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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.

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.

The objective of this study was to investigate the effect of interferon (IFN) beta-1b on the serum levels of soluble tumor necrosis factor receptor 1 (sTNF-R1) and sTNF-R2 in patients with multiple sclerosis (MS) in correlation with clinical and magnetic resonance image (MRI) activity. Serum samples were obtained every 3 months from 24 patients treated with 8 × 106 U of IFN beta-1b every other day (treatment group) and from 21 patients without any immunomodulatory therapy (control group) over a 15-month observation period. The cytokine receptor levels were assessed by ELISA. Cranial MRI was performed every 6 months to determine the burden of disease. In the treatment group, the MRI responders had significantly larger mean values for the area under the concentration-time curve of sTNF-R1 (p = 0.04) and sTNF-R2 (p = 0.01) when compared to the MRI nonresponders during the 15-month observation period. With regard to an increase in sTNF-R1 and -2 of more than 20% during the first 3 months of treatment, we observed a sensitivity of 33 and 58%, respectively, a specificity of 90 and 60%, respectively, and a positive predictive value of 80 and 64%, respectively, for MRI response during the 15-month observation period. A decrease in sTNF-R1 and -2 of more than 20% during the first 3 months of treatment had a sensitivity of 40 and 20%, respectively, a specificity of 100 and 100%, respectively, and a positive predictive value of 100 and 100%, respectively, for further MRI nonresponse (during the 15-month observation period). The present data suggest that assessment of sTNF-Rs may contribute to the identification of subgroups of patients who are likely to respond better than others to treatment with IFN beta-1b. This could help to establish a cost-effective prescription pattern for this expensive treatment, which is of importance for the future management of patients with MS.

Case Report A 40-year-old man presented with agitation, disorientation and optical hallucinations. He had a history of a malignant seminoma that had been treated with orchiectomy 7 years previously. He was admitted to a psychiatric ward of an outside general hospital but was transferred to our neurology service after he had had an epileptic seizure on admission day. At admission in our department, he was mildly disoriented. He also showed moderate amnestic symptoms and mild dysarthria, but neurological examination revealed no other abnormalities. A cranial magnetic resonance imaging study including contrast enhancement with gadolinium and a routine electroencephalogram were both normal. Cerebrospinal fluid (CSF) analysis showed 18 lymphocytes with no other abnormalities. He was treated with aciclovir until herpes simplex virus polymerase chain reaction proved to be negative, and additionally with ampicillin and ceftriaxone. Within 2 days he became increasingly agitated and suffered 2 more epileptic seizures necessitating anticonvulsive therapy with carbamazepine. Within the next few days, he became somnolent and developed severe swallowing and breathing difficulties. In addition, the patient developed Dear Sir, In addition to the well-known paraneoplastic-syndrome-associated antineuronal autoantibodies anti-Hu, anti-Yo and anti-Ri, a variety of different autoantibodies has been described in paraneoplastic neurological syndromes (PNS). One of these antibodies is an autoantibody binding to collapsin-response-mediating protein 5 (anti-CRMP-5) [1] , a phosphoprotein belonging to a group of proteins being important for axonal growth and also expressed in oligodendrocytes [2] . This antibody is most likely identical with the antibody labeled anti-CV-2 some years earlier [3, 4] . There is no distinguishable neurological syndrome related to the presence of anti-CRMP-5, but most patients suffer from peripheral neuropathy, including optic neuropathy or movement disorders [5] . Most cases are associated with small-cell lung cancer, but association with other tumors like thymoma has been reported as well [1] ( table 1 ). An association with germinal cell tumors has not been reported so far. These patients may have anti-Ma autoantibodies, a group of antineuronal nucleolar autoantibodies. We here describe a patient presenting with symptoms of a limbic encephalitis and choreiform dyskinesias associated with anti-CRMP-5 due to a testicular tumor. Received: September 29, 2006 Accepted: November 12, 2006 Published online: March 26, 2007

Recently, the disappearance of oligoclonal bands (OCBs) from the cerebrospinal fluid (CSF) of a few natalizumab-treated patients with multiple sclerosis (MS) has been reported. This is interesting since CSF-restricted OCB are believed to persist in MS. We pooled CSF data from 14 MS centers to obtain an adequate sample size for investigating the suspected changes in central nervous system (CNS)-restricted humoral immune activities in the context of natalizumab therapy. In a retrospective chart analysis, CSF parameters of blood–CSF barrier integrity and intrathecal IgG production from 73 natalizumab-treated MS patients requiring a diagnostic puncture for exclusion of progressive multifocal leukoencephalopathy were compared with CSF data obtained earlier in the course of disease before natalizumab therapy. At the time of repeat lumbar puncture, local IgG production (according to Reibergram) was significantly reduced ( p < 0.0001) and OCB had disappeared in 16% of the patients. We therefore conclude that natalizumab therapy interferes with intrathecal antibody production at least in a significant number of patients.

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