Predicting multiple sclerosis at optic neuritis onset

Using multivariate analyses, individual risk of clinically definite multiple sclerosis (CDMS) after monosymptomatic optic neuritis (MON) was quantified in a prospective study with clinical MON onset during 1990-95 in Stockholm, Sweden. During a mean follow-up time of 3.8 years, the presence of MS-like brain magnetic resonance imaging (MRI) lesions and oligoclonal immunoglobulin (Ig) G bands in cerebrospinal fluid (CSF) were strong prognostic markers of CDMS, with relative hazard ratios of 4.68 [95% confidence interval (CI) 2.21-9.91] and 5.39 (95% CI 1.56-18.61), respectively. Age and season of clinical onset were also significant predictors, with relative hazard ratios of 1.76 (95% CI 1.02-3.04) and 2.21 (95% CI 1.13-3.98), respectively. Based on the above two strong predictors, individual probability of CDMS development after MON was calculated in a three-quarter sample drawn from a cohort, with completion of follow-up at three years. The highest probability, 0.66 (95% CI 0.48-0.80), was obtained for individuals presenting with three or more brain MRI lesions and oligoclonal bands in the CSF, and the lowest, 0.09 (95% CI 0.02-0.32), for those not presenting with these traits. Medium values, 0.29 (95% CI 0.13-0.53) and 0.32 (95% CI 0.07-0.73), were obtained for individuals discordant for the presence of brain MRI lesions and oligoclonal bands in the CSF. These predictions were validated in an external one-quarter sample.     

Bilateral and recurrent optic neuritis in multiple sclerosis

Burman J, Raininko R, Fagius J. Bilateral and recurrent optic neuritis in multiple sclerosis.
Acta Neurol Scand: 2011: 123: 207–210.
© 2010 John Wiley & Sons A/S. Objective – To assess the frequency of bilateral and recurrent optic neuritis (ON) in multiple sclerosis (MS) and to compare these results with epidemiological data of ON in neuromyelitis optica (NMO) and recurrent ON without other signs of disease. Methods – We identified 472 patients with diagnosis of MS from the Swedish Multiple Sclerosis Register. These patients were evaluated for the presence of ON and whether the ON was the presenting symptom of MS; unilateral or bilateral; monophasic or recurrent. Results – Twenty‐one percent presented with ON as their first manifestation of MS. The proportion of patients developing a second attack of ON before demonstration of other manifestations of MS was 5.5% and the frequency of recurrent bilateral ON as the presenting symptom was 3.8%. Only two patients presented with simultaneously appearing bilateral ON corresponding to 0.42%. Conclusion – Recurrent ON, whether unilateral or bilateral, is a common presentation of MS. As MS is a much more common disease than NMO, care must be taken when evaluating the work‐up of patients with recurrent ON. In some cases repeated MRI and lumbar punctures are warranted to improve diagnostic accuracy, even in the presence of the serological marker NMO‐IgG.     

New directions in optic neuritis and multiple sclerosis

Optic neuritis (ON) is the initial presentation in 15% to 20% of cases of multiple sclerosis (MS). Thirty-eight percent to 50% of patients with MS develop ON at some point during the course of their disease. The Optic Neuritis Treatment Trial (ONTT) provided much prospective data about the clinical presentation, clinical course with respect to treatment, and development of MS in patients with ON. The clinical course of MS initially involves episodes of demyelination followed by full recovery; however, later attacks often leave persistent deficits that lead to secondary progression of the disease. The risk of developing progressive neurologic deficits can be reduced by starting therapy with immunomodulating drugs early in the course of the disease. Optical coherence tomography is a noninvasive way to monitor patients with ON to determine if they are undergoing subclinical axonal loss of ganglion cells. Progression of axonal loss on optical coherence tomography may prompt a change in therapy or further imaging.     

Electrophysiological disorders in multiple sclerosis and optic neuritis

Visual evoked response (VER), auditory brainstem evoked response (ABER), somatosensory evoked response (SSER), blink reflex and electronystagmographic (ENG) investigative methods were applied to a group of 89 patients with Multiple Sclerosis (MS) and Optic Neuritis (ON). The MS patients were classified as definite (n = 31), probable (n = 31) and possible (n = 27). The aim of this study was to determine the diagnostic value of the five electrophysiological tests in MS. VER and ABER recordings were found to reveal the highest number of asymptomatic abnormalities (33 and 31 percent respectively). The combination of VER, ABER and ENG revealed all possible electrophysiological disorders. As these tests are completely non-invasive it is proposed, that a combination of two of these three tests is useful for the detection of a second silent lesion in patients with suspected MS showing purely spinal signs (VER, ENG, ABER) and/or a history of uncomplicated ON (ABER, ENG).     

The electroretinogram in multiple sclerosis and demyelinating optic neuritis

The electroretinogram (ERG) to flashes of white light presented under photopic conditions and the pattern reversal visual evoked potentials (PR-VEPs) from both eyes were recorded from 14 patients with multiple sclerosis (MS) with monocular demyelinating optic neuritis (DON) and from 11 patients soon after presenting with monocular demyelinating optic neuritis alone. Fifteen and 10 normal subjects, matched for age and sex, were used as controls for each group of patients respectively. In the DON group of patients and controls the flicker following ERG (FF-ERG) to white flashes of light at 40 Hz was also recorded. Skin electrodes and averaging procedures were used for all the recordings. The PR-VEP elicited with stimulation of the affected eye was absent or abnormally delayed, and the amplitude of the 'b' wave of ERG of the affected eye was diminished in all patients. The 'b' wave latency, however, was similar in both affected and non-affected eyes and the controls. There was no difference in 'a' wave amplitude and latency between eyes of patients and normal subjects. The FF-ERG in 8 out of 10 patients with satisfactory recordings was diminished in the affected eye. These results provide neurophysiological evidence that retinal damage is not due to loss of myelin but is an early feature of demyelinating optic neuritis. This damage preferentially affects the retinal elements associated with the generation of the 'b' wave of the ERG, probably the glial cells of Müller.     

Clinico-immunogenetic characteristics of multiple sclerosis with optic neuritis in children

The frequency of multiple sclerosis (MS) with clinical onset before 16 years of age in different regions of Russia fluctuates from 2 to 10% of all MS patients. One of the most frequent signs of MS manifestation and/or exacerbation at this age is optic neuritis (ON). Forty-seven children with MS were observed in Moscow. Diagnosis of MS in every case was clinically definite and proved by serial MRI. Clinico-tomographic dissociation was noticed: numerous large lesions, typical for MS on T2 images were often seen in children with mild or moderate residual neurological symptoms. All patients had relapsing/remitting MS course, mean EDSS was 2.24+/-0.26. Thirty-eight children (80%) had ON at least once, ten (21.3%) - twice or more times. In several cases ON had subclinical course or might be missed and the damage of the optic nerve with partial atrophy was found only after complex ophthalmological investigation including visual evoked potentials. Thus, the clinical course of MS and ON have some peculiarities in children and may be genetically based. Analyses of allelic polymorphisms of HLA-DR and TNF loci on chromosome 6 was performed. Data from children with MS were compared with data from their parents, healthy controls and other MS patients from the same ethnic group. Children with MS had increased frequency of DR2(15) and TNF-a11, but not TNF-a9 as adult MS patients from the same ethnic group. The presence of TNF-a7, rare in adult patients, could be proposed as a marker of early MS onset.     

Oligoclonal bands predict multiple sclerosis in children with optic neuritis

We retrospectively evaluated predictors of conversion to multiple sclerosis (MS) in 357 children with isolated optic neuritis (ON) as a first demyelinating event who had a median follow‐up of 4.0 years. Multiple Cox proportional‐hazards regressions revealed abnormal cranial magnet resonance imaging (cMRI; hazard ratio [HR] = 5.94, 95% confidence interval [CI] = 3.39–10.39, p < 0.001), presence of cerebrospinal fluid immunoglobulin G oligoclonal bands (OCB; HR = 3.69, 95% CI = 2.32–5.86, p < 0.001), and age (HR = 1.08 per year of age, 95% CI = 1.02–1.13, p = 0.003) as independent predictors of conversion, whereas sex and laterality (unilateral vs bilateral) had no influence. Combined cMRI and OCB positivity indicated a 26.84‐fold higher HR for developing MS compared to double negativity (95% CI = 12.26−58.74, p < 0.001). Accordingly, cerebrospinal fluid analysis may supplement cMRI to determine the risk of MS in children with isolated ON. Ann Neurol 2015;77:1076–1082     

Cell-mediated immunity in acute idiopathic optic neuritis and multiple sclerosis

Lymphocyte transformation responses to phytohaemagglutinin, measles antigen and tuberculin and the absolute numbers of circulating T and SIg+ cells were determined in 16 patients with acute idiopathic optic neuritis (ON), 42 patients with multiple sclerosis (MS) and 78 healthy controls.
Patients with acute ON showed impaired lymphocyte transformation responses in both autologous plasma and AB serum similar in extent to those seen in MS patients in relapse. They were not associated with a reduced total number of circulating T cells.     

The early risk of multiple sclerosis after optic neuritis.

Serial brain MRI was performed in 53 patients with clinically isolated optic neuritis. Using clinical and imaging evidence for relapse, multiple sclerosis developed within a mean of 12 months in 19 of 34 cases (56%) with brain lesions at presentation, and in only 3 of 19 cases (16%) without (Relative Risk = 6.8, p less than 0.005).     

Acute optic neuritis and the prognosis for multiple sclerosis.

In a retrospective survey of acute optic neuritis 144 cases in adults were found and, of these, 127 were reviewed, five had died of causes related to multiple sclerosis, and 12 were lost to follow-up. There was a statistically significant seasonal variation in the incidence of optic neuritis. When the life-table method of analysis was used, the probability of developing multiple sclerosis rises to 78% 15 years after an episode of optic neuritis. At review, 49 (73%) of the 67 patients with multiple sclerosis were independent and leading active lives.     

Seasonal patterns in optic neuritis and multiple sclerosis: a meta-analysis

To quantify and characterize seasonal variation in monosymptomatic optic neuritis (MON) onsets, multiple sclerosis (MS) onsets and MS exacerbations (MSE), a meta-analysis was performed, using established methods and pooling weighted information obtained from nine reports on MON, six reports on MS onsets and nine reports on MSE, which fulfilled specific criteria for report quality and data homogeneity. The results suggested that MON, MS onsets and MSE in the Northern hemisphere present a similar pattern with highest frequencies in spring and lowest in winter. These differences were highest for MS onsets, 45% with 95% CI 36-55%, and lowest for MSE, 10% with 95% CI 7-13%, statistically significant and robust, insensitive to an alternative seasonal definition, not unduly influenced by any single primary study, and supported by fail-safe N calculations. Random variation, misclassification and publication bias were less likely to account for the reported generalized seasonal patterns.     

The incidence of optic neuritis and its prognosis for multiple sclerosis

An incidence study of idiopathic optic neuritis (ON) was carried out in 2 geographic areas of Finland for the 9-year period 1970 to 1978. The southern province of Uusimaa composes a medium-risk and the western province of Vaasa a high-risk area for multiple sclerosis (MS). The risk for subsequent MS was determined. A total of 315 attacks on ON were recorded in 296 patients. The mean annual age-adjusted incidence for ON in Uusimaa was 2.2 and in Vaasa 2.5 per 100,000 population. The incidence figures remained unchanged all the time. The mean age at onset was 30 years. 19% of ON patients developed MS during the mean follow-up period of 5.1 years. When the life-table method of analysis was used, the probability of developing MS was 38% in Uusimaa and 24% in Vaasa 9 years after acute optic neuritis. In Uusimaa the risk of women for MS was significantly higher than in men. In 47%, the MS symptoms and signs developed within 1 year and in 90% within 5 years after the initial bout of ON. It is possible that only one part of idiopathic ON cases do have a relationship with MS.     

Distribution of HLA-Dw2 in optic neuritis and multiple sclerosis indicates heterogeneity

Introduction – The human leukocyte antigen (HLA) phenotype Dw2 is known to be increased in multiple sclerosis (MS), but only slightly in optic neuritis (ON). Materials and methods — 127 consecutive patients with unilateral monosymptomatic ON were typed genomically for HLA-DR and -DQ genes. Results - The frequency of HLA-Dw2 among ON patients (47%) was found to be significantly higher than among 250 controls (30%) but significantly lower than in a group of 245 MS patients (60%), all of the same ethnic origin. At the group level, these figures can be calculated to indicate that 53% of the ON patients belong to the group of "MS-type ON" (95% confidence limits 25–78%). A compilation of published data on the frequency of the HLA-DR17(3), DQ2 haplotype, prompted by a slight increase in this material, revealed a significant association with this haplotype in ON, after compensation for the increase of Dw2. Conclusion — ON differs from both MS and controls regarding HLA-Dw2. Thus, a substantial number of patients with ON may suffer from conditions not immuno-genetically related to MS, which might be designated as non-MS type ON. This condition may be more common in men and in young patients of both sexes.     

Optical coherence tomography (OCT) in optic neuritis and multiple sclerosis

Optical coherence tomography (OCT) is a non-invasive imaging technique routinely used in ophthalmology to visualize and quantify the layers of the retina. It also provides information on optic nerve head topography, peripapillary retinal nerve fiber layer thickness, and macular volume, which correlate with axonal loss. These measurements are of particular interest in optic neuropathies and in multiple sclerosis, and OCT parameters are now used as endpoints in neurologic clinical trials.