cells in in non-optic neuritis eyes of Multiple Sclerosis patients (MS-NON) has recently been demonstrated. However, the pathological basis of this loss at present is not clear. Therefore, the aim of the current study was to investigate associations of clinical (high and low contrast visual acuity) and electrophysiological (electroretinogram and multifocal Visual Evoked Potentials) measures of the visual pathway with neuronal and axonal loss of RGC in order to better understand the nature of this loss. Methods Sixty-two patients with relapsing remitting multiple sclerosis with no previous history of optic neuritis in at least one eye were enrolled. All patients underwent a detailed ophthalmological examination in addition to low contrast visual acuity, Optical Coherence Tomography, full field electroretinogram (ERG) and multifocal visual evoked potentials (mfVEP). Results There was significant reduction of ganglion cell layer thickness, and total and temporal retinal nerve fibre layer (RNFL) thickness (p<0.0001, 0.002 and 0.0002 respectively). Multifocal VEP also demonstrated significant amplitude reduction and latency delay (p<0.0001 for both). Ganglion cell layer thickness, total and temporal RNFL thickness inversely correlated with mfVEP latency (r = −0.48, p<0.0001 respectively; r = −0.53, p<0.0001 and r = −0.59, p<0.0001 respectively). Ganglion cell layer thickness, total and temporal RNFL thickness also inversely correlated with the photopic b-wave latency (r = −0.35, p = 0.01; r = −0.33, p = 0.025; r = −0.36, p = 0.008 respectively). Multivariate linear regression model demonstrated that while both factors were significantly associated with RGC axonal and neuronal loss, the estimated predictive power of the posterior visual pathway damage was considerably larger compare to retinal dysfunction. Conclusion The results of our study demonstrated significant association of RGC axonal and neuronal loss in NON-eyes of MS patients with both retinal dysfunction and post-chiasmal damage of the visual pathway.

Progressive Loss of Retinal Ganglion Cells and Axons in Nonoptic Neuritis Eyes in Multiple Sclerosis: A Longitudinal Optical Coherence Tomography Study.

PURPOSE To examine the rate of retinal ganglion cell (RGC) layer and retinal nerve fiber layer (RNFL) changes in nonoptic neuritis (NON) eyes of relapsing remitting multiple sclerosis (RRMS) patients, and to find a specific imaging parameter useful for identifying disease progression. METHODS Forty-five consecutive RRMS patients and 20 age- and sex-matched healthy subjects were enrolled. All patients were followed up for 3 years with annual optical coherence tomography (OCT) scans, which included a peripapillary ring scan protocol for RNFL analysis and a macular radial star-like scan to obtain RGC/inner plexiform layer (IPL) thickness measures. Healthy controls were scanned twice, 3 years apart. RESULTS Retinal ganglion cell/inner plexiform layer and temporal RNFL (tRNFL) demonstrated highly significant thinning (P < 0.01), but all nasal segments and global RNFL (gRNFL) were not significantly different from normal controls. While receiver operating characteristics (ROC) analysis showed no advantage of RGC/IPL over tRNFL in cross-sectional detection of thinning, cut-off point based of fifth percentile in healthy controls demonstrated higher rate of abnormality for RGC/IPL. There was a significant progressive loss of RGC/IPL and tRNFL during the follow-up period. The largest thickness reduction was observed in tRNFL. ROC analysis demonstrated that tRNFL provided better sensitivity/specificity for detecting change over time than RGC/IPL (area under the curve [AUC] 0.78 vs. 0.52), which was confirmed by higher detection rate when 95th percentile of progression in healthy controls was used as a cut-off. CONCLUSIONS This study confirmed significant thinning of RGC/IPL and tRNFL in NON eyes of RRMS patients. Progressive losses were more apparent on tRNFL, while RGC/IPL showed less change over the follow-up period.

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.