Optic neuritis: findings on MRI,CSF examination and HLA class II typing in 60 patients and results of a short-term follow-up

Optic neuritis (ON) is a common first manifestation of multiple sclerosis (MS), and examination of patients with ON provides opportunities to study the early clinical stages of MS. This prospective study compares results of brain magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) examinations and HLA-Dw2 phenotyping in 60 consecutive patients with ON. At a median of 17 days after the onset of ON, 69% had oligoclonal IgG bands, and at a median on 79 days after onset, 53% had multiple ( 3) white matter lesions on MRI. Subgroup analyses revealed that MRI abnormalities and oligoclonal IgG bands were equally common in patients examined early or late after the onset of ON. Strong correlations were found between the presence of MRI abnormalities and oligoclonal IgG bands. The HLA-Dw2 phenotype was significantly increased in ON patients compared with controls, but also significantly different from a group of MS patients from the same geographical area. A significant relation was found between Dw2 phenotype and oligoclonal IgG bands. During a mean follow-up time of about 2 years, the diagnosis in 17 of the patients changed to clinically definite MS. Initially, 16 of them had oligoclonal IgG bands and 12 had three or more MRI lesions. Both MRI and CSF studies are important diagnostic tools in the work-up of ON patients.     

The clinical and paraclinical profile of optic neuritis: A prospective study

To define the clinical and paraclinical profile of optic neuritis (ON), patients with a suspicion of ON among a population of 1.5 million were examined over 2.5 years. A diagnosis of monosymptomatic ON was established in 74 patients. Cerebrospinal fluid (CSF) studies in 73 patients revealed oligoclonal IgG bands in 67% and 32 of 60 patients examined (53%) had three or more high signal lesions on magnetic resonance imaging (MRI). A strong correlation was found between oligoclonal bands and abnormal MRI. In 52 patients, two or more CSF examinations revealed strong variations in individual patients for mononuclear cell count and IgG index. In contrast, of 39 patients with oligoclonal bands in the first sample, none showed the disappearance of bands, and of 13 patients initially negative for bands, only one developed bands. There was no correlation between exacerbation or remission and CSF findings. During a short-term follow-up of 6–40 months, 19 patients converted to MS.This study was supported by grants from the Swedish Multiple Sclerosis Society (NHR) and Carmen and Bertil Regnér's fund.     

Monosymptomatic sensory symptoms and cerebrospinal fluid immunoglobulin levels in relation to multiple sclerosis

Of 53 patients with monosymptomatic paresthesiae, 55% had oligoclonal bands and 28% an elevated cerebrospinal fluid (CSF) IgG index. Over a mean observation period of 64 months, nine patients developed clinically definite multiple sclerosis (MS); all of these patients had IgG bands, illustrating the prognostic importance of this CSF aberration. Two lumbar punctures more than one year apart were performed in 31 of the patients, of whom 20 had oligoclonal bands. This abnormality was constant between the time of punctures in all subjects except one, thus behaving as in MS. Similarly, the CSF findings in the 11 patients without oligoclonal bands remained normal over the observation period. The majority of patients with oligoclonal bands had cells in their CSF producing immunoglobulin of one or more of the three main classes, while none of those without oligoclonal bands displayed immunoglobulin-producing cells in CSF. Occurrence of oligoclonal bands in CSF is common in patients with paresthesiae and increases the risk for future development of MS.     

Relation between Genetic markers and oligoclonal IgG in CSF in optic neuritis.

Thirty patients with acute, unilateral optic neuritis (ON), where re-examination after a mean observation period of 5 years did not reveal any aetiology, were investigated with regard to laboratory abnormalities frequently observed in multiple sclerosis. Eleven patients had oligoclonal IgG in CSF. In 5 of these a measles virus antibody response within the CNS was demonstrable. The remaining 19 patients did not display oligoclonal CSF IgG, nor an antibody response. The major histocompatibility antigens HL-A3 and HL-A7 occurred at similar frequencies in ON and in controls, irrespective of the presence of oligoclonal CSF IgG. The HL-A7 associated MLC determinant LD-7a occurred in ON at a frequency between that observed in controls and in MS. However, an association of the same magnitude as observed in MS was found between ON with oligoclonal CSF IgG and the presence of LD-7a. This association was absent in those ON patients who lacked oligoclonal CSF IgG. The present data indicate that the finding of oligoclonal CSF IgG may increase the risk of developing MS.     

The intrathecal immune response in the early stage of multiple sclerosis

Sequential pairs of cerebrospinal fluid (CSF) and serum samples from 10 patients followed for 2.5-12 years after onset of unilateral optic neuritis (ON) were studied. Eight patients developed definite multiple sclerosis (MS) during the observation period. All patients had normal CSF protein patterns on agar or agarose gel electrophoresis at onset. Six patients developed oligoclonal immunoglobulin (Ig) bands in the CSF during the observation period. Imprint immunofixation of electrofocused specimens disclosed intrathecal synthesis of oligoclonal IgG antibodies to 1 or more of 6 viruses (measles, herpes simplex type 1, varicella-zoster, cytomegalo, mumps, rota) during the observation period in 8 patients. Changes in patterns of intrathecally synthesized viral antibodies, characterized by the appearance of "new" antibody populations and the waxing or waning of others were observed in 6 patients. The results suggest that the early stage of MS in some patients is associated with transient as well as permanent recruitment of B cell clones producing viral antibodies of different specificities.     

Myelinotoxic activity on tadpole optic nerve of cerebrospinal fluid from patients with optic neuritis

The myelinotoxic activity of unconcentrated cerebrospinal fluid (CSF) from eight optic neuritis (ON) and five multiple sclerosis (MS) patients with oligoclonal IgG, and from five ON patients without oligoclonal IgG, was tested in the tadpole optic nerve system. CSF from ON or MS patients with oligoclonal CSF IgG gave a significantly greater number of myelinotoxic lesions than did CSF from ON patients without oligoclonal CSF IgG, CSF from control patients, or physiologic saline. Induction of myelinotoxic lesions may be coupled with the presence of oligoclonal IgG. The findings support the hypothesis that there are two different forms of ON, of which one, characterized by oligoclonal IgG in the CSF, is more closely related to MS.     

Optic neuritis and distribution of genetic markers of the HLA system

Thirty patients with optic neuritis (ON), in which neither multiple sclerosis (MS) nor any other etiology could be discriminated, were reexamined after a mean observeation period of 5 years. Eleven patients revealed oligoclonal IgG in the CSF and in five of them a measles virus antibody response within the CNS was demonstrable. the remaining 19 patients did not display oligoclonal CSF IgG and no local antibody production was detectable.
The occurrence of the HLA antigens A3 and B7 in ON did not correlate to the presence of oligoclonal IgG in CSF. the frequencies did not differ from those found in controls. the HLA-B7 linked lymphocyte defined antigen HLA-Dw2 occurred in ON at increased frequency, which was intermediate to that observed in MS and controls. an association was found in ON between oligoclonal IgG in CSF and Dw2. This association was of the same magnitude as in 22 MS patients who had ON as their first symptom of MS. In ON without oligoclonal CSF IgG the frequency of Dw2 was similar to that of controls.
No association was observed between the occurrence of the HLA antigens A3, B7 and Dw2, and increased measles antibody titers in serum or a measles virus antibody response in the CNS.
The occurrence of oligoclonal IgG in CSF in patients with ON may be assumed to increase the risk of developing MS.     

Identification of light chain type bands in CSF and serum oligoclonal IgG from patients with multiple sclerosis

The light (L) chain types (kappa and lambda) of oligoclonal IgG bands of matching CSF and serum from 10 MS patients were identified in immunofixation after isoelectric focusing in polyacrylamide gel. Each specimen showed 10-15 oligoclonal bands in pH region of 7.5-9.3. In 7 MS CSF and 5 sera a greater number of oligoclonal IgG bands were of kappa (kappa)-type whereas in 3 CSF and 2 sera the majority was of lambda (lambda)-type. In 3 sera a clearcut correlation of bands with either type of L chain was not observed due to diffuse staining background. Only a small number of oligoclonal IgG bands in 7 of 10 CSF and serum pairs had identical isoelectric points and the same type of L chain. The results show that the individual MS patient had oligoclonal IgG bands in serum, differ with respect to number, isoelectric point and L chain type from the oligoclonal IgG profile seen in the patient's CSF.     

Detection of oligoclonal free kappa chains in the absence of oligoclonal IgG in the CSF of patients with suspected multiple sclerosis

BACKGROUND: Oligoclonal free kappa bands are present as frequently as oligoclonal IgG bands in the cerebrospinal fluid (CSF) from patients with definite multiple sclerosis (MS) and can even occur in the absence of oligoclonal IgG. As such, they too are markers of an ongoing intrathecal immune process. OBJECTIVES: To determine how frequently oligoclonal free kappa bands are detectable in the CSF from patients with clinical signs and symptoms suggestive of MS in the absence of CSF restricted oligoclonal IgG. METHODS: An immunoaffinity mediated immunoblotting technique specific for free kappa chains was used, after isoelectric focusing of paired CSF and serum samples from 33 patients with clinical signs and symptoms suggestive of MS but without CSF oligoclonal IgG. CSF data were correlated with MRI results in the context of the new diagnostic criteria from McDonald et al. RESULTS: Eighteen CSF samples contained oligoclonal free kappa bands (54%), mainly from patients with motor dysfunction (83%) and optic neuritis (64%). All patients with a positive MRI according to Barkhof's criteria (n = 6) had free kappa bands in their CSF. CONCLUSIONS: (1) Oligoclonal free kappa bands in the CSF are related to the dissemination of MS lesions; (2) such bands should be looked for in oligoclonal IgG negative CSF, and (3) the presence of free kappa bands in the CSF may be a substitute for oligoclonal IgG in the McDonald's criteria for diagnosis of MS.     

The occurrence of oligoclonal IgG in tears from patients with MS and systemic immune disorders

Using isoelectric focusing (IEF) and immunoperoxidase staining of proteins transferred to nitrocellulose membranes, we have examined the IgG band pattern in tears and matched serum and CSF specimens of 28 patients with MS, 4 patients with optic neuritis (ON), 30 individuals with systemic, inflammatory, or other neurologic diseases, and 5 patients with tension headache. We found no evidence of positive oligoclonal IgG in tears in any MS or ON patients, while 10 out of 16 cases with systemic immune disorders or infections of the CNS had positive tear oligoclonal bands. We are thus not able to support the hypothesis that tears from MS patients reveal abnormalities in their humoral immune response.     

Paraclinical tests in acute-onset optic neuritis: basal data and results of a short follow-up

Up to now it is still doubtful whether there is a real risk of developing multiple sclerosis (MS) after initial monosymptomatic optic neuritis (ON). In this study we evaluated 43 patients with isolated acute-onset ON, in order to demonstrate the presence of oligoclonal bands (OBs) in the cerebrospinal fluid (CSF) and any additional clinically silent central nervous system (CNS) lesions. All examinations were performed from 5 days to 4 months (mean 43 days), from the onset of visual disturbances. Brain magnetic resonance imaging (MRI) detected white matter areas with increased signal in 21 patients (49%), while somatosensory and brainstem auditory evoked potentials revealed CNS abnormalities in only 5 patients (12%). OBs were present in the CSF of 20 patients (46%). Visual evoked potentials were abnormal in 39 patients (91%). Seven out of the 37 patients (19%) with at least one year follow-up, (mean duration of the follow-up = 32 months, range = 12-74), developed clinically definite MS (CDMS). All 7 patients had positive brain MRI and 6 had positive CSF examination at the basal evaluation. Our data suggest that MRI and CSF-OBs are the most reliable means of identifying patients with isolated ON who subsequently develop CDMS. They may therefore have a predictive value in defining MS risk.     

Magnetic resonance imaging, evoked responses and cerebrospinal fluid findings in a follow-up study of children with optic neuritis

Fourteen patients with previous optic neuritis (ON) in childhood were examined by magnetic resonance (MR) imaging from two months to 14 years after the onset of symptoms. Five patients had a single monosymptomatic course of ON but 7 developed multiple sclerosis (MS); 2 had another demyelinating disease. Eight patients had high signal intensity areas in the T2 weighted images compatible with MS plaques in MR scan; 2 with monosymptomatic ON, 5 with MS and one with another demyelinating disease. The plaques were periventricular or in the optic radiation. The plaques could already be seen during the first symptoms of ON. All 7 MS patients had abnormal visual evoked response, 3/4 abnormal somatosensory evoked response and 5/6 intrathecal immunoglobulin production, when examined at onset of optic neuritis or at follow-up. All patients except one, with lesions in MR, had either oligoclonal CSF antibodies or Dr2 HLA antigen. We suggest that MR is a very sensitive test showing MR abnormalities in children with ON. It is an important tool in the early assessment of MS.     

Relation between benign course of multiple sclerosis and low-grade humoral immune response in cerebrospinal fluid.

The prognosis in multiple sclerosis (MS) is related to the presence of an abnorma humoral immune response within the central nervous system: 14/17 MS patients (82%) without oligoclonal CSF IgG displayed no or slight disability after a mean duration of MS of 17 years, while 53% of 88 patients with oligoclonal CSF IgG had a benign course after a mean duration of 13 years (p less than 0.05). A benign course also was more often accompanied by a normal CSF IgG index. MS patients without oligoclonal CSF IgG had elevated CSF/serum ratios of albumin in 6%, and of the complement factors C3 in 0% and C4 in 6%, as against 20%, 27% and 37%, respectively, in MS patients with oligoclonal CSF IgG.     

Cerebrospinal fluid levels of brain specific proteins in optic neuritis

This study evaluates levels of cerebrospinal fluid (CSF) brain-specific proteins (BSP) in subjects with optic neuritis (ON) who are at high risk of progression to multiple sclerosis (MS). Forty-one subjects had acute ON and 17 subjects with other neurological diseases (OND) served as controls. Twenty-one subjects with ON had white matter lesions on magnetic resonance imaging (MRI) and intrathecal synthesis of oligoclonal IgG bands (OB) consistent with being at high risk of progression to MS; eight of whom later were diagnosed with clinically definite MS (CDMS). Levels of S100B, ferritin and two neurofilament heavy chain phosphoforms (NfH(SM134) and NfH(SM135)) were analysed using ELISA technique. A putative index of 'axonal health' was expressed as a ratio of NfH(SM134) to NfH(S135). NfH(SM134) and the NfH(SM134:SM135) were significantly elevated in subjects with ON compared to controls. No significant differences in levels of CSF BSP were seen between ON subjects with CDMS plus those at high risk of progression to MS and ON subjects with normal MRI and negative CSF analysis. In conclusion, there is evidence of axonal damage in subjects who present with ON, which is independent of the diagnosis of CDMS.     

Acute transverse myelitis with normal brain MRI

Objective To investigate the long-term risk of developing MS in patients presenting with acute transverse myelitis (ATM) and normal brain MRI scans at onset. Methods We studied 58 ATM patients with normal brain MRI at presentation for up to 5 years with serial neurologic and imaging studies. All patients underwent CSF analysis at onset which was defined positive if two or more IgG oligoclonal bands and/or elevated IgG index were present. Brain and spinal cord MRI scans were obtained every 6 months for the first 2 years, and annually thereafter unless the patient experienced a second neurologic attack different from the initial episode to confirm CDMS or there was demonstration of MRI lesions confirming dissemination in time and space to fulfill McDonald imaging criteria to diagnose MS. Results Seventeen of 58 (29%) patients developed MS of which 7 (41%) patients developed CDMS and 10 (59%) developed MS using McDonald Imaging Criteria. Mean time to CDMS by a second clinical attack was 11. 1 months compared to 19. 2 months by MRI lesions (P = 0. 03). None of the patients developed MS after 24 months of onset. All 17 patients who developed MS had positive CSF although 15 patients who had positive CSF did not develop MS during the 5 years of follow-up. Conclusions The majority of patients with ATM and normal brain MRI do not develop MS after 5 years of follow-up confirming the relatively low risk compared to patients with abnormal brain MRI scans. CSF is helpful in distinguishing patients more likely to develop MS. Compared to clinical attacks, serial imaging may not lead to an earlier diagnosis in ATM patients with normal brain MRI.     

Prognosis of optic neuritis with special reference to cerebrospinal fluid immunoglobuhs and measles virus antibodes

Forty-eight patients with optic neuritis (ON), first seen in 1970 to 1973, were neurologically and neuroophthal mologically reexamined after 7 to 10 years. Twenty-seven patients (56%) had probable MS, and 9 (19%) had possible MS. During the attack of ON, the cerebrospinal fluid (CSF) samples and serum/CSF measles antibody ratios were studied. Twenty patients had increased relative immunoglobulin G (IgG % of total protein) in their CSF; 19 of these had probable or possible MS. However, 17 of 28 patients with a normal relative IgG value had also developed MS. CSF electrophoresis was abnormal in 20 patients with ON; reexamination showed that 19 had probable or possible MS. Sixteen of 27 patients with normal electrophoresis had also developed MS. Serum/CSF measles antibody ratio had decreased in 19 patients; 13 of these had probable MS and 3 had possible MS. Of 29 patients with a normal measles antibody ratio, 14 had probable MS and 6 had possible MS. The conclusion is that examination of the CSF in ON gives valuable prognostic information because increased relative IgG, abnormal electrophoresis, or a decreased measles antibody ratio implies a high risk of developing MS. A normal CSF does not, however, rule out the possibility of dissemination.     

Predicting the Outcome of Optic Neuritis

Background Multiple sclerosis (MS) is a common disease with considerable risk for disability. Optic neuritis (ON) is a common first symptom of MS but it can also remain an isolated episode. Therefore, predicting the outcome of ON has gained in importance, particularly in light of current discussions of early disease modifying treatments in individuals at risk of developing MS. We reported previously on our cohort of 86 patients with acute monosymptomatic unilateral ON of whom 33 had progressed to MS after up to 18 years. Three patients had died. The present study extends the observation period to 31 years. Methods Patients were followed for up to 31 years or until a diagnosis of MS was made. Cerebrospinal fluid (CSF) was examined at onset. HLA class I and II antigens were determined. Magnetic Resonance Imaging (MRI) was performed during follow up. Findings Only one of 50 patients at risk developed clinical manifestations of MS during the extended follow up period. The estimated 15–year–risk of MS was 40 % (confidence interval [CI] 31%–52%). Most cases, 20 of 34 or 60%, occurred within three years. Among factors present at onset, CSF with mononuclear pleocytosis and/or oligoclonal Ig increased the risk for subsequent MS significantly, 49% (CI 38%–65%) compared with 23 % (CI 12%–44%) for those with normal CSF, p = 0·02. Younger patients and those with winter onset also had greater risk. Recurrence of ON similarly elevated the risk significantly, p < 0·001. After 19–31 years MRI lesions suggestive of demyelinating disease were detected in 20 of 30 individuals although no clinical manifestations of MS had occurred. Conclusion The risk of MS in this large population–based prospective ON patient series was 40% and significantly higher in those with inflammatory CSF abnormalities at onset. Clinically silent MRI lesions suggestive of MS were detected in a majority of those with ON-only. This finding should be taken into account when discussing prognosis and early intervention in patients with clinically isolated ON.     

Identification of IgG subclasses'' oligoclonal bands in multiple sclerosis CSF

IgG subclasses' oligoclonal bands in unconcentrated CSF from MS patients were detected by isoelectric focusing in agarose gel with subsequent immunoblotting using mouse monoclonal antibodies to human IgG subclasses and double-antibody avidin-biotin-alkaline phosphatase system. All MS CSF showed presence of oligoclonal bands specific to the IgG1 subclass; in addition, several of these samples also had oligoclonal bands specific to IgG3, IgG2, or IgG4, in order of decreasing frequency. Since the CSF of a greater number of MS patients showed oligoclonal bands specific to the IgG1 and IgG3 subclasses, the findings are consistent with those reported in patients with chronic viral infections and autoimmune diseases.     

Oligoclonal IgA bands in multiple sclerosis and subacute sclerosing panencephalitis

CSF oligoclonal IgG bands are often found in MS or cerebral diseases in which there is chronic antigenic stimulation. Using agarose isoelectric focusing followed by immunoblotting, we found oligoclonal IgA bands in CSF from 16 of 20 randomly selected patients with MS, 7 of 7 with subacute sclerosing panencephalitis (SSPE), and 0 of 10 with noninflammatory neurologic or psychiatric disease. IgA bands did not correlate with the course or stage of MS. Serial samples from two patients with MS and one with SSPE demonstrated only minor changes in IgA banding pattern. One MS patient without oligoclonal IgG bands had oligoclonal IgA bands, indicating that the latter test may be helpful in the diagnosis of MS.     

Immunoglobulin class and light chain type of oligoclonal bands in CSF in multiple sclerosis determined by agarose gel electrophoresis and immunofixation.

Agarose gel electrophoresis and immunofixation of CSF and serum from 39 patients with multiple sclerosis (MS) revealed oligoclonal IgG in the CSF in all cases and oligoclonal IgA and IgM in 1 patient each. IgG kappa bands only were found in 10 patients, while no patient had IgG lambda bands alone. IgG kappa bands predominated in 20 patients and IgG lambda bands in 5, while 4 patients had the same number of IgG kappa and IgG lambda bands. Twenty-seven patients also displayed IgG bands with kappa and lambda present simultaneously. Bands of free lambda chains were found in 7 patients, while free kappa chain bands were not seen. One or 2 faint IgG bands in 4 patients constituted the only serum abnormality. In 4 additional MS patients selected on the basis of normal findings on agarose gel electrophoresis of the CSF, immunofixation did not reveal oligoclonal Ig, while isoelectric focusing showed bands in 1. Immunofixation is recommended for proving the presence of oligoclonal Ig in CSF and for characterizing oligoclonal Ig into classes and types of light chains.