[Show abstract][Hide abstract]ABSTRACT: Objective: To evaluate serum cytokine profiles for their utility to determine the heterogeneous responses to interferon (IFN)-β treatment in patients with multiple sclerosis (MS).
Methods: Patients with relapsing-remitting MS (RRMS) or clinically isolated syndrome (CIS) receiving de novo IFN-β treatment were included into this prospective, observational study. Number of relapses and changes in disability were assessed two years prior to and two years after initiation of treatment. Sera were collected at baseline and after three months on therapy. Cytokine levels in sera were assessed by Luminex multiplex assays. Baseline cytokine profiles were grouped by hierarchical clustering analysis. Demographic features, changes in cytokines and clinical outcome were then assessed in the clustered patient groups.
Results: 157 patients were included into the study and clustered into six distinct subsets by baseline cytokine profiles. These subsets differed significantly in their clinical and biological response to IFN-β therapy. Two subsets were associated with patients that responded poorly to therapy. Two other subsets, associated with a good response to therapy, showed a significant reduction in relapse rates and no worsening of disability. Each subset also had differential changes in cytokine levels after three months of IFN-β treatment.
Conclusions: There is heterogeneity in the immunological pathways of the RRMS population, which correlates with IFN-β response.
[Show abstract][Hide abstract]ABSTRACT: Neutralizing antibodies (NAb) affect efficacy of interferon-beta (IFN-b) treatment in multiple sclerosis (MS) patients. NAbs evolve in up to 44% of treated patients, usually between 6-18 months on therapy.
To investigate whether early binding antibody (BAb) titers or different IFN-b biomarkers predict NAb evolution.
We included patients with MS or clinically isolated syndrome (CIS) receiving de novo IFN-b treatment in this prospective European multicenter study. Blood samples were collected at baseline, before and after the first IFN-b administration, and again after 3, 12 and 24 months on that therapy; for determination of NAbs, BAbs, gene expression of MxA and protein concentrations of MMP-9, TIMP-1, sTRAIL, CXCL-10 and CCL-2.
We found that 22 of 164 (13.4%) patients developed NAbs during a median time of 23.8 months on IFN-b treatment. Of these patients, 78.9% were BAb-positive after 3 months. BAb titers ≥ 1:2400 predicted NAb evolution with a sensitivity of 74.7% and a specificity of 98.5%. Cross-sectionally, MxA levels were significantly diminished in the BAb/NAb-positive samples; similarly, CXCL-10 and sTRAIL concentrations in BAb/NAb-positive and BAb-positive/NAb-negative samples, respectively, were also diminished compared to BAb/NAb-negative samples.
BAb titers reliably predict NAbs. CXCL-10 is a promising sensitive biomarker for IFN-b response and its abrogation by anti-IFN-b antibodies.
[Show abstract][Hide abstract]ABSTRACT: Neutralizing antibodies against interferon-beta are associated with a reduction of the efficacy of this drug. Continuing treatment leads to a decline or even loss of neutralizing antibodies over years. No strategies are currently available to shorten the period of neutralizing antibody positivity. The objective of this study was to investigate the effect of switching between high and low immunogenic interferon-beta products on neutralising antibody titres. Twenty-four patients treated with the subcutaneously administered interferon-beta 1b or 1a and high titres of neutralizing antibodies were included. At baseline interferon-beta therapy was interrupted for 3 months and two pulses of high dose methylprednisolone were applied. Patients were then randomized to receive either the previous interferon-beta preparation or the low immunogenic intramuscular interferon-beta 1a. The primary end-point was the change of neutralizing antibody titres 12 months after randomization. Twelve patients were switched to interferon-beta 1a intramuscularly and 12 patients remained on previous treatment. Median neutralizing antibody titres were 846 NU at baseline and 196 NU at the end of the study. The median change of neutralizing antibody titres did not differ significantly between therapy switchers and non-switchers. Baseline and final neutralizing antibody titres correlated significantly. In conclusion, neither switching nor continuous therapy with any subcutaneous interferon-beta preparation significantly changed neutralizing antibody titres.
[Show abstract][Hide abstract]ABSTRACT: Cigarette smoking increases the risk for development of multiple sclerosis and modifies the clinical course of the disease. In this study, we determined whether smoking is a risk factor for early conversion to clinically definite multiple sclerosis after a clinically isolated syndrome.
We included 129 patients with a clinically isolated syndrome, disseminated white-matter lesions on brain magnetic resonance imaging, and positive oligoclonal bands in the cerebrospinal fluid. The patients' smoking status was obtained at the time of the clinically isolated syndrome.
During a follow-up time of 36 months, 75% of smokers but only 51% of non-smokers developed clinically definite multiple sclerosis, and smokers had a significantly shorter time interval to their first relapse. The hazard ratio for progression to clinically definite multiple sclerosis was 1.8 (95% confidence interval, 1.2-2.8) for smokers compared with non-smokers (P = 0.008).
Smoking is associated with an increased risk for early conversion to clinically definite multiple sclerosis after a clinically isolated syndrome, and our results suggest that smoking is an independent but modifiable risk factor for disease progression of multiple sclerosis. Therefore, it should be considered in the counseling of patients with a clinically isolated syndrome.
[Show abstract][Hide abstract]ABSTRACT: In tierexperimentellen Studien konnte die Bedeutung des vestibulären Systems für die Navigation und räumliche Orientierung
bereits nachgewiesen werden: Vestibuläre Signale sind z.B. wichtig für die sog. place cells im Hippocampus, die ein neuronales
Substrat der räumlichen Repräsentation darstellen. Um die Bedeutung des vestibulären Systems für Navigation und räumliche
Orientierung beim Menschen zu untersuchen, haben wir bei 10 Patienten mit kompletter bilateraler Vestibulopathie (beidseitige
Neurektomie aufgrund bilateraler Akustikusneurinome bei Neurofibromatose Typ II) a) das räumliche Gedächtnis mittels eines
PC adaptieren virtuellen „Morris water task“ (d.h. die Messung erfolgt im Sitzen ohne zusätzliche vestibuläre oder somatosensorische
Informationen) getestet, b) andere kognitive und mnestische Funktionen untersucht und c) das Hippocampusvolumen mittels MRT
Volumetrie bestimmt; diese Daten wurden mit einer alters-, geschlechts- und IQ-adaptierten Kontrollgruppe verglichen. Die
Patienten mit bilateraler Vestibulopathie zeigten sowohl signifikante Defizite des räumlichen Gedächtnisses und der Navigation
(ohne weitere zusätzliche neuropsychologische Störungen) als auch eine signifikante Atrophie des Hippocampus (−16.9%). Diese
Studie belegt zum einen, dass der Hippocampus eine zentrale Rolle für die räumliche Orientierung und Navigation spielt; dies
wird durch andere Studien gestützt, die eine positive Korrelation zwischen der Größe des Hippocampus, Navigationsvermögen
und räumlichem Gedächtnis gezeigt haben. Zum anderen lässt sich aus den Befunden schließen, dass ein intaktes vestibuläres
System eine Voraussetzung für diese wichtigen Funktionen darstellt.
[Show abstract][Hide abstract]ABSTRACT: The human hippocampal formation plays a crucial role in various aspects of memory processing. Most literature on the human hippocampus stresses its non-spatial memory functions, but older work in rodents and some other species emphasized the role of the hippocampus in spatial learning and memory as well. A few human studies also point to a direct relation between hippocampal size, navigation and spatial memory. Conversely, the importance of the vestibular system for navigation and spatial memory was until now convincingly demonstrated only in animals. Using magnetic resonance imaging volumetry, we found that patients (n = 10) with acquired chronic bilateral vestibular loss (BVL) develop a significant selective atrophy of the hippocampus (16.9% decrease relative to controls). When tested with a virtual variant (on a PC) of the Morris water task these patients exhibited significant spatial memory and navigation deficits that closely matched the pattern of hippocampal atrophy. These spatial memory deficits were not associated with general memory deficits. The current data on BVL patients and bilateral hippocampal atrophy revive the idea that a major--and probably phylogenetically ancient--function of the archicortical hippocampal tissue is still evident in spatial aspects of memory processing for navigation. Furthermore, these data demonstrate for the first time in humans that spatial navigation critically depends on preserved vestibular function, even when the subjects are stationary, e.g. without any actual vestibular or somatosensory stimulation.
[Show abstract][Hide abstract]ABSTRACT: The role of the vestibular system for navigation and spatial memory has been demonstrated in animals but not in humans. Vestibular signals are necessary for location-specific "place cell" activity in the hippocampus which provides a putative neural substrate for the spatial representation involved in navigation. To investigate the spatial memory in patients with bilateral vestibular failure due to NF2 with bilateral neurectomy, a virtual variant (on a PC) of the Morris water task adapted to humans was used. Significant spatial learning and memory deficits were shown in 12 patients as compared to 10 healthy controls. These data suggest that functional hippocampal deficits manifest due to a chronic lack of vestibular input in these patients. These deficits can even be demonstrated with the subjects stationary, i.e., without any actual vestibular or somatosensory stimulation.
Article · Nov 2003 · Annals of the New York Academy of Sciences
[Show abstract][Hide abstract]ABSTRACT: Most patients with multiple sclerosis initially present with a clinically isolated syndrome. Despite the fact that clinically definite multiple sclerosis will develop in up to 80 percent of these patients, the course of the disease is unpredictable at its onset and requires long-term observation or repeated magnetic resonance imaging (MRI). We investigated whether the presence of serum antibodies against myelin oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP) in patients with a clinically isolated syndrome predicts the interval to conversion to clinically definite multiple sclerosis.
A total of 103 patients with a clinically isolated syndrome, positive findings on cerebral MRI, and oligoclonal bands in the cerebrospinal fluid were studied. At base line, serum samples were collected to test for anti-MOG and anti-MBP antibodies with Western blot analysis, and the lesions detected by cerebral MRI were quantified. Neurologic examinations for relapse or disease progression (defined as conversion to clinically definite multiple sclerosis) were performed at base line and subsequently every three months.
Patients with anti-MOG and anti-MBP antibodies had relapses more often and earlier than patients without these antibodies. Only 9 of 39 antibody-seronegative patients (23 percent) had a relapse, and the mean (+/-SD) time to relapse was 45.1+/-13.7 months. In contrast, 21 of 22 patients (95 percent) with antibodies against both MOG and MBP had a relapse within a mean of 7.5+/-4.4 months, and 35 of 42 patients (83 percent) with only anti-MOG antibodies had a relapse within 14.6+/-9.6 months (P<0.001 for both comparisons with antibody-seronegative patients). The adjusted hazard ratio for the development of clinically definite multiple sclerosis was 76.5 (95 percent confidence interval, 20.6 to 284.6) among the patients who were seropositive for both antibodies and 31.6 (95 percent confidence interval, 9.5 to 104.5) among the patients who were seropositive only for anti-MOG antibodies, as compared with the seronegative patients.
Analysis of antibodies against MOG and MBP in patients with a clinically isolated syndrome is a rapid, inexpensive, and precise method for the prediction of early conversion to clinically definite multiple sclerosis. This finding may be important for the counseling and care of patients with a first demyelinating event suggestive of multiple sclerosis.
Full-text Article · Aug 2003 · New England Journal of Medicine
[Show abstract][Hide abstract]ABSTRACT: Several drugs that primarily act on gamma-aminobutyrate or muscarinic receptors have been used to treat downbeat nystagmus (DBN) syndrome despite their having only moderate success and causing several side effects that limit their effectiveness. These drugs were tested under the assumption that DBN was caused by a disinhibition of a physiologic inhibitory cerebellar input on vestibular nuclei.
To evaluate the effects of a single dose of the potassium channel blocker 3,4-diaminopyridine (3,4-DAP), which is known to increase the excitability of Purkinje cells, on DBN in a prospective, placebo-controlled, double-blind study with a crossover design.
Seventeen patients with DBN due to cerebellar atrophy (5), infarction (3), Arnold-Chiari malformation (1), or unknown etiology (8) were included in the study (1 of 18 patients had to be excluded). Mean peak slow-phase velocity (PSPV) was measured before and 30 minutes after randomized ingestion of 20 mg of 3,4-DAP or placebo orally; at least 1 week later, the treatments were switched.
3,4-DAP reduced mean PSPV of DBN from 7.2 +/- 4.2 degrees /s (mean +/- SD) before treatment to 3.1 +/- 2.5 degrees/s 30 minutes after ingestion of the 3,4-DAP (p < 0.001, two-way analysis of variance). Placebo had no measurable effect. In 10 of 17 subjects, the mean PSPV decreased by >50% and in 12 of 17 by >40%. In parallel, the subjects had less oscillopsia and felt more stable while standing and walking. Nine of the subjects continued to take the drug with success. Except for transient minor perioral or digital paresthesia reported by three subjects and nausea and headache reported by one, no other side effects were observed.
In this study, the authors demonstrated that a single dose of 3,4-DAP significantly improved DBN. In view of animal studies reporting that micromolar concentrations of 4-aminopyridine increased the excitability of Purkinje cells, it is suggested that the efficacy of 3,4-DAP may be due to an increase of the physiologic inhibitory influence of the vestibulocerebellum on the vestibular nuclei.
[Show abstract][Hide abstract]ABSTRACT: There is evidence that neutralizing antibodies (NAB) have a negative influence on the clinical and magnetic resonance imaging effects of interferon-beta (IFNbeta) in multiple sclerosis (MS) patients. The current methods for NAB detection are restricted to specialized laboratories because they require a cell culture and sometimes a viral culture. Results are typically obtained after several weeks. Therefore, the development of a simple and rapid assay for the detection of NAB was sought. Whole blood samples from 28 NAB-positive patients and 110 NAB-negative patients (52 with IFNbeta and 58 without IFNbeta therapy) were incubated with IFNbeta 976 IU/mL for 24 hours. MxA protein levels--a specific marker of class I IFN bioactivity--were measured in paired samples with and without IFNbeta incubation and the difference in MxA levels was calculated. The mean increase of MxA levels after stimulation with IFNbeta in the NAB-positive group was 8 ng/mL (range 0-44 ng/mL) and in the NAB-negative group was 84 ng/mL (range 0-302 ng/mL). Using an increase of 22.5 ng/mL as cut-off) the specificity of the MxA stimulation assay was 81.2% and the sensitivity was 96.4%. The whole blood MxA stimulation assay is virtually as sensitive as the conventional NAB assay but somewhat less specific. However, this is outweighed by the procedural advantage of the assay, which is simpler, quicker and much less expensive.