Hela-Felicitas Petereit

International quality control survey of neurochemical dementia diagnostics.

UNLABELLED Currently, neurochemical dementia diagnostics (NDD) are increasingly entering routine clinical neurochemistry, offering improved early and differential diagnosis of dementias. However, there is an obvious lack of standardization in pre-analytical sample handling and systematic quality surveys. Therefore, in this study, 14 laboratories in Germany, Austria, and Switzerland were given aliquots of a human cerebrospinal fluid (CSF) sample, and were asked to measure Alzheimers disease (AD) biomarkers (amyloid beta (Abeta) peptides, total Tau protein, and phosphorylated Tau protein (P-tau(181P))) according to their routine protocols. RESULTS The inter-laboratory coefficients of variation of the results obtained by the laboratories participating in this study were in the range of 20-30%. Although the results of this quality control survey are promising, the quality of measurements has to be further optimized.

Polyspecific, antiviral immune response distinguishes multiple sclerosis and neuromyelitis optica

Background: A polyspecific, intrathecal humoral immune response against neurotropic viruses such as measles, rubella and varicella zoster virus (MRZ reaction, MRZR) is present in 80–100% of patients with multiple sclerosis (MS), but has not to date been evaluated in patients with neuromyelitis optica (NMO). Aims: To evaluate whether MRZR distinguishes NMO and MS. Methods: 20 patients with NMO and 42 with MS were included. The intrathecal synthesis of antibodies against measles, rubella and varicella zoster virus was detected by calculation of the respective antibody indices (AI). Results: A positive MRZ reaction, as defined by a combination of at least two positive AIs, was found in 37/42 MS, but in only 1/20 NMO patients (p<0.0001). Median AI values differed significantly between the groups (p<0.0005). Conclusions: The polyspecific antiviral humoral immune response characteristic for MS is widely missing in NMO, irrespective of the NMO-IgG status of the patients. Our findings further strengthen the case for NMO being pathologically distinct from MS.

Expansion of antibody reactivity in the cerebrospinal fluid of multiple sclerosis patients - follow-up and clinical implications.

BackgroundAn intrathecal polyspecific antibody response is a well known finding in multiple sclerosis. However, little is known about the evolution of intrathecal antibodies over time and their impact on the disease progress. Therefore, we focused in this study on the intrathecal polyspecific antibody response in multiple sclerosis.MethodsHere we present a follow-up study of 70 patients with multiple sclerosis over 1 to 106 months. Serum and cerebrospinal fluid sample pairs were obtained from 1 to 5 consecutive lumbar punctures. CSF cell count, the IgG index, local IgG synthesis, oligoclonal bands and the antibody index for measles, rubella or varicella zoster were calculated. Results were analysed with regard to clinical characteristics of the patients.ResultsOnce an intrathecal antibody response was established, it persisted. De novo antibody response against measles virus developed in 7% of the patients between the first and the second spinal tap. In two of seven patients where 5 consecutive CSF samples were available, the intrathecal antibody response expanded from one to three antigens. Furthermore, an intrathecal measles antibody production was associated with a rapid progression of the disease.ConclusionThese data stress the importance of activated B cells for the disease process and the clinical outcome in multiple sclerosis.

Low interferon gamma producers are better treatment responders: a two-year follow-up of interferon beta-treated multiple sclerosis patients.

As response to interferon beta (IFNB) treatment, a 50% reduction of the mean relapse rate compared to pretreatment values has been reported. However, individual responses vary considerably, ranging from no reduction in exacerbation frequency to complete suppression of relapses for at least two years. At the moment, valid predictors for IFNB response are lacking. Here we present a prospective evaluation of 33 patients with primary relapsing multiple sclerosis, who were followed for two years of IFNB treatment. A low interferon gamma (IFG) production before treatment predicted a two-year term without exacerbations in 68.8% of cases correctly, whereas a high pretreatment IFG production implied the risk of at least one relapse in the first two years in 70.6%. These preliminary results encourage further evaluation of IFG as predictor of an IFNB treatment response.

No effect of intravenous immunoglobulins on cytokine-producing lymphocytes in secondary progressive multiple sclerosis

Intravenous immunoglobulins (IVIG) have been effective in reducing multiple sclerosis (MS) disease activity and improving disability scores. However, the mechanism by which this beneficial effect is achieved remains unclear. An effect of IVIG on pro- and anti-inflammatory cytokines- which are thought to play a role in the disease process- has been postulated in a number of animal and ex vivo studies. Hence, we performed a study on 34 patients with secondary progressive (SP) MS being treated with monthly IVIG or placebo for two years according to the protocol of the ESIMS study. Clinical outcome measures and cytokine production (interferon gamma, tumour necrosis factor alpha, interleukin-4 and -10) were recorded in all patients and compared with respect to the treatment group. Against our expectations, IVIG did not reduce the relapse rate or the progression of disability or cytokine production. Our data argue against an enduring immunomodulating effect of IVIG, at least in SPMS.

Identification and management of cognitive disorders in multiple sclerosis : A consensus approach

Cross-sectional studies have shown cognitive deficits of varying degree in about 50 % of MS patients (Rao et al. 1991a; Grafman et al. 1991), even in the early stages of the disease. Those symptoms are in part responsible for a reduced quality of life and a decreased vocational status (Rao et al. 1991b; Benedict et al. 2005). In the course of the disease, a secondary chronic progressive type of MS seems to be associated most frequently with cognitive deficits. Reversible cognitive disorders may also occur in relation to relapses. Disturbances developed unrelated to a relapse will usually not regress (Kujala et al. 1997). From current knowledge, the existence of a cognitive impairment constitutes the strongest risk factor regarding further cognitive decline, while physical disability was found to be only weakly correlated with cognitive disturbances. Since the assessment of cognitive disorders by adopting standardized patients’ self-reports is only of limited use, the identification of cognitive problems in MS requires objective psychometric testing.

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.

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