Selecting a prospective test for early detection of diabetic polyneuropathy.

Microneurolysis of entrapped peripheral nerve has the best chance of success when compression has not created significant axonal loss. The purpose of this study is to learn the best way to identify potential surgical candidates at the earliest time for intervention, by examining patients in a clinical setting using objective, electrodiagnostic nerve conduction studies (NCS), and subjective touch threshold studies, Semmes-Weinstein monofilaments (SWM) and Pressure-Specified Sensory Device™ (PSSD). Fifty-five patients with diabetic polyneuropathy over the age of 30 years were included. Neuropathy symptom score was the gold standard for statistical calculation, with a prevalence of 70%. In the symptomatic population, prevalence was 64% for NCS (n = 25), 59% for SWM (n = 43), and 88% for PSSD (n = 51). In the asymptomatic population, prevalence was 70% for NCS, 27% for SWM, and 92% for PSSD. It is concluded that the PSSD is the most sensitive device of those tested for identifying peripheral neuropathy in an at risk population of patients.

Tumefactive MS lesions under fingolimod: a case report and literature review.

OBJECTIVE: To report about a possible association between fingolimod treatment and tumefactive demyelinating lesions (TDL) as seen in a patient developing repeated TDL on continued fingolimod therapy. METHODS: We performed serial clinical and radiologic assessments and immunophenotyping of blood and CSF immune cells. We also present a literature review about recent similar cases. RESULTS: Clinical course and radiologic findings were consistent with diagnosis of TDL. Immune cell phenotyping showed pronounced shifts in the immune cell composition related to fingolimod treatment. In addition, we observed a subset of highly differentiated effector cells (CD45R0negCCR7neg) within the CD8+ T-cell population, which was about 2-fold enriched in the CSF compared to the peripheral blood. CONCLUSION: Our observations add further evidence for the development of atypical demyelinating lesions in some patients receiving fingolimod. These might be related to a treatment-associated shift in the immunopathology of specifically susceptible individuals.

Lymphocyte subsets show different response patterns to in vivo bound natalizumab--a flow cytometric study on patients with multiple sclerosis.

Natalizumab is an effective monoclonal antibody therapy for the treatment of relapsing-remitting multiple sclerosis (RRMS) and interferes with immune cell migration into the central nervous system by blocking the α(4) subunit of very-late activation antigen-4 (VLA-4). Although well tolerated and very effective, some patients still suffer from relapses in spite of natalizumab therapy or from unwanted side effects like progressive multifocal leukoencephalopathy (PML). In search of a routine-qualified biomarker on the effectiveness of natalizumab therapy we applied flow cytometry and analyzed natalizumab binding to α(4) and α(4) integrin surface levels on T-cells, B-cells, natural killer (NK) cells, and NKT cells from 26 RRMS patients under up to 72 weeks of therapy. Four-weekly infusions of natalizumab resulted in a significant and sustained increase of lymphocyte-bound natalizumab (p<0.001) which was paralleled by a significant decrease in detectability of the α(4) integrin subunit on all lymphocyte subsets (p<0.001). We observed pronounced natalizumab accumulations on T and B cells at single measurements in all patients who reported clinical disease activity (n = 4). The natalizumab binding capacity of in vitro saturated lymphocytes collected during therapy was strongly diminished compared to treatment-naive cells indicating a therapy-induced reduction of α(4). Summing up, this pilot study shows that flow cytometry is a useful method to monitor natalizumab binding to lymphocytes from RRMS patients under therapy. Investigating natalizumab binding provides an opportunity to evaluate the molecular level of effectiveness of natalizumab therapy in individual patients. In combination with natalizumab saturation experiments, it possibly even provides a means of studying the feasability of patient-tailored infusion intervals. A routine-qualified biomarker on the basis of individual natalizumab saturation on lymphocyte subsets might be an effective tool to improve treatment safety.

Natalizumab therapy decreases surface expression of both VLA-heterodimer subunits on peripheral blood mononuclear cells.

Natalizumab interferes with immune cell migration into the central nervous system via blocking the alpha-4 subunit of very-late activation antigen-4 (VLA-4). Occurrence of rare but serious progressive multifocal leukoencephalopathy during prolonged natalizumab therapy of multiple sclerosis (MS) calls for a more detailed understanding of potential coeffects. We longitudinally studied alpha-4 and beta-1 surface levels on blood cells from 18 MS patients by flow cytometry. Expectedly, detectability of natalizumab-blocked alpha-4 was diminished on all investigated cell subsets. In addition, we report a concurrent and significant decrease of beta-1 surface levels on T-cells, B-cells, natural killer cells, and natural killer T cells, but not on monocytes. Uncovering secondary effects of natalizumab is mandatory to increase safety in MS therapy.

Current endovascular treatment of acute stroke and future aspects.

Acute ischemic stroke remains a condition of high morbidity and mortality. Until now, the only established therapy has been intravenous (IV) tissue-type plasminogen activator (tPA). Only 3-10% of patients with acute ischemic stroke receive this treatment. On the basis of data from part 3 of the European Collaborative Acute Stroke Study (ECASS III), the time window for beneficial treatment of ischemic stroke with IV tPA has been extended from 3 to 4.5h after the onset of stroke symptoms. Beyond that window of opportunity, and additionally to IV treatment, interventional stroke therapy has assumed an important role for the treatment of acute ischemic stroke. Currently, new promising pharmacological and mechanical treatment options are being established as routine procedures to achieve a further improved outcome for stroke patients.

First detection of the Anaplasma phagocytophilum groEL-A genotype in man.

OBJECTIVE: Human Granulocytic Anaplasmosis (HGA) is an emerging disease caused by the gram-negative bacterium Anaplasma phagocytophilum which is transmitted by ticks of the genus Ixodes ricinus. For molecular detection of the pathogen by PCR, a conserved portion of the groEL gene within the groESL operon is frequently used as a target. A single G/A polymorphism in this region allows to discriminate between two genotypes, groEL-G and groEL-A. METHODS: Total DNA from peripheral blood samples of two HGA patients was analysed by RealTime PCR, employing a protocol designed for genotyping groEL-G- and groEL-A variants of A. phagocytophilum. RESULTS: We confirmed two clinical cases of HGA by PCR; in one patient, and for the first time in a human host, the groEL-A variant was detected, in the other case the pathogen was recognised as the groEL-G variant, up to now representing the only genotype reported in man. CONCLUSIONS: It is documented that HGA infections can be caused by two A. phagocytophilum groEL genotypes. At present, the preference of the A. phagocytophilum groEL-G genotype in humans remains unclear, as we describe the first patient with HGA caused by the groEL-A variant. For a conclusive interpretation, more data from HGA patients will be required.

Interferon-beta 1b leads to a short-term increase of soluble but long-term stabilisation of cell surface bound adhesion molecules in multiple sclerosis.

Adhesion molecules (AMs) are believed to regulate the transmigration of blood leukocytes across the blood-brain barrier (BBB), which is an essential step in the pathogenesis of multiple sclerosis (MS). Previous studies have investigated changes of the soluble forms of AM during interferon-beta1b (IFN-beta1b) treatment in MS patients. In this study, we analysed the influence of IFN-beta1b treatment on the cell surface bound forms of the AMs cICAM-1 and cICAM-3 on blood mononuclear cells (MNC). Sixty-eight patients with relapsing-remitting MS were enrolled in this open study; thirty of them were treated with IFN-beta1b. Blood samples were collected every three months over a period of 18 months. The expression levels of cell surface bound forms of AM on blood MNC were measured by two colour flow cytometry analysis. sVCAM-1, sICAM-1 and sICAM-3 were determined by ELISA. We found a short-term induction effect on the serum concentrations of sICAM-1 and sVCAM-1 after three months of IFN-beta1b treatment. The expression levels of cell surface bound AMs on blood MNC remained stable during treatment. Untreated MS patients, however, showed a continuous decrease in the expression of cell surface bound AM expression over 18 months. Stabilisation of the expression of cell surface bound AMs on blood MNC may indicate the beneficial effects of IFN-beta1b therapy in MS patients.