Michael Schroeter

The clinical value of therapeutic plasma exchange in multifocal motor neuropathy

OBJECTIVE Although there is evidence for a pathogenic role of humoral factors in multifocal motor neuropathy (MMN), plasma exchange (PE) is assumed to be an ineffective treatment. We set out to elucidate possible reasons for this apparent contradiction. METHODS A retrospective analysis of seven patients with MMN, who underwent 4 to 18 sessions of PE. Clinical response, electrophysiological parameter and anti-ganglioside antibody titers were reviewed. RESULTS Two patients, who had anti-ganglioside antibodies, exhibited transient clinical responses to PE, manifested by improved neurological function. Whereas electrophysiological parameters continued to worsen in all patients, anti-ganglioside antibody titers declined during PE, but increased after PE. CONCLUSION PE is of limited therapeutic value in patients with MMN, who do not respond to established treatment options. It may only be useful as an adjunctive treatment in a subset of patients. The transient decrease of anti-ganglioside-antibodies titers suggests that pathogenic humoral factors in MMN are only temporarily reduced. Further, PE treatment alone is insufficient to prevent axons from continuing degeneration, which may explain the failure of PE to substantially influence the disease course of patients with MMN.

Volumetry of [¹¹C]-methionine positron emission tomographic uptake as a prognostic marker before treatment of patients with malignant glioma.

The purpose of this positron emission tomography (PET) study was to compare the prognostic value of pretreatment volume of [11C] methionine (MET) uptake and semiquantitative MET uptake ratio in patients with malignant glioma. The study population comprised 40 patients with malignant glioma. Pretreatment magnetic resonance imaging (MRI) and MET-PET imaging were performed before the initiation of glioma treatment in all patients. The pretreatment MET uptake ratios and volumes were assessed. To create prognostically homogeneous subgroups, patients′ pretreatment prognostic factors were stratified according to the six classes of Radiation Therapy Oncology Group recursive partitioning analysis (RTOG RPA). Univariate and multivariate analyses were performed to determine significant prognostic factors. Survival analyses identified the pretreatment volume of MET uptake and a higher RTOG RPA class as significant predictors. In contrast, pretreatment maximum areas of contrast enhancement on MRI and semiquantitative MET uptake ratios could not be identified as significant prognostic factors. The patients′ outcomes and Karnofsky Performance Scale scores were significantly correlated with pretreatment volume of MET uptake but not with semiquantitative MET uptake ratio. The data suggest that pretreatment volumetry of MET uptake but not the semiquantitative MET uptake ratio is a useful biologic prognostic marker in patients with malignant glioma.

Identification of a B cell-dependent subpopulation of multiple sclerosis by measurements of brain-reactive B cells in the blood

B cells are increasingly coming into play in the pathogenesis of multiple sclerosis (MS). Here, we screened peripheral blood mononuclear cells (PBMC) from patients with clinically isolated syndrome (CIS), MS, other non-inflammatory neurological, inflammatory neurological or autoimmune diseases, and healthy donors for their B cell reactivity to CNS antigen using the enzyme-linked immunospot technique (ELISPOT) after 96 h of polyclonal stimulation. Our data show that nine of 15 patients with CIS (60.0%) and 53 of 67 patients with definite MS (79.1%) displayed CNS-reactive B cells, compared to none of the control donors. The presence of CNS-reactive B cells in the blood of the majority of patients with MS or at risk to develop MS along with their absence in control subjects suggests that they might be indicative of a B cell-dependent subpopulation of the disease.

Imaging biological activity of a glioblastoma treated with an individual patient-tailored, experimental therapy regimen

Purpose To monitor the metabolic effects of an individual patient-tailored, experimental glioma therapy regimen that included repetitive multiple neurosurgical resections, radiosurgical interventions, and an adjuvant maintenance therapy based on the tyrosine kinase inhibitor imatinib in combination with the chemotherapeutic agent hydroxyurea (HU). Procedures Therapeutic effects were monitored in a 26-year-old male patient with a glioblastoma multiforme by multimodal imaging using sequential l-[methyl-(11)C]-methionine positron emission tomography (MET–PET) and MRI. The normalized MET uptake and volume of the metabolically active tumor were assessed sequentially. Results The individual patient-tailored, experimental glioma therapy caused a continuous decline of metabolically active tumor volume, associated with clinical remission over a period of more than two years. Conclusions MET–PET seems to be useful for monitoring patient-tailored, experimental glioma therapy regimens, especially when patients are treated with a multi-step therapeutic regimen. Monitoring and guidance of those experimental therapy regimens by MET–PET in a larger patient group are needed to confirm its clinical value.

Impact of immunomodulatory treatment on leukocyte cytokine production in multiple sclerosis patients and healthy donors.

Objectives: Treatment with interferon(IFN) β, glatiramer acetate (GLAT) and intravenous immunoglobulins (IVIG) alters the cytokine production in multiple sclerosis (MS) patients. To date, it is not clear whether the effect on cytokines varies among these drugs. Therefore, we analyzed the effects of these drugs on the cytokine profiles of MS patients as well as healthy controls. Methods: The in vitro effects of IFNβ, GLAT and IVIG on leukocyte subsets producing the p40 subunit of interleukin 12 (IL12p40), IFNγ, tumor necrosis factor (TNF) and interleukin (IL) 10 were assessed in 21 MS patients and 11 healthy volunteers using flow cytometry. Results: In peripheral vein blood of healthy volunteers, IVIG reduced IL12p40-producing monocytes (p = 0.003) and IFNγ in CD4+ lymphocytes (p = 0.003). IFNβ treatment increased the proportion of IFNγ-producing CD4+ lymphocytes (p = 0.003) whereas GLAT reduced TNF production (p = 0.012). In MS patients, IVIG induced a suppression of leukocytes producing IL12p40 (p < 0.001) and IFNγ (p = 0.001). IFNβ decreased monocytes producing IL12p40 (p < 0.001) and increased IL10 (p = 0.005). GLAT reduced IL12p40 (p < 0.001), IFNγ (p = 0.001 in CD4+ and CD8+ lymphocytes) and TNF production of leukocytes (p < 0.001). In addition, the baseline cytokine patterns were inherently different between individual MS patients. Conclusions: IFNβ, GLAT and IVIG had different effects on cytokine patterns, which might point towards different mechanisms of action. Since the baseline cytokine patterns differed among MS patients, the evaluation of the cytokine pattern might serve as a surrogate marker before starting immunomodulatory treatments and might be helpful to tailor MS therapy effectively to the needs of each individual patient.

Four different synthetic peptides of proteolipid protein induce a distinct antibody response in MP4-induced experimental autoimmune encephalomyelitis.

Here we studied the autoantibody specificity elicited by proteolipid protein (PLP) in MP4-induced experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis (MS). In C57BL/6 (B6) mice, antibodies were induced by immunization with one of the two extracellular and by the intracellular PLP domain. Antibodies against extracellular PLP were myelin-reactive in oligodendrocyte cultures and induced mild spinal cord demyelination upon transfer into B cell-deficient J(H)T mice. Remarkably, also antibodies against intracellular PLP showed binding to intact oligodendrocytes and were capable of inducing myelin pathology upon transfer into J(H)T mice. In MP4-immunized mice peptide-specific T(H)1/T(H)17 responses were mainly directed against the extracellular PLP domains, but also involved the intracellular epitopes. These data suggest that both extracellular and intracellular epitopes of PLP contribute to the pathogenesis of MP4-induced EAE already in the setting of intact myelin. It remains to be elucidated if this concept also applies to MS itself.

A novel organizational structure to provide medical care in specialized hospital departments

Purpose – The purpose of this study is to investigate the implementation of a novel organizational structure in a specialized hospital department. The key issue was to optimize the efficacy of the process “hospital treatment” in a patient‐oriented approach.Design/methodology/approach – A new organizational concept, i.e. the Cologne Consultant Concept (CCC), was developed by and implemented at the Department of Neurology, Cologne University Hospital in August 2007. The outcome of this reorganization was evaluated via a number of critical performance parameters (effects on daily routines and performance data, feedback from quality control and house officers). Furthermore, the strengths and weaknesses of this novel system were compared to the traditional ward‐based system in Germany, the Anglo‐American consultant model and care provided by sub‐specialized teams.Findings – The reorganization of the healthcare services by the CCC provided flexible medical care for inpatients. The independent assignment of pati...

Acknowledgement to the Reviewers

R. Ader, Rochester, N.Y., USA M. Anthracopoulos, Rio Patras, Greece E.G. Araujo, Rio de Janeiro, Brazil E. Arzt, Buenos Aires, Argentina A. Aubert, Tours, France L. Barbeito, Montevideo, Uruguay M. Bauer, Porto Alegre, Brazil I. Berczi, Winnipeg, Man., Canada H.O. Besedovsky, Marburg, Germany S. Bornstein, Dresden, Germany O. Bottasso, Santa Fe, Argentina S.D. Brain, London, UK A. Buske-Kirschbaum, Dresden, Germany M. Canal, Manchester, UK E. Charmandari, Athens, Greece D. Chiasserini, Perugia, Italy F.A. Costa-Pinto, São Paulo, Brazil M. Dardenne, Paris, France E.G. de Moura, Rio de Janeiro, Brazil K. Dornmair, Martinsried, Germany R.L. Doty, Philadelphia, Pa., USA J. Drouin, Montreal, Que., Canada G.E. Duffield, Notre Dame, Ind., USA A.J. Dunn, Honolulu, Hawaii, USA I. Elenkov, Rome, Italy G.G. Freund, Urbana, Ill., USA R. Furlan, Milan, Italy R.C. Gaillard, Lausanne, Switzerland Y. Gidron, Tilburg, The Netherlands N. Gilhus, Bergen, Norway F. Haour, Paris, France K. Hirata, Kyushu, Japan S.K. Jindal, Chandigarh, India J. Kasckow , Pittsburgh, Pa., USA T. Katafuchi, Fukuoka, Japan