Norman Putzki

CD4 + CD25 + FoxP3 + T lymphocytes fail to suppress myelin basic protein-induced proliferation in patients with multiple sclerosis

Multiple sclerosis (MS) is an autoimmune disorder directed against self antigens of the central nervous system. CD4(+)CD25(+)FoxP3(+) regulatory T cell (T(reg)) mediated suppression is an essential mechanism of self-tolerance. We studied whether changes in the suppressive function of a mixture of CD25(high) and CD25(intemediate) expressing T(reg) cells in myelin basic protein (MBP)-induced proliferation occurred in untreated MS patients. Suppression of MBP-induced proliferation was observed in 13 out of 29 (45%) MS patients; this was significantly (p<0.05) less compared with 17 out of 19 (89%) healthy individuals. Relative T(reg) counts was significantly increased in MS patients (mean+/-S.D.; 20+/-8%) compared with healthy individuals (15+/-5%). These findings suggest that impaired T(reg) function may be involved in pathogenesis of MS.

Quality Assessment in Multiple Sclerosis Therapy (QUASIMS): a comparison of interferon beta therapies for relapsing-remitting multiple sclerosis.

Interferon beta (IFNβ) preparations are the most frequently prescribed therapies for patients with relapsing multiple sclerosis (MS). Several open-label observational studies report similar efficacy among IFNβ preparations. The Quality Assessment in Multiple Sclerosis Therapy (QUASIMS) study is a large, open-label observational study designed to compare the effectiveness and tolerability of available IFNβ preparations as disease-modifying therapies for relapsing MS across a wide range of clinical practice settings. This retrospective, controlled cohort study was conducted by chart review at 510 sites in Germany, Austria, and Switzerland. Enrolled patients had received one of the four available IFNβ preparations/dosing regimens (intramuscular IFNβ-1a 30xa0µg 1×/week [Avonex®], subcutaneous (SC) IFNβ-1a 22 or 44xa0µg 3×/week [Rebif®], or SC IFNβ-1b 250xa0µg 3.5×/week [Betaferon/Betaseron®]) forxa0≥xa02 years. Preplanned outcomes at 1 and 2 years included change from baseline Expanded Disability Status Scale (EDSS) score, percentage of progression-free patients (<xa01.0 EDSS point), annualised relapse rate (RR), percentage of relapse-free patients, and reasons for therapy change. Of 4754 evaluable patients, 3991 (84%) received IFNβ as initial therapy. There were no significant differences among IFNβs when used as initial or follow-up therapy on almost all outcome variables. Relapse rate was consistently higher and percentage of relapse-free patients consistently lower for all products used as follow-up versus initial therapy. Results of QUASIMS showed similar effectiveness among IFNβ products. Benefits were consistently superior when IFNβ was used as initial rather than follow-up therapy. Our results suggest that patients do not benefit in terms of disease outcome from switching between IFNβ preparations/dosing regimens.

Effects of Natalizumab on Circulating B Cells, T Regulatory Cells and Natural Killer Cells

Background: Natalizumab is a humanized monoclonal antibody directed against very late activation antigen 4 (VLA-4) and has a potent effect on disease activity in multiple sclerosis. Blockade of VLA-4 with natalizumab may not only interfere with autoimmunological mechanisms but also with central nervous system immune surveillance. Methods: Longitudinal ex vivo and in vitro study to determine the effect of natalizumab on the frequency of distinct immune cells and on the frequency and suppressive function of natural CD4+CD25+ regulatory T cells (Tregs). Results: Natalizumab binding to VLA-4 was more marked for B cells than for T cells (49% reduction in VLA-4-expressing B cells compared to 24.5% reduction of T cells). There was an increase in circulating B cells over T cells (2.6 vs. 1.5 fold, p < 0.001). Natural killer cells increased 1.5-fold (p = 0.01). Natalizumab led to a relative decrease in CD4+CD25+ Tregs from 18.9 to 14.1% (p = 0.04). The impaired suppressive capacity of Tregs was not restored. Conclusion: Natalizumab reduces VLA-4 expression on all investigated immune cells, but changes were most marked for B cells. Further differential effects on immune cells may be relevant to opportunistic central nervous system infections during treatment with natalizumab.

Kinesthesia is impaired in focal dystonia.

Parkinsons disease (PD) and focal dystonia (FD) are both predominantly characterized by motor symptoms. Also, recent research has shown that sensory processing is impaired in both movement disorders. FD is characterized by involuntary movements and abnormal limb postures; thus, abnormal kinesthesia could be involved in the pathogenesis. We examined passive index finger movements in patients with FD (n = 12) and PD (n = 11) and in age‐matched healthy controls (n = 13). Compared to healthy controls, patients with PD and FD were significantly impaired in the correct detection of the movement direction. The perceptual thresholds for 75% correct responses of movement direction were 0.21 degrees for FD and 0.28 degrees for PD patients compared to 0.13 degrees in control subjects. Subjects with PD and FD were also significantly impaired when they had to judge consecutive amplitudes. Results of the present study point to impaired kinesthesia in FD. Defective sensory processing could be involved in the pathophysiology of the disease and may influence dystonic contractions.

Prevalence and Severity of Multiple-Sclerosis-Associated Fatigue in Treated and Untreated Patients

Fatigue is one of the most frequent and most disabling symptoms in multiple sclerosis (MS). We investigated the possible association of the MS-related fatigue syndrome with the available disease-modifying therapies and the main disease characteristics in a cross-sectional study on 320 consecutive patients. The prevalence of severe fatigue (Fatigue Severity Scale score ≧5) was 50%. In a multivariate regression model controlling for age, disease subtype, duration and disability we did not find a significant association between the use of immunosuppressive or immunomodulatory drugs compared to no treatment (OR = 1.34, p = 0.38 for immunosuppressants; OR = 0.95, p = 0.85 for immune-modulating agents). Although all used disease-modifying agents successfully reduce disease activity and inflammation, they do not appear to exhibit a significant effect on MS-related fatigue.

Increased basal-ganglia activation performing a non-dystonia-related task in focal dystonia

Background and purpose:u2002 We tried to determine whether altered sensorimotor cortex and basal‐ganglia activation in blepharospasm (BSP) and cervical dystonia (CD) are restricted to areas directly responsible for the innervation of dystonic muscles, or whether impairment in focal dystonia reaches beyond these direct associations supporting a more global disturbance of sensory and motor control in focal dystonia.

Secondary myelodysplastic syndrome following long-term treatment with azathioprine in patients with multiple sclerosis.

Azathioprine (Aza) is a widely used immunosuppressive drug in multiple sclerosis (MS) treatment. Recently, the incidence of secondary myelodysplastic syndromes (sMDS) associated with a poor prognosis was found to be elevated in patients treated with Aza for non-malign disorders. Three hundred and seventeen MS patients were retrospectively analysed and complete blood counts were examined for those exposed to Aza. We identified one case of sMDS (cumulative dose 627 g) in a young patient and two further malignancies (cumulative doses 27 g and 54 g) in the Aza group (n=81; 3.7%). In the non-Aza (n=236) group, five malignancies (2.1%, P=0.419) were identified. Including our patient, four cases of sMDS after long-term Aza therapy in MS have been reported so far. Cases suggest a time- and dose-dependent risk of sMDS in long-term therapy of MS with Aza. Long-term Aza therapy needs careful monitoring.

Effect of functional NMDA-antagonist flupirtine on automatic postural responses in Parkinson's disease

Abstract. Animal studies have demonstrated potent antiparkinsonian and other motor effects of the functional NMDA-antagonist flupirtine and suggest a therapeutic use in Parkinsons disease (PD). In healthy subjects flupirtine decreases the functionally destabilizing medium latency (ML) response following toe-up rotations of a moving platform. Because ML responses are known to be increased in PD, this study examined s the effects of flupirtine on postural responses in patients with PD. During 22 days 21 patients with PD took 50 mg, 100 mg flupirtine or placebo following a randomized, double-blind design. Clinical impairment was assessed by means of the Unified Parkinsons Disease Rating Scale (UPDRS). No significant difference between the effect of flupirtine and placebo on ML responses was observed. There was an unspecific improvement of overall UPDRS scores in placebo and flupirtine conditions compared with baseline measures which was more marked in the placebo condition. No improvement in the UPDRS motor subscale was observed. As no beneficial effect on the clinical presentation and no effect on postural responses could be demonstrated, flupirtine does not seem to be a therapeutic option in PD.

Habituation of the Auditory Startle Response in Cervical Dystonia and Parkinson’s Disease

The auditory startle response (ASR) is a brainstem reflex elicited by an unexpected acoustic stimulus. In focal dystonia (FD), the excitability of brainstem neurons is abnormally enhanced. To identify a possible impact of this pathology on the processing of acoustic stimuli, we studied the habituation of the ASR in patients (n = 11) with FD and compared the findings to those of patients with Parkinson’s disease (PD; n = 11) and controls (n = 11). Latencies in FD patients did not differ from those of controls but were delayed in PD patients compared to controls (p < 0.0001). Habituation was normal at the orbicularis oculi muscles but reduced at the sternocleidomastoid muscles in FD (p = 0.005). Habituation in PD was comparable to controls. Normal latencies and sequence activation indicate intact neural pathways mediating the ASR in FD. Impaired habituation of the ASR points towards a reduced inhibition of acoustic stimuli in FD.

Mitoxantrone Does Not Restore the Impaired Suppressive Function of Natural Regulatory T Cells in Patients Suffering from Multiple Sclerosis

CD4+CD25+ regulatory T (Treg) cells play a major role in controlling autoimmunity by suppressing self-reactive T cells. Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the central nervous system, where T cells are of major importance. Treg cell frequency and function are potential therapeutic targets of MS treatment. Mitoxantrone (MX) is a potent immunosuppressant for the treatment of active MS. We investigated the long-term effects of MX on the suppressive function of Treg after mitogen and myelin basic protein (MBP) stimulation in 20 MX-treated patients. MX therapy did not restore the reduced suppressive activity of a mixture of CD25intermediate or CD25high expressing Treg (healthy controls, MBP: 37.3%; MS patients, MBP: –1.9 vs. 6.6% suppression after MX treatment for 6 months, p > 0.2). The frequency of Treg cells was not affected by MX. A single infusion of MX (10 mg/m2 body surface) induced a selective and persistent reduction of approximately 30% of absolute and relative counts of B lymphocytes (p < 0.05). MX therapy does not influence Treg cell frequency or function. MX seems to exhibit its efficacy in MS mainly by a suppression of humoral immunity.