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Background. The pharmacological treatment options of Parkinson’s disease (PD) have considerably evolved during the last decades. However, therapeutic regimes are complicated due to individual differences in disease progression as well as the occurrence of complex nonmotor impairments such as mood and anxiety disorders. Antidepressants in particular are commonly prescribed for the treatment of depressive symptoms and anxiety in PD. Case Presentation. In this case report, we describe a case of a 62-year-old female patient with PD and history of depressive symptoms for which she had been treated with moclobemide concurrent with anti-Parkinson medications pramipexole, rasagiline, and L-DOPA+benserazide retard. An increase in the dosage of moclobemide 12 months prior to admission progressively led to serotonergic overstimulation and psychovegetative exacerbations mimicking the clinical picture of an anxiety spectrum disorder. After moclobemide and rasagiline were discontinued based on the hypothesis of serotonergic overstimulation, the patient’s psychovegetative symptoms subsided. Conclusions. The specific pharmacological regime in this case probably caused drug-drug interactions resulting in a plethora of psychovegetative symptoms. Likely due to the delayed onset of adverse effects, physicians had difficulties in determining the pharmacologically induced serotonin toxicity. This case report emphasizes the complexity of pharmacological treatments and the importance of drug-drug interaction awareness in the treatment of PD patients with complicating nonmotor dysfunctions such as depression.

Pain is frequent in multiple sclerosis (MS) and includes different types, with neuropathic pain (NP) being most closely related to MS pathology. However, prevalence estimates vary largely, and causal relationships between pain and biopsychosocial factors in MS are largely unknown. Longitudinal studies might help to clarify the prevalence and determinants of pain in MS. To this end, we analyzed data from 410 patients with newly diagnosed clinically isolated syndrome or relapsing-remitting MS participating in the prospective multicenter German National MS Cohort Study (NationMS) at baseline and after 4 years. Pain was assessed by self-report using the PainDETECT Questionnaire. Neuropsychiatric assessment included tests for fatigue, depression, and cognition. In addition, sociodemographic and clinical data were obtained. Prevalence of pain of any type was 40% and 36% at baseline and after 4 years, respectively, whereas prevalence of NP was 2% and 5%. Pain of any type and NP were both strongly linked to fatigue, depression, and disability. This link was even stronger after 4 years than at baseline. Moreover, changes in pain, depression, and fatigue were highly correlated without any of these symptoms preceding the others. Taken together, pain of any type seems to be much more frequent than NP in early nonprogressive MS. Moreover, the close relationship between pain, fatigue, and depression in MS should be considered for treatment decisions and future research on a possible common pathophysiology.

Multiple sclerosis is a disease of the central nervous system characterized by recurrent inflammatory demyelinating lesions in the early disease stage. Lesion formation and mechanisms leading to lesion remyelination are not fully understood. Matrix Assisted Laser Desorption Ionisation Mass Spectrometry imaging (MALDI-IMS) is a technology which analyses proteins and peptides in tissue, preserves their spatial localization, and generates molecular maps within the tissue section. In a pilot study we employed MALDI imaging mass spectrometry to profile and identify peptides and proteins expressed in normal-appearing white matter, grey matter and multiple sclerosis brain lesions with different extents of remyelination. The unsupervised clustering analysis of the mass spectra generated images which reflected the tissue section morphology in luxol fast blue stain and in myelin basic protein immunohistochemistry. Lesions with low remyelination extent were defined by compounds with molecular weight smaller than 5300Da, while more completely remyelinated lesions showed compounds with molecular weights greater than 15,200Da. An in-depth analysis of the mass spectra enabled the detection of cortical lesions which were not seen by routine luxol fast blue histology. An ion mass, mainly distributed at the rim of multiple sclerosis lesions, was identified by liquid chromatography and tandem mass spectrometry as thymosin beta-4, a protein known to be involved in cell migration and in restorative processes. The ion mass of thymosin beta-4 was profiled by MALDI imaging mass spectrometry in brain slides of 12 multiple sclerosis patients and validated by immunohistochemical analysis. In summary, our results demonstrate the ability of the MALDI-IMS technology to map proteins within the brain parenchyma and multiple sclerosis lesions and to identify potential markers involved in multiple sclerosis pathogenesis and/or remyelination.

Summary The autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) syndrome is a genetic disorder caused by a mutation in the autoimmune regulator (AIRE) gene. Immune deficiency, hypoparathyroidism and Addison’s disease due to autoimmune dysfunction are the major clinical signs of APECED. We report on a 21-year-old female APECED patient with two inactivating mutations in the AIRE gene. She presented with sudden onset of periodic nausea. Adrenal insufficiency was diagnosed by means of the ACTH stimulation test. Despite initiation of hormone replacement therapy with hydrocortisone and fludrocortisone, nausea persisted and the patient developed cognitive deficits and a loss of interest which led to the diagnosis of depression. She was admitted to the psychiatric department for further diagnostic assessment. An EEG showed a focal epileptic pattern. Glutamic acid decarboxylase (GAD) antibodies, which had been negative eight years earlier, were now elevated in serum and in the cerebrospinal fluid. Oligoclonal bands were positive indicating an inflammatory process with intrathecal antibody production in the central nervous system (CNS). The periodic nausea was identified as dialeptic seizures, which clinically presented as gastrointestinal aura followed by episodes of reduced consciousness that occurred about 3–4 times per day. GAD antibody-associated limbic encephalitis (LE) was diagnosed. Besides antiepileptic therapy, an immunosuppressive treatment with corticosteroids was initiated followed by azathioprine. The presence of nausea and vomiting in endocrine patients with autoimmune disorders is indicative of adrenal insufficiency. However, our case report shows that episodic nausea may be a symptom of epileptic seizures due to GAD antibodies-associated LE in patients with APECED. Learning points: Episodic nausea cannot only be a sign of Addison’s disease, but can also be caused by epileptic seizures with gastrointestinal aura due to limbic encephalitis. GAD antibodies are not only found in diabetes mellitus type 1, but they are also associated with autoimmune limbic encephalitis and can appear over time. Limbic encephalitis can be another manifestation of autoimmune disease in patients with APECED/APS-1 that presents over the time course of the disease.

Objectives There is convergent evidence for an important role of interleukin-16 (IL-16) in the pathogenesis of multiple sclerosis (MS). IL-16 serves as a chemoattractant for different immune cells that are involved in developing lesions. Here, we compared IL-16 levels of MS patients and controls and addressed the long-term effect of IFN-β, the most common immunomodulatory MS therapy, on IL-16 serum levels in MS patients over 2 years. Beyond this, we analysed the expression of IL-16 in two CD4+ T-cell subsets, Th1 and Th17 cells, which are important autoimmune mediators and affected by IFN-β treatment, derived from myelin-specific T-cell transgenic mice. Materials and methods IL-16 serum levels of 17 controls and of 16 MS patients before therapy and at months 1, 2, 3, 6, 9, 12 and 24 during IFN-β1a therapy were determined by ELISA. MRI was performed before therapy, at months 12 and 24. IL-16 expression of in vitro differentiated murine myelin oligodendrocyte glycoprotein (MOG)-specific Th1 and Th17 cells was quantified by real-time PCR. Results Before therapy, MS patients showed significantly elevated IL-16 levels compared with controls irrespective of disease activity determined by MRI. Therapy with IFN-β1a led to a significant linear decrease in IL-16 serum levels beginning after 2 months. MOG-specific Th17 cells expressed more IL-16 than Th1 cells. Conclusions Reduction in increased IL-16 levels may be of relevance for the therapeutic effect of IFN-β1a in MS. Easily accessible IL-16 serum levels hold a potential as biomarker of treatment efficacy in MS.

Multiple sclerosis (MS) is characterized by inflammation, axonal and oligodendrocyte pathology and progressive neurological disability. Epidemiologic data indicate that MS may be caused by interplay of genetic and environmental factors. Large samples collected in cooperative efforts and new technologies such as high throughput single nucleotide polymorphism (SNP) genotyping allowed recently to discover non-HLA genes associated with MS susceptibility that are mostly involved in the immune response. In addition, several studies indicate an effect of genetic variations on disease onset, progression and response to therapy. However, the polymorphisms discovered so far explain the genetic variation in MS only in part and are mostly common variants that have only low impact on MS susceptibility. Functional studies are required to validate the importance of the newly identified SNPs. Taking into account the interplay of genetic and environmental factors a combination of genome wide genotyping including HLA-typing and genome wide expression profiling as well as a collection on relevant or putatively relevant environmental factors in patients well characterized clinically and by MRI is a promising way to identify new disease relevant biomarkers.

Nischwitz S, Cepok S, Kroner A, Wolf C, Knop M, Muller-Sarnowski F, Pfister H, Rieckmann P, Hemmer B, Ising M, Uhr M, Bettecken T, Holsboer F, Muller-Myhsok B, Weber F. More CLEC16A gene variants associated with multiple sclerosis. Acta Neurol Scand: 2011: 123: 400–406. © 2010 John Wiley & Sons A/S. Objectives – Recently, associations of several single-nucleotide polymorphisms (SNPs) within the CLEC16A gene with multiple sclerosis (MS), type-I diabetes, and primary adrenal insufficiency were reported. Methods – We performed linkage disequilibrium (LD) fine mapping with 31 SNPs from this gene, searching for the region of highest association with MS in a German sample consisting of 603 patients and 825 controls. Results – Four SNPs located in intron 19 of the CLEC16A gene were found associated. We could replicate the finding for SNP rs725613 and were able to show for the first time the association of rs2041670, rs2080272 and rs998592 with MS. Conclusion – All described base polymorphisms are mapping to one LD block of approximately 50 kb within intron 19 of the CLEC16A gene, suggesting a pivotal role of this region for susceptibility of MS and possibly also for other autoimmune diseases.

Matrix metalloproteinase 9 (MMP9) plays an important role in the pathogenesis of multiple sclerosis (MS). However, the impact of genetic variants affecting MMP9 on MS susceptibility is still in debate. We could not detect an association of MMP9 SNPs with MS on a genome-wide significance level by SNP genotyping, followed by imputation of SNPs within a region stretching 2Mbp up- and down-stream of MMP9. Rs6073751, located within WFDC2, was found associated with MS most strongly. Rs3918242, associated with MS according to previous reports, showed nominal significance only. Meta-analysis of our own and published data did not confirm this effect.

In a genome wide association study consisting of 592 German multiple sclerosis (MS) patients and 825 controls we were able to replicate the association of the HLA region with MS independently of previous case control studies. No SNPs outside the HLA region reached a genome wide level of significance. Nevertheless, we found suggestive evidence for an association of MS with variants in two new genes, the VAV2 gene and the gene for ZNF433.