Tania Kümpfel

Ludwig-Maximilian-University of Munich, München, Bavaria, Germany

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Publications (103)487.24 Total impact

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    02/2015; 2(1):e55.
  • F Hoffmann, A Kraft, F Heigl, E Mauch, J Koehler, L Harms, T Kümpfel, W Köhler, R Klingel, C Fassbender, S Schimrigk
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    ABSTRACT: 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. 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. 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. 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. 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.
    Der Nervenarzt 01/2015; · 0.86 Impact Factor
  • Melania Spadaro, Lisa Ann Gerdes, Marie C. Mayer, Birgit Ertl‐Wagner, Sarah Laurent, Markus Krumbholz, Constanze Breithaupt, Tobias Högen, Andreas Straube, Armin Giese, Reinhard Hohlfeld, Hans Lassmann, Edgar Meinl, Tania Kümpfel
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    ABSTRACT: We present histological, MRI, and clinical features of an adult patient with relapsing encephalomyelitis and antibodies against myelin oligodendrocyte glycoprotein (MOG). Furthermore, we report molecular details of the recognized epitope that is specific for human MOG. A brain biopsy revealed multiple sclerosis (MS)-type II pathology. Some features overlapped with both MS and neuromyelitis optica spectrum disorders (NMOSD), whereas others were distinct from both MS and NMOSD. Immunoadsorption and rituximab induced clinical stabilization. This case contributes a new, so far missing link in the emerging spectrum of MOG-antibody-associated encephalomyelitis.
    Annals of Clinical and Translational Neurology. 01/2015;
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    ABSTRACT: BAFF and a proliferation-inducing ligand (APRIL), which control B cell homeostasis, are therapeutic targets in autoimmune diseases. TACI-Fc (atacicept), a soluble fusion protein containing the extracellular domain of the BAFF-APRIL receptor TACI, was applied in clinical trials. However, disease activity in multiple sclerosis unexpectedly increased, whereas in systemic lupus erythematosus, atacicept was beneficial. In this study, we show that an endogenous soluble TACI (sTACI) exists in vivo. TACI proteolysis involved shedding by a disintegrin and metalloproteinase 10 releasing sTACI from activated B cells. The membrane-bound stub was subsequently cleaved by γ-secretase reducing ligand-independent signaling of the remaining C-terminal fragment. The shed ectodomain assembled ligand independently in a homotypic way. It functioned as a decoy receptor inhibiting BAFF- and APRIL-mediated B cell survival and NF-κB activation. We determined sTACI levels in autoimmune diseases with established hyperactivation of the BAFF-APRIL system. sTACI levels were elevated both in the cerebrospinal fluid of the brain-restricted autoimmune disease multiple sclerosis correlating with intrathecal IgG production, as well as in the serum of the systemic autoimmune disease systemic lupus erythematosus correlating with disease activity. Together, we show that TACI is sequentially processed by a disintegrin and metalloproteinase 10 and γ-secretase. The released sTACI is an immunoregulator that shares decoy functions with atacicept. It reflects systemic and compartmentalized B cell accumulation and activation. Copyright © 2014 by The American Association of Immunologists, Inc.
    Journal of immunology (Baltimore, Md. : 1950). 12/2014;
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    ABSTRACT: Natalizumab for multiple sclerosis (MS) increases the risk of progressive multifocal leukoencephalopathy (PML).
    Multiple Sclerosis 11/2014; · 4.86 Impact Factor
  • Journal of Neuroimmunology 10/2014; 275(s 1–2):14. · 2.79 Impact Factor
  • Journal of Neuroimmunology 10/2014; 275(s 1–2):5–6. · 2.79 Impact Factor
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    ABSTRACT: Background Heterogeneous hypothalamo-pituitary-adrenal (HPA) system dysregulation has been shown in multiple sclerosis (MS), and cross-sectional studies suggested increasing hyperactivity with longer, progressing disease. Longitudinal studies to confirm this hypothesis and to study the impact of disease modifying treatment (DMT) have not been performed. Objective/Method In order to determine the longitudinal evolution of HPA system activity in patients with MS, we performed an open follow-up evaluation of sixty patients with definite MS. Patients were untreated at baseline; at follow-up, 40 received DMT. From the combined dexamethasone/CRH test, performed at baseline and follow-up, we derived neuroendocrine indicators (maximum, maximum rise, mean location and area under the curve) for cortisol, ACTH and ACTH/cortisol ratio. Results In 20 patients who remained untreated (test-retest interval 28.8+/-5.4 months), ACTH/cortisol ratios decreased significantly, driven by both mild increase in cortisol and reduction of ACTH secretion. In 40 patients with DMT (test-retest interval 15.5+/-2.5 months), secretion of cortisol, ACTH and ACTH/cortisol ratios did not change significantly. There was significant, moderate correlation between baseline and follow-up tests for cortisol, but not for ACTH indicators. In untreated, but not in treated patients, change in ACTH/cortisol ratios showed moderate inverse correlation to the time interval between tests (Pearson: beta–0.52 to -0.56, p < 0.05); the relation to progression of neurological disability was not significant. Conclusions HPA axis activation in untreated MS drifts from hypothalamo-pituitary to more adrenal activation, consistent with adrenal sensitization or hypertrophy due to chronic HPA axis activation. HPA system regulation remains more stable in MS patients on DMT.
    Psychoneuroendocrinology 07/2014; · 5.59 Impact Factor
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    ABSTRACT: Risks of natalizumab (NAT) therapy have to be weighed against disease recurrence after stopping NAT.
    Multiple Sclerosis 05/2014; · 4.86 Impact Factor
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    ABSTRACT: IMPORTANCE Natalizumab reduces multiple sclerosis relapses very effectively; however, severe disease activity may return once natalizumab treatment is withdrawn, as recommended during pregnancy. Sometimes restarting natalizumab treatment may be the best option for the mother, but the consequences for the infant are unknown. Except for a few single case reports, to our knowledge, comprehensive data about third-trimester natalizumab exposure are scant. OBSERVATIONS In a case series of 12 women with 13 pregnancies and highly active multiple sclerosis who were treated with natalizumab during their third trimester of pregnancy, we assessed the clinical and laboratory effects on the newborns. We observed mild to moderate hematologic alterations in 10 of 13 infants including thrombocytopenia and anemia. In a subsample of 5 mother-child pairs, we analyzed natalizumab levels in the umbilical cord blood. Natalizumab was detectable in all 5 newborns. CONCLUSION AND RELEVANCE Natalizumab can be a therapeutic option in patients with highly active multiple sclerosis during pregnancy. We recommend that a pediatrician be available at the time of delivery to evaluate for potential complications of anemia and thrombocytopenia in newborns exposed to natalizumab during the third trimester.
    JAMA Neurology 05/2014; · 7.01 Impact Factor
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    ABSTRACT: IMPORTANCE Natalizumab reduces multiple sclerosis relapses very effectively; however, severe disease activity may return once natalizumab treatment is withdrawn, as recommended during pregnancy. Sometimes restarting natalizumab treatment may be the best option for the mother, but the consequences for the infant are unknown. Except for a few single case reports, to our knowledge, comprehensive data about third-trimester natalizumab exposure are scant. OBSERVATIONS In a case series of 12 women with 13 pregnancies and highly active multiple sclerosis who were treated with natalizumab during their third trimester of pregnancy, we assessed the clinical and laboratory effects on the newborns. We observed mild to moderate hematologic alterations in 10 of 13 infants including thrombocytopenia and anemia. In a subsample of 5 mother-child pairs, we analyzed natalizumab levels in the umbilical cord blood. Natalizumab was detectable in all 5 newborns. CONCLUSION AND RELEVANCE Natalizumab can be a therapeutic option in patients with highly active multiple sclerosis during pregnancy. We recommend that a pediatrician be available at the time of delivery to evaluate for potential complications of anemia and thrombocytopenia in newborns exposed to natalizumab during the third trimester.
    JAMA neurology. 05/2014;
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    ABSTRACT: Background: Progressive multifocal leukoencephalopathy (PML), caused by JC virus (JCV), can occur in patients receiving natalizumab for multiple sclerosis (MS). JCV detection by quantitative polymerase chain reaction (qPCR) in cerebrospinal fluid (CSF), or brain biopsy is required for probable or definite diagnosis of PML. However, in some patients only low levels of JCV-DNA (<100 copies/ml) are present in CSF, making the diagnosis challenging.Objective: To assess the complementary value of a CSF JCV antibody index (AIJCV) in the diagnosis of natalizumab-associated PML.Methods: In 37 cases of natalizumab-associated PML and 89 MS-patients treated with natalizumab without PML AIJCV was assessed. Sera and CSF were tested in a capture ELISA, using JCV-VP1 fused to glutathione S-transferase (GST) as antigen. Albumin levels and total IgG concentration were determined by immunonephelometry, and the AIJCV was calculated as published.Results: Twenty-six of 37 (70%) patients with natalizumab-associated PML exhibited an AIJCV >1.5, while this was seen in none of the controls (p<0.0001). At time of the first positive qPCR for JCV-DNA, 11/20 (55%) of patients with natalizumab-associated PML had an AIJCV>1.5. JCV-DNA levels of <100 copies/ml were seen in 14/20 (70%) of these patients of which 8 (57%) demonstrated an AIJCV >1.5.Interpretation: Determination of the AIJCV could be an added tool in the diagnostic workup for PML and should be included in the case definition of natalizumab-associated PML. ANN NEUROL 2014. © 2014 American Neurological Association
    Annals of Neurology 04/2014; · 11.91 Impact Factor
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    ABSTRACT: Recent large-scale association studies have identified over 100 MS risk loci. One of these MS risk variants is single-nucleotide polymorphism (SNP) rs17066096, located ~14 kb downstream of IL22RA2. IL22RA2 represents a compelling MS candidate gene due to the role of IL-22 in autoimmunity; however, rs17066096 does not map into any known functional element. We assessed whether rs17066096 or a nearby proxy SNP may exert pathogenic effects by affecting microRNA-to-mRNA binding and thus IL22RA2 expression using comprehensive in silico predictions, in vitro reporter assays, and genotyping experiments in 6,722 individuals. In silico screening identified two predicted microRNA binding sites in the 3'UTR of IL22RA2 (for hsa-miR-2278 and hsa-miR-411-5p) encompassing a SNP (rs28366) in moderate linkage disequilibrium with rs17066096 (r (2) = 0.4). The binding of both microRNAs to the IL22RA2 3'UTR was confirmed in vitro, but their binding affinities were not significantly affected by rs28366. Association analyses revealed significant association of rs17066096 and MS risk in our independent German dataset (odds ratio = 1.15, P = 3.48 × 10(-4)), but did not indicate rs28366 to be the cause of this signal. While our study provides independent validation of the association between rs17066096 and MS risk, this signal does not appear to be caused by sequence variants affecting microRNA function.
    Neurogenetics 03/2014; · 2.66 Impact Factor
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    ABSTRACT: Neuromyelitis optica (NMO, Devic's syn-drome), long considered a clinical variant of multiple sclerosis, is now regarded as a distinct disease entity. Major progress has been made in the diagnosis and treatment of NMO since aquaporin-4 antibodies (AQP4-Ab; also termed NMO-IgG) were first described in 2004. In this review, the Neuromyelitis Optica Study Group (NEMOS) summarizes recently obtained knowledge on NMO and highlights new developments in its diagnosis and treatment, based on current guidelines, the published literature and expert dis-cussion at regular NEMOS meetings. Testing of AQP4-Ab is essential and is the most important test in the diagnostic work-up of suspected NMO, and helps to distinguish NMO from other autoimmune diseases. Furthermore, AQP4-Ab testing has expanded our knowledge of the clinical pre-sentation of NMO spectrum disorders (NMOSD). In addition, imaging techniques, particularly magnetic reso-nance imaging of the brain and spinal cord, are obligatory in the diagnostic workup. It is important to note that brain lesions in NMO and NMOSD are not uncommon, do not rule out the diagnosis, and show characteristic patterns. Other imaging modalities such as optical coherence tomography are proposed as useful tools in the assessment of retinal damage. Therapy of NMO should be initiated early. Azathioprine and rituximab are suggested as first-line treatments, the latter being increasingly regarded as an established therapy with long-term efficacy and an acceptable safety profile in NMO patients. Other immu-nosuppressive drugs, such as methotrexate, mycophenolate Members of Neuromyelitis Optica Study Group (NEMOS) are listed in the appendix.
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    ABSTRACT: Neuromyelitis optica (NMO, Devic's syndrome), long considered a clinical variant of multiple sclerosis, is now regarded as a distinct disease entity. Major progress has been made in the diagnosis and treatment of NMO since aquaporin-4 antibodies (AQP4-Ab; also termed NMO-IgG) were first described in 2004. In this review, the Neuromyelitis Optica Study Group (NEMOS) summarizes recently obtained knowledge on NMO and highlights new developments in its diagnosis and treatment, based on current guidelines, the published literature and expert dis-cussion at regular NEMOS meetings. Testing of AQP4-Ab is essential and is the most important test in the diagnostic work-up of suspected NMO, and helps to distinguish NMO from other autoimmune diseases. Furthermore, AQP4-Ab testing has expanded our knowledge of the clinical pre-sentation of NMO spectrum disorders (NMOSD). In addition, imaging techniques, particularly magnetic reso-nance imaging of the brain and spinal cord, are obligatory in the diagnostic workup. It is important to note that brain lesions in NMO and NMOSD are not uncommon, do not rule out the diagnosis, and show characteristic patterns. Other imaging modalities such as optical coherence tomography are proposed as useful tools in the assessment of retinal damage. Therapy of NMO should be initiated early. Azathioprine and rituximab are suggested as first-line treatments, the latter being increasingly regarded as an established therapy with long-term efficacy and an acceptable safety profile in NMO patients. Other immu-nosuppressive drugs, such as methotrexate, mycophenolate mofetil and mitoxantrone, are recommended as second-line treatments. Promising new therapies are emerging in the form of anti-IL6 receptor, anti-complement or anti-AQP4-Ab biologicals.
    Journal of Neurology 01/2014; 261(1):1-16. · 3.84 Impact Factor
  • Joachim Havla, Reinhard Hohlfeld, Tania Kümpfel
    Journal of Neurology 11/2013; · 3.84 Impact Factor
  • Annika Plate, Joachim Havla, Tania Kümpfel
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    ABSTRACT: Late-onset neutropenia (LON) has been described as a side effect of rituximab (RX) therapy in patients with rheumatological and/or haematooncological diseases but not neuromyelitis optica (NMO). We describe a 71-year old female patient, who had NMO for 22 years, had been treated with RX monotherapy five times (cumulative dosage: 11g; duration of treatment: 3 years) before she developed severe neutropenia (IV) 3 months after the last RX infusion.1 After exclusion of other causes, the diagnosis of LON was made. No complications occurred and neutropenia resolved without therapy. RX therapy was continued with intensive monitoring without any further LON and/or complications. In conclusion LON is a possible side effect during RX therapy and may also occur in NMO patients.
    Multiple Sclerosis and Related Disorders. 09/2013; in press.
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    ABSTRACT: Recurrent myelitis is one of the predominant characteristics in patients with neuromyelitis optica (NMO). While paresis, visual loss, sensory deficits, and bladder dysfunction are well known symptoms in NMO patients, pain has been recognized only recently as another key symptom of the disease. Although spinal cord inflammation is a defining aspect of neuromyelitis, there is an almost complete lack of data on altered somatosensory function, including pain. Therefore, eleven consecutive patients with NMO were investigated regarding the presence and clinical characteristics of pain. All patients were examined clinically as well as by Quantitative Sensory Testing (QST) following the protocol of the German Research Network on Neuropathic Pain (DFNS). Additionally, plasma endocannabinoid levels and signs of chronic stress and depression were determined. Almost all patients (10/11) suffered from NMO-associated neuropathic pain for the last three months, and 8 out of 11 patients indicated relevant pain at the time of examination. Symptoms of neuropathic pain were reported in the vast majority of patients with NMO. Psychological testing revealed signs of marked depression. Compared to age and gender-matched healthy controls, QST revealed pronounced mechanical and thermal sensory loss, strongly correlated to ongoing pain suggesting the presence of deafferentation-induced neuropathic pain. Thermal hyperalgesia correlated to MRI-verified signs of spinal cord lesion. Heat hyperalgesia was highly correlated to the time since last relapse of NMO. Patients with NMO exhibited significant mechanical and thermal dysesthesia, namely dynamic mechanical allodynia and paradoxical heat sensation. Moreover, they presented frequently with either abnormal mechanical hypoalgesia or hyperalgesia, which depended significantly on plasma levels of the endogenous cannabinoid 2-arachidonoylglycerole (2-AG). These data emphasize the high prevalence of neuropathic pain and hyperalgesia in patients with NMO. The degree of mechanical hyperalgesia reflecting central sensitization of nociceptive pathways seems to be controlled by the major brain endocannabinoid 2-AG.
    PLoS ONE 08/2013; 8(8):e71500. · 3.53 Impact Factor
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    ABSTRACT: Recurrent myelitis is one of the predominant characteristics in patients with neuromyelitis optica (NMO). While paresis, visual loss, sensory deficits, and bladder dysfunction are well known symptoms in NMO patients, pain has been recognized only recently as another key symptom of the disease. Although spinal cord inflammation is a defining aspect of neuromyelitis, there is an almost complete lack of data on altered somatosensory function, including pain. Therefore, eleven consecutive patients with NMO were investigated regarding the presence and clinical characteristics of pain. All patients were examined clinically as well as by Quantitative Sensory Testing (QST) following the protocol of the German Research Network on Neuropathic Pain (DFNS). Additionally, plasma endocannabinoid levels and signs of chronic stress and depression were determined. Almost all patients (10/11) suffered from NMO-associated neuropathic pain for the last three months, and 8 out of 11 patients indicated relevant pain at the time of examination. Symptoms of neuropathic pain were reported in the vast majority of patients with NMO. Psychological testing revealed signs of marked depression. Compared to age and gender-matched healthy controls, QST revealed pronounced mechanical and thermal sensory loss, strongly correlated to ongoing pain suggesting the presence of deafferentation-induced neuropathic pain. Thermal hyperalgesia correlated to MRI-verified signs of spinal cord lesion. Heat hyperalgesia was highly correlated to the time since last relapse of NMO. Patients with NMO exhibited significant mechanical and thermal dysesthesia, namely dynamic mechanical allodynia and paradoxical heat sensation. Moreover, they presented frequently with either abnormal mechanical hypoalgesia or hyperalgesia, which depended significantly on plasma levels of the endogenous cannabinoid 2-arachidonoylglycerole (2-AG). These data emphasize the high prevalence of neuropathic pain and hyperalgesia in patients with NMO. The degree of mechanical hyperalgesia reflecting central sensitization of nociceptive pathways seems to be controlled by the major brain endocannabinoid 2-AG.
    PLoS ONE 08/2013; 8(8):e71500. · 3.53 Impact Factor
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    ABSTRACT: To find biomarkers identifying patients at risk for the development of progressive multifocal leukoencephalopathy (PML) during natalizumab treatment. Patients were recruited from 10 European and US cohorts. Of 289 patients with multiple sclerosis (MS), 224 had been treated with natalizumab (18-80 months), 21 received other immune-modulatory treatments, and 28 were untreated. We had access to samples from 16 natalizumab PML patients. Eight of these patients had given blood before the diagnosis of PML. We also analyzed non-natalizumab-treated patients who developed PML (n = 10) and age- and sex-matched healthy donors (n = 31). All flow cytometric assessments were done on previously cryopreserved, viable peripheral blood mononuclear cells. The percentage of l-selectin-expressing CD4+ T cells was significantly lower in patients treated long-term with natalizumab (40.2%) when compared with patients not receiving natalizumab treatment (47.2%; p = 0.016) or healthy controls (61.0%; p < 0.0001). An unusually low percentage (9-fold lower; 4.6%) was highly correlated with the risk of developing PML in the patient group with available pre-PML samples when compared with non-PML natalizumab-treated patients (p ≤ 0.0001). Samples were gathered between 4 and 26 months before PML diagnosis. The cell-based assessment of the percentage of l-selectin-expressing CD4 T cells could provide an urgently needed biomarker for individual PML risk assessment.
    Neurology 08/2013; · 8.30 Impact Factor

Publication Stats

2k Citations
487.24 Total Impact Points

Institutions

  • 2002–2014
    • Ludwig-Maximilian-University of Munich
      • • Institute of Clinical Neuroimmunology
      • • Institute for Clinical Neuroimmunology
      München, Bavaria, Germany
    • University Hospital München
      München, Bavaria, Germany
  • 2012
    • Johannes Gutenberg-Universität Mainz
      • Department of Neurobiology
      Mayence, Rheinland-Pfalz, Germany
  • 1999–2007
    • Max Planck Institute of Psychiatry
      München, Bavaria, Germany
  • 2002–2005
    • Max Planck Institute of Neurobiology
      München, Bavaria, Germany