Prevention of post-dural puncture headache: a randomized controlled trial.

BACKGROUND AND PURPOSE: We investigated 952 subjects undergoing diagnostic lumbar puncture (LP) to study the effects of needle size, needle design and stylet reinsertion on the risk of post-dural puncture headache (PDPH). METHODS: This randomized double-blind study was performed at Umeå University Hospital in Sweden during 2013-2018. Subjects were randomly assigned one of three needles [22 gauge (G) atraumatic, 25G atraumatic and 25G cutting] and stylet reinsertion before needle withdrawal or not. The main outcome measure was PDPH assessed by standardized telephone interview(s) 5 days after the LP, repeated until headache cessation. We used logistic regression to calculate odds ratios (ORs) with 95% confidence intervals (CI) for PDPH. RESULTS: The mean (SD) age was 51.1 (16.7) years and 53.6% were females. The smaller bore (25G) atraumatic needle incurred a lower risk of headache compared with the larger bore (22G) atraumatic needle [22.0% (69/314) vs. 30.2% (98/324); OR, 0.65; 95% CI, 0.45-0.93] and compared with the cutting needle [32.8% (103/314); OR, 0.58; 95% CI, 0.40-0.82]. Reinserting the stylet before needle withdrawal did not reduce the risk of headache. CONCLUSIONS: These data suggest that a 25G atraumatic needle is superior to a larger atraumatic needle, and to a same-sized cutting needle, in preventing PDPH after diagnostic LP. In contrast to one earlier report, this study did not find that stylet reinsertion was effective in preventing PDPH. This study provides class I evidence that a small atraumatic needle decreases the risk of PDPH and that stylet reinsertion does not influence PDPH risk.

Natalizumab, rituximab and fingolimod as escalation therapy in multiple sclerosis.

BACKGROUND AND PURPOSE: Breakthrough disease on first-line injectables in relapsing-remitting multiple sclerosis (RRMS) is a common clinical situation where comparative studies between different escalation therapies are lacking. The aim of this study was to compare the efficacy, safety and medication persistence of natalizumab (NTZ), rituximab (RTX) and fingolimod (FGL) as escalation therapy in RRMS. METHODS: Patients switching from interferon or glatiramer acetate to NTZ, RTX or FGL due to breakthrough disease were identified through the Swedish multiple sclerosis (MS) registry at four large MS centers in this retrospective observational study. Data were collected from the MS registry and medical charts. Hazard ratios (HRs) for relapses, adverse events and drug discontinuation with 95% confidence interval (CI) were calculated using multivariable confounder-adjusted Cox proportional hazard models. RESULTS: A total of 241 patients were included. The annualized relapse rates were 0.02 for NTZ, 0.03 for RTX and 0.07 for FGL. Compared with NTZ, the adjusted HR for relapse was 1.0 (95% CI, 0.2-5.6) for RTX and 3.4 (95% CI, 1.3-9.2) for FGL. The annualized drug discontinuation rates were 0.15, 0.01 and 0.15 for NTZ, RTX and FGL, respectively. The adjusted HR for drug discontinuation was 0.05 (95% CI, 0.01-0.38) for RTX and 1.0 (95% CI, 0.6-1.7) for FGL vs. NTZ. CONCLUSIONS: In patients with RRMS on interferon/glatiramer acetate with breakthrough disease, switching to NTZ or RTX was associated with less disease activity compared with FGL. RTX displayed superior medication persistence compared with both NTZ and FGL.

Guidelines for the use of magnetic resonance imaging in diagnosing and monitoring the treatment of multiple sclerosis: recommendations of the Swedish Multiple Sclerosis Association and the Swedish Neuroradiological Society.

Multiple sclerosis (MS) is associated with inflammatory lesions in the brain and spinal cord. The detection of such inflammatory lesions using magnetic resonance imaging (MRI) is important in the consideration of the diagnosis and differential diagnoses of MS, as well as in the monitoring of disease activity and predicting treatment efficacy. Although there is strong evidence supporting the use of MRI for both the diagnosis and monitoring of disease activity, there is a lack of evidence regarding which MRI protocols to use, the frequency of examinations, and in what clinical situations to consider MRI examination. A national workshop to discuss these issues was held in Stockholm, Sweden, in August 2015, which resulted in a Swedish consensus statement regarding the use of MRI in the care of individuals with MS. The aim of this consensus statement is to provide practical advice for the use of MRI in this setting. The recommendations are based on a review of relevant literature and the clinical experience of workshop attendees. It is our hope that these recommendations will benefit individuals with MS and guide healthcare professionals responsible for their care.

Vitamin D and axonal injury in multiple sclerosis.

BACKGROUND: Previous studies in patients with multiple sclerosis (MS) have shown an association between high serum 25-hydroxyvitamin D (25[OH]D) levels and decreased inflammatory activity. OBJECTIVE: The purpose of this study was to examine the association between 25(OH)D levels and axonal injury in MS. Cerebrospinal fluid neurofilament light (CSF-NFL) was used as a marker for axonal injury. METHODS: Patients were identified through clinical practice at the Department of Neurology in Umeå University Hospital, Sweden. Blood draw, magnetic resonance imaging, scoring of disability and lumbar puncture were performed at inclusion in 153 patients, and also at median 12 months follow-up in 87 patients. For analyses of serum 25(OH)D levels and CSF-NFL, enzyme-linked immunosorbent assays were used. RESULTS: There was an inverse association between serum 25(OH)D and CSF-NFL levels in categorical (dichotomized at 75 or 100 nmol/l) analyses. A dose-response effect for 25(OH)D levels on CSF-NFL levels (p for trend=0.034) was also present. Serum 25(OH)D levels above 100 nmol/l were associated with lower CSF-NFL levels independently of ongoing MS treatment. CONCLUSION: High 25(OH)D levels are associated with decreased axonal injury in MS.

Increasing prevalence of multiple sclerosis in Västerbotten County of Sweden.

OBJECTIVES: To update the incidence and prevalence of multiple sclerosis (MS) in Västerbotten County, Sweden, and to compare this to previous investigations in the same area. BACKGROUND: Northern Sweden is a high-risk area for developing MS. Västerbotten County has previously been surveyed in detail regarding the occurrence of MS. In several countries, increases in MS prevalence and incidence as well as a change in the sex ratio have been reported. MATERIALS AND METHODS: Multiple sources were used to identify MS cases in Västerbotten that either had their onset of the disease from 1998 to 2010 and/or lived in Västerbotten, the two dates chosen for prevalence calculation: the 31st of December 2005 and 2010. RESULTS: The mean yearly incidence of MS in Västerbotten during the entire period 1998-2010 was 6.0/100,000. The female to male ratio was 2.1. The prevalence of MS in Västerbotten was 188/100,000 on 31st of December 2005 and 215/100,000 on 31st of December 2010. The MS prevalence increased over time from 1990 to 2010. CONCLUSIONS: The prevalence of MS in Västerbotten County has increased between 1990 and 2010, while no statistically significant increase in incidence was seen.

Autologous haematopoietic stem cell transplantation: a viable treatment option for CIDP.

OBJECTIVE: Only 70-80% of patients with chronic inflammatory demyelinating polyneuropathy (CIDP) respond satisfactorily to the established first-line immunomodulatory treatments. Autologous haematopoietic stem cell transplantation (AHSCT) has been performed as a last treatment resort in a few therapy-refractory cases with CIDP. We describe the results of AHSCT in 11 consecutive Swedish patients with therapy-refractory CIDP with a median follow-up time of 28 months. METHOD: Case data were gathered retrospectively for AHSCT treatments in 11 patients with CIDP refractory to the first-line immunomodulatory treatments, intravenous high-dose immunoglobulin, corticosteroids and plasma exchange and to one or more second-line treatments used in 10 of the 11 patients. RESULTS: The median Inflammatory Neuropathy Cause and Treatment (INCAT) score within 1 month prior to AHSCT was 6 and the Rankin score 4. Total INCAT and Rankin scores improved significantly within 2-6 months after AHSCT and continued to do so at last follow-up. The motor action potential amplitudes (CMAP) improved already within 4 months (median) after AHSCT. Three of the 11 patients relapsed during the follow-up period, requiring retransplantation with AHSCT in one. Eight of the 11 patients maintained drug-free remission upon last follow-up. AHSCT was safe but on the short term associated with a risk of cytomegalovirus (CMV) and Epstein-Barr virus reactivation, CMV disease, haemorrhagic cystitis and pancreatitis. CONCLUSIONS: Our results though hampered by the limited number of patients and the lack of a control group suggest AHSCT to be efficacious in therapy-refractory CIDP, with a manageable complication profile. Confirmation of these results is necessary through randomised controlled trials.

Effectiveness of first generation disease-modifying therapy to prevent conversion to secondary progressive multiple sclerosis.

BACKGROUND: The use of disease-modifying therapies (DMTs) in multiple sclerosis (MS) has been associated with reduced relapse rates and accumulation of disability. However, studies examining impact of DMT on risk of transition to secondary progressive MS (SPMS) leveraging population-based nationwide data are still rare. Here, we determine the population incidence of conversion to SPMS using two consecutive nation-wide cohorts, one immediately before and one after the introduction of DMT in Sweden. METHODS: We included two consecutive population cohorts of relapsing-remitting MS (RRMS) from the Swedish national MS register for the periods 1975-1994 (n = 2161), before DMT availability, and 1995-2011 (n = 3510), in which DMTs, mainly first generation DMT (injectables), became available and eventually were used by 70% of patients. We explored the risk of transition to SPMS as a calendar year function encompassing the two cohorts. In addition, we determined the incidence of transition to SPMS through age strata below and above 50 years in untreated and treated patient subgroups. RESULTS: The risk of conversion to SPMS (adjusted for current age, current time since onset, calendar year and sex) was significantly lower in the second compared with the first population cohort (hazard ratio 0.58; CI 0.48, 0.70). The risk of SPMS conversion per calendar year decreased by 2.6% annually (p < 0.001) after 1995. The risk of SPMS conversion increased with age until age 50. Thereafter, it was unchanged or decreased among those with early MS onset age (<35 years), but continued to increase with onset at higher age, with similar trends in treated and untreated subgroups. CONCLUSION: The incidence of SPMS conversion significantly decreased at the population level after introduction of first generation DMTs by 1995. DMT efficiency was confirmed by a downward turn of the annual trajectory of the risk of SPMS conversion after 1995. An onset age determined pattern of variable SPMS incidence in higher age appeared in both treated and untreated strata. While first generation DMT delayed conversion to SPMS, their long-term effect was only moderate.

Season of birth and multiple sclerosis in Sweden.

OBJECTIVE: To estimate the risk of multiple sclerosis (MS) by month of birth in Sweden. MATERIALS AND METHODS: Cases (n = 9361) were obtained from the Swedish MS Registry. All births in Sweden 1900-2007 served as controls (n = 12,116,853). The risk of MS was analyzed for each month of birth separately compared with birth during the other 11 months. RESULTS: More (11%) cases with MS than expected were born in June. Fewer (8% and 10%) cases with MS than expected were born in December and January (non-significant after correction for multiple analyses). More (5%) cases with MS than expected were born in February-July as compared with August-January. CONCLUSIONS: This study supports previous results suggesting an association between the risk of MS and the season of birth. Decreased exposure to sun in the winter leading to low vitamin D levels during pregnancy is a possible explanation that needs further research.

Season of birth and multiple sclerosis in Sweden.

OBJECTIVE: To estimate the risk of multiple sclerosis (MS) by month of birth in Sweden. MATERIALS AND METHODS: Cases (n = 9361) were obtained from the Swedish MS Registry. All births in Sweden 1900-2007 served as controls (n = 12,116,853). The risk of MS was analyzed for each month of birth separately compared with birth during the other 11 months. RESULTS: More (11%) cases with MS than expected were born in June. Fewer (8% and 10%) cases with MS than expected were born in December and January (non-significant after correction for multiple analyses). More (5%) cases with MS than expected were born in February-July as compared with August-January. CONCLUSIONS: This study supports previous results suggesting an association between the risk of MS and the season of birth. Decreased exposure to sun in the winter leading to low vitamin D levels during pregnancy is a possible explanation that needs further research.

NFL and CXCL13 may reveal disease activity in clinically and radiologically stable MS.

BACKGROUND: Cerebrospinal fluid (CSF) levels of neurofilament light (NFL), a biomarker of axonal damage, and CXCL13, a chemokine involved in B-cell regulation, are both associated with disease activity in multiple sclerosis (MS). OBJECTIVE: To explore the potential of NFL and CXCL13 to detect residual disease activity in patients with no signs of clinical or ongoing radiological activity and to study the clinical relevance of such activity. METHODS: NFL and CXCL13 concentrations were determined with ELISA in CSF obtained from 90 relapsing-remitting (RR) MS and 47 Progressive (Pr) MS (including primary and secondary PrMS) at baseline and after 12 months of follow-up. The patients were assessed at baseline, before initiating or switching disease modifying therapy (DMT) and again after 12 and 27 months of follow-up. RESULTS: All patients with ongoing disease activity (relapse or contrast-enhancing lesions on MRI) had increased NFL or CXCL13. The proportion of RRMS and PrMS patients without ongoing disease activity with elevation of either NFL or CXCL13 (residual disease activity) was 39% and 50%, respectively, and both were increased in 11% and 16%, respectively. The treatment with DMTs decreased the proportion with residual disease activity in both RRMS and PrMS significantly. We could not show any significant association between residual disease activity and clinical or MRI measures at 12 or 27 months of follow-up. CONCLUSIONS: Although most of this real-world study population had been treated with second-line DMTs and achieved clinical and radiological stability, a significant proportion of patients still displayed increased CSF levels of both NFL and CXCL13, indicating residual disease activity. Thus, these markers seemed considerably more sensitive to disease activity than clinical and MRI measures. However, the long-term clinical significance of such activity remains to be determined.

Population-based cohort study on the epidemiology of acute appendicitis in children in Sweden in 1987-2013.

BACKGROUND: The long-term incidence of acute appendicitis has been reported to be declining in Europe and North America. Recent reports, however, indicate stabilized or even increased rates. The aim of this study was to investigate the present epidemiology of acute appendicitis and appendicectomy in a population-based cohort of Swedish children. METHODS: The Swedish National Patient Register was queried for all children with acute appendicitis and/or appendicectomy in 1987-2013. Population-based incidence rates were calculated. Rates were age- and sex-adjusted, and analysed for temporal and regional trends. RESULTS: Some 56 774 children with acute appendicitis were identified, of whom 53 478 (94·2 per cent) underwent appendicectomy. The incidence rate of acute appendicitis declined by 43·7 per cent over 26 years, from 177·7 to 100·1 per 100 000 person-years between 1987 and 2013. The most significant reduction was for non-perforated appendicitis, from 138·5 to 68·4 per 100 000 person-years between 1987 and 2009. The incidence rate of perforated appendicitis decreased from 28·0 to 19·9 per 100 000 person-years and negative appendicectomies reduced from 48·5 to 3·6 per 100 000 person-years during the study interval. CONCLUSION: The incidence rates of acute appendicitis and negative appendicectomy have reduced markedly in Swedish children over time, with significantly different trends amongst non-perforated appendicitis and perforated appendicitis. The full explanation for the observed findings is unclear.

HIV-1 in postmortem brain tissue from patients with AIDS: a comparison of different detection techniques.

OBJECTIVE: The presence of HIV-1 in postmortem brain tissue from 31 patients with AIDS and 12 HIV-1-negative controls was investigated. DESIGN: Most laboratories have access to the methods used. We readily applied in situ hybridization and immunohistochemistry to archival formalin-fixed paraffin-embedded (FFPE) brain specimens. METHODS: The techniques used to detect HIV-1 were explant culture, in situ hybridization with 35S-labeled polymerase (pol) gene riboprobes and immunohistochemistry with monoclonal antibody to gp41. RESULTS: HIV-1 was isolated from explant cultures in 13 out of 20 (65%) patients, whereas HIV-1-infected cells were detected in FFPE brain tissue from nine out of 26 (35%) patients examined by in situ hybridization and in seven out of 26 (27%) patients examined by immunohistochemistry. CONCLUSIONS: Although the isolation technique was the most sensitive of the three techniques tested, infected cells may be identified with in situ hybridization in conjunction with immunohistochemistry.

HIV-1 propagates in human neuroblastoma cells.

A major question in the pathogenesis of AIDS encephalopathy and dementia is whether HIV-1 directly infects cells of the central nervous system (CNS). The propagation of HIV was attempted in six cell lines: three related and three unrelated to the nervous system. HIV was able to propagate in two human neuroblastoma cell lines and a lymphocytic cell line control but did not result in infections of African green monkey kidney cells, human cervix carcinoma cells, and one human brain astrocytoma cell line. Neuroblastoma cell lines infected with HIV showed peaks of reverse transcriptase activity at 10-14 days postinfection. After prolonged growth in cell cultures, one of the neuroblastoma cell lines showed multiphasic virus production, additional high peaks of reverse transcriptase activity, 20-fold greater than the first, lasting from 36 to 74 days and 110 to 140 days postinfection. The presence of HIV was confirmed by p24 antigen capture. The neuroblastoma cell lines had weak but detectable levels of CD4 immunoreactivity by immunoperoxidase and flow immunocytometric analysis. Although no T4-specific RNA sequences were detected by hybridization of Northern blots of total and poly A-selected RNA extracted from the two neuroblastoma cell lines by using a T4 specific complimentary DNA probe, monoclonal antibodies to the CD4 receptor blocked HIV infection in both neuroblastoma cell lines. Thus, the infection of neuroblastoma cells by HIV occurs in part by a CD4-dependent mechanism. Passaging the neuroblastoma cell lines weekly and bimonthly resulted in similar cell cycle-DNA content patterns for the more permissive cell line and with significant numbers of cells in the S phase. HIV-infected neuroblastoma cell lines provide an in vitro model for the evaluation of virus-host cell interactions and may be useful in addressing the issue of the persistence of HIV in the human CNS.

Tropical spastic paraparesis-like illness occurring in a patient dually infected with HIV-1 and HTLV-II.

We describe a 34-year-old man from southern Florida with a history of intravenous drug use, dually infected with human immunodeficiency virus type 1 (HIV-1) and human T-lymphotropic virus type II (HTLV-II), who developed a myelopathy clinically indistinguishable from HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). This myelopathy was characterized by spastic lower extremity weakness, distal paresthesias, sensory loss with a discrete thoracic level to pinprick, back pain, impotence, and sphincter disturbances. Nerve conduction studies revealed an associated mixed axonal and demyelinative neuropathy. Despite a lack of response to 10 months of zidovudine therapy, the myeloneuropathy improved dramatically 2 years after its onset in the absence of any therapeutic intervention.

Nitric oxide metabolites in CSF of patients with MS are related to clinical disease course.

In this study, we have analyzed the stable metabolites of nitric oxide (NO), nitrite and nitrate, in the CSF of patients with MS, lymphocytic meningitis, and in healthy control subjects. Patients with MS with an active disease course exhibited increased CSF nitrite levels compared with patients with stable MS and healthy control subjects, whereas CSF nitrate levels did not differ between these groups. High CSF levels of both metabolites were seen in patients with meningitis. These data indicate that CSF nitrite levels may reflect clinical disease activity in MS.

The role of HTLV in HIV-1 neurologic disease.

We performed a serologic survey for antibodies to HTLV-I/II in the course of a longitudinal study of the neurologic complications of HIV-1 infection. Nine (3.7%) of 242 HIV-1 seropositive subjects and none of 60 HIV-1 seronegative control subjects had antibodies to HTLV-I/II by ELISA. Western blot and polymerase chain reaction confirmed the presence of HTLV-I in 2 subjects and HTLV-II infection in 2 others. Both HIV-1/HTLV-I coinfected subjects and 1 HIV-1/HTLV-II coinfected subject had a slowly progressive myelopathy clinically identical tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM). The presence of a myelopathy resembling TSP/HAM in the coinfected subjects suggests that HIV-1 may enhance the expression of neurologic disease caused by HTLV. Patients with a progressive myelopathy occurring in association with HIV-1 infection should be serologically tested for the presence of HTLV. Establishing dual infection has therapeutic and prognostic import as 1 of the HIV-1/HTLV-I subjects substantially improved with corticosteroids and the HIV-1/HTLV-II subject with myelopathy had a marked improvement in the absence of therapeutic intervention.

Linomide reduces the rate of active lesions in relapsing-remitting multiple sclerosis.

The synthetic immunomodulator Linomide, a quinoline-3-carboxamide, has a profound inhibitory influence in several experimental autoimmune diseases, including acute and chronic experimental allergic encephalomyelitis. In a double-blind trial, 31 patients with relapsing-remitting multiple sclerosis were randomized to oral doses of 2.5 mg Linomide or placebo once a day for six months. Fourteen patients receiving Linomide and 14 receiving placebo completed the trial, and the results were based on this population. The mean number of active (new and enlarged T2 weighted) lesions per monthly MRI scan was 1.37 in the patients receiving Linomide and 4.22 in the patients receiving placebo (p = 0.043). The percentage of scans with active MRI lesions was lower in the Linomide-treated group (p = 0.0064). When neurologic deficit was assessed by the Regional Functional Scoring System (RFSS), the Linomide group showed an improvement of 1% of the maximal RFSS range and the placebo group a deterioration of 0.2% (p = 0.14). There were three patients with relapses in the Linomide-treated group and six in the placebo group (p = 0.22). A slightly decreased proportion of natural killer cells in cerebrospinal fluid and peripheral blood was noted in the Linomide group. A severe adverse event of pleuropericarditis occurred in one of the Linomide-treated patients. The most frequent adverse event was musculoskeletal pain, of mild to severe degree, which tended to diminish after three months on Linomide therapy.

Lymphocyte phenotype and subset distribution in normal cerebrospinal fluid.

The distribution of lymphocyte subpopulations in cerebrospinal fluid (CSF) and their phenotypic characteristics were extensively investigated in a group of 18 healthy individuals using two- and three-color flow cytometry. Generally, CD3+ T lymphocytes constituted the vast majority of CSF lymphocytes while the number of B lymphocytes and NK cells were low. Most T lymphocytes exhibited the phenotype of memory/primed cells in both the CD4+ and CD8+ subpopulations. Two markers for recent activation, HLA-DR and interleukin-2 receptor (CD25) were not upregulated when compared with peripheral blood (PB) in the majority of CSF T lymphocytes. However, a fraction of T lymphocytes co-expressing the NK cells markers CD56 and/or CD16 showed a pronounced upregulation of HLA-DR in CSF as compared with PB. This study documents that the cellular composition of the normal CSF differs profoundly from PB regarding all major lymphocyte subpopulations. This has to be taken into account in studies addressing questions regarding cellular immune reactions in the central nervous system under pathological conditions.

Increased expression of B7-1 costimulatory molecule on cerebrospinal fluid cells of patients with multiple sclerosis and infectious central nervous system disease.

The expression of the costimulatory molecule B7-1 (BB-1; CD80) and its ligand CD28 was investigated on peripheral blood (PB) and cerebrospinal fluid (CSF) T and B lymphocytes and monocytes in 11 patients with relapsing-remitting multiple sclerosis (MS) 21 age-matched healthy controls and 10 patients with central nervous system (CNS) infectious disease (CID). Three channel flow cytometry was used with a novel gating technique in order to unambiguously identify the low numbers of B lymphocytes present in normal CSF. There was a significantly higher fraction of B7-1+ B lymphocytes in the CSF of patients with MS (72%) and CID (69%) when compared with healthy individuals (53%; p < 0.0001 and p < 0.002, respectively). Furthermore, two patients with a clinical picture of encephalitis showed a profoundly increased B7-1 expression on CSF monocytes. Comparison of absolute numbers of B7-1+ B lymphocytes/mL CSF between MS patients and healthy controls revealed a highly increased frequency of these cells among MS patients (235 cells/mL in MS patients versus 3.9 cells/mL in controls; p < 0.0001) with no overlap between the groups, which was otherwise seen for all other analyzed cell populations. We therefore hypothesize that activated B lymphocytes expressing high levels of B7-1 may be of pathogenetic importance in the development and maintenance of the MS disease.

Intra-CNS activation by antigen-specific T lymphocytes in experimental autoimmune encephalomyelitis.

Identification and quantitation of autoreactive T lymphocytes is crucial in order to understand the pathogenesis of autoimmune diseases. We used flow cytometry to analyze autoantigen-specific T cellular responses in the well characterized rat experimental autoimmune encephalomyelitis (EAE) model. Cells isolated from both the central nervous system (CNS) tissue and peripheral lymph nodes were analyzed directly ex vivo or after short term in vitro culture with specific autoantigen. CNS infiltrating T lymphocytes displaying an interferon-gamma response to selected encephalitogenic myelin protein epitopes were measured kinetically during an individual disease episode and also between relapses in a chronic rat EAE model. One of the EAE models used displays a restriction towards TCRBV8S2 chain usage by the encephalitogenic T cells. In this model, in vitro production of intracellular interferon-gamma was selectively detected within this T cell subset derived from both the CNS and peripheral lymph nodes. Furthermore, antigen-specific cells infiltrating the CNS in this model produced several-fold higher amounts of interferon-gamma upon antigen stimulation and displayed a significantly increased in vivo proliferation compared with peripheral lymphocytes. These data thus directly demonstrates that T cells stimulated by a specific autoantigen in the periphery primarily acquire effector functions in the cellular environment of the target organ of the autoantigen.