Adapted timed up and go: a rapid clinical test to assess gait and cognition in multiple sclerosis.

BACKGROUND/AIMS: To measure the Timed Up and Go (TUG), imagined TUG (iTUG), and the difference of time between these two tests (delta time) in 20 patients with relapsing-remitting multiple sclerosis (RRMS) and 20 healthy age-matched controls and to examine whether an association with cognitive functions, motor impairment, and behavioral changes can be determined. METHODS: The mean ± SD of TUG, iTUG and delta time were used as outcomes. Spatiotemporal gait parameters were recorded by a 12-camera optoelectronic system during straight walking at usual self-selected speed. Cognitive functions were assessed by a standardized neuropsychological examination. RESULTS: Patients performed the TUG slower than the controls (10.00 ± 1.70 s vs. 8.71 ± 1.04 s, p = 0.01, respectively). The TUG was correlated with gait parameters, cognitive functions, and behavior, whereas delta time was correlated only with cognitive functions. CONCLUSION: TUG represents an interesting test to reveal subtle deficits in RRMS patients with low disability and is related to motor, cognitive, and behavioral functioning. Combining with the TUG, delta time could easily give additional information on specific cognitive functions in the assessment of patients with RRMS.

Hypereosinophilia in patients with multiple sclerosis treated with natalizumab.

OBJECTIVE: To report asymptomatic hypereosinophilia as a potential side effect in patients treated with natalizumab, an α-4 integrin blocking agent. METHODS: A case series of 3 patients treated with natalizumab for relapsing-remitting multiple sclerosis including functional and phenotypic characterization of their peripheral blood lymphocytes and eosinophils is presented. RESULTS: Marked peripheral blood eosinophilia with more than 2,000 cells/mm(3) emerged in all 3 patients after the fourth natalizumab infusion and was asymptomatic. Hypereosinophilia was associated with enhanced Th2 activity, ceased with drug discontinuation, and in 2 of 3 patients recurred with drug resumption. Despite persistently high eosinophil counts, there were no signs of end-organ damage. CONCLUSIONS: Hypereosinophilia may occur during treatment with natalizumab. It seems to reflect enhanced Th2 activity and recedes with systemic corticosteroids. If the patient is asymptomatic, natalizumab may be continued, provided that other causes of eosinophilia are excluded and the patient is carefully monitored.

[Multiple sclerosis and pregnancy]. / Sclérose en plaques et grossesse.

Mulltiple sclerosis and pregnancy Multiple sclerosis (MS) is diagnosed between the second and fourth decade. More than 2/3 of patients are women and are often in childbearing age. We may ask two main questions: Which implication of pregnancy on the evolution of MS has to be considered ? Which influence of MS on the pregnancy is expected? In other words could the pregnancy worsen MS and could MS represent specific risks for the pregnancy?

[Autoantibodies in neurological diseases: clinical implications]. / Autoanticorps en neurologie: implications cliniques.

Autoantibodies are defined as antibodies directed against self antigens, i.e., against a normal antigenic endogenous tissue constituent. They can be the immediate cause of the neurological syndrome or be detected as an epiphenomenon of the pathogenic process. Autoantibodies are often considered useful biomarkers for the improvement of diagnostic accuracy, for the staging of disease progression or for the follow up of a biological response to a therapeutic intervention. The purpose of this article is to review the autoantibodies that are available to investigate immune-mediated neurological conditions. The detection of some of these autoantibodies may help the clinician to establish a definite diagnosis which may further facilitate the therapeutic decision.

Interferon-beta induces brain-derived neurotrophic factor in peripheral blood mononuclear cells of multiple sclerosis patients.

Interferon-beta (IFN-beta) achieves its beneficial effect on multiple sclerosis (MS) via anti-inflammatory properties. In this study, we assessed the expression of the brain-derived neurotrophic factor (BDNF) in peripheral blood mononuclear cells (PBMC) from relapsing-remitting multiple sclerosis (RRMS) patients treated or not with IFN-beta. Intracellular BDNF was measured by Western blot and ELISA and compared with serum BDNF. We found higher levels of BDNF in PBMC of IFN-beta-treated versus non-treated patients, whereas serum levels of BDNF were similar. We hypothesize that the increased intracellular BDNF secondary to IFN-beta is not released in the periphery. This release is probably not tissue specific but in MS patients, BDNF could be specifically delivered by PBMC at the site of re-activation, i.e. within the central nervous system.

[Neuromyelitis optica/Devic's syndrome: new perspectives]. / Neuromyélite optique/syndrome de Devic: avancées et perspectives.

Neuromyelitis optica (NMO) or Devic's syndrome is a severe demyelinating disease of the central nervous system involving preferentially the optic nerves and the spinal cord. Until recently, NMO was described as an atypical multiple sclerosis IMS), characterized by an unusual clinical presentation, a severe relapsing progression, and a poor response to usual MS treatments. The recent discovery of the so-called NMO-IgG, a highly NMO-specific antibody directed against the blood brain barrier and the aquaporine-4, allowed to refine diagnostic criteria and to classify this disease as an autoimmune channelopathy. According to this recent advance, early diagnostic and specific treatment targeting the humoral response should be considered.

Inhibition of naive Th1 CD4+ T cells by glatiramer acetate in multiple sclerosis.

We investigated whether glatiramer acetate (GA) treatment may affect Th1 differentiation at various T-cell maturation stages. Specifically, we analyzed the effect of in vivo GA treatment on intracellular synthesis of IL-2 and TNF-alpha by naive, memory and effector CD4(+) and CD8(+) T cells by five-colour flow cytometry. Our data indicate that GA treatment downregulates/normalizes an accelerated Th1 differentiation of CD4(+) T cells in RRMS patients at all stages of T-cell maturation. Most notably, we conclude that, by altering naive, unprimed CD4(+) T cells, GA treatment appears to affect T-cell differentiation, at least in part, in an antigen-independent manner.

[Immunity and neurodegeneration: new concepts in multiple sclerosis]. / Immunité et neurodégénérescence: nouveaux concepts dans la sclérose en plaques.

Multiple sclerosis is an autoimmune demyelinating disease of the central nervous system that leads to a progressive deterioration of the neurological functions. The concept of primary myelin and oligodendrocyte damage with axon sparing (axon-myelin dissociation) has been recently reconsidered with the demonstration that neuro-axonal lesions are an early phenomenon, linked to the inflammatory process, observed outside demyelinated areas, and correlated with the progression of the disease. Neurodegeneration in MS, long considered as a late process following recurrent episodes of demyelination, is now accepted as an early and major trigger of MS pathogenesis on which research should focus in the

A recommended treatment algorithm in relapsing multiple sclerosis: report of an international consensus meeting.

An International Working Group for Treatment Optimization in MS met to recommend evidence-based therapeutic options for the management of suboptimal responses or intolerable side-effects in patients treated with disease-modifying drugs (DMDs) for multiple sclerosis (MS). Several DMDs are now available for the treatment of MS that have been shown to alter the clinical course of the disease by decreasing disease activity and delaying the progression of disability. Nevertheless, many patients continue to experience disease activity whilst on treatment, and recommendations have been made on how the success of therapy in an individual patient can be assessed. However, even after having identified criteria for a suboptimal response to current treatments, clinicians require guidance on how to improve the outcomes. This report summarizes the conclusions from a workshop at which this issue was addressed. We suggest treatment pathways for optimizing therapy for those patients with suboptimal responses to DMDs, and therapeutic options for patients with unacceptable side-effects on their current therapy.

[Immunomodulatory/suppressive treatments in neurology]. / Traitements immunomodulateurs/ suppresseurs en neurologie.

Immunomodulatory/suppressive treatments are frequently used in neurological disorders affecting the central and peripheral nervous system. Demyelinating disorders are a good example of a wide application of the various types of existing therapies. Although these therapies are still mostly not disease specific, their combination with more targeted molecules appears most relevant for diseases with multiple pathogenic mechanisms.

Bullous pemphigoid antigen 1 isoforms: potential new target autoantigens in multiple sclerosis?

BACKGROUND: The simultaneous occurrence of bullous pemphigoid (BP) and multiple sclerosis (MS), two autoimmune diseases involving the skin and the central nervous system (CNS), respectively, has been described. OBJECTIVES: As the BPAG1 gene encodes the epithelial isoform of BP antigen 1 (BPAG1-e), a major autoantigen of BP, as well as additional variants expressed in the neurones of the CNS and peripheral nervous system and in Schwann cells, we tested the hypothesis that products of the BPAG1 gene act as shared autoantigens in both BP and MS. METHODS: The reactivity of cerebrospinal fluid (CSF) obtained from 18 patients with MS, 10 patients with other inflammatory CNS diseases and 20 normal controls was assayed by immunoblotting against two recombinant fragments of BPAG1-e encompassing regions that are also found in the neuronal variants BPAG1-n and BPAG1-a. RESULTS: The recombinant protein glutathione-S-transferase (GST)-BPAG1-e1-887 was recognized by five of 18 (27%) CSF samples obtained from patients with MS, two of 10 (20%) samples from patients with other inflammatory neurological diseases and five of 20 (25%) samples from normal controls. Furthermore, two of 18 (11%) CSF samples from patients with MS bound to GST-BPAG1-e1880-2649, whereas none of the samples obtained from patients with other inflammatory neurological diseases or from control subjects showed reactivity. CONCLUSIONS: These results raise the possibility that a subset of patients with MS develops an autoantibody response to the neuronal variants of BPAG1. These findings potentially open the avenue of neuronal BPAG1 variants being novel targets of autoantibodies in neurological diseases.

Escalating immunotherapy of multiple sclerosis--new aspects and practical application.

Recent clinical studies in multiple sclerosis (MS) provide new data on the treatment of clinically isolated syndromes, on secondary progression, on direct comparison of immunomodulatory treatments and on dosing issues. All these studies have important implications for the optimized care of MS patients. The multiple sclerosis therapy consensus group (MSTCG) critically evaluated the available data and provides recommendations for the application of immunoprophylactic therapies. Initiation of treatment after the first relapse may be indicated if there is clear evidence on MRI for subclinical dissemination of disease. Recent trials show that the efficacy of interferon beta treatment is more likely if patients in the secondary progressive phase of the disease still have superimposed bouts or other indicators of inflammatory disease activity than without having them. There are now data available, which suggest a possible dose-effect relation for recombinant beta-interferons. These studies have to be interpreted with caution, as some potentially important issues in the design of these studies (e. g. maintenance of blinding in the clinical part of the study) were not adequately addressed. A meta-analysis of selected interferon trials has been published challenging the value of recombinant IFN beta in MS. The pitfalls of that report are discussed in the present review as are other issues relevant to treatment including the new definition of MS, the problem of treatment failure and the impact of cost-effectiveness analyses. The MSTCG panel recommends that the new diagnostic criteria proposed by McDonald et al. should be applied if immunoprophylactic treatment is being considered. The use of standardized clinical documentation is now generally proposed to facilitate the systematic evaluation of individual patients over time and to allow retrospective evaluations in different patient cohorts. This in turn may help in formulating recommendations for the application of innovative products to patients and to health care providers. Moreover, in long-term treated patients, secondary treatment failure should be identified by pre-planned follow-up examinations, and other treatment options should then be considered.

Beneficial effect of co-polymer 1 on cytokine production by CD4 T cells in multiple sclerosis.

Multiple sclerosis (MS) has been associated with an imbalance in the T helper type 1 (Th1) and Th2 subsets. We investigated, at the single-cell level, the synthesis of pro-inflammatory cytokines by CD4 and CD8 T cells from MS patients. We report the relationship between priming of CD4 and CD8 T cells for interleukin-2 (IL-2), interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha) and disease evolution in MS patients, clinically subdivided into relapsing-remitting MS (RRMS) in remission, RRMS in relapse, or chronic progressive MS (CPMS). Moreover, we report the in vivo influence of co-polymer 1 (COP) treatment on the pattern of cytokine producers in RRMS patients. We show that the frequency of CD4 T cells primed for TNF-alpha synthesis increased in all stages of MS, including RRMS remitting, and was normalized to control values in COP-treated patients (43.2 +/- 11.8% in treated patients versus 47 +/- 7.3% in RRMS remitting versus 40.3 +/- 8% in controls). In addition, a significant decrease in the frequency of CD4 T cells primed for IL-2 was found in COP-treated patients as compared to the other groups of patients, reaching values below that of controls (59.1 +/- 9.9% in treated patients versus 70 +/- 11.6% in RRMS remitting versus 67.1 +/- 7.4% in controls). Unexpectedly, COP-treated patients also showed a significantly decreased priming for IFN-gamma at the CD4 T-cell level (9.1 +/- 3.4% in treated patients versus 18.8 +/- 0.6.4% in RRMS remitting versus 15.4 +/- 4.7% in controls), but not at the CD8 T-cell level. This bystander suppression on the inflammatory cells should be considered in the monitoring of MS patients submitted to COP treatment, in order to evaluate better its clinical efficacy.

Recombinant human interferon beta in relapsing-remitting multiple sclerosis: a review of the major clinical trials.

The beneficial effects of interferon beta (IFN-beta) on disease activity in relapsing-remitting multiple sclerosis (RRMS) have been confirmed in several clinical trials. Three IFN-beta products are currently available and licensed for use in RRMS at different dosages and with different routes of administration. For the prescribing physician, therefore, questions remain about the effect these differences may have on the success of therapy. This paper reviews the four large placebo-controlled clinical trials that have been conducted with IFN-beta in patients with RRMS. The evidence available indicates that optimal results are likely to be achieved with the highest tolerable dosage of IFN-beta. Furthermore, as inflammatory brain lesions in MS have been shown to exhibit more extensive and early axonal damage than previously suspected, early treatment may be advisable in order to delay disease progression in RRMS.

Cerebrospinal fluid in acute peripheral facial palsy.

Cerebrospinal fluid (CSF) is rarely analyzed in peripheral facial palsy, and reports in the literature are scarce. We report the CSF findings in 265 patients with acute isolated peripheral facial palsy. The CSF findings were abnormal in 11% of 230 patients with idiopathic peripheral facial palsy, in 60% of 17 patients with Ramsay Hunt syndrome (pleocytosis), in 25% of 8 patients with Lyme disease, in all of 8 patients with HIV infection, and in 2 other patients (sarcoidosis and herpes simplex). We conclude from this large series that the CSF is usually normal in idiopathic peripheral facial palsy. If the CSF is abnormal, a specific cause should be sought.

[Brown-Vialetto-Van Laere syndrome: a case with anti-ganglioside GM1 antibodies and literature review]. / Syndrome de Brown-Vialetto-Van Laere. Un cas avec anticorps anti-ganglioside GM1 et revue de la littérature.

We report the case of a woman suffering from progressive bulbopontine paralysis in whose the first symptom, bilateral hypoacousia, began in childhood. This clinical picture is that of the Brown-Vialetto-Van Laere (BVVL) syndrome. Anti-ganglioside GM1 antibodies were moderately elevated in this patient. Intravenous immunoglobulins produced little benefit. The main clinical characteristics of 29 BVVL patients reported in literature are reviewed, and the pathological significance of anti-GM1 antibodies is discussed in the context of this disorder.

Corticosteroid-responsive postmalaria encephalopathy characterized by motor aphasia, myoclonus, and postural tremor.

OBJECTIVES: To study the clinical spectrum of an acute severe encephalopathy occurring in 2 patients after recovery from falciparum malaria infection and to compare it with the reported clinical features of the postmalaria neurological syndrome. DESIGN: Case report. SETTING: Tertiary care hospital. PATIENTS: Two patients presented with acute onset of fluctuating motor aphasia, severe generalized myoclonus, and postural tremor. Additional signs were cerebellar ataxia, and in 1 patient, generalized epileptic seizures. Magnetic resonance imaging of the brain revealed patchy white matter lesions in 1 patient. Clinically, the patients' conditions continued to worsen until corticosteroids were introduced, the use of which induced a rapid, albeit incomplete, recovery. CONCLUSIONS: We describe a new, severe variant of the still poorly defined postmalaria neurological syndrome. We propose a preliminary classification of this syndrome, according to its clinical characteristics, as follows: a mild or localized form, characterized by isolated cerebellar ataxia or postural tremor; a diffuse, but relatively mild encephalopathic form, characterized by acute confusion or epileptic seizures; and a severe, corticosteroid-responsive encephalopathy that is characterized by motor aphasia, generalized myoclonus, postural tremor, and cerebellar ataxia.