Florian Then Bergh

Neuromyelitis optica: Evaluation of 871 attacks and 1,153 treatment courses.

Neuromyelitis optica (NMO) attacks often are severe, are difficult to treat, and leave residual deficits. Here, we analyzed the frequency, sequence, and efficacy of therapies used for NMO attacks.

Activity of the hypothalamic-pituitary-adrenal axis in multiple sclerosis: correlations with gadolinium-enhancing lesions and ventricular volume.

The known interaction between the immune system and the hypothalamic–pituitary–adrenal axis led us to explore the interrelation between magnetic resonance imaging findings and the hypothalamic–pituitary–adrenal axis activity in 53 multiple sclerosis patients. The cortisol release induced by the dexamethasone‐corticotropin‐releasing hormone test was negatively associated with the presence and number of gadolinium‐enhancing lesions and positively associated with ventricular size. This finding suggests a protective effect of the hypothalamic– pituitary–adrenal drive on acute lesional inflammation in multiple sclerosis, probably by limiting immune overshoot. In contrast, the nature of the correlation between hypothalamic–pituitary–adrenal hyperdrive and brain atrophy remains to be determined.

Monthly intravenous methylprednisolone in relapsing-remitting multiple sclerosis - reduction of enhancing lesions, T2 lesion volume and plasma prolactin concentrations

BackgroundIntravenous methylprednisolone (IV-MP) is an established treatment for multiple sclerosis (MS) relapses, accompanied by rapid, though transient reduction of gadolinium enhancing (Gd+) lesions on brain MRI. Intermittent IV-MP, alone or with immunomodulators, has been suggested but insufficiently studied as a strategy to prevent relapses.MethodsIn an open, single-cross-over study, nine patients with relapsing-remitting MS (RR-MS) underwent cranial Gd-MRI once monthly for twelve months. From month six on, they received a single i.v.-infusion of 500 mg methylprednisolone (and oral tapering for three days) after the MRI. Primary outcome measure was the mean number of Gd+ lesions during treatment vs. baseline periods; T2 lesion volume and monthly plasma concentrations of cortisol, ACTH and prolactin were secondary outcome measures. Safety was assessed clinically, by routine laboratory and bone mineral density measurements. Soluble immune parameters (sTNF-RI, sTNF-RII, IL1-ra and sVCAM-1) and neuroendocrine tests (ACTH test, combined dexamethasone/CRH test) were additionally analyzed.ResultsComparing treatment to baseline periods, the number of Gd+ lesions/scan was reduced in eight of the nine patients, by a median of 43.8% (p = 0.013, Wilcoxon). In comparison, a pooled dataset of 83 untreated RR-MS patients from several studies, selected by the same clinical and MRI criteria, showed a non-significant decrease by a median of 14% (p = 0.32). T2 lesion volume decreased by 21% during treatment (p = 0.001). Monthly plasma prolactin showed a parallel decline (p = 0.027), with significant cross-correlation with the number of Gd+ lesions. Other hormones and immune system variables were unchanged, as were ACTH test and dexamethasone-CRH test. Treatment was well tolerated; routine laboratory and bone mineral density were unchanged.ConclusionMonthly IV-MP reduces inflammatory activity and T2 lesion volume in RR-MS.

Breastfeeding is associated with lower risk for multiple sclerosis.

Background: Multiple sclerosis (MS) is an autoimmune disease with known genetic and environmental susceptibility factors. Breastfeeding has been shown to be protective in other autoimmune diseases. Objective: This case-control study analyzed the association of breastfeeding in infancy on the risk of developing MS. Methods: A case-control study was performed in Berlin of 245 MS patients and 296 population-based controls, who completed a standardized questionnaire on their history and duration of breastfeeding in infancy and demographic characteristics. Univariable and multivariable logistic regression analysis was performed to investigate the association between breastfeeding and MS. The multivariate model was adjusted for age, gender, number of older siblings, number of inhabitants in place of domicile between ages 0 and 6 (categorized in each case), and daycare attendance between ages 0 and 3. Results: In multivariable analysis, breastfeeding showed an independent association with MS (adjusted OR 0.58; p = 0.028). However, with no breastfeeding as reference, the protective effect only emerges after four months of breastfeeding (multivariable analysis for ≤ four months adjusted OR 0.87; p = 0.614 and for > four months OR 0.51; p = 0.016). Conclusion: The results of this case-control study support the hypothesis that breastfeeding is associated with a lower risk of MS. These results are in line with findings of previous studies on other autoimmune diseases, in which breastfeeding was shown to have protective effects.

Environmental factors in early childhood are associated with multiple sclerosis: a case-control study

BackgroundMultiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) with increasing incidence mainly in high-income countries. One explanation of this phenomenon may be a higher prevalence of allergic and autoimmune diseases in industrialized countries as a consequence of otherwise beneficial advances in sanitation (hygiene hypothesis). We investigated environmental factors in early childhood associated with MS.MethodsA case-control study was performed of 245 MS patients and 296 population-based controls in Berlin. The study participants completed a standardized questionnaire on environmental factors in childhood and youth, including aspects of personal and community hygiene. Multivariable logistic regression analysis was performed to investigate factors in childhood and youth associated with the occurrence of MS.ResultsMean age was 46 years (range, 20-80) in the MS group and 42 years (range 18-80) in the control group, of which 73.9% in the MS and 61.5% in the control group were female. The multivariable analysis showed that having at least two older siblings (OR 0.54; p = 0.05, for individuals with two older siblings compared to individuals without older siblings), attending a day-care center (OR 0.5; p = 0.004) and growing up in an urban center with more than 100, 000 inhabitants (OR 0.43; p = 0.009) were factors independently associated with a lower chance for MS.ConclusionsThe hygiene hypothesis may play a role in the occurrence of MS and could explain disease distribution and increasing incidence.

Humoral and cellular immune parameters before and during immunosuppressive therapy of a patient with stiff-man syndrome and insulin dependent diabetes mellitus

OBJECTIVES Humoral and cellular immune reactivity are reported for two neuroendocrine autoantigens—glutamic acid decarboxylase (GAD) and the protein tyrosine phosphatase IA-2—in a patient with the autoimmune type of stiff-man syndrome and insulin dependent diabetes (IDDM). METHODS Antibodies and T cell proliferation against GAD and IA-2 and cytokine release of antigen stimulated T cells (IFN-γ) were determined before and several times during immunosuppressive therapy with prednisolone. RESULTS Raised GAD antibodies against full length GAD65 or chimeric constructs were detected before therapy and they remained at a high concentration despite a marked clinical improvement during cortisone treatment. Antibodies to IA-2 were undetectable, but weak T cell responses to both GAD and IA-2 were seen before therapy and once on reduction of high cortisone dosages when the patient showed signs of clinical deterioration. Cytokine profiles showed increased IFN-γ production after stimulation with GAD or IA-2 suggesting increased activation of TH1 cells. CONCLUSION Immunosuppressive therapy —even with extremely high doses of 500 mg a day—does not lead to the reduction of antibody concentrations in the periphery nor to a switch in epitope recognition of such antibodies despite clinical improvement. The amount of T cell reactivity to various antigens, however, may be a useful marker to monitor the effectiveness of immunotherapy.

Cerebellar manifestation of PML under fumarate and after efalizumab treatment of psoriasis

Fumaric acid, first applied topically in psoriasis, has also been used orally since the mid-1980s. A preparation of dimethyl fumarate, BG-12, reduces disease activity in multiple sclerosis (MS) [2] and has been licensed, with recent market introduction in Europe. Despite common lymphopenia, no serious opportunistic infections had been attributed to it before two recent cases of progressive multifocal leukoencephalopathy (PML) [1, 9], with two more cases on file with the manufacturer [8]. We report details of one of these additional cases. A Caucasian man, diagnosed with psoriasis in 1995, received local corticosteroids and occasionally steroid tablets, vitamin D3-analogues, UVB therapy, and acitretin. Treatment with efalizumab (2006–2007) was satisfactory, but discontinued for superficial spreading malignant melanoma on the cheek (Clark-level II, excision in sano). Oral fumarate (Fumaderm , Biogen-Idec) was initiated in 2007 (Fig. 1, top panel). He was referred in July 2010 with a two-month history of slurred speech, unstable walking, and progressive decline in left-sided coordination that eventually left him unable to climb stairs. Examination showed left-sided hemiataxia and dysarthria without motor, sensory, or cognitive impairment. On brain magnetic resonance imaging (MRI, Fig. 1 bottom panel), lesions in the left cerebellar peduncle and pons enhanced with gadolinium. Polymerase chain reaction (qPCR) detected [2,000 copies of JCV-DNA/ml (Universities Leipzig, Düsseldorf) in the cerebrospinal fluid (CSF), which was otherwise normal. Peripheral blood analysis revealed lymphopenia, CD4? T cell deficiency (131/ll), and reduced IgG concentration (Fig. 1, middle panel). After exclusion of malignoma, HIV, and tuberculosis, lymphopenia was regarded as fumarate-induced. We discontinued fumarate, substituted immunoglobulin, and initiated mirtazapine [5] in August 2010. Clinical course stabilized and improved to walking for 20 min with bilateral assistance. In October 2010, an acute lower respiratory tract infection led to clinical worsening, but resolved with antibiotic treatment. In March 2011, JCVPCR of CSF was reported negative (University Leipzig). In September 2011, walking distance decreased to 410 m with walking frame; brain MRI showed a new, non-enhancing lesion in the right cerebellar peduncle; CSF JCV-PCR detected 19 copies/ml (NIH), identifying only the virulent ‘‘prototype’’, with undetectable non-virulent ‘‘archetype’’. Since deterioration was gradual rather than acute, and in the absence of Gd-enhancing lesions, the relapse was not considered PML-associated ‘‘immune reconstitution induced syndrome’’ (PML-IRIS). Treatment with M. Stoppe E. Thomä J. Claßen F. Then Bergh (&) Department of Neurology, University of Leipzig, Liebigstraße 20, 04103 Leipzig, Germany e-mail: ThenBerF@medizin.uni-leipzig.de

Binding characteristics of the glucocorticoid receptor in peripheral blood lymphocytes in multiple sclerosis

Abstract Although the exact etiology of multiple sclerosis (MS) remains unresolved, immune reactions are believed to be the central pathogenic mechanisms. Endogenous and therapeutic steroid hormones affect the immune system, and inflammatory diseases are associated with activation of the hypothalamic-pituitary-adrenal axis, providing evidence of an immune-endocrine interplay. Function tests in MS have revealed dysregulation of the hypothalamic-pituitary-adrenal system in a substantial proportion of patients. We characterized glucocorticoid receptor (GR) binding in peripheral blood lymphocytes from 39 MS patients and 14 age- and sex-matched controls with respect to dissociation constant and binding capacity, using a whole-cell binding assay with [3H]dexamethasone as the ligand. GR binding parameters did not differ significantly between patients (Kd 8.98 ± 1.07 nM, Bmax 183 ± 29.8 fmol/mg) and controls (Kd 9.36 ± 1.17 nM, Bmax 158 ± 16 fmol/mg). No effect of age, sex, course, duration or severity of disease, or prior steroid treatments was detected. GR binding parameters were analyzed in relation to the results of the combined dexamethasone-CRH test, which reflects corticosteroid receptor function at the hypothalamus, in 30 patients and 9 controls. While controls showed a moderate correlation between binding affinity of the GR in lymphocytes and regulatory function at the hypothalamic level, the patients did not. These data suggest that the physiological relationship between binding and function of the glucocorticoid receptor is disturbed in MS.

Pain in patients with multiple sclerosis: a complex assessment including quantitative and qualitative measurements provides for a disease-related biopsychosocial pain model.

Background: Pain of various causes is a common phenomenon in patients with Multiple Sclerosis (MS). A biopsychosocial perspective has proven a useful theoretical construct in other chronic pain conditions and was also started in MS. To support such an approach, we aimed to investigate pain in MS with special emphasis on separating quantitative and qualitative aspects, and its interrelation to behavioral and physical aspects. Materials and methods: Pain intensity (NRS) and quality (SES) were measured in 38 consecutive outpatients with MS (mean age, 42.0 ± 11.5 years, 82% women). Pain-related behavior (FSR), health care utilization, bodily complaints (GBB-24) and fatigue (WEIMuS) were assessed by questionnaires, and MS-related neurological impairment by a standardized neurological examination (EDSS). Results: Mean pain intensity was 4.0 (range, 0–10) and mean EDSS 3.7 (range, 0–8) in the overall sample. Currently present pain was reported by 81.6% of all patients. Disease duration and EDSS did not differ between patients with and without pain and were not correlated to quality or intensity of pain. Patients with pain had significantly higher scores of musculoskeletal complaints, but equal scores of exhaustion, gastrointestinal and cardiovascular complaints. Pain intensity correlated only with physical aspects, whereas quality of pain was additionally associated with increased avoidance, resignation and cognitive fatigue. Conclusion: As in other conditions, pain in MS must be assessed in a multidimensional way. Further research should be devoted to adapt existing models to a MS-specific model of pain.

Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation.

Genome-wide study in Germans identifies four novel multiple sclerosis risk genes and confirms already known gene loci. We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3, MAZ, ERG, and SHMT1. The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation. SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis.