HHV‐6 infection in multiple sclerosis. A clinical and laboratory analysis

Background and purpose: To elucidate the role of human herpesvirus‐6 (HHV‐6) in the development of multiple sclerosis (MS). Patients and methods: Nine patients with MS and with acute or chronic HHV‐6 infection were evaluated. Results: Intrathecal antibody production to HHV‐6 and oligoclonal IgG bands in the cerebrospinal fluid (CSF) was observed in two patients with a clinically definite MS and chronic HHV‐6 infection (based on the presence of HHV‐6 specific antibodies in the CSF). A temporal association between the symptoms of clinically possible MS and acute primary HHV‐6A infection (based on avidity of HHV‐6 specific antibodies) was observed in two patients. Conclusions: Human herpesvirus‐6 infection may be an associated agent in some MS cases. Viral studies are needed to identify a possible viral etiology and give specific therapy.     

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.     

Intrathecal IgG synthesis and autoantibody-secreting cells in multiple sclerosis

We studied intrathecal IgG synthesis and autoantibody-secreting cells in 148 patients with possible onset symptoms of MS (POSMS) or clinically definite MS (CDMS). In POSMS intrathecal synthesis of IgG oligoclonal bands and abnormalities on T2-weighted magnetic resonance imaging were associated but the former were more prevalent. The cerebrospinal fluid (CSF) leukocyte count and the number of anti-protelipid protein antibody-secreting cells in cerebrospinal fluid (CSF) correlated with disease activity in POSMS. Intrathecal IgG synthesis levels and the number of anti-myelin basic protein antibody-secreting cells in CSF correlated with disease activity in CDMS. Our results support recent reports of pathogenetic heterogeneity and a pathogenetic role of the antibody response in MS.     

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.     

Virus antibodies in the cerebrospinal fluid of multiple sclerosis patients detected with ELISA tests

The enzyme-linked immunosorbent assay (ELISA) was used to determine levels of specific IgG antibodies against measles, rubella, vaccinia, corona (OC43) and mumps viruses in cerebrospinal fluid (CSF) and serum of 18 patients with clinically definite multiple sclerosis (MS), 8 patients with optic neuritis (ON), 27 patients with other neurological disease (OND), and 88 control subjects without central nervous system disease. Serum antibody levels were not significantly different between the four groups. Differences in the frequency and levels of CSF antibodies between the four groups were observed. Control patients had serum/CSF antibody ratios from 2.0 to 3.0 (log) with an average of 2.5 corresponding to a 320-fold difference between serum and CSF antibody levels. MS patients had ratios from 1.1 to 2.1 with an average of 1.6. The average was 2.0 for the ON patients. The average for the OND patients was similar to the controls. The altered serum/CSF ratios for several viruses within an individual patient was similar. These results suggest that nonspecific immunostimulation is responsible for the increased levels of CSF virus antibodies.     

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.     

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.     

The cerebrospinal fluid in multiple sclerosis. Quantitative assessment of intrathecal immunoglobulin synthesis by empirical formulae

Intrathecal synthesis of IgG occurs in more than 90% of patients with clinically definite multiple sclerosis. The prevalence and significance of intrathecal synthesis of IgA and IgM are, however, less thoroughly characterized. We estimated intrathecal synthesis of IgG, IgA and IgM with various empirical formulae. The concentrations of albumin, IgG, IgA and IgM and the presence of IgG oligoclonal bands were determined in CSF and serum from 350 patients, including 97 with clinically definite multiple sclerosis. Intrathecal synthesis of IgG oligoclonal bands was detected in 95% of patients with multiple sclerosis (95% confidence interval 88–98%). The IgG-index, an extended IgG-index, and a hyperbolic IgG formula performed approximately equally in identifying patients with MS, but they were all inferior to the detection of IgG oligoclonal bands. In quantitative measurements, the extended immunoglobulin indices appeared to perform well; studies comparing the extended IgA- and IgM-indices to qualitative analyses (electrophoresis or isoelectric focusing) are, however, needed to confirm this. Detection of intrathecal synthesis of IgA of IgM was of little value in the diagnosis of multiple sclerosis.     

Mumps meningitis: Specific and non-specific antibody responses in the central nervous system *

Intrathecal production of oligoclonal mumps-specific IgG was demonstrated in nine out of 10 children with mumps meningitis by imprint immunofixation (IIF) of sera and cerebrospinal fluids (CSF) separated by agarose electropheresis and by thin-layer electrofocusing. Four of the patients had intrathecal mumps antibody synthesis demonstrable also by conventional serological tests. Oligoclonal CSF IgG was demonstrable by agarose electrophoresis in four of the patients. A dominance of λ over κ type oligoclonal Ig and mumps antibodies was observed in the CSF of three of these patients. The bulk of the oligoclonal CSF IgG was concluded to represent mumps-specific antibodies on the basis of the IIF as well as virus absorption analysis. Intrathecal production of oligoclonal IgG antibodies to one, two, or three other (measles, rubella, herpes simplex) viruses was demonstrated by IIF in four patients. These antibodies were not associated with the oligoclonal CSF IgG present in three of the patients. It is concluded that a specific intrathecal IgG antibody response is a common feature in children with mumps meningitis. This response sometimes reaches a magnitude that permits detection of oligoclonal IgG in the CSF. In some patients, the specific response appears to be associated with a non-specific activation of cells producing antibodies of other (unrelated) specificity.     

Secondary lymphoid organ chemokines are elevated in the cerebrospinal fluid during central nervous system inflammation

Secondary lymphoid organ chemokines have been implicated in chronic inflammation. Their expression in the central nervous system (CNS) has not been studied. Here, levels of secondary lymphoid organ chemokines CCL19 (Exodus-3, MIP-3beta), CCL21 (Exodus-2, 6Ckine, SLC) and CXCL12 (SDF-1alpha) were analysed by ELISA in cerebrospinal fluid (CSF) and plasma from patients with multiple sclerosis (MS); acute optic neuritis (ON) with oligoclonal IgG in the CSF (i.e., first bout of MS); acute ON without oligoclonal IgG (non-MS-type ON); other inflammatory neurological diseases (OIND); and non-inflammatory neurological diseases (NIND). NIND CSF contained CCL19 and CXCL12, while CCL21 was not detected. Intrathecal production of CCL19 and CCL21 was elevated in MS, MS-type ON, and OIND, but not in non-MS-type ON. In MS, CSF levels of CCL19 weakly correlated with CSF cell counts. Intrathecal production of CXCL12 was elevated only in OIND. The role of elevated CCL19 and CCL21 in MS could be retention of mature dendritic cells (DC) in the CNS, recruitment of nai;ve T cells and activated B cells, as well as de novo formation of secondary lymphoid structures in MS plaques.     

Common infectious agents in multiple sclerosis: a case-control study in children

Environmental factors, in particular infections, have been linked with the risk of developing multiple sclerosis (MS). The association of Epstein-Barr virus infection with childhood onset of MS has been recently recognized. As other infections characteristically experienced during childhood have not yet been studied in larger cohorts of paediatric MS, we conducted a study on 152 German children with MS (age at onset <16 years) and matched controls in the hope of gaining evidence for their possible aetiological role in MS. Patterns of antibody responses were determined to a range of infections which, in prior studies principally on adult patients, had revealed possible associations with MS. In this study on children the serology of several infections showed associations with MS. In the exceptional case of Chlamydia pneumoniae there was a significantly higher prevalence of IgM antibody but, more typically, as in the case of influenza A, measles, parainfluenza 2, varicella/zoster viruses and particularly to the herpes simplex virus type 2 (HSV-2) lysate antigen, there were significantly higher concentrations of IgG antibody. Additional investigations, however, make it highly unlikely that a relevant number of children have experienced infections with HSV-2. In general this study supports and emphasizes a complex infectious and immunologic background of MS.     

Childhood autoimmune neurologic diseases of the central nervous system

An autoimmune mechanism for ADEM and MS can be supported by the similar patterns of pathologic changes seen in both diseases with the animal model EAE induced by inoculating animals with nervous tissue and the occurrence of ADEM in patients exposed to nervous tissue during vaccination. Whereas there are no universally agreed-upon criteria for the diagnosis of ADEM, a combination of prodromal illness or preceding vaccination, MRI signs of demyelination, and an acute presentation of neurologic symptoms are the triad most commonly looked for in making the diagnosis of ADEM. An ever-increasing number of infections and vaccinations (nonspecific URIs being most common) has been associated with ADEM. Fever and encephalopathy are seen frequently at presentation. Seizures also are common, as are cranial nerve abnormalities and motor symptoms. A mild pleocytosis or protein elevation is found in the majority of patients with ADEM. Intrathecal IgG synthesis and oligoclonal bands are relatively infrequent but should not be considered inconsistent with the diagnosis of ADEM. White matter changes on T2 in a bilateral although asymmetric distribution with relative sparing of the periventricular region with or without deep gray matter involvement is consistent and to some a requirement for the diagnosis. Low-dose steroids have no beneficial effect in the treatment of ADEM and may be contraindicated. High-dose steroids may have a beneficial effect, particularly in more prolonged illnesses, although the evidence is primarily anecdotal. If steroids are used to improve morbidity, 30 mg/kg/d of methylprednisolone for three to five days is the dose with a six-week taper to reduce the risk of recurrence. The prodromal infection may be a major factor in the ultimate mortality and morbidity of the disease. The current mortality of ADEM is quite low. Whether or not this is an effect of different triggering agents or changes in medical care cannot be determined. In larger series of patients with ADEM, 10% to 20% of children experience some sort of recurrence with the majority occurring in the initial one to two months after the first event. This is sometimes associated with steroid withdrawal. A second group of children have a late second recurrence that clinically may not be MS but a recurrence of ADEM, although longer follow-up may change that assessment. Two months should be allowed before a second relapse is considered a manifestation of MS, whereas a second attack also may occur years after an initial attack of ADEM and still be consistent with ADEM recurrence. MS does occur during childhood, with the youngest children at the least risk, and risk increasing with age. The criteria of Poser et al can be used to diagnose MS in childhood [40]. The presentation of MS in childhood is most often sensory, motor, and brainstem signs and symptoms. A relapsing-remitting course is most common with a first relapse occurring in the year after presentation. MRI findings in MS typically show periventricular changes. Oligoclonal bands and CSF IgG synthesis are found in the majority. Treatments of childhood MS have not been studied adequately, but, when treatments studied in adults are used in children, they are well tolerated. Efficacy has not been shown. The long-term outcome of MS in childhood can be either severe or benign with no clear consensus that childhood MS is either a less or more severe disease than the adult form. ATM and ON treatments and outcomes are particularly difficult to evaluate because of the heterogeneity of populations included in case series and the small numbers reported. Steroids are used with anecdotal reports of their superiority to nontreatment. Outcome in ATM often can be poor, whereas in ON it rarely is. A multinational collaborative effort to study and collect the large numbers necessary to address the important questions in these childhood autoimmune disorders would be of great benefit and the only way likely to demonstrate good evidenced-based medicine practiced in this field.     

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.     

Long-term persistence of intrathecal virus-specific antibody responses after herpes simplex virus encephalitis

Summary Paired sera and cerebrospinal fluids (CSF) from nine surviving patients were collected 4.5 to 8 years after acute herpes simplex (HS) virus encephalitis. Oligoclonal bands of IgG were detected in the CSF of all, and seven patients had an elevated CSF IgG index. Antibodies to HS, varicella-zoster (VZ), measles, and cytomegalo viruses were analysed by enzyme-linked immunosorbent assay (ELISA) and by imprint immunofixation (IIF) of specimens separated by electrophoresis and by thin-layer electrofocusing. Intrathecal synthesis of HS and VZ IgG antibodies was demonstrated in all and of measles IgG antibodies in one patient by both methods. Intrathecal synthesis of HS IgA antibodies was demonstrated by ELISA in three and by IIF in seven patients; the latter method also disclosed intrathecal synthesis of VZ IgA antibodies in two. No patient had intrathecal synthesis of viral IgM antibodies. The intrathecally synthesized antibodies demonstrated by IIF displayed oligoclonal characteristics. The IIF analyses as well as virus absorption tests indicated that the intrathecally synthesized VZ IgG and IgA antibodies could be explained as HS antibodies cross-reacting with VZV. The results indicate that a long-term persistence of intrathecal antibody reesponses to HS virus is a common feature after acute HS encephalitis. The intrathecal production of measles IgG antibodies in one case may reflect a similar persistence of non-specific immune responses induced during the acute infection.     

A prospective study of the risk of developing multiple sclerosis in uncomplicated optic neuritis

We prospectively studied 60 patients with uncomplicated optic neuritis (ON) to determine the risk of subsequent multiple sclerosis (MS). All patients were followed for at least 5 years (mean, 7.1 years). Seventeen patients (28 percent) developed definite MS and four (7 percent) developed probable or possible MS. Six of the 17 patients who developed definite MS did so within the first year. Forty-five percent of the women but only 11 percent of the men developed MS. Both sexes were at highest risk if the ON occurred between the ages of 21 and 40. Fifty-one percent of patients in this age group progressed to MS, whereas the risk for others was 12 percent. There was an overall increased risk of MS with recurrent ON. The course of the MS appeared to be benign during the period of observation.     

The relationship of interleukin-2 and soluble interleukin-2 receptors to intrathecal immunoglobulin synthesis in patients with multiple sclerosis

The in vivo relationship of interleukin-2 (IL-2) to the local humoral immune response within the central nervous system (CNS) in patients with multiple sclerosis (MS) is hitherto largely unknown. Intrathecal levels of IL-2 and soluble IL-2 receptors (sIL-2R) were correlated to the local CNS synthesis of immunoglobulin G, A, D, and M isotypes in 70 patients with clinically definite MS. Levels were also determined in 19 normal control subjects to establish normal reference limits. High cerebrospinal fluid levels of IL-2 and sIL-2R were detected mainly in patients with acute relapsing-remitting MS and were significantly higher than corresponding serum levels. Intrathecal levels of IL-2 significantly correlated with local CNS synthesis of IgD and IgM, while no correlation was found with either IgG or IgA. Similarly, intrathecal sIL-2R levels significantly correlated with local CNS production of IgD and IgM, but not IgG or IgA. These findings further extend previous reports and also suggest that IL-2 and sIL-2R are involved in the early intrathecal humoral immune response in 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.     

Intrathecal synthesis of free immunoglobulin light chains in multiple sclerosis

Objective – The detection of oligoclonal immunoglobulin free light chains (FLC) in the diagnosis of multiple sclerosis (MS) was compared to IgG isoelectric focusing. Material and methods – Cerebrospinal fluid and serum samples from 69 patients with possible first attacks of MS, 50 patients with clinically definite MS (CDMS), and 118 patients with other neurological diseases (OND) were analyzed. IgG and FLC oligoclonal bands were detected by isoelectric focusing and immunoperoxidase staining. Results – Intrathecal synthesis of IgG, kappa FLC, and lambda FLC oligoclonal bands, respectively, was seen in 92%, 92%, and 86% of MS patients; in 61%, 62%, and 64% of patients with possible first attacks of MS; and in 3%, 3%, and 8% of the patients with OND. In control patients without IgG synthesis intrathecal lambda FLC synthesis was more common than kappa FLC synthesis ( P =0.03). Conclusion – Kappa FLC detection proved as useful as IgG analysis for the laboratory diagnosis of MS whereas the presence of intrathecal lambda FLC synthesis was less specific.     

Multiple sclerosis is associated with enhanced B cell responses to the ganglioside GD1a

The occurrence and role of autoantibodies to gangliosides and other lipid-containing components of the central nervous system in Multiple Sclerosis (MS) are unsettled. Using sensitive ELISAs, we measured IgG and IgM antibody titers and absorbances to the three major gangliosides GD1a, GD1b and GM1, and to sulfatides, cardiolipin and myelin proteins in paired serum and cerebrospinal fluid (CSF) from patients with untreated MS, optic neuritis (ON), acute aseptic meningo-encephalitis (AM) and other neurological diseases (OND). Twenty-three per cent of 30 MS (P<0.04) and 18% of 32 ON patients (P<0.05) presented elevated IgG antibody titers to GD1a in serum compared to 9% of patients with OND. Six (40%) of the patients with malignant MS had elevated serum IgG antibody titers to GD1a compared to one (6%) of the patients with benign MS (P<0.04). In CSF, elevated IgG antibody titers to GD1a were measured in 13% of MS and 20% of ON patients compared to 4% of patients with OND (P<0. 03 and P<0.02, respectively). The augmented IgG response to GD1a in serum also separated MS from Guillain-Barré syndrome. Compared to OND increased IgM absorbances to sulfatides and cardiolipin were observed in CSF of patients with MS, but also in AM. Elevated IgG antibody titers to myelin proteins were found more often in MS patients' serum and MS, ON and AM patients' CSF compared to OND. The data implicate that among the multitude of enhanced B-cell responses occurring in MS and ON, that directed to GD1a is common and more discriminative, and should be evaluated in future MS treatment studies.     

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.