[Tryptophan immunoadsorption for multiple sclerosis and neuromyelitis optica: therapy option for acute relapses during pregnancy and breastfeeding]. / Tryptophan-Immunadsorption bei Multipler Sklerose und Neuromyelitis optica : Therapieoption bei akuten Schüben in der Schwangerschaft und Stillphase.

BACKGROUND: Approximately 25 % of women with multiple sclerosis (MS) suffer clinically relevant relapses during pregnancy. Almost all disease-modifying drugs are contraindicated in pregnancy. High-dose glucocorticoids have some serious risks, especially within the first trimester. Tryptophan immunoadsorption (IA) provides a safe option to treat MS relapses during pregnancy. OBJECTIVES: In this case series we describe for the first time the use of tryptophan IA for MS and neuromyelitis optica (NMO) relapses during pregnancy and breastfeeding. PATIENTS AND METHODS: In this study a total of 9 patients were retrospectively analyzed of which 7 patients received IA treatment during pregnancy, 2 during breastfeeding and 4-6 tryptophan IA treatments were performed per patient with the single use tryptophan adsorber. Primary outcome was symptom improvement of the relapse. RESULTS: In this study four patients with MS and one with NMO relapse during pregnancy were treated with IA without preceding glucocorticoid pulse therapy. The MS patients showed improvement in the expanded disability status scale (EDSS) by at least one point, the NMO patient showed significant improvement in visual acuity and two pregnant patients with steroid-refractory relapses showed clinically relevant improvement after IA. Of the patients two suffered from steroid-refractory relapses during breastfeeding and relapse symptoms improved in both cases after treatment with IA. All treatments were well tolerated and no serious adverse events occurred. CONCLUSION: Tryptophan IA was found to be safe, well-tolerated and effective in the treatment of MS and NMO relapses during pregnancy and breastfeeding, sometimes without preceding glucocorticoid pulse therapy. A binding recommendation is limited without prospective clinical studies.

Reproductive counselling, treatment and course of pregnancy in 73 German MS patients.

Multiple sclerosis (MS) often affects women during the reproductive years of their life. During this period, issues such as choice of immunomodulatory treatment, seeking advice from specialists, relapse-induced steroid application before, during or after pregnancy in combination with breastfeeding gain importance. The objective was to investigate these issues retrospectively using a questionnaire among 73 MS patients with a total of 88 pregnancies. Eighty per cent of the participants consulted their neurologists before and 60% during pregnancy. The annual relapse rate decreased during pregnancy and significantly increased during the first 3 months after delivery. Immunomodulatory treatment was stopped due to desired pregnancy for a mean of 4 years. Fourteen of the MS patients received intravenous immunoglobulin treatment post-natal. Ninety per cent of the study subjects started breastfeeding. However, nearly 30% ablactated, as they received steroids due to a relapse. Weight and height of the full-term children of singleton pregnancies from MS patients were significantly lower compared with the ones of age-matched healthy controls. Our results confirm the known reduced relapse rate during pregnancy, which is followed by an increased relapse rate after delivery. They shed light on the epidemiology of childbirth in patients with MS.

Diffusion tensor imaging-based fractional anisotropy quantification in the corticospinal tract of patients with amyotrophic lateral sclerosis using a probabilistic mixture model.

BACKGROUND AND PURPOSE: In amyotrophic lateral sclerosis (ALS), fiber degeneration within the corticospinal tract (CST) can be quantified by diffusion tensor imaging (DTI) as an indirect marker of upper motor neuron involvement. A new method of measuring quantitative DTI parameters using a probabilistic mixture model for fiber tissue and background in the corticospinal tract of patients with ALS is evaluated. MATERIALS AND METHODS: Axial echo-planar imaging (EPI) DTI datasets (6 gradient directions, 10 repetitions) were acquired for 10 patients and 20 healthy control subjects. The diffusion tensor was visualized in a multiplanar viewer using a unique color coding method. Pure fiber tissue inside a region is separated from background and mixture voxels using a probabilistic mixture model. This allows for a reduction of errors as a result of partial volume effects and measurement variability. RESULTS: Fractional anisotropy (FA) was measured within the CST at levels ranging from internal capsule to pons. Mean coefficients of variation of intrarater, scan-rescan, and inter-rater reproducibility were 2.4%, 3.0%, and 5.7%, respectively. Optimal measurement positions along the CST with respect to minimum variability and maximum difference between patients and healthy subjects were identified in the caudal half of the internal capsule. Moreover, a negative correlation between the age-corrected FA and the disease duration but not the ALS Severity scale score was found. CONCLUSION: The new software for fiber integrity quantification is suited to assess FA in the corticospinal tract with high reproducibility. Thus, this tool can be useful in future studies for monitoring disease status and potential treatment efficiency.

Blockade of chemokine signaling in patients with multiple sclerosis.

We assessed the safety and efficacy of orally administered CC chemokine receptor 1 (CCR1) antagonist in 105 patients with relapsing/remitting MS (RRMS) in a 16-week, randomized, double-blind, placebo-controlled trial. The primary endpoint was the cumulative number of newly active lesions on serial MRI scans. Other MRI, immunologic, and clinical outcomes were also explored. No significant treatment difference was observed for any tested MRI variable. CCR1 does not contribute to initial leukocyte infiltration in RRMS.

Oral fumaric acid esters for the treatment of active multiple sclerosis: an open-label, baseline-controlled pilot study.

An exploratory, prospective, open-label study of fumaric acid esters (FAE, Fumaderm(R)) was conducted in patients with relapsing-remitting multiple sclerosis (RRMS). The study consisted of the following four phases: 6-week baseline, 18-week treatment (target dose of 720 mg/day), 4-week washout, and a second 48-week treatment phase (target dose of 360 mg/day). Ten patients with an Expanded Disability Status Scale (EDSS) score of 2.0-6.0 and at least one gadolinium-enhancing (Gd+) lesion on T1-weighted magnetic resonance imaging (MRI) brain scans participated in the study. Safety was assessed by adverse events (AEs), blood chemistry/hematology, electrocardiogram, and urinalysis. The primary efficacy outcomes were number and volume of Gd+ lesions. Other clinical outcomes included EDSS score, ambulation index (AI), and nine-hole peg test (9-HPT). Effects of FAE on intracellular cytokine profiles, T-cell apoptosis, and soluble adhesion molecules were also assessed. Three patients withdrew during the first 3 weeks of the study because of side effects, non-compliance, and follow-up loss. The most common AEs were gastrointestinal symptoms and flushing; all AEs were reported as mild and reversible. FAE produced significant reductions from baseline in number (P < 0.05) and volume (P < 0.01) of Gd+ lesions after 18 weeks of treatment; this effect persisted during the second treatment phase at half the target dose after the 4-week washout period. EDSS scores, AI, and 9-HPT remained stable or slightly improved from baseline in all patients. Measures of T-cell function demonstrated alterations in cytokines and circulating tumor necrosis factor. The results of this exploratory study suggest that further studies of FAE in patients with MS are warranted.

Repeat intrathecal triamcinolone acetonide application is beneficial in progressive MS patients.

Available immunomodulatory and conventional steroid treatment regimens provide a limited symptomatic benefit for patients with progressive multiple sclerosis (MS). We performed an open trial on the short-term efficacy of repeated intrathecal application of the sustained release steroid triamcinolone acetonide (TCA) in 27 progressive MS patients. Six TCA administrations, performed every third day, reduced the Expanded Disability Status Scale (EDSS) score [initial: 5.4+/-1.3, 3-7.5 (mean+/-SD, range); end: 4.9+/-1.1; 2.5-6.5; P<0.001] and significantly increased the walking distance and speed in particular after the fourth TCA injection. Concomitantly serially determined cerebrospinal fluid (CSF) markers of cell injury, neuron-specific enolase, total tau-protein, S-100, and beta-amyloid did not significantly change within the interval of TCA treatment. No serious side effects appeared. We conclude that repeat intrathecal injection of 40 mg TCA provides a substantial benefit in progressive MS patients with predominant spinal symptoms and does not alter CSF markers of neuronal cell injury.

[MS registry in Germany--design and first results of the pilot phase]. / MS-Register in Deutschland -- Design und erste Ergebnisse der Pilotphase.

In the summer of 2001, a nationwide epidemiological multiple sclerosis (MS) register was initiated under the auspices of the German MS Society (DMSG). This project aimed at collecting epidemiological data on the number of patients with MS, course of the disease, and their social situation in Germany. During the 2-year pilot phase, five MS centers with various regional differences and treatment methods participated, leading to a representative selection of patients. In December 2003, standardised data sets of 3,458 MS patients were available for evaluation. After examining the quality of the data, 3,223 sets remained for further analysis. The demographics were similar to those obtained from other epidemiological studies: 72% of the patients were female, mean age was 42.9+/-11.2 years, mean disease duration 12.6+/-8.7 years, and 64% suffered from the relapsing-remitting form of the disease. The median EDSS was 3.0, and 69% of patients had an EDSS

Diagnosis of multiple sclerosis: comparison of the Poser criteria and the new McDonald criteria.

OBJECTIVES: A confident and accurate diagnosis of multiple sclerosis (MS) is important, but a specific diagnostic test for the disease does not exist. The traditional diagnostic criteria of Poser et al. were published in 1983, and recently, McDonald et al. recommended new criteria for the diagnosis of MS. PATIENTS AND METHODS: In this study these two diagnostic schemes were compared by prospectively applying both of them to 76 patients with clinical features suggesting a new diagnosis of MS. RESULTS: Using the Poser criteria, 29 patients (38%) were classified as clinically definite and 35 patients (46%) as laboratory definite MS. According to the new McDonald criteria, MS was diagnosed in 39 (52%) patients, 37 patients (48%) had 'possible MS'. All patients with a clinically definite MS with the Poser criteria were also given the diagnosis of MS as recommended by McDonald et al. Of those 35 patients with laboratory definite MS according to Poser et al., four patients could be classified as having MS with the McDonald criteria, 89% of them had 'possible MS'. Conversely, 75% of the 39 patients, who fulfilled the new McDonald criteria for MS were assigned to the category of clinically definite MS according to the Poser criteria, and 83% of the patients with a 'possible MS' using the McDonald criteria, had a laboratory definite MS with the Poser criteria. CONCLUSION: MS according to the McDonald criteria was diagnosed more often than 'clinically definite MS' according to Poser et al., but combining the categories of clinically and laboratory definite MS, the diagnosis of MS could clearly be established more frequently using the Poser criteria.

Inhibitors in the NFkappaB cascade comprise prime candidate genes predisposing to multiple sclerosis, especially in selected combinations.

Multiple sclerosis (MS) is an autoimmune disease displaying different clinical courses. In this multifactorial disease complex environmental as well as genetic predisposition factors contribute to the disease manifestation. Following the candidate gene approach we analysed several genes of the NFkappaB cascade, which are prime candidates for MS because of their involvement in almost all immunological reactions. MS association was excluded for the NFKB1 and NFKB3 genes, which show remarkably low degrees of polymorphism. The genes of NFkappaB inhibitors exhibit more sequence variations. In the IKBL gene a predisposing allele was identified (13.1% vs 7.5% in the control group, P < 0.001). This difference in the allelic distribution was even increased in the group of MS patients with a relapsing remitting course of the disease (14.9%, P < 0.0001). A protecting allele was found in the NFKBIA promotor for the patients with primary progressive MS (15.4% vs 28.4% in the control group, P < 0.01). Given predisposing alleles increase MS risk dramatically in certain combinations.

Multiple sclerosis: modulation of apoptosis susceptibility by glatiramer acetate.

OBJECTIVES: We investigated whether therapy of multiple sclerosis (MS) with glatiramer acetate (GA) involves the modulation of programmed cell death (apoptosis) in disease-relevant T-helper lymphocytes. MATERIAL AND METHODS: Blood was drawn from 15 relapsing-remitting MS patients both before (baseline) as well as 6, 12, and 18 weeks after GA therapy and from 15 healthy controls. Detection of apoptosis was performed in response to in vitro stimulation with GA, myelin basic protein or medium alone. RESULTS: T-helper lymphocytes from untreated MS patients displayed an overall increased apoptosis susceptibility in vitro, compared to controls. During subsequent GA therapy, apoptosis vulnerability of these T cells in MS patients significantly declined under the initial baseline before treatment, and was finally equal in treated patients and controls. GA itself had no direct apoptosis-modulatory properties in vitro. CONCLUSION: Our findings indicate that therapy of multiple sclerosis with glatiramer acetate presumably involves the compensation of altered apoptosis in T-helper lymphocytes.

Therapeutic immunoadsorption increases the level of circulating soluble HLA molecules.

BACKGROUND AND OBJECTIVES: Immunoadsorption (IA) is an established procedure to remove Igs and immune complexes from peripheral blood. Since Igs reportedly bind to human leucocyte antigen (HLA) molecules, we were interested to know whether removal of Ig will also influence the plasma concentration of soluble HLA (sHLA). PATIENTS AND METHODS: Nine patients suffering from severe autoimmune disease and undergoing 17 single courses of IA treatment were monitored for their sHLA class I (sHLA-I) and sHLA-DR plasma levels. Plasma was separated by a hollow-fiber-type separator. Plasma samples were taken before therapy, after 15 min of recirculation (without operating the adsorber), after 1 and 2 liters of plasma adsorption, and 24 and 48 h after the end of IA. RESULTS: Before treatment the mean levels of sHLA-I and sHLA-DR were 0.37 (+/-0.06 SEM) and 0. 32+/-0.05 microg/ml, respectively. After 2 liters of plasma filtration, an increase in sHLA-DR (0.80+/-0.10 microg/ml) was observed (p<0.001), whereas sHLA-I was only slightly affected (mean: 0.45+/-0.06 microg/ml). sHLA concentrations returned to initial levels after 24 h. CONCLUSION: The significant increase in sHLA-DR may contribute to the immunomodulatory effect of IA.

[Mechanisms of action of intravenous immunoglobulins]. / Wirkmechanismen intravenöser Immunglobuline.

Intravenous immunoglobulins (IVIG) are now used to treat various diseases, including autoimmune diseases, systemic inflammatory diseases, allografts and for replacement therapy in the case of IgG deficiency. Only in some of the indications has the efficacy of this treatment been confirmed in large-scale studies. Also, in many cases the modes of action remain unclear. Principally, the following therapeutic strategies can be differentiated: Replacement treatment, blocking of the effector molecules, influencing of the cellular and humoral limbs of the immune defence system and interaction with cytokines. In certain CNS diseases, displacement of pathological immunoglobulins may be involved. It would be desirable to acquire more detailed knowledge about modes of action with the aim of using IVIG with greater specificity in the future.