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.

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.

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.

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.

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.

Automated determination of brain parenchymal fraction in multiple sclerosis.

BACKGROUND AND PURPOSE: Brain atrophy is a manifestation of tissue damage in MS. Reduction in brain parenchymal fraction is an accepted marker of brain atrophy. In this study, the approach of synthetic tissue mapping was applied, in which brain parenchymal fraction was automatically calculated based on absolute quantification of the tissue relaxation rates R1 and R2 and the proton attenuation. MATERIALS AND METHODS: The BPF values of 99 patients with MS and 35 control subjects were determined by using SyMap and tested in relationship to clinical variables. A subset of 5 patients with MS and 5 control subjects were also analyzed with a manual segmentation technique as a reference. Reproducibility of SyMap was assessed in a separate group of 6 healthy subjects, each scanned 6 consecutive times. RESULTS: Patients with MS had significantly lower BPF (0.852 ± 0.0041, mean ± SE) compared with control subjects (0.890 ± 0.0040). Significant linear relationships between BPF and age, disease duration, and Expanded Disability Status Scale scores were observed (P < .001). A strong correlation existed between SyMap and the reference method (r = 0.96; P < .001) with no significant difference in mean BPF. Coefficient of variation of repeated SyMap BPF measurements was 0.45%. Scan time was <6 minutes, and postprocessing time was <2 minutes. CONCLUSIONS: SyMap is a valid and reproducible method for determining BPF in MS within a clinically acceptable scan time and postprocessing time. Results are highly congruent with those described using other methods and show high agreement with the manual reference method.

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.

Neurofilament and glial fibrillary acidic protein in multiple sclerosis.

OBJECTIVE: To evaluate levels of neurofilament light (NFL) and glial fibrillary acidic protein (GFAP) in CSF from patients with multiple sclerosis (MS) in relation to clinical progress of the disease. METHODS: CSF levels of NFL and GFAP were determined by sensitive ELISAs in 99 patients with different subtypes of MS, classified in terms of "ongoing relapse" or "clinically stable disease," and 25 control subjects. Levels were compared with paraclinical data such as immunoglobulin G index and inflammatory cell count in the CSF, and the levels were related to Expanded Disability Status Scale score and progression index at clinical follow-up evaluations later in the disease course. RESULTS: NFL and GFAP levels were elevated in MS patients as compared with control subjects (p < 0.001). The NFL levels were higher at relapses, whereas GFAP levels were unaffected. High NFL levels correlated with progression in patients with an active relapse (r = 0.49; p < 0.01) and in clinically stable patients (r = 0.29; p < 0.05). GFAP correlated to progression in the total patient cohort (r = 0.24; p < 0.05). Moreover, a strong correlation between NFL levels and inflammatory cell counts was evident in the group of patients with an ongoing relapse (r = 0.52; p = 0.001). CONCLUSIONS: CSF levels of neurofilament light and glial fibrillary acidic protein may have prognostic value in multiple sclerosis.

An altered immune response to Epstein-Barr virus in multiple sclerosis: a prospective study.

OBJECTIVE: To investigate the association between human herpesviruses and multiple sclerosis (MS), as well as between measles virus and MS. METHODS: The authors identified prospectively collected serum samples from 73 MS cases and retrospective sera from 161 MS cases in two population-based serum bank registers. Analyses of IgG antibody responses in cases and matched referents were performed for Epstein-Barr virus (EBV [EBNA-1 and VCA]), human herpesvirus 6 (HHV-6), herpes simplex virus (HSV), varicella zoster virus (VZV), and measles. RESULTS: All cases showed signs of past EBV infection. High activity to EBNA-1 and HHV-6 significantly (borderline significance for HHV-6) increased the risk for MS in prospective sera. A discrepancy between activities to EBNA-1 and VCA was striking in MS samples collected less than 5 years before relapsing-remitting MS onset, where high activity to EBNA-1 significantly increased, and high VCA activity significantly decreased the risk for MS. There was no support for major causal roles for HSV, VZV, or measles. CONCLUSION: Individuals who will develop MS exhibit an altered immune response against the EBV virus characterized by a high IgG activity to EBNA-1 in the absence of high activity to VCA, this being most pronounced in the 5-year period preceding MS onset.

Clinical characteristics of multiple sclerosis in Västerbotten County in northern Sweden.

BACKGROUND: Most clinical data for multiple sclerosis are hospital based-that is, derived from patients referred to clinics specialising in the disease. OBJECTIVES: To present data derived from two population based multiple sclerosis populations, an incidence cohort and a prevalence population, from Västerbotten County, northern Sweden. METHODS: The two populations were identified from multiple sources, and case ascertainment was assured through a personal clinical review, including interviews and examination of the patients. RESULTS: Characteristics at onset for the different clinical subtypes of multiple sclerosis are presented, including the clinical spectrum of the first attack, the anatomical correlation between the first and second attacks, sex distribution, and disability distribution. CONCLUSIONS: Based on the comparison of present and earlier natural history data, multiple sclerosis appears to be a slightly more benign disease than previously recognised.

Sick leave and professional assistance for multiple sclerosis individuals in Västerbotten County, northern Sweden.

The aims of this study of a cross-sectional multiple sclerosis (MS) population in Västerbotten County, northern Sweden, were to estimate the prevalence of sick leave, professional assistance and housing; to study risk factors for sick leave; and to estimate the odds for sick leave in comparison with the general population of the county. The consequences of MS-related incapacity on the socioeconomic factors studied were considerable. Almost half (45%) of prevalent MS cases aged 18-64 years were fully sick listed and only one-third (35%) were not sick listed at all. Every fourth individual in the prevalence population received professional assistance, and 9% were living in care homes or special apartments for the disabled. Multiple logistic regression analysis identified the Expanded Disability Status Scale (EDSS) as the strongest predictor of sick leave. The time from symptom onset to full sick leave leading to temporary or permanent disability pension was significantly shorter for cases with progressive onset, higher age at onset and in males. The risk of full sick leave due to MS was six times higher than in the general population.

Differential expression of neurotrophic factors and inflammatory cytokines by myelin basic protein-specific and other recruited T cells infiltrating the central nervous system during experimental autoimmune encephalomyelitis.

Recent evidence suggests that autoimmune reactions in the central nervous system (CNS) not only have detrimental consequences but can also be neuroprotective, and that this effect is mediated by the expression of neuronal growth factors by infiltrating leucocytes. Here we dissect these two phenomena in guinea pig myelin basic protein peptide (gpMBP 63-88)-induced experimental autoimmune encephalomyelitis (EAE) in the Lewis rat. Real-time TaqMan polymerase chain reaction (PCR) was used to measure mRNA for the nerve growth factors, brain-derived neurotrophic factor (BDNF) and neurotrophin (NT)-3. As reference, the well-known proinflammatory mediator molecules interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha were quantified. In whole lumbar cord tissue, both the nerve growth factors and the proinflammatory cytokines, IFN-gamma and TNF-alpha, displayed similar expression patterns, peaking at the height of the disease. Among the infiltrating inflammatory cells isolated and sorted from the CNS, alphabeta+/T-cell receptor (TCR)BV8S2+, but not alphabeta+/TCRBV8S2-, recognized the encephalitogenic MBP peptide. Interestingly, these two populations displayed contrasting expression patterns of nerve growth factors and proinflammatory cytokines with higher inflammatory cytokine mRNA levels in alphabeta+/TCRBV8S2+ cells at all time intervals, whereas the levels of BDNF and NT3 were higher in alphabeta+/TCRBV8S2- cells. We conclude that a potentially important neuroprotective facet of CNS inflammation dominantly prevails within other non-MBP peptide-specific lymphoid cells and that there are independent regulatory mechanisms for neurotrophin and inflammatory cytokine expression during EAE.

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.

Neuroprotection by encephalomyelitis: rescue of mechanically injured neurons and neurotrophin production by CNS-infiltrating T and natural killer cells.

In experimental autoimmune encephalomyelitis (EAE), CD4(+) self-reactive T cells target myelin components of the CNS. However, the consequences of an autoaggressive T cell response against myelin for neurons are currently unknown. We herein demonstrate that EAE induced by active immunization with an encephalitogenic myelin basic protein peptide dramatically reduces the loss of spinal motoneurons after ventral root avulsion in rats. Both brain-derived neurotophic factor (BDNF)- and neurotrophin-3 (NT-3)-like immunoreactivities were detected in mainly T and natural killer (NK) cells in the spinal cord. In addition, very high levels of BDNF, NT-3, and glial cell line-derived neurotrophic factor mRNAs were present in T and NK cell populations infiltrating the CNS. Interestingly, bystander recruited NK and T cells displayed similar or higher neurotrophic factor levels compared with the EAE disease-driving encephalitogenic T cell population. High levels of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) mRNAs were also detected, and both these cytokines can be harmful to several types of CNS cells, including neurons. However, treatment of embryonic motoneuron cultures with TNF-alpha or IFN-gamma only had a deleterious effect in cultures deprived of neurotrophic factors. These results suggest that the potentially neurodamaging consequences of severe CNS inflammation are curbed by the production of several potent neurotrophic factors in leukocytes.

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.