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MRI in multiple sclerosis: correlation with expanded disability status scale (EDSS).

Magnetic resonance (MR) imaging is very sensitive in showing disseminated MS lesions. Subclinical MR progression occurs frequently, explaining why MR is now used to monitor treatment, even without measurable consequences, of new MR lesions to the patient at this moment. In the light of this clinico-radiological paradox, the significance of MR in MS is discussed, particularly in relation with the expanded disability status scale (EDSS). Gadolinium-enhancing lesions correlate with the occurrence of relapses, CSF myelin breakdown products and, in patients with relapsing-remitting disease, with higher EDSS. However, the predictive value of the frequency of enhancement for changes in EDSS is only weak. For conventional T2-weighted MR imaging, the cross-sectional correlation with EDSS varies between 0.15 and 0.60, and is limited mainly by the inherent lack of tissues specificity of T2-weighted images. Both T1 black holes and magnetisation transfer (MT) parameters show a better correlation with EDSS; it should be noted that lesions in which those abnormalities are found go through an initial phase of enhancement as well. For T1 black holes, a correlation up to 0.81 has been reported for SP patients. Post-mortem studies show that black holes and low MT ratios are in vivo markers of axonal loss. Preliminary data indicate that progressive atrophy also correlates with progression on the EDSS scale. More should be learned about the fate of new MR lesion with regards to development of axonal loss, which at present is difficult to predict in the enhancing stage. The existence of escape mechanisms, including remyelination, make a simple correlation with EDSS extremely unlikely, and perhaps not even desirable. Nevertheless, while the clinical effect of a given new lesion may be difficult to ascertain, the absence of (new) MR lesions is prognostically favourable, as will be the degree to which new lesions are prevented by treatment.

Contrast Media↗

Serial MR imaging of experimental autoimmune encephalomyelitis induced by human white matter or by chimeric myelin-basic and proteolipid protein in the common marmoset.

BACKGROUND AND PURPOSE: Experimental autoimmune encephalomyelitis (EAE) in the marmoset was monitored by serial MR imaging to determine correlates to the natural-history MR studies in multiple sclerosis (MS). The relationships of MR-revealed lesions to clinical status and histopathologic findings were also explored. METHODS: We induced EAE by subcutaneous inoculation in two marmosets by human white matter (HWM) and in seven marmosets by MP4 (a chimeric recombinant fusion protein of myelin-basic and proteolipid protein) in adjuvant along with intravenous inactivated pertussis vaccine to facilitate the disease process. The HWM-inoculated animals were induced with Freund's adjuvant as the established model of marmoset EAE. The MP4-inoculated animals were induced with either Freund's incomplete adjuvant or TiterMax as part of a preclinical treatment trial. MR imaging was performed at 1.5 T at baseline, and repeated at 1- to 2-week intervals for a period of up to 16 weeks in six EAE-induced marmosets, and intermittently for up to 70 weeks in three EAE-induced and two control marmosets. Proton density- (PD-) and T2-weighted, pre- and postgadopentetate dimeglumine enhancement, T1-weighted, and magnetization transfer (MT) images were obtained. The brains were prepared for histologic evaluation of lesion distribution and counts, characterization of lesions as demyelinating or inflammatory, and histopathologic scoring. The clinical, MR, and pathologic scoring were done on grading systems, and correlated for evaluation. RESULTS: White matter (WM) changes after EAE induction were observed first at 9 days in the HWM-induced animals and at 2.5 weeks in the MP4-induced animals, with subsequent week-to-week fluctuations on PD- and T2-weighted images. Contrast-enhancing lesions were not observed in all animals. MR-revealed WM lesions correlated to histopathologic analysis of EAE lesions, measuring from 0.5 mm to 1.5 mm. The lesion count and extent of demyelination was greater in the HWM-induced animals than in the MP4-induced animals. Some MR-revealed lesions correlated directly to clinical symptoms, but the majority of lesions were clinically silent. CONCLUSION: On MR images, lesions in the EAE marmoset model were confined to the WM, and their development, resolution, distribution, and enhancing characteristics fluctuated over the duration of the study. The dynamic presentation of MR-revealed lesions confirms the parallels between EAE in the marmoset and relapsing-remitting MS. Clinical symptoms alone were not representative of ongoing pathologic brain lesions. Therefore, serial MR imaging serves as a very important adjunct to clinical and histologic surveillance of the development of new and the persistence of existing brain lesions in this animal model of MS.

Animals↗

Evidence of interferon beta-1a dose response in relapsing-remitting MS: the OWIMS Study. The Once Weekly Interferon for MS Study Group.

OBJECTIVE: To compare efficacy of interferon beta-1a, 22 microg or 44 microg weekly, with placebo in relapsing MS. BACKGROUND: Uncertainty exists concerning the optimal dose regimen for interferon beta in relapsing-remitting MS. Many patients and physicians prefer the convenience and lesser side effects of an injection given once weekly (qw) as opposed to three times weekly. Pharmacokinetic data and information on biologic markers suggest that this frequency may be suboptimal. METHODS: Randomized, double-blind study of interferon beta-1a 22 microg, 44 microg, or placebo administered by weekly subcutaneous injection for 48 weeks. Proton density (PD)/T2-weighted and T1-weighted-gadolinium MRI scans during 24 weeks of therapy were analyzed for the number of combined unique (CU) lesions (primary outcome). Biannual PD/T2 scans were analyzed for T2 activity and burden of disease (BOD). RESULTS: CU lesions at 24 weeks had a median of 0.71/scan with placebo, 0.5/scan with 22 microg (not significant), and 0.33/scan with 44 microg (p = 0.002). T2 new lesion count/scan (mean/median) at 48 weeks was 3.2/1.5 for placebo, 2.4/1.0 for 22 microg (p = 0.03), and 1.5/1.0 for 44 microg (p = 0.0005). BOD at 48 weeks showed a median increase of 5.9% for placebo compared with a decrease of 1.4% in the 44 microg group (p = 0.0058) and 2% in the 22 microg group (p = 0.0018). No clinical variable, apart from steroid use in the 44 microg qw group (p = 0.014), showed significance. CONCLUSIONS: These data confirm an MRI benefit of interferon beta-1a at low dose in MS, but highlight the limited clinical effect. Taken together with other studies, the data demonstrate a dose-effect relationship for both clinical and MRI variables.

Adjuvants, Immunologic↗

Changes of serum sICAM-1 and MMP-9 induced by rIFNbeta-1b treatment in relapsing-remitting MS.

OBJECTIVE: To correlate changes in serum levels of intercellular adhesion molecule-1 (sICAM-1) and matrix metalloproteinases (MMP) with clinical and MRI evidence of disease activity in MS patients receiving treatment with interferon-beta (rIFNbeta)-1b. BACKGROUND: rIFNbeta reduces the frequency of gadolinium-enhancing (Gd+) MRI in relapsing-remitting MS (RRMS). Its mechanism of action on improving the integrity of the blood-brain barrier remains unclear. METHODS: sICAM-1 and MMP-9 and MMP-2 serum levels were longitudinally (24 months) investigated (ELISA; zymography) in correlation with the modifications of the integrated area under the curve of Expanded Disability Status Scale scores normalized to entry baseline (deltaEDSS AUC) and of GD+ MRI scans, and with neutralizing antibodies (NAB) to rIFNbeta-1b production (MxA) in 36 RRMS patients. RESULTS: During the first 12 months of treatment, levels of sICAM-1 increased and MMP-9 decreased significantly. After 12 months, levels returned toward baseline. Levels of sICAM-1 and MMP-9 were significantly negatively correlated. MMP-2 levels did not change significantly during the same period. During the second semester of the study, deltaEDSS AUC was significantly reduced. The percentage of patients with Gd+ MRI decreased significantly in the first (33%), second (29%), third (20%), and fourth (28%) semesters of treatment compared to baseline (62%). The NAB+ patients (14%) tended to have lower sICAM-1 levels at the ninth month; a higher MMP-9 activity at the sixth, 12th, and 18th months; and a greater deltaEDSS AUC in the third semester of treatment in comparison with the NAB- patients. CONCLUSIONS: These results show that rIFNbeta-1b therapy increases sICAM-1 serum levels and reduces serum MMP-9 activity.

Adjuvants, Immunologic↗

Discontinuation of treatment with IFN-beta leads to exacerbation of experimental autoimmune encephalomyelitis in Lewis rats. Rapid reversal of the antiproliferative activity of IFN-beta and excessive expansion of autoreactive T cells as disease promoting mechanisms.

IFN-beta has recently been shown to exert remarkable beneficial effects on disease development in patients with early stage relapsing-remitting MS. The specific immune mechanism(s) by which IFN-beta ameliorates this human demyelinating disease is at present undefined. One potential mechanism may reside in the antiproliferative activity of IFN-beta which may inhibit the expansion of autoaggressive T cells thereby limiting disease progression. In the present study we investigated whether the administration of recombinant rat IFN-beta (rrIFN-beta) to Lewis rats with actively induced experimental autoimmune encephalomyelitis (EAE) inhibits the expansion of encephalitogenic T cells in lymphoid organs and as such may contribute to suppression of disease activity in this widely used animal model for MS. Our data show that daily administrations of > or = 3 x 10(5) u rrIFN-beta to EAE rats, starting two days before MBP sensitization and continued for 10 days led to a dramatic and dose-dependent reduction in encephalitogenic T cells in both spleen and inguinal lymph nodes at day 8 post-immunization (p.i.). However, the rrIFN-beta-mediated reduction in effector T cells did not ameliorate paralytic disease as expected but significantly enhanced the severity of EAE. Analyses of lymphoid organs in the remission phase of EAE revealed strongly elevated numbers of encephalitogenic T cells in rrIFN-beta-treated versus control rats suggesting a rapid reversal of the antiproliferative action of rrIFN-beta followed by an overshoot in the subsequent expansion of these effector T cells. In conformity with higher numbers of encephalitogenic T cells and worsening of disease, animals also showed significantly greater perivascular inflammation in the CNS. The relevance of our findings in relation to the beneficial effects of IFN-beta in MS is discussed.

Adjuvants, Immunologic↗

Natural killer cells in relapsing-remitting MS: effect of treatment with interferon beta-1B.

OBJECTIVE: To determine the effect of treatment with interferon beta-1b (IFN-beta) on natural killer (NK) cell function and phenotype in relapsing-remitting MS (RRMS) patients, and their relationship to disease activity assessed both clinically and with serial MRI. BACKGROUND: NK cells may play a role in the immunopathogenesis of MS. Previously the authors reported a positive relationship between mean NK cell functional activity (FA) and total number of active lesions on MRI in a serial study of RRMS. Cycles in NK cell FA over time created a series of peaks and valleys, and a significant relationship has been identified between the valleys and the appearance of active lesions on MRI or onset of clinical attacks. The development of valleys in NK cell FA before the appearance of active lesions on MRI was statistically significant. METHODS: The authors studied the effect of alternate-day therapy with 8.0 mIU (high dose [HD]) or 1.6 mIU (low dose [LD]) IFN-beta on NK cell FA, assessed by an in vitro 51Cr release K-562 target cell assay, and phenotype determination in RRMS patients. RESULTS: Treatment with HD IFN-beta results in an inverse relationship between mean NK cell FA and total number of active lesions on MRI over 2 years. A stronger inverse relationship was found in those patients who did not develop neutralizing antibodies to IFN (HD-) compared with a positive relationship in those who did (HD +). Treatment with IFN-beta did not affect the cyclic nature of NK cell FA, mean NK cell FA, variability around the mean, mean length of the cycle, time spent in valleys and peaks, or the significant relationship between the appearance of active lesions on MRI/onset of clinical attacks and valleys in NK cell FA. In contrast, treatment with HD but not LD IFN-beta did result in a significant reduction in CD57+ (a cell surface marker for subsets of NK cells) peripheral blood lymphocytes (PBL) compared with placebo. This effect, which originated largely from the HD- group of patients, developed shortly after treatment was initiated and was maintained throughout the study. CONCLUSIONS: RRMS patients with higher mean NK cell FA may be not only at greater risk for the development of active lesions but also may be more likely to respond to IFN-beta. Development of neutralizing antibodies to IFN-beta could interfere with this effect. This effect may be mediated through an action on a CD57+ subset of PBL.

Adjuvants, Immunologic↗

Cyclosporine versus azathioprine in the long-term treatment of multiple sclerosis--results of the German multicenter study.

In a double-blind controlled trial of 194 patients with clinically definite active multiple sclerosis, 98 were randomized to treatment with cyclosporine (CyA, 5 mg/kg/day), and 96 to treatment with azathioprine (Aza, 2.5 mg/kg/day). Eighty-five patients in the CyA group and 82 in the Aza group completed a treatment period of 24 to 32 months in accordance with the study protocol. No significant differences could be detected between the two treatment groups at the end of the trial. Assessment was done by serial quantitative neurological examinations and Kurtzke's Expanded Disability Status Scale. Frequency of relapse and patient self-evaluation also failed to show significant differences. Overall deterioration observed in both groups during the trial was only minor. The incidence of side effects in the CyA group was more than two times that in the Aza group. We conclude that CyA as a single agent cannot be the drug of final choice in long-term immunosuppressive treatment of relapsing-remitting and relapsing-progressive multiple sclerosis.

Adolescent↗

Induction of active and adoptive relapsing experimental autoimmune encephalomyelitis (EAE) using an encephalitogenic epitope of proteolipid protein.

Proteolipid protein (PLP) is a major component of the central nervous system (CNS) myelin membrane and has been shown to induce acute experimental autoimmune encephalomyelitis (EAE) in genetically susceptible animals. Here we describe conditions by which a relapsing-remitting form of EAE can be reliably induced in SJL/J mice either actively immunized with the major encephalitogenic PLP peptide, PLP13-151(S), or following adoptive transfer of PLP139-151(S)-specific T cells. The disease follows a reliable relapsing-remitting course with acute clinical signs first appearing 6-20 days after priming or transfer and relapses first appearing at 30-45 days. The initial onset of disease correlates with delayed-type hypersensitivity (DTH) reactivity specific for PLP139-151(S), in the apparent absence of T cell reactivity to the major myelin basic protein (MBP) peptide. Histologically, both the active and adoptive forms of the disease are characterized by extensive mononuclear cell infiltration and severe demyelination of the CNS. These results suggest that T cell responses specific for PLP139-151(S) are sufficient to induce clinical and histological R-EAE in SJL/J mice. This model should prove useful for examination of the cellular and molecular events involved in clinical relapses and perhaps in determining the role of PLP-specific T cell responses in multiple sclerosis (MS).

Amino Acid Sequence↗

EBV reactivation priming of the peripheral immune system in multiple sclerosis relapse.

Despite decades of research, the cellular and molecular events preceding multiple sclerosis (MS) relapse remain incompletely understood. Here, in this observational study of longitudinal blood samples from patients with relapsing-remitting MS, we used single-cell RNA sequencing, bulk transcriptomics, multiparameter flow cytometry and targeted viral reverse transcription quantitative polymerase chain reaction (RT-qPCR) to construct a time-resolved atlas of immune perturbations surrounding relapse. A reproducible pre-relapse signature in monocytes and B cells, emerging up to 3 months before clinical onset, was enriched for host genes responsive to Epstein-Barr virus (EBV) lytic reactivation factors. RT-qPCR confirmed elevated EBV LMP-1 transcripts in pre-relapse B cells, and flow cytometry demonstrated expansion of CD11c+ atypical B cell populations displaying EBV surface protein gp350. Pre-relapse transcriptional modules overlapped with MS genome-wide association study (GWAS) risk loci and EBNA-2-bound enhancers, suggesting that inherited MS susceptibility and EBV-responsive programs operate through shared regulatory elements. How this peripheral activation relates to central nervous system lesion formation remains to be established. These findings nonetheless suggest that EBV reactivation, when occurring within a genetically predisposed peripheral immune environment, is a proximal precursor of MS relapse.

Journal Article↗

CSF myelin basic protein, IgG and IgM levels in 101 MS patients before and after treatment with high-dose intravenous methylprednisolone.

A total of 101 patients (62 women; 39 men) with definite MS were treated with 1000 mg methylprednisolone (MP) intravenously for 10 consecutive days. Immediately before and after MP treatment clinical scoring (Kurtzke's Expanded Disability Status Scale) and CSF analysis were performed. Before MP treatment CSF MBP, IgG and IgM immunoglobulin levels (CSF Ig, index and intrathecal synthesis) were significantly elevated. The mean CSF MBP levels were significantly higher in the relapsing-remitting (RR) and chronic progressive MS patients with relapses (CP + RR) than in the CP group without a RR disease course, respectively 2.1, 2.3 and 1.5 micrograms/l. A weak positive correlation was found between CSF MBP level and EDSS in the RR MS group (r = 0.34). CSF MBP was significantly correlated with IgM index (r = 0.36), IgM synthesis (r = 0.26), but not with the IgG levels. Therefore demyelination seems to be related to intrathecal IgM production. After MP treatment mean (median) EDSS decreased from 4.4 (4.0) to 3.3 (3.0). Except for Q albumin and IgM index, all CSF immunoglobulin levels decreased significantly after MP. The mean CSF MBP returned to reference values. In the RR group the decrease in CSF MBP was significantly correlated with the change in EDSS (r = 0.39). CSF MBP seems to be a good parameter for disease activity in relapsing MS. Following treatment CSF MBP was found to be related with the change in IgM index (r = 0.30). MP treatment reduces CSF MBP and intrathecal IgM in a similar way indicating a relation between these 2 parameters.

Adult↗

Serial analysis of circulating adhesion molecules and TNF receptor in serum from patients with multiple sclerosis: cICAM-1 is an indicator for relapse.

We determined the serum levels for circulating adhesion molecules (circulating intercellular adhesion molecule-1 [cICAM-1], circulating endothelial leukocyte adhesion molecule-1 [cELAM-1], and circulating L-selectin [cL-selectin]) and circulating tumor necrosis factor receptor (cTNF-R) p60 in 29 patients with relapsing-remitting MS serially over a period of 12 months. During this period there were 27 relapses in 14 patients (48%). There was progression of disease activity in 12/25 patients (48%), as assessed by the occurrence of new lesions on nonenhancing, T2-weighted MRIs of the head. Clinically active patients with relapse or disease progression on MRI (n = 18) had frequent fluctuations in their serum levels for cICAM-1 if compared to patients with stable MS (n = 11). There were significant differences in the cumulative cICAM-1 production between the two groups (502 +/- 218 ng/ml in active versus 225 +/- 82 ng/ml in stable MS patients; p < 0.001). cTNF-R p60 serum levels were higher in patients with stable compared to active disease (2.3 +/- 0.5 ng/ml versus 1.5 +/- 0.6 ng/ml; p < 0.005). A significant increase in cICAM-1 levels was present at the time of a relapse (799 +/- 263 ng/ml versus 449 +/- 95 ng/ml; p < 0.001), whereas the highest serum levels for cTNF-R p60 occurred 4 weeks after the onset of a relapse (1.8 +/- 0.5 ng/ml at relapse versus 2.3 +/- 0.6 ng/ml 4 weeks after a relapse; p < 0.01). Interestingly, the cL-selectin serum levels in all MS patients were significantly higher than in healthy donors, whereas there were no differences for cELAM-1. These results reflect distinct changes of inflammatory variables in serum of patients with MS and revealed that cICAM-1 is an indicator for disease activity and that high serum levels for cTNF-R p60 are associated with remission.

Adult↗

Intravenous immunoglobulin G reduces MRI activity in relapsing multiple sclerosis.

We wanted to assess whether intravenous immunoglobulin G (IVIG) decreases disease activity on MRI in relapsing MS. Previous trials of IVIG in relapsing-remitting MS demonstrated a reduction of acute relapses, but these studies did not include MRI. We treated 26 patients in a randomized, double-blind, crossover study of IVIG 1 g/kg daily or placebo on 2 consecutive days every month during two 6-month treatment periods. The primary end point was the number of gadolinium-enhancing lesions on monthly serial MRI. Secondary efficacy variables were the occurrence of exacerbations, clinical neurologic ratings, total MS lesion load on T2-weighted MRI, and multimodal evoked potentials. Eighteen patients completed the entire trial; eight patients did not. Twenty-one patients completed the first treatment period and at least two MRI examinations in the second treatment period and were included in the intention-to-treat analysis. On serial MRI, we observed fewer enhancing lesions per patient per scan during IVIG treatment (median, 0.4; range, 0 to 9.3) than during placebo treatment (median, 1.3; range, 0.2 to 25.7; p = 0.03). During IVIG treatment, 15 patients were exacerbation free compared with only 7 on placebo (p = 0.02). The total number of exacerbations in the IVIG period was 11 and in the placebo period, 19 (not significant). None of the remaining secondary efficacy measures were significantly different between the two treatment periods. The number of adverse events, in particular eczema, was significantly higher during IVIG therapy than during placebo treatment. These results suggest that IVIG treatment is beneficial to patients with relapsing MS.

Adolescent↗

Elevated serum and CSF levels of soluble CD30 during clinical remission in multiple sclerosis.

OBJECTIVE: To ascertain the presence of the Th2 response in MS patients by evaluating the level of soluble (s) CD30 across the clinical spectrum of MS and during relapse and remission. BACKGROUND: MS is considered a T-cell-mediated disorder with the immune attack dominated by a Thl cytokine response. Elevated levels of sCD30 have been associated with CD4+ cells that secrete Th2-type cytokines. METHODS: Levels of sCD30 were determined in the serum and CSF of patients with primary progressive MS, secondary progressive MS, relapsing-remitting MS (RRMS), both in relapse and remission, and in patients with other inflammatory neurologic disease (IND) and noninflammatory neurologic disease (NIND). None of the patients were on immunomodulatory treatment. RESULTS: Higher serum levels of sCD30 were detected in all MS subgroups and IND patients compared with NIND patients. RRMS patients in remission had significantly higher levels than those in relapse (median, 45.7 U/mL versus 18.3 U/mL; p = 0.04). Significantly higher CSF levels were also found in all groups, except those with RRMS in relapse compared with NIND patients. Again, RRMS patients in remission had higher CSF sCD30 levels compared with those in relapse (median, 4.0 U/mL versus 3.0 U/mL; p = 0.08). CONCLUSIONS: Serum and CSF levels of sCD30 are increased in MS, particularly during remission. The results provide additional evidence for the presence of a Th2 response and indicate that sCD30 may be of value as a marker of lesion resolution.

Biomarkers↗

The effect of anti-alpha4 integrin antibody on brain lesion activity in MS. The UK Antegren Study Group.

OBJECTIVE: To determine the effect of humanized monoclonal antibody against alpha4 integrin (reactive with alpha4beta1 integrin or very-late antigen-4) on MRI lesion activity in MS. METHODS: A randomized, double-blind, placebo-controlled trial in 72 patients with active relapsing-remitting and secondary progressive MS was performed. Each patient received two IV infusions of anti-alpha4 integrin antibody (natalizumab; Antegren) or placebo 4 weeks apart and was followed up for 24 weeks with serial MRI and clinical assessment. RESULTS: The treated group exhibited significantly fewer new active lesions (mean 1.8 versus 3.6 per patient) and new enhancing lesions (mean 1.6 versus 3.3 per patient) than the placebo group over the first 12 weeks. There was no significant difference in the number of new active or new enhancing lesions in the second 12 weeks of the study. The number of baseline-enhancing lesions (i.e., lesions that enhanced on the baseline scan) that continued to enhance 4 weeks following the first treatment was not significantly different between the two groups. The number of patients with acute MS exacerbations was not significantly different in the two groups during the first 12 weeks (9 in the treated group versus 10 in placebo) but was higher in the treatment group in the second 12 weeks (14 versus 3; p = 0.005). The study was not, however, designed to look definitively at the effect of treatment on relapse rate. Treatment was well tolerated. CONCLUSIONS: Short-term treatment with monoclonal antibody against alpha4 integrin results in a significant reduction in the number of new active lesions on MRI. Further studies will be required to determine the longer term effect of this treatment on MRI and clinical outcomes.

Adult↗

Dysregulation of the hypothalamo-pituitary-adrenal axis is related to the clinical course of MS.

OBJECTIVE: To investigate whether dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis is related to clinical characteristics in MS. METHODS: The authors performed the combined dexamethasone-corticotropin-releasing hormone test (Dex-CRH test) in 60 MS patients and 29 healthy control subjects. In addition, the short adrenocorticotropic hormone (ACTH) test was performed in 39 consecutive patients. All patients had active disease and none were treated with glucocorticoids, immunosuppressants, or immunomodulators. RESULTS: The patients had an exaggerated rise in plasma cortisol concentrations in the Dex-CRH test (p < 0.05), indicating hyperactivity of the HPA system. The degree of hyperactivity was moderate in relapsing-remitting MS patients (n = 38; area under the time-course curve for cortisol [AUC-Cort] 226.2+/-38.9 arbitrary units [AU], mean +/- SEM), intermediate in secondary progressive MS patients (n = 16; AUC-Cort, 286.8+/-60.2 AU), and marked in primary progressive MS patients (n = 6; AUC-Cort, 670.6+/-148.6 AU). Differences were significant between the three patient groups (p < 0.005), and between control subjects (n = 29; AUC-Cort, 150.8+/-34.1 AU) and each patient group. Indicators of HPA axis activation correlated with neurologic disability (Kurtzke's Expanded Disability Status Scale), but not with the duration of the disease, number of previous relapses, previous corticosteroid treatments, or depressed mood (Hamilton Depression Scale). The ACTH test was normal in 31 of the 33 patients studied. CONCLUSION: HPA axis hyperactivity in MS is related to the clinical type of disease, with a suggestion of increasing HPA axis dysregulation with disease progression.

Adrenocorticotropic Hormone↗

Chronic relapsing necrotizing encephalomyelitis produced by myelin basic protein in mice.

Chronic relapsing experimental autoimmune encephalomyelitis is commonly seen in a number of species after a single injection of whole white matter in adjuvant but not after inoculation with myelin basic protein, the major encephalitogen of central myelin. In the present report on large groups of SJL mice, we describe a form of chronic relapsing experimental autoimmune encephalomyelitis with destructive lesions after a single inoculation of myelin basic protein in complete Freund's adjuvant. This condition was studied for up to 19 months postinoculation and was characterized by a relapsing-remitting or a chronic progressive course, usually with a prolonged latent period. Higher doses of 400 and 800 micrograms of myelin basic protein were more effective in inducing this condition than were lower doses of 100 and 200 micrograms. Large lesions were apparent in the white matter. These comprised widespread destruction and Wallerian degeneration with some demyelination towards the margins. Demyelination was an initial, albeit transient, event which was subsequently masked by nerve fiber destruction. Polymorphonuclear leukocytes were early and prominent components of the inflammatory infiltrate and together with macrophages appeared to be involved in the lysis of myelin and axons. Thus, despite the clinical similarities, these features contrast the model with the more purely demyelinative lesions of chronic relapsing experimental autoimmune encephalomyelitis in other species and multiple sclerosis in man.

Adjuvants, Immunologic↗

Neuroimaging in multiple sclerosis.

Modern neuroimaging, and in particular magnetic resonance imaging (MRI), has made a major contribution to the assessment of patients with multiple sclerosis. Brain MRI is the single most useful diagnostic investigation, and recent improvements in the quality of spinal cord imaging make MRI of this region a powerful tool in the evaluation of patients with undiagnosed myelopathies or with probable multiple sclerosis but equivocal findings on brain imaging. Putative MR markers of inflammation and axonal loss have, respectively, provided new insights into the mechanisms of relapse and remission on the one hand and persistent disability on the other. Monthly MRI is a powerful method for screening new therapies in relapsing-remitting and relapsing-progressive disease, but because of the uncertain relationship between short-term MRI activity and long-term disability, definitive trials should continue to have primary clinical endpoints.

Diagnostic Imaging↗

[Course of illness and prognosis of multiple sclerosis. 1: The natural illness course].

This review summarizes the natural history of multiple sclerosis (MS) in terms of disease type, survival, relapse rate and recovery as well as disability. The course of Ms is highly variable and individually difficult to predict. In epidemiological studies, the most common type of MS is the relapsing-remitting form. However, after 10-15 years of disease duration, 30-40% of patients will develop chronic progressive MS. Survival of all MS patients is only mildly affected, but markedly decreased in severely disabled patients mainly due to secondary complications. Suicide is more frequent in MS patients than in normals, especially within the first 5 years of the disease. The mean relapse rate ranges from approximately 0.5 to 0.8 relapses per year and decreases with time. Most patients will recover from relapses within 4 weeks. 50% of patients will require some form of walking aid within 15-18 years from onset. 20-40% of patients have ,,benign" MS, i.e. no or only mild disability after 10 years of MS.

Activities of Daily Living↗