Fluoxetine as disease modifying treatment in multiple sclerosis : rationale, evaluation of the use of MRI to monitor treatment, and preliminary findings

Patients with multiple sclerosis (MS) lack astrocytic β2-adrenergic receptors and this may contribute to the focal inflammatory demyelinating lesions and axonal degeneration that characterize this disease. We hypothesized that the antidepressant fluoxetine might be able to compensate for the loss of the β2-adrenergic receptors. In this thesis we evaluated the use of cerebral MRI scans to monitor disease activity and we performed several exploratory studies to evaluate effects of fluoxetine on patients with MS. A convenient way to find out whether a drug is able to reduce disease activity in MS is by measuring the development of new focal lesions on serial MRI scans of the brain. MS patients who received fluoxetine during 6 months had a trend towards the development of less new focal lesions compared to patients receiving placebo. To assess whether preventing new lesions formation reduces disability on the long term, we studied the relationship between the focal (T2) lesions and disease progression. The number of focal lesions predicted progression of disability and conversion to a progressive disease course in patients with relapsing remitting MS. However, once patients had entered the progressive phase, T2 lesions were no longer predictive for further progression of disability. In another study, we found that 2 weeks use of fluoxetine resulted in an increase in NAA/Cr (a marker of axonal function) in the white matter of MS patients. These preliminary studies suggest that fluoxetine reduces new focal lesion formation and may improve axonal metabolism in MS patients.

Fluoxetine in Progressive Multiple Sclerosis (FLUOX-PMS) : study protocol for a randomized controlled trial

Background: Currently available disease-modifying treatments acting by modifying the immune response are ineffective in progressive multiple sclerosis (MS), which is caused by a widespread axonal degeneration. Mechanisms suspected to be involved in this widespread axonal degeneration are reduced axonal energy metabolism, axonal glutamate toxicity, and reduced cerebral blood flow. Fluoxetine might theoretically reduce axonal degeneration in MS because it stimulates energy metabolism through enhancing glycogenolysis, stimulates the production of brain-derived neurotrophic factor, and dilates cerebral arterioles. The current document presents the protocol of a clinical trial to test the hypothesis that fluoxetine slows down the progressive phase of MS. Methods/Design: The FLUOX-PMS trial is a multi-center, randomized, controlled and double-blind clinical study. A total of 120 patients with the diagnosis of either secondary or primary progressive MS will be treated either by fluoxetine (40 mg daily) or placebo for a total period of 108 weeks. The primary endpoint is the time to confirmed disease progression defined as either at least a 20% increase in the timed 25-Foot Walk or at least a 20% increase in the 9-Hole Peg Test. Secondary endpoints include the Hauser ambulation index, cognitive changes, fatigue, magnetic resonance imaging of the brain, and in a small subgroup optical coherence tomography. Discussion: The FLUOX-PMS trial will gives us information as to whether fluoxetine has neuroprotective effects in patients with progressive MS

Tremor in multiple sclerosis

Tremor is estimated to occur in about 25 to 60 percent of patients with multiple sclerosis (MS). This symptom, which can be severely disabling and embarrassing for patients, is difficult to manage. Isoniazid in high doses, carbamazepine, propranolol and gluthetimide have been reported to provide some relief, but published evidence of effectiveness is very limited. Most trials were of small size and of short duration. Cannabinoids appear ineffective. Tremor reduction can be obtained with stereotactic thalamotomy or thalamic stimulation. However, the studies were small and information on long-term functional outcome is scarce. Physiotherapy, tremor reducing orthoses, and limb cooling can achieve some functional improvement. Tremor in MS remains a significant challenge and unmet need, requiring further basic and clinical research

Clinical outcome measures in SPMS trials: An analysis of the IMPACT and ASCEND original trial data sets

Background: Still too little is known about the natural history of clinical outcome measures beyond the Expanded Disability Status Scale (EDSS), such as the timed 25-foot walk (T25FW) and nine-hole peg test (9HPT) in secondary progressive multiple sclerosis (SPMS). Objective: To describe progression on the EDSS, T25FW, 9HPT, and their combinations. To investigate the association of the baseline characteristics age, sex, EDSS, T25FW, gadolinium-enhancing lesions, and relapse activity with EDSS and T25FW progression. Methods: Using original trial data from the placebo arms of the IMPACT and ASCEND randomized controlled trials, we describe disability progression (with and without 3- or 6-month confirmation). We investigated the association of selected baseline characteristics with EDSS and T25FW progression over 2 years using binary logistic regression. Results: T25FW was the single outcome measure with the largest proportion of patients progressing, followed by EDSS and 9HPT. EDSS and T25FW at baseline were associated with EDSS and T25FW progression in both data sets. Age and relapse activity were only mild and inconsistent predictors, while sex and gadolinium enhancement at baseline did not predict disability progression in either data set. Conclusion: Our analyses inform the selection of primary outcome measures as well as inclusion criteria for clinical trials in SPMS

Dysfunctional astrocytes as key players in the pathogenesis of central nervous system disorders

Once considered little more than the glue that holds neurons in place, astrocytes are now becoming appreciated for the key roles they play in central nervous system functions. They supply neurons and oligodendrocytes with substrates for energy metabolism, control extracellular water and electrolyte homeostasis, regulate neurotransmitter release, modulate immune responses, produce trophic factors, and control synapse formation. Astrocytes express receptors for many neurotransmitters, peptides, hormones and cytokines, and show excitability based on intracellular Ca(2+) variations. Evidence is mounting that alterations in astrocyte functionality play a crucial role in the pathogenesis of disorders with diverse properties, including migraine, epilepsy, leukodystrophies, inflammatory demyelinating diseases, infections, brain edema and metabolic disorders, metal intoxications, neurodegenerative disorders, and schizophrenia. Targeting astrocyte dysfunction may lead to new therapeutic strategies for these disorders. (C) 2007 Elsevier B.V. All rights reserved

Progression in multiple sclerosis:Further evidence of an age dependent process

The relapsing-remitting phase and the progressive phase of multiple sclerosis (MS) seem to be the result of distinct pathophysiological processes. Previous research on the natural history of MS was largely focussed on relapses and disability scores. In this study we evaluated 438 patients with secondary or primary progressive MS. The influence of gender, initial disease course, onset manifestation and age at disease onset on age at progression and time to progression were evaluated with Kaplan-Meier survival analysis and Cox multivariate regression models. The analysis of these data showed that the initial disease course (SPMS or PPMS) had no influence on the age at progression. Gender had no influence on age at progression in PPMS and SPMS patients nor on time to progression in SPMS patients. PPMS patients with visual or brainstem/cerebellar onset had a significantly younger age at progression. SPMS patients with motor onset had a significantly higher age at progression and longer time to progression. Time to progression was significantly shorter in SPMS patients with higher age at disease onset. Our data give further support to the notion that progression in MS is an age dependent process independent of relapses. (c) 2007 Elsevier B.V. All rights reserved

A comparison of clinical outcomes in PPMS in the INFORMS original trial data set

Background: The expanded disability status scale (EDSS) is the standard clinical outcome measure in primary progressive multiple sclerosis (PPMS), even though the timed 25-foot walk (T25FW), nine-hole peg test (NHPT) or combinations of these measures may be more useful. The paced auditory serial addition test (PASAT) is a widely used cognitive measure in MS, but little is known about change in PASAT scores over time in PPMS. Objective: The objective of this study is to compare clinical outcome measures in a large PPMS trial data set. Methods: We determined significant worsening events on the EDSS, T25FW and NHPT, and PASAT scores over the course of this 3-year trial. We compared unconfirmed, confirmed and sustained disability worsening and contrasted disability worsening with similarly defined improvement. We examined the association of baseline characteristics with the risk of disability worsening at 12, 24 and 36 months with logistic regression models. Results: The EDSS and T25FW showed most worsening events, while only few patients worsened on the NHPT. Adding the NHPT to a combined outcome added only few further worsening events. PASAT scores slightly increased over time, possibly due to a practice effect. Conclusion: Both the EDSS and T25FW, but not NHPT or PASAT, appear to be useful outcome measures in PPMS