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Evaluation of IL-2, sIL2R, IL-6, TNF-alpha, and IL-1 beta levels in serum and CSF of patients with optic neuritis.

Optic neuritis (ON) is characterized by immune-mediated demyelination of the optic nerve. In this study we addressed the question of cytokine signalling as part of activation of the immune system. 20 patients with first episode of acute idiopathic unilateral ON, prolonged visual evoked potentials, but normal 1.5 tesla MRI of the brain, and normal somatosensory evoked potentials were included into the study. Paired cerebrospinal fluid (CSF) and serum samples of these patients were analyzed for the presence of interleukin (IL-)-2, soluble IL-2R (sIL2R), IL-6, tumor necrosis factor (TNF)-alpha, and IL-1 beta by an enzyme-linked immunosorbent assay (IL-2, sIL2R, TNF-alpha, IL-1 beta) or a bioassay (IL-6). IL-2 was significantly elevated in the CSF (P < 0.01), whereas sIL2R (P < 0.01) and IL-6 (P < 0.01) were significantly increased in serum. TNF-alpha could not be detected in CSF or serum, and IL-1 beta was negative in serum in all but one sample and positive in only low amount (mean 9 pg/ml) in the CSF of 6/20 patients. This cytokine pattern in ON indicates an activation of the immune system within and outside the central nervous system with a predominance of T-cell activation.

Adolescent↗

The SKILL Card test in optic neuritis: experience of the Optic Neuritis Treatment Trial. Smith-Kettlewell Institute Low Luminance. Optic Neuritis Study Group.

OBJECTIVES: To assess the value of the Smith-Kettlewell Institute Low Luminance (SKILL) Card test, designed to measure vision at reduced contrast and luminance, among patients with previous optic neuritis. MATERIALS AND METHODS: The SKILL Card test was administered to 295 patients participating in the Optic Neuritis Treatment Trial (ONTT) follow-up study, concurrent with measurement of visual acuity, visual field, contrast sensitivity, and color vision. Health-related quality of life (HRQL) was also assessed in a subset of patients using the National Eye Institute Visual Function Questionnaire and an ONTT-developed questionnaire. RESULTS: The SKILL Card difference score (high-contrast acuity score minus low-contrast acuity score) was only weakly associated with the other measures of vision function (rs absolute range, 0.05-0.31) and with the HRQL measures (rs absolute range, 0.02-0.15). In contrast, the light and dark component scores of the SKILL Card test had higher associations with the other vision measures (rs absolute range, 0.27-0.54) and with the HRQL measures (rs absolute range, 0.10-0.40). CONCLUSIONS: The SKILL Card difference score is not a meaningful measure for patients with optic neuritis; however, the test appears to have clinical usefulness as a method to measure high-contrast and low-contrast acuity.

Adolescent↗

Corticosteroid therapy for the treatment of optic neuritis.

Optic neuritis is frequently the first clinical sign of multiple sclerosis (MS). Study results indicate that methylprednisolone pulse therapy reduces the rate of development of MS over a two year period. Patients also experience quicker recovery of vision. This short duration therapy presents immediate and intense nursing care challenges. Coordination of care between three departments at the University of Michigan Medical Center enables many patients to complete IV [intravenous] pulse therapy at home. Although coordination is challenging for providers, ambulatory care and home care benefit patients and their families with potential healthcare cost savings.

Anti-Inflammatory Agents↗

A role for calpain in optic neuritis.

Optic neuritis (ON) is one of the most commonly presenting symptoms of multiple sclerosis (MS), which is a neurodegenerative disease of the central nervous system (CNS) thought to be caused by an attack on myelin by autoreactive T cells and other immune cells. Experimental autoimmune encephalomyelitis (EAE) is a widely used model for MS and ON, which are characterized by demyelination, axonal damage, and neuronal death. The mechanisms of neurodegeneration are unclear; however, the calcium (Ca2+)-dependent neutral protease calpain is thought to be involved. The focus of this article is to summarize the evidence suggesting that calpain plays a role in the development of EAE-ON in Lewis rats.

Animals↗

Multicenter clinical trial for evaluating methylprednisolone pulse treatment of idiopathic optic neuritis in Japan. Optic Neuritis Treatment Trial Multicenter Cooperative Research Group (ONMRG).

BACKGROUND: A randomized, controlled clinical trial was conducted in 1991 to compare an intravenous megadose of methylprednisolone with a control drug (mecobalamin) for treating acute idiopathic optic neuritis. CASES: Sixty-six cases from 22 clinical centers throughout Japan were examined to evaluate the treatment on visual function parameters, such as visual acuity, visual field, color vision, contrast sensitivity, and critical flicker frequency. OBSERVATIONS: The methylprednisolone pulse treatment group showed faster recovery of visual function, particularly the visual acuity at 1 week (P<.05), Humphrey field analyzer mean deviation at 3 weeks (P<.05), and color vision at 1 week (P<.05). Recovery of contrast sensitivity at several different spatial frequencies was significant in the pulse treatment group at 1 (P<.01), 2 (P<.05), and 4 weeks (P<.05) after the start of treatment. Visual function test results at 12 weeks and 1 year were essentially the same in the two treatment groups. Side effects appeared more frequently in the pulse treatment group than in the control (P<.05). CONCLUSIONS: Pulse treatment does not appear effective for idiopathic optic neuritis even though visual function in the pulse treatment group of this trial recovered more quickly during the initial phase compared to the controls. More effective and specific treatment should be established for optic neuritis.

Adolescent↗

Quantifying axonal loss after optic neuritis with optical coherence tomography.

OBJECTIVE: To determine to what degree changes in retinal nerve fiber layer (RNFL) thickness after optic neuritis (ON) correlate with either visual recovery or impairment. METHODS: ON can cause visible defects within the RNFL, which can be quantified using optical coherence tomography (OCT). It may be possible to predict visual recovery by measuring RNFL loss after ON. Fifty-four patients underwent repeated evaluations with optical coherence tomography and standardized ophthalmic testing after ON. Regression analyses were used to determine the relationship between RNFL thickness and visual function. RESULTS: Thinning of the RNFL was seen in the majority of patients (74%), and it tended to occur within 3 to 6 months of ON. The average RNFL value was thinner (p<0.0001) in the affected (78 microm) compared with the unaffected eye (100 microm). Patients with incomplete visual recovery demonstrated greater RNFL loss after ON. Regression analyses demonstrated a threshold of RNFL thickness (75 microm), below which RNFL measurements predicted persistent visual dysfunction. INTERPRETATION: Determination of RNFL thickness may predict visual recovery after ON, and lower RNFL values correlate with impaired visual function. Optical coherence tomography may have a potential role as a surrogate marker for axonal integrity within the optic nerve among patients with ON.

Adolescent↗

Visual function more than 10 years after optic neuritis: experience of the optic neuritis treatment trial.

PURPOSE: To assess visual function more than 10 years after an episode of optic neuritis in patients enrolled in the Optic Neuritis Treatment Trial. DESIGN: Longitudinal follow-up of a randomized clinical trial. METHODS: Vision testing included measures of visual acuity, contrast sensitivity, and visual field. Quality of life was assessed with the National Eye Institute Visual Function Questionnaire. RESULTS: Examinations were completed on 319 patients. In most patients, visual function test results in the eyes that experienced optic neuritis at study entry ("affected eyes") were normal or only slightly abnormal after 9.9 to 13.7 years. Visual acuity in the affected eyes was >or=20/20 in 74%, 20/25 to 20/40 in 18%, <20/40 to 20/200 in 5%, and <20/200 in 3%. On average, visual function was worse in patients with multiple sclerosis (MS) than in those without MS. Recurrent optic neuritis in either eye occurred in 35% of patients. Such attacks were more frequent in patients with MS (P <.001). The National Eye Institute Visual Function Questionnaire scores were lower when visual acuity was abnormal and when MS was present. CONCLUSIONS: Most patients retained good to excellent vision more than 10 years after an attack of optic neuritis. Recurrences were more frequent in patients with MS.

Adolescent↗

High- and low-risk profiles for the development of multiple sclerosis within 10 years after optic neuritis: experience of the optic neuritis treatment trial.

OBJECTIVE: To identify factors associated with a high and low risk of developing multiple sclerosis after an initial episode of optic neuritis. METHODS: Three hundred eighty-eight patients who experienced acute optic neuritis between July 1, 1988, and June 30, 1991, were followed up prospectively for the development of multiple sclerosis. Consenting patients were reassessed after 10 to 13 years. RESULTS: The 10-year risk of multiple sclerosis was 38% (95% confidence interval, 33%-43%). Patients (160) who had 1 or more typical lesions on the baseline magnetic resonance imaging (MRI) scan of the brain had a 56% risk; those with no lesions (191) had a 22% risk (P<.001, log rank test). Among the patients who had no lesions on MRI, male gender and optic disc swelling were associated with a lower risk of multiple sclerosis, as was the presence of the following atypical features for optic neuritis: no light perception vision; absence of pain; and ophthalmoscopic findings of severe optic disc edema, peripapillary hemorrhages, or retinal exudates. CONCLUSIONS: The 10-year risk of multiple sclerosis following an initial episode of acute optic neuritis is significantly higher if there is a single brain MRI lesion; higher numbers of lesions do not appreciably increase that risk. However, even when brain lesions are seen on MRI, more than 40% of the patients will not develop clinical multiple sclerosis after 10 years. In the absence of MRI lesions, certain demographic and clinical features seem to predict a very low likelihood of developing multiple sclerosis. This natural history information is a critical input for estimating a patient's 10-year multiple sclerosis risk and for weighing the benefit of initiating prophylactic treatment at the time of optic neuritis or other initial demyelinating events in the central nervous system.

Acute Disease↗

Fellow eye abnormalities in acute unilateral optic neuritis. Experience of the optic neuritis treatment trial.

BACKGROUND: Visual function in the fellow eye at the onset of unilateral optic neuritis has not been systematically evaluated. The authors prospectively determined the prevalence of abnormalities in the fellow eyes of the 448 eligible patients entered into the Optic Neuritis Treatment Trial. METHODS: All patients underwent testing of visual acuity, contrast sensitivity, color vision, and visual field, as well as magnetic resonance imaging (MRI) of the brain and a neurologic examination. RESULTS: Abnormalities in the fellow eye were found on measurement of visual acuity in 13.8%, contrast sensitivity in 15.4%, color vision in 21.7%, and visual field in 48.0% of patients. The majority of the fellow eye deficits resolved over several months. A higher prevalence of MRI changes consistent with demyelination of the brain was found in patients with a past history of optic neuritis in the fellow eye compared with patients without such a history (P = 0.004). Patients with abnormal fellow eyes but no history of previous optic neuritis were no more likely to have clinical (P = 0.658) or MRI evidence (P = 0.166) of multiple sclerosis than patients with normal fellow eyes. CONCLUSIONS: The improvement of many of the visual deficits indicates that visual abnormalities detected in the fellow eye at the onset of symptomatically unilateral optic neuritis may not represent preexisting optic nerve demyelination. Whether the presence of these deficits is predictive of the development of clinical multiple sclerosis cannot be determined at this time.

Acute Disease↗

Brain magnetic resonance imaging in acute optic neuritis. Experience of the Optic Neuritis Study Group.

OBJECTIVE: Changes in the brain on magnetic resonance images are common in patients with optic neuritis even when there is no other clinical evidence of multiple sclerosis. The current study was designed to determine systematically the prevalence of brain abnormalities on magnetic resonance images in the patients entered into the Optic Neuritis Treatment Trial. DESIGN: Prospective multicenter clinical trial. SETTING: Referral centers. PATIENTS AND METHODS: Brain magnetic resonance images from 418 patients with acute optic neuritis (77% women; mean age, 32.0 years) were evaluated at a central reading center with the use of a standardized classification system (ranging from 0 for normal to IV for most extensive changes). RESULTS: Of the scans, 40.9% were classified as grade 0, 10.8% as grade I, 9.1% as grade II, 6.7% as grade III, and 32.5% as grade IV. For patients with isolated (monosymptomatic) optic neuritis, 26.7% had two or more lesions. CONCLUSIONS: We found a lower prevalence of brain magnetic resonance imaging abnormalities in isolated optic neuritis than previous studies have reported. This likely is due to our study having a higher degree of standardization of patient inclusion criteria, which limited patient selection bias.

Acute Disease↗

The 5-year risk of MS after optic neuritis. Experience of the optic neuritis treatment trial.

The objective of our study was to assess the 5-year risk of and prognostic factors for the development of clinically definite multiple sclerosis (CDMS) following optic neuritis. In a prospective cohort study design, 388 patients, who did not have probable or definite MS at study entry enrolled in the Optic Neuritis Treatment Trial between 1988 and 1991, and were followed for the development of CDMS. The 5-year cumulative probability of CDMS was 30% and did not differ by treatment group. Neurologic impairment in the patients who developed CDMS was generally mild. Brain MRI performed at study entry was a strong predictor of CDMS, with the 5-year risk of CDMS ranging from 16% in the 202 patients with no MRI lesions to 51% in the 89 patients with three or more MRI lesions. Independent of brain MRI, the presence of prior nonspecific neurologic symptoms was also predictive of the development of CDMS. Lack of pain, the presence of optic disk swelling, and mild visual acuity loss were features of the optic neuritis associated with a low risk of CDMS among the 189 patients who had no brain MRI lesions and no history of neurologic symptoms or optic neuritis in the fellow eye. The 5-year risk of CDMS following optic neuritis is highly dependent on the number of lesions present on brain MRI. However, even a normal brain MRI does not preclude the development of CDMS. In these patients with no brain MRI lesions, certain clinical features identify a subgroup with a particularly low 5-year risk of CDMS.

Adult↗

Cerebrospinal fluid in acute optic neuritis: experience of the optic neuritis treatment trial.

The Optic Neuritis Treatment Trial (ONTT) is a prospective study of corticosteroid treatment of acute optic neuritis (ON), with subsequent longitudinal follow-up to determine development of clinically definite multiple sclerosis (CDMS). We analyzed the CSF of 83 patients with clinically isolated ON who underwent lumbar puncture within 24 hours of enrollment into the ONTT to determine the value of CSF changes in ON, especially regarding diagnostic utility, immunologic changes, MRI correlations, and progression to CDMS. All patients had baseline MRI scans graded for changes typical of MS. CSF measurements included immunoglobulin G (IgG) synthesis, IgG ratio, myelin basic protein, IgG kappa light chains, and oligoclonal banding. No patients had their diagnosis or management altered as a result of CSF findings. Except for oligoclonal bands, few patients showed any abnormalities on CSF tests, and no tests correlated with the 2-year development of CDMS. Oligoclonal banding, present at baseline in 11 of 13 patients who developed CDMS, did predict progression to CDMS, but this was not independent of MRI abnormalities. Two patients with oligoclonal bands and a normal MRI did progress to CDMS. We conclude that CSF analysis may not be necessary in the routine evaluation of patients presenting with a typical clinical profile of acute ON, and that most CSF tests add little additional information to MRI results for predicting the 2-year development of CDMS. However, the precise role of oligoclonal banding in the analysis of such patients awaits longer follow-up of this cohort.

Administration, Oral↗

Visual symptoms after optic neuritis. Results from the Optic Neuritis Treatment Trial.

As part of the Optic Neuritis Treatment Trial, vision-specific quality-of-life data were collected on the patients at their 6-month visits. The purpose of this study was to determine the types of visual tasks in day-to-day living in which patients have difficulty and to compare the patients' subjective assessment of visual impairment with measurements of visual acuity, contrast sensitivity, mean deviation, and color vision. The questionnaire was completed by 382 (87%) of the 438 patients who had 6-month study visits. Associations between ophthalmic test scores and self-reported vision were examined using both a summary problem index and selected individual items. Although a substantial percentage of the patients (63%) indicated that vision had not recovered to normal in the affected eye, the reported visual deficits generally were mild. For most of the visual tasks of daily living, patients reported little or no problem. Among the 215 patients who perceived their vision at 6 months to be somewhat or much worse than it was before optic neuritis, 20% had normal results on none of the four visual function tests, 14% had normal results on one of the four tests, 23% had two of four, 23% had three of four, and 20% had normal results on all four. Reported visual symptoms 6 months after optic neuritis generally were mild. When patients were symptomatic, the four visual function tests often did not detect abnormality. This finding supports previous reports that visual deficits are frequently perceived even when vision testing is normal.

Adult↗

The course of visual recovery after optic neuritis. Experience of the Optic Neuritis Treatment Trial.

PURPOSE: To define the time course of visual recovery after optic neuritis and factors predictive of this course in the patients enrolled in the Optic Neuritis Treatment Trial. METHODS: The cohort for this study consisted of the 438 patients who completed the 6-month follow-up visit. Visual acuity was measured at baseline and at seven follow-up visits during the first 6 months. Factors predictive of recovery were evaluated with univariate and multivariate statistical tests. RESULTS: Visual recovery was rapid in all three treatment groups. In almost all patients, regardless of treatment group and initial severity of visual loss, improvement began within the first month. Among the 278 patients with baseline visual acuity of 20/50 or worse, all patients improved at least one line of visual acuity, and all except six improved at least three lines, during the 6-month follow-up period. Baseline visual acuity was the best predictor of the 6-month visual acuity outcome (P = 0.0001). Older age was statistically associated with a slightly worse outcome (P = 0.02), but this appeared to be of no clinical importance. CONCLUSIONS: In most patients with optic neuritis, visual recovery is rapid. The only factor of value in predicting the visual outcome is initial severity of visual loss. However, even when initial loss is severe, visual recovery is still good in most patients. Patients not following the usual course of visual recovery should be considered atypical. For such patients, further investigation in regard to etiology of the visual loss may be appropriate.

Acute Disease↗

Interaction between HLA-DR2 and abnormal brain MRI in optic neuritis and early MS. Optic Neuritis Study Group.

The association of the human leukocyte antigen (HLA)-DR2 allele with brain MRI signal abnormalities and with the development of MS was assessed in 178 patients enrolled in the Optic Neuritis Treatment Trial. HLA haplotype DR2 was present in 85 (48%) of the 178 patients. Its presence was associated with increased odds of probable or definite MS at 5 years (odds ratio, 1.92; 95% confidence interval, 1.01 to 3.67; p = 0.04). The association was most apparent among patients with signal abnormalities on baseline brain MRI.

Administration, Oral↗