Fluoxetine in progressive multiple sclerosis: The FLUOX-PMS trial.

BACKGROUND: Preclinical studies suggest that fluoxetine has neuroprotective properties that might reduce axonal degeneration in multiple sclerosis (MS). OBJECTIVE: To determine whether fluoxetine slows accumulation of disability in progressive MS. METHODS: In a double-blind multicenter phase 2 trial, patients with primary or secondary progressive MS were randomized to fluoxetine 40 mg/day or placebo for a period of 108 weeks. Clinical assessments were performed every 12 weeks by trained study nurses who visited the patients at their home. The primary outcome was the time to a 12-week confirmed 20% increase in the Timed 25 Foot Walk or 9-Hole Peg test. Secondary outcomes included the Hauser ambulation index, cognitive tests, fatigue, and brain magnetic resonance imaging (MRI). RESULTS: In the efficacy analysis, 69 patients received fluoxetine and 68 patients received placebo. Using the log-rank test (p = 0.258) and Cox regression analysis (p = 0.253), we found no significant difference in the primary outcome between the two groups. Due to an unexpected slow rate of progression in the placebo group, there was insufficient statistical power to detect a potential benefit of fluoxetine. We found no differences between the two groups for secondary outcomes. CONCLUSION: The trial failed to demonstrate a neuroprotective effect of fluoxetine in patients with progressive MS.

Diagnostic criteria for chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS).

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a central nervous system inflammatory syndrome predominantly affecting the brainstem, cerebellum, and spinal cord. Following its initial description, the salient features of CLIPPERS have been confirmed and expanded upon, but the lack of formalized diagnostic criteria has led to reports of patients with dissimilar features purported to have CLIPPERS. We evaluated clinical, radiological and pathological features of patients referred for suspected CLIPPERS and propose diagnostic criteria to discriminate CLIPPERS from non-CLIPPERS aetiologies. Thirty-five patients were evaluated for suspected CLIPPERS. Clinical and neuroimaging data were reviewed by three neurologists to confirm CLIPPERS by consensus agreement. Neuroimaging and neuropathology were reviewed by experienced neuroradiologists and neuropathologists, respectively, both of whom were blinded to the clinical data. CLIPPERS was diagnosed in 23 patients (18 male and five female) and 12 patients had a non-CLIPPERS diagnosis. CLIPPERS patients' median age of onset was 58 years (interquartile range, 24-72) and were followed a median of 44 months (interquartile range 38-63). Non-CLIPPERS patients' median age of onset was 52 years (interquartile range, 39-59) and were followed a median of 27 months (interquartile range, 14-47). Clinical symptoms of gait ataxia, diplopia, cognitive impairment, and facial paraesthesia did not discriminate CLIPPERS from non-CLIPPERS. Marked clinical and radiological corticosteroid responsiveness was observed in CLIPPERS (23/23), and clinical worsening occurred in all 12 CLIPPERS cases when corticosteroids were discontinued. Corticosteroid responsiveness was common but not universal in non-CLIPPERS [clinical improvement (8/12); radiological improvement (2/12); clinical worsening on discontinuation (3/8)]. CLIPPERS patients had brainstem predominant perivascular gadolinium enhancing lesions on magnetic resonance imaging that were discriminated from non-CLIPPERS by: homogenous gadolinium enhancing nodules <3 mm in diameter without ring-enhancement or mass effect, and homogenous T2 signal abnormality not significantly exceeding the T1 enhancement. Brain neuropathology on 14 CLIPPERS cases demonstrated marked CD3-positive T-lymphocyte, mild B-lymphocyte and moderate macrophage infiltrates, with perivascular predominance as well as diffuse parenchymal infiltration (14/14), present in meninges, white and grey matter, associated with variable tissue destruction, astrogliosis and secondary myelin loss. Clinical, radiological and pathological feature define CLIPPERS syndrome and are differentiated from non-CLIPPERS aetiologies by neuroradiological and neuropathological findings.

Do Flexible Goal Adjustment and Acceptance Help Preserve Quality of Life in Patients with Multiple Sclerosis?

BACKGROUND: Goal regulation strategies such as flexible goal adjustment and acceptance are believed to be protective factors in persons with chronic illness, but research on their relative contributions to quality of life in multiple sclerosis (MS) is lacking. PURPOSE: We aimed to test the idea that acceptance and flexible goal adjustment (in contrast to tenacious goal pursuit) may help preserve the quality of life in persons with MS. METHOD: A sample of 117 patients with MS was recruited. They completed questionnaires measuring quality of life (physical functioning, psychological distress), acceptance, flexible goal adjustment, and tenacious goal pursuit. RESULTS: Acceptance significantly accounted for variance in all three indexes of quality of life, beyond the effects of demographic and illness characteristics. The role of goal regulation style was less clear. Flexible goal adjustment significantly accounted for psychological well-being only. Surprisingly, tenacious goal pursuit predicted better psychological functioning and less psychological distress. No support was found for the hypothesis that acceptance and flexible goal adjustment would moderate the relation between illness severity and quality of life. CONCLUSION: The findings suggest the potential importance of acceptance in understanding MS patients' quality of life, although its hypothesized protective function could not be confirmed. Further conceptual work on acceptance and goal regulation style is needed, as well as prospective work investigating their causal status.

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS).

The classification and pathological mechanisms of many central nervous system inflammatory diseases remain uncertain. In this article we report eight patients with a clinically and radiologically distinct pontine-predominant encephalomyelitis we have named 'chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids' (CLIPPERS). The patients were assessed clinically, radiologically and pathologically at Mayo Clinic, USA and Ghent University Hospital, Belgium from 1999 to 2009. Median follow-up duration from clinical onset was 22 months (range 7-144 months). Patients underwent extensive laboratory (serum and cerebrospinal fluid), radiological and pathological testing (conjunctival, transbronchial and brain biopsies) to search for causes of an inflammatory central nervous system disorder. All eight patients (five female, three male) presented with episodic diplopia or facial paresthesias with subsequent brainstem and occasionally myelopathic symptoms and had a favourable initial response to high dose glucocorticosteroids. All patients had symmetric curvilinear gadolinium enhancement peppering the pons and extending variably into the medulla, brachium pontis, cerebellum, midbrain and occasionally spinal cord. Radiological improvement accompanied clinical response to glucocorticosteroids. Patients routinely worsened following glucocorticosteroid taper and required chronic glucocorticosteroid or other immunosuppressive therapy. Neuropathology of biopsy material from four patients demonstrated white matter perivascular, predominantly T lymphocytic, infiltrate without granulomas, infection, lymphoma or vasculitis. Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids is a definable, chronic inflammatory central nervous system disorder amenable to immunosuppressive treatment. The T cell predominant inflammatory pathology in affected central nervous system lesions and the clinical and radiological response to immunosuppressive therapies is consistent with an immune-mediated process.

Transverse diffusivity of cerebral parenchyma predicts visual tracking performance in relapsing-remitting multiple sclerosis.

This study investigated the relation between cerebral damage related to multiple sclerosis (MS) and cognitive decline as determined by two classical mental tracking tests. Cerebral damage in 15 relapsing-remitting MS patients was measured by diffusion tensor imaging (DTI). Fractional anisotropy, longitudinal and transverse diffusivity were defined in the cerebral parenchyma. Cognitive performance of the MS patients was assessed with the oral response format of the Symbol Digit Modalities Test (SDMT) and the Paced Auditory Serial Addition Test (PASAT). A significant correlation was found between performance on the SDMT and the fractional anisotropy in the brain. This correlation was predominantly induced by transverse diffusivity. Transverse diffusivity refers to the diffusion across fibers rather than along the fibers and is believed to be a specific marker for axonal loss and demyelination associated with MS. No significant association between DTI-measures and PASAT performance was found and this negative finding was mainly attributed to psychometric qualities. These results indicate that diffusivity along the non-principal diffusion direction, a possible signature of MS-related white matter pathology, contributes to information processing speed as measured with the SDMT, a task that requires close visual tracking and a widely used clinical marker for cognitive decline in MS.

The relation between goal adjustment, goal disturbance, and mental well-being among persons with multiple sclerosis.

OBJECTIVE: This study investigated the role of goal adjustment, i.e. disengaging from blocked goals and reengaging into alternative goals, in mental well-being and goal disturbance in persons with multiple sclerosis (MS). DESIGN: A cross-sectional design was used with self-report data from questionnaires and Personal Project Analysis (PPA). MAIN OUTCOME MEASURES: Dependent variables were mental well-being, indicated by depression/anxiety (HADS; Hospital Anxiety and Depression Scale) and mental functioning (SF-36; Short Form Health Survey), and goal disturbance, indicated by goal manageability and goal interference (PPA). Independent variables were patient-reported physical impairment (SF-36) and goal disengagement and reengagement (GAS; Goal Adjustment Scale). RESULTS: Higher goal reengagement was associated with better mental well-being, but unrelated to goal disturbance. Goal disengagement only showed a negative association with anxiety. High disengagement was associated with lower goal interference but only for those also scoring high on reengagement. Goal adjustment did not buffer the effects of physical impairment on mental well-being and goal disturbance. Contrary to expectations, higher goal reengagement increased the association between physical impairment and goal interference. CONCLUSION: Although goal reengagement is associated with better mental well-being in persons with MS, it might also strengthen the perceived effect of physical impairment on goal interference.

Diffusion weighted callosal integrity reflects interhemispheric communication efficiency in multiple sclerosis.

We aimed to investigate the relation between damage in the corpus callosum and the performance on an interhemispheric communication task in patients with multiple sclerosis (MS). Relative callosal lesion load defined as the ratio between callosal area and the total lesion load in the total corpus callosum, and the diffusion tensor imaging (DTI) derived measures fractional anisotropy (FA) and transverse and longitudinal diffusivity were calculated in sixteen female MS patients and sixteen age and education matched female controls. The redundancy gain task was used to behaviorally evaluate interhemispheric communication efficiency. During this task, simple reaction times to uni- and bilateral presented stimuli are recorded. The advantage in reaction time for bilateral as compared to unilateral trials, the redundancy gain, was significantly larger for the MS-group. The DTI data showed significantly decreased FA and increased diffusivity parameters in the corpus callosum for the MS patients compared with the control group. Moreover, we found a significant correlation between the DTI-derived measures in the corpus callosum and the redundancy gain effect. Callosal damage in MS, as measured by DTI and defined as transverse diffusivity, is associated with alterations in a behavioral task that relies on interhemispheric transfer and communication.

Callosal function in MS patients with mild and severe callosal damage as reflected by diffusion tensor imaging.

In this study, callosal function was behaviourally tested in MS patients with a redundant stimuli task. Reaction times to uni- and bilateral visual stimuli are recorded. Normal subjects respond faster to bilateral than to unilateral stimuli. This effect is called the redundancy gain effect. In patients with agenesis of the corpus callosum, the redundancy gain exceeds that predicted by probability summation, suggesting a mediating influence of the corpus callosum in healthy controls. The aim of this study is to investigate the effect of callosal damage on the redundancy gain in MS patients by investigating the probability summation model. Seventeen MS patients and as many matched healthy controls performed the redundancy gain task. In order to objectify callosal damage in our MS group, diffusion tensor imaging (DTI) derived measures such as fractional anisotropy (FA) and mean diffusivity (MD) in the corpus callosum were obtained. Callosal FA and MD significantly differed in our MS group compared to the healthy controls, indicating pathological callosal involvement. Since the amount of callosal damage was highly variable within the MS group, the MS cohort was split into a low and a high callosal-injured group as quantified by FA. The high FA group performed like the healthy controls, whereas violations of the probability (race) model were found for the low FA group. We conclude that behavioural measures obtained by the redundancy gain paradigm reflect callosal pathology in MS as measured by DTI.

Targeting phosphocreatine metabolism in relapsing-remitting multiple sclerosis: evaluation with brain MRI, 1H and 31P MRS, and clinical and cognitive testing.

BACKGROUND/OBJECTIVES: Fluoxetine and prucalopride might change phosphocreatine (PCr) levels via the cAMP-PKA pathway, an interesting target in the neurodegenerative mechanisms of MS. METHODS: We conducted a two-center double-blind, placebo-controlled, randomized trial including 48 relapsing-remitting MS patients. Patients were randomized to receive placebo (n = 13), fluoxetine (n = 15), or prucalopride (n = 14) for 6 weeks. Proton (1H) and phosphorus (31P) magnetic resonance spectroscopy (MRS) as well as volumetric and perfusion MR imaging were performed at weeks 0, 2, and 6. Clinical and cognitive testing were evaluated at weeks 0 and 6. RESULTS: No significant changes were observed for both 31P and 1H MRS indices. We found a significant effect on white matter volume and a trend towards an increase in grey matter and whole brain volume in the fluoxetine group at week 2; however, these effects were not sustained at week 6 for white matter and whole brain volume. Fluoxetine and prucalopride showed a positive effect on 9-HPT, depression, and fatigue scores. CONCLUSION: Both fluoxetine and prucalopride had a symptomatic effect on upper limb function, fatigue, and depression, but this should be interpreted with caution. No effect of treatment was found on 31P and 1H MRS parameters, suggesting that these molecules do not influence the PCr metabolism.

Semiquantification of the peripheral-type benzodiazepine ligand [11C]PK11195 in normal human brain and application in multiple sclerosis patients.

OBJECTIVES: [11C]PK11195 is a peripheral-benzodiazepine-receptor radioligand used for detection of microglial inflammation. Normal uptake by means of semiquantification was measured in order to establish reference data. The applicability of this semiquantitative approach was tested in three multiple sclerosis patients. MATERIALS AND METHODS: Seven controls and three patients underwent MR and PET scanning. Coregistered static scans 40 minutes postinjection of [11C]PK11195 were used for assessment of relative ligand uptake by comparison to whole-brain uptake. RESULTS: For static scans acquired in near steady-state, the relative ligand uptake was significantly higher in gray matter structures as compared to the whole brain (ratio: 1.041 +/- 0.06, p = 0.036) whereas it was comparable in white matter (1.010 +/- 0.035). Intersubject reproducibility was 11.4% and 12.9% for white and grey matter. Intrasubject reproducibility was of the same order: 14.0% and 14.5% respectively. In two clinically active patients with Gadolinium-positive T1-weighted lesions on MRI the focal ligand uptake was significantly increased (1.36 and 1.14, p = 0.001). In one clinically stable patient, the uptake value corresponding with a T2-weighted MR lesion was not different from normal brain measurements. CONCLUSION: The current investigations show that normal brain uptake of [11C]PK11195 is very low and shows the feasibility of a semiquantitative method which can be applied to larger cohorts of patients subgroups.

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. TRIAL REGISTRATION: Eudra-CT: 2011-003775-11.

Safety and efficacy of natalizumab in Belgian multiple sclerosis patients: subgroup analysis of the natalizumab observational program.

Natalizumab (Tysabri(®)) is highly efficacious in controlling disease activity in relapsing multiple sclerosis (MS) patients. As it is one of the more recent therapies for MS, there remains a need for long-term safety and efficacy data of natalizumab in a clinical practice setting. The Tysabri observational program (TOP) is an open-label, multicenter, multinational, prospective observational study, aiming to recruit up to 6,000 patients with relapsing-remitting MS from Europe, Canada and Australia. The objectives of this study are to collect long-term safety and efficacy data on disease activity and disability progression. We report here the interim results of the 563 patients included in TOP between December 2007 and 2012 from Belgium. This patient cohort was older at baseline, had longer disease duration, higher neurological impairment, and a higher baseline annualized relapse rate, when compared to patients included in the pivotal phase III AFFIRM trial. Nevertheless, the efficacy of natalizumab was comparable. The annualized relapse rate on treatment was reduced by 90.70 % (p < 0.0001) with a cumulative probability of relapse of 26.87 % at 24 months. The cumulative probabilities of sustained disability improvement and progression at 24 months were 25.68 and 9.01 %, respectively. There were no new safety concerns over the follow-up period. Two cases of progressive multifocal leukoencephalopathy were diagnosed. Our results are consistent with other observational studies in the post-marketing setting.

Consensus guidelines on the neurologist's role in the management of neurogenic lower urinary tract dysfunction in multiple sclerosis.

OBJECTIVE: To review current management of neurogenic lower urinary tract dysfunction (NLUTD) in MS patients and give recommendations on the joint role of the neurologist and urologist in NLUTD management. METHODS: An algorithm for evaluation and referral of MS patients to urologists was created. It is an outcome of discussions about current knowledge, existing guidelines, and key issues during two Belgian consensus meetings attended by neurologists, urologists and other stakeholders involved in MS management. At these meetings, updated information on management of NLUTD in MS was exchanged and the neurologists' opinion on how to integrate this in the other aspects of care in MS patients was explored. RESULTS: Short evaluation of NLUTD in MS patients by neurologists and appropriate referral to urologists could accelerate proper diagnosis and treatment. Neurologists can play a central role in the inter-disciplinary communication on interactions between disease manifestations of MS and their treatments. CONCLUSION: The coordinating role of neurologists in NLUTD management may considerably improve QoL in MS patients. More research is needed to evaluate outcomes of urological assessments and treatment.

White-matter astrocytes, axonal energy metabolism, and axonal degeneration in multiple sclerosis.

In patients with multiple sclerosis (MS), a diffuse axonal degeneration occurring throughout the white matter of the central nervous system causes progressive neurologic disability. The underlying mechanism is unclear. This review describes a number of pathways by which dysfunctional astrocytes in MS might lead to axonal degeneration. White-matter astrocytes in MS show a reduced metabolism of adenosine triphosphate-generating phosphocreatine, which may impair the astrocytic sodium potassium pump and lead to a reduced sodium-dependent glutamate uptake. Astrocytes in MS white matter appear to be deficient in ß(2) adrenergic receptors, which are involved in stimulating glycogenolysis and suppressing inducible nitric oxide synthase (NOS2). Glutamate toxicity, reduced astrocytic glycogenolysis leading to reduced lactate and glutamine production, and enhanced nitric oxide (NO) levels may all impair axonal mitochondrial metabolism, leading to axonal degeneration. In addition, glutamate-mediated oligodendrocyte damage and impaired myelination caused by a decreased production of N-acetylaspartate by axonal mitochondria might also contribute to axonal loss. White-matter astrocytes may be considered as a potential target for neuroprotective MS therapies.