Effects of a Short Physical Exercise Intervention on Patients with Multiple Sclerosis (MS).

BACKGROUND: The aim of this prospective randomized controlled trial was to investigate if a short-term endurance or combined endurance/resistance exercise program was sufficient to improve aerobic capacity and maximum force in adult patients (18-65 years) with multiple sclerosis (MS). METHODS: All patients performed a three-month exercise program consisting of two training sessions per week, lasting 40 min each, with moderate intensity. All patients had a maximum value of 6 (low to moderate disability) on the Expanded Disability Status Scale (EDSS). One group (combined workout group (CWG); 15 females, 4 males) completed a combined endurance/resistance workout (20 min on a bicycle ergometer, followed by 20 min of resistance training), while the other group (endurance workout group (EWG); 13 females, 5 males) completed a 40 min endurance training program. Aerobic capacity was assessed as peak oxygen uptake, ventilatory anaerobic threshold, and workload expressed as Watts. Maximum force of knee and shoulder extensors and flexors was measured using isokinetic testing. Quality of life was assessed with the SF-36 questionnaire, and fatigue was measured using the Modified Fatigue Impact Scale. RESULTS: Both training groups increased in aerobic capacity and maximum force. EWG, as well as CWG, showed improvement in several subscales of the SF-36 questionnaire and decrease of their fatigue. CONCLUSION: A short exercise intervention increased both aerobic capacity and maximum force independent of whether endurance or combined endurance/resistance workouts were performed.

Effects of pedunculopontine area and pallidal DBS on gait ignition in Parkinson's disease.

BACKGROUND: Freezing of gait is a disabling feature of Parkinson's disease, and so far no established treatment exists. Deep brain stimulation of the pedunculopontine area has been proposed to treat refractory gait disorders, yet data on measurable effects, especially in combination with stimulation of other targets, are scarce. METHODS: Acute effects of either low frequency pedunculopontine stimulation or high frequency stimulation of the posteroventral lateral globus pallidus internus and a combination of both in a 66-year-old man with advanced Parkinson's disease were assessed. Four weeks after the intervention, the gait was examined with patient blinded in each condition using computerized gait analysis. RESULTS: Isolated pedunculopontine or pallidal stimulation had a mild impact on gait ignition and freezing of gait, but combined stimulation had a marked effect. CONCLUSIONS: Combined multifocal stimulation may be a promising option for gait ignition and freezing of gait in advanced Parkinson's disease.

Early identification of interferon-beta responders by ex vivo testing in patients with multiple sclerosis.

Interferon-beta (IFN-beta) is an effective treatment for a subgroup of patients with multiple sclerosis (MS). The mechanism of action as well as the pathophysiological basis of responsiveness to IFN-beta is not well understood. To improve treatment considerations in MS patients predictive markers for response to IFN-beta therapy at early timepoints are needed. Here we correlated changes in serum cytokine levels (IL-13, IL-10, IL-5, IL-4, IFN-gamma) with the clinical response to IFN-beta treatment. Serum cytokine levels of 77 untreated and 43 IFN-beta treated relapsing-remitting MS patients (RRMS) were measured by ELISA, including longitudinal measurements in 17 patients. We found a significant upregulation of IL-10 and IL-5 serum cytokine levels during IFN-beta therapy. However, clinical response was only associated with IL-10 serum levels (p=0.038; positive predictive value 0.95, negative predictive value 0.43) but not with IL-5. The predictive power was increased by a combined testing of IL-10 with expression of co-signaling molecules on monocytes, that were previously shown to change during IFN-beta therapy. In a subgroup of 17 patients testing of 4 markers had a positive and negative predictive value of 1.0 for at least 2 of these markers being positive in treatment responders. The results suggest that serum IL-10 is useful to predict treatment response to IFN-beta particularly in combination with a panel of other IFN-beta dependent parameters.

Effects of interferon-beta on co-signaling molecules: upregulation of CD40, CD86 and PD-L2 on monocytes in relation to clinical response to interferon-beta treatment in patients with multiple sclerosis.

Interferon-beta (IFN-beta) reduces disease activity in a subgroup of patients with relapsing remitting multiple sclerosis (MS). The mechanism of action as well as the pathophysiological basis of responsiveness to IFN-beta is not well understood. Since T-cell activation plays an important part in the pathophysiology of MS, we here investigated the effect of IFN-beta on the expression of co-signaling pathways (CD28-CD80/CD86, CD154-CD40, ICOS-ICOSL, PD-1-PD-L1/2) in MS patients and correlated the results with the clinical response to IFN-beta in individual patients. Expression of co-signaling molecules was measured by flow cytometry in vitro on peripheral blood mononuclear cells after incubation with IFN-beta, and in vivo in whole blood samples of 32 untreated and 24 IFN-beta treated MS patients, including 13 patients longitudinal. IFN-beta treatment induced upregulation of CD40, CD80, CD86, PD-L1 and PD-L2 on monocytes as well as PD-L1 on CD4+-T-cells in vitro and in vivo. IFN-beta treated MS patients were grouped into responders and non-responders on the basis of Kurtzkés EDSS (expanded disability status scale) progression and relapse rate. Upregulation of CD40, CD86 and PD-L2 on monocytes was associated with treatment response to IFN-beta (P < 0.001, P = 0.028 and P = 0.028, respectively). Our results show that IFN-beta upregulates co-stimulatory as well as co-inhibitory molecules in vitro and in vivo implicating that modulation of the balance between positive and negative co-stimulatory signals might be an important part of the mechanism of action of IFN-beta in MS. Upregulation of the expression of CD40, CD86 and PD-L2 may be useful as a predictive marker for clinical response to IFN-beta treatment at early timepoints during IFN-beta therapy.

Treatment of hepatitis C virus-associated inflammatory polyneuropathy with pegylated interferon-alpha and ribavirin.

Peripheral neuropathy is common in patients with hepatitis C virus infection and cryoglobulinemia. Here, we report a patient with axonal polyneuropathy associated with type III mixed cryoglobulinemia and hepatitis C virus infection without significant liver disease, who was successfully treated with pegylated interferon-alpha-2a and ribavirin. This case illustrated that clinical improvement was paralleled by a decrease of cryocrit but not necessarily by a decrease of viral replication rate. Treatment of hepatitis C virus-cryoglobulinemia-associated neuropathy should therefore be continued even if response of viral replication is lacking or delayed as long as a clinical benefit can be observed.

Spontaneous intracranial hypotension: correlation of imaging findings with clinical features.

BACKGROUND: Spontaneous intracranial hypotension (SIH) is increasingly recognized as a clinically variable and likely underdiagnosed syndrome caused by non-traumatic CSF leaks. The aim of this study was to correlate the findings of imaging studies - magnetic resonance imaging (MRI), radionuclide cisternography - with clinical features and CSF pressure in SIH in order to improve the diagnostic yield and management in patients with SIH. METHODS: Clinical case study of 10 consecutive cases of SIH, MRI, radio-isotope cisternography. RESULTS: 5 out of 10 patients had unusual clinical symptoms of SIH(2 subdural haematomas, 1 gait ataxia, 1 tinnitus, 1 haemodialysis-associated headache). In 7 patients pachymeningeal gadolinium enhancement was detected in MRI accompanied by a reduced CSF opening pressure. In contrast, the 3 patients with normal MRI also had a normal CSF pressure. Radio-isotope cisternography was abnormal in all patients tested. There was no correlation between the severity of clinical symptoms and MRI or radionuclide cisternography findings. CONCLUSIONS: The spectrum of clinical symptoms and imaging findings in SIH is highly variable. There- fore the diagnosis of SIH is often delayed. Radio-isotope cisternography is an important additional diagnostic method to detect CSF leaks or pathological kinetics of radio-isotope movement particularly in cases with normal MRI findings.

The 77C->G mutation in the human CD45 (PTPRC) gene leads to increased intensity of TCR signaling in T cell lines from healthy individuals and patients with multiple sclerosis.

The 77C-->G mutation in exon A of the human CD45 gene occurs with low frequency in healthy individuals. An enhanced frequency of 77C-->G individuals has been reported in cohorts of patients suffering from multiple sclerosis, systemic sclerosis, autoimmune hepatitis, and HIV-1. To investigate the mechanisms by which the variant allele may contribute to disease susceptibility, we compared T cell reactivity in heterozygous carriers of the mutation (healthy individuals and multiple sclerosis patients) and wild-type controls. In vitro-generated T cell lines and freshly isolated CD4+CD45R0+ primed/memory T cells from 77C-->G individuals aberrantly expressed CD45RA isoforms and showed enhanced proliferation and IL-2 production when stimulated with anti-TCR/CD3 mAb or Ag. Mutant T cell lines contained a more active pool of p56lck tyrosine kinase and responded with increased phosphorylation of Zap70 and TCR-zeta and an enhanced Ca2+ flux to TCR/CD3 stimulation. These data suggest that 77C-->G may act as a risk factor for certain diseases by increasing the intensity of TCR signaling.

Interferon-beta increases the stimulatory capacity of monocyte-derived dendritic cells to induce IL-13, IL-5 and IL-10 in autologous T-cells.

Dendritic cells (DCs) are key regulators of immune responses and have been associated with autoimmunity in animal models and human disease. The effects of interferon beta (IFN-beta), an immunomodulatory cytokine used in multiple sclerosis (MS) therapy, on DCs are not well understood. Monocyte-derived DCs at different stages of maturation were stimulated with IFN-beta and DC-phenotype and stimulatory function were measured. IFN-beta inhibited the development of DCs at early stages but enhanced DC maturation. Moreover, IFN-beta enhanced the capacity of DCs to stimulate autologous T-cells to secrete IL-13, IL-10 and IL-5. Thus, IFN-beta has both immunostimulatory and immunosuppressive effects on DCs depending on the stage of maturation.