Metabolic syndrome and the phenotype of multiple sclerosis.

BACKGROUND: Comorbidities, particularly vascular comorbidities, have been shown to exacerbate the progression of disability in multiple sclerosis (MS). Metabolic syndrome (MetS) is a cluster of conditions including abdominal obesity, insulin resistance, atherogenic dyslipidemia, and vascular dysfunction, which contribute to vascular morbidity and chronic inflammation. OBJECTIVE: To describe the characteristics of MetS in a cohort of MS patients and evaluate its relationship with the MS phenotype. METHODS: A monocentric cohort study was conducted on MS patients, collecting demographic, clinical, radiological, and therapeutic data, as well as metabolic data including waist circumference, blood pressure, serum triglycerides, high-density lipoprotein cholesterol, and fasting blood glucose. RESULTS: Among the 84 patients included in the study, 27% were diagnosed with MetS. MetS was found to be associated with secondary progressive MS (SPMS). Patients with SPMS had a higher prevalence of MetS compared to those with relapsing-remitting MS (RRMS), even after adjusting for disease duration. While MetS was associated with Expanded Disability Status Scale (EDSS) progression in the 3-year period according to univariate analysis, it did not show a significant association with disease activity. CONCLUSION: This study provides evidence supporting the connection between MetS and the progression of disability in MS, independent of disease relapse activity.

Atypical myelitis in patients with multiple sclerosis: Characterization and comparison with typical multiple sclerosis and neuromyelitis optica spectrum disorders.

BACKGROUND: Atypical myelitis in multiple sclerosis (MS) is characterized by extensive myelitis in the longitudinal (longitudinally extensive transverse myelitis) or axial plane (transverse myelitis). OBJECTIVE: To characterize a cohort of MS patients with atypical myelitis. METHODS: Atypical myelitis was extracted from the French and Luxembourg MS databases and compared to two cohorts of MS patients with typical myelitis and neuromyelitis optica spectrum disorders (NMOSDs) patients with myelitis. RESULTS: We enrolled 28 MS patients with atypical myelitis, 68 MS patients with typical myelitis and 119 NMOSD patients with a first episode of myelitis. MS patients with atypical myelitis were characterized by a mean age of 34.0 (±10.7) years and 64.3% were women. In 82.1% of the patients, atypical myelitis was the first episode of MS. Mean Expanded Disability Status Scale (EDSS) scores at nadir and 3-6 months after onset were 4.1 ± 2.1 and 3.3 ± 2, respectively. Differences between groups revealed a predominance of cervicothoracic myelitis and a higher level of disability in NMOSD patients. Disability in MS patients with atypical myelitis was more severe than in the MS patients with typical myelitis; 28% had already converted to progressive MS within our mean follow-up of 39.6 (±30.4) months. CONCLUSION: Atypical myelitis may be the first presentation of MS and is associated with poorer prognosis.

The evaluation of depression in multiple sclerosis using the newly proposed Multiple Sclerosis Depression Rating Scale.

Fatigue and depression are frequent symptoms in multiple sclerosis (MS). Both are overlapping and shadowing each other and may impair the quality of life. For detection of depression symptoms in MS, the Multiple Sclerosis Depression Rating Scale (MSDRS) has been proposed recently. Here, we compare the performance of MSDRS in MS patients with and without fatigue to that of established rating scales, i.e. Hospital Anxiety and Depression Scale and Beck Depression Inventory. Twenty-nine MS patients were screened for fatigue and depression symptoms. Patients with fatigue showed significantly higher depression scores compared to patients without fatigue, whereas the number of depressed patients did not differ between the two groups. MSDRS seems to have higher sensitivity to detect severe depression than established rating scales. However, one should keep in mind that such a finding might be due to an increase in false positive cases when using MSDRS. Implementing this scale in future studies might be of help to enhance the understanding of its potential utility.

Guillain-Barré syndrome: 100 years on.

The Guillain-Barré syndrome is associated with acute polyradiculoneuritis for almost one century. Its spectrum has considerably been enlarged since its first description. It now includes pure motor or sensory syndromes, focal forms, demyelinating and axonal neurophysiological features that characterise excitability dysfunctions, and immunological differentiations. We can hope that this improved classification will facilitate development of treatment innovations for a condition that is still a life-threatening condition with a severe functional prognosis in a significant proportion of cases.

Minocycline added to subcutaneous interferon ß-1a in multiple sclerosis: randomized RECYCLINE study.

BACKGROUND AND PURPOSE: Combining different therapies may improve disease control in patients with relapsing-remitting multiple sclerosis (RRMS). This study assessed the efficacy and safety of minocycline added to subcutaneous (sc) interferon (IFN) ß-1a therapy. METHODS: This was a double-blind, randomized, placebo-controlled multicentre study. Within 3 months (±1 month) of starting sc IFN ß-1a 44 µg three times weekly, patients with RRMS were randomized to minocycline 100 mg twice daily or placebo, added to sc IFN ß-1a, for 96 weeks. The primary efficacy endpoint was the time to first qualifying relapse. Secondary efficacy endpoints were the annualized relapse rate for qualifying relapses, the number of new/enlarging T2-weighted lesions and change in brain volume [magnetic resonance imaging (MRI) was performed only in a few selected centres]. In addition, a number of tertiary efficacy endpoints were assessed. RESULTS: One hundred and forty-nine patients received minocycline and 155 received placebo; MRI data were available for 23 and 27 patients, respectively. The time to first qualifying relapse did not differ significantly for minocycline versus placebo (hazard ratio 0.85; 95% confidence interval 0.53, 1.35; log-rank = 0.50; P = 0.48). There were no statistically significant differences between the two groups on other efficacy endpoints, although some numerical trends in favour of minocycline were observed. No unexpected adverse events were reported, but more patients discontinued because of adverse events with minocycline versus placebo. CONCLUSION: Minocycline showed no statistically significant beneficial effect when added to sc IFN ß-1a therapy.

Diagnosis of small fiber neuropathy: A comparative study of five neurophysiological tests.

The diagnosis of small fiber neuropathy (SFN) is a challenge for clinical neurophysiology. Conventional nerve conduction studies are inappropriate for this purpose and therefore various neurophysiological tests have been proposed. In this study, we compared the diagnostic value of five of these tests in 87 patients with clinically definite (n=33) or possible (n=54) SFN related to amyloid neuropathy secondary to transthyretin gene mutation or monoclonal gammopathy (n=30), primary Sjögren's syndrome (n=20), Fabry's disease (n=2), or unknown cause (n=35). Neurophysiological tests included quantitative sensory testing with determination of warm and cold detection thresholds (WDT, CDT), recording of laser-evoked potentials (LEP) and sympathetic skin responses (SSRs), and measurement of electrochemical skin conductance (ESC) using Sudoscan(®) device. All tests were performed at the four extremities (hands and feet). All patients with clinically definite SFN and 70% of the patients with possible SFN had at least one abnormal test. The LEP was the most sensitive test (altered in 79% of the patients with at least one abnormal test), followed by ESC (61%), WDT (55%), SSR (41%), and CDT (32%). The combination of LEP, assessing A-delta sensory fibers, WDT, assessing sensory C fibers, and ESC, assessing autonomic C fibers, appears a relevant approach for the diagnosis of SFN. Compared to SSR and CDT, these three tests, LEP, WDT, and ESC, had a significantly better diagnostic sensitivity and their combination further improved diagnostic accuracy.

Sicca syndrome and dementia in a patient with hepatitis C infection: a case report with unusual bifocal extrahepatic manifestations.

INTRODUCTION: Hepatitis C virus (HCV) infections are associated with extrahepatic manifestations in 40-75 % of cases. Sialitis and secondary Sjögren syndrome are well characterized complications of chronic HCV infections but the mechanisms (primary or secondary) leading to xerostomia are not understood. Similarly, brain lesions due to HCV can be primary or secondary but the pathology of primary HCV-related brain lesions is not well described. CASE REPORT: We report the postmortem case of a 60-year old patient initially presenting with sicca syndrome and dementia. HCV was identified in the brain but not in the salivary glands using transcription-mediated amplification (TMA). Focal sialitis was found in submandibular glands. Neuropathological examination revealed the presence of multiple dot-sized demyelination foci. CONCLUSION: Sicca syndrome is a common concern in chronic HCV infections and may be due to secondary immune mechanisms (we could not isolate HCV in salivary gland tissues). TMA had never been applied to the detection of viruses in salivary glands and neural tissues and proves to be a promising technique. Neuropathological reports in HCV infections are rare and the lesions we report may be the first characterization of the direct effect of HCV on brain cells. More cases are needed to define the full spectrum of lesions potentially caused by the direct action of the HCV on salivary glands and neural tissues.

Analysis of tremor in multiple sclerosis using Hilbert-Huang Transform.

Tremor is frequently described in patients with multiple sclerosis (MS) but remains poorly characterized using neurophysiological techniques. Accelerometric (ACC) and electromyographic (EMG) recordings were performed in 26 MS patients complaining of clumsiness, associated (n = 16) or not associated (n = 10) with visible tremor. Seventeen healthy subjects with physiological tremor (PT) and eight patients with essential tremor (ET) served as controls. Signals were analyzed using non-linear Empirical Mode Decomposition (EMD) and related Hilbert-Huang Transform (HHT), compared to the standard linear spectral analysis using Fast Fourier Transform (FFT). The presence of cerebellar signs and motor deficit was assessed on clinical examination. Using FFT, tremor was found in all patients with ET and 12% of subjects with PT, but in none of the MS patients, even in the presence of visible tremor. In contrast, EMD-HHT analysis of ACC-EMG coupling showed common frequency peaks characterizing tremor related to a central generator in 62.5% of MS patients with visible tremor, 40% of MS patients without visible tremor, 29% of subjects with PT, and all patients with ET. In EMD-HHT analysis, tremor characteristics were similar in subjects with PT and MS patients, regardless of the presence of a visible tremor, but these characteristics clearly differed in patients with ET. A visible tremor in MS patients was associated with more frequent cerebellar signs and less motor deficit at the upper limb. The low-frequency tremor observed in MS patients could therefore originate in lesions of the brainstem (midbrain) or cerebellothalamic circuits, or may correspond to an enhanced PT, partly favored by cerebellar dysfunction and being more visible during movement execution in the absence of concomitant motor deficit.

Relapses in multiple sclerosis: effects of high-dose steroids on cortical excitability.

BACKGROUND AND PURPOSE: High-dose steroid administration is the usual treatment of multiple sclerosis (MS) relapse, but it remains to determine whether this treatment may act by changing the excitability of cortical circuitry. METHODS: The functional cortical effects of high-dose steroids in 21 MS patients before and after 3 days of intravenous administration of methylprednisolone (1 g/day) for the treatment of MS relapse were studied. Investigations included various clinical scales [Kurtzke Functional System Scale (KFSS), Expanded Disability Status Scale and Fatigue Severity Scale, 10-m walk] and transcranial magnetic stimulation (TMS) tests of cortical excitability [resting motor threshold, recruitment curve of motor evoked potentials, short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) at various interstimuli intervals (ISIs), cortical silent period and interhemispheric inhibition]. RESULTS: Following steroid administration, clinical improvement was significant for the KFSS pyramidal (motor) and total scores, whilst TMS showed a reduction of SICI (mean and maximum values) and an increase of ICF at 10 ms ISI. CONCLUSIONS: Very rapid functional changes in the excitability of cortical circuits involved in motor control can be induced by steroids, before any process of remyelination or axonal regeneration has time to occur. The net effect of steroids on the balance between intracortical GABAergic inhibition and glutamatergic facilitation was in favour of weaker inhibition or stronger facilitation, which could lead to improving the motor performance in MS patients.

Iron depletion induced by bloodletting and followed by rhEPO administration as a therapeutic strategy in progressive multiple sclerosis: a pilot, open-label study with neurophysiological measurements.

OBJECTIVES: To evaluate the concept that iron depletion (ID) induced by bloodletting and followed by recombinant human erythropoietin (rhEPO) administration could be a therapeutic strategy in progressive multiple sclerosis (PMS) and that it could be assessed by neurophysiological measurements. PATIENTS AND METHODS: In four patients with PMS, bloodletting was performed until ID was induced, and then rhEPO was administered (300 UI/kg/week). The changes induced by the treatment were assessed by clinical scores, biological tests, and neurophysiological study of cortical excitability using transcranial magnetic stimulation techniques. RESULTS: The treatment was well tolerated except for muscle cramps and one popliteal vein thrombosis in a patient confined to chair. ID was obtained within 28 weeks and was associated with endogenous production of EPO. No bloodletting was further required during a six-month period after introduction of rhEPO. At the end of the follow-up (up to one year), fatigue and walking capacities tended to improve in two patients. Neurophysiological changes were characterized by an increased cortical excitability, including a decrease of motor thresholds and an enhancement of intracortical facilitation and cerebellothalamocortical inhibition. CONCLUSIONS: The combined ID-rhEPO therapy could authorize a prolonged administration of rhEPO in PMS patients, able to modify cortical excitability of the glutamatergic and gabaergic circuits. These preliminary data are encouraging to design a larger, controlled therapeutical trial to assess the value of such a strategy to improve functional symptoms in PMS patients, and maybe to prevent axonal degeneration. Neurophysiological measurements based on cortical excitability studies could provide sensitive parameters to evaluate treatment-induced changes in this context.

[Cavitary lesions in multiple sclerosis: multicenter study on twenty patients]. / Formes cavitaires de sclérose en plaques: étude multicentrique sur vingt patients.

INTRODUCTION: Cavitary white matter changes are mainly described in leukodystrophies and especially in vanishing white matter disease. Large cavitary lesions are not typical for multiple sclerosis (MS). METHODS: We studied MS patients with large cavitary brain lesions. Patient characteristics, disease onset/duration/subtype, expanded disability status scale (EDSS), mini mental state (MMS), vanishing white matter disease genetic analysis, and MRI characteristics of the cavitary lesions were analyzed. RESULTS: Twenty patients were analyzed (6 men and 14 women). Mean age at disease onset was 37.6 (range 17-58). Mean disease duration was 10 years (range 2-20). Five patients had initial relapsing-remitting MS and nine patients had primary-progressive MS. Mean EDSS was 5.5 (range 2-8). Mean MMS was 20/30. Vanishing white matter disease genetic analysis was performed and negative in seven patients. Inferior corpus callosum lesions were seen in all patients with available sagittal FLAIR sequences. Cavitary lesions were strictly supratentorial, and located inside the diffuse leukoencephalopathy, with often a posterior predominance. CONCLUSION: MS patients with large cavitary lesions seem to represent a MS subgroup, predominantly women, with relatively late disease onset, predominantly primary-progressive type, relatively high EDSS scores, and severe cognitive dysfunction.

Rapidly progressive amyotrophic lateral sclerosis initially masquerading as a demyelinating neuropathy.

Rare cases of demyelinating neuropathy have been described in association with amyotrophic lateral sclerosis (ALS). We report two patients with typical ALS whose initial electroneuromyographic (ENMG) presentation could suggest the existence of a process of motor nerve fiber demyelination. However, subsequent ENMG examinations and the fatal course of the disease in a few months rather supported severe ongoing axonal degeneration at the origin of motor nerve conduction abnormalities. Repeated examinations could be required to distinguish between ENMG features of concomitant demyelinating neuropathy and rapidly progressive motor neuron loss in ALS.

Neuromyelitis optica in France: a multicenter study of 125 patients.

BACKGROUND: There have been few epidemiologic studies on neuromyelitis optica (NMO) and none used the recent 2006 diagnostic criteria. Here we describe the clinical, laboratory, MRI, and disability course of NMO in a French cohort of 125 patients. METHODS: We performed an observational, retrospective, multicenter study. Data were collected from September 2007 through August 2008, corresponding to the endpoint of the study. We identified 125 patients fulfilling the 2006 NMO criteria. Selection was made using hospital files and a specific clinical questionnaire for NMO. RESULTS: Mean age at onset was 34.5 years (range 4-66) with a mean disease duration of 10 +/- 7.8 years at the endpoint. The patients were mainly (87%) Caucasian, with a female:male ratio of 3:1. In 90% of cases, the association of optic neuritis, longitudinal extensive myelitis, and a Paty-negative initial brain MRI was sufficient to fulfill the supportive criteria. Eighty-eight percent of patients were treated with immunosuppressive therapies. Median delay from onset to Expanded Disability Status Scale (EDSS) score 4 was 7 years; score 6, 10 years; and score 7, 21 years. The first episode of myelitis was immediately followed by an EDSS score > or = 4 in 37.3% of cases, and a severe residual visual loss was observed in 22% of patients after the first episode of optic neuritis. Multivariate analysis did not reveal any predictors of a poor evolution other than a high number of MRI brain lesions at diagnosis, which were predictive of a residual visual acuity < or = 1/10. CONCLUSIONS: Our demographic data provide new data on disability in patients with neuromyelitis optica, most of whom were receiving treatment.

Late-onset cervicoscapular muscle atrophy and weakness after radiotherapy for Hodgkin disease: a case series.

Patients with cervical or mediastinal Hodgkin disease (HD) classically underwent chemotherapy plus extended-field radiation therapy. We report six patients who gradually developed severe atrophy and weakness of cervical paraspinal and shoulder girdle muscles 5-30 years after mantle irradiation for HD. Although clinical presentation was uniform, including a dropped head syndrome, electrophysiological and pathological findings were rather heterogeneous. Either neurogenic or myogenic processes may be involved and sometimes combined. We discuss the pathophysiological mechanisms underlying these cervicoscapular motor complications of mantle irradiation in HD.

Home administration of intravenous methylprednisolone for multiple sclerosis relapses: the experience of French multiple sclerosis networks.

BACKGROUND: One single center study has provided support for a home-based approach to the therapeutic management of multiple sclerosis (MS) relapse. OBJECTIVE: To report a multicenter series of patients with MS who were treated at home for a relapse with a 3-day course of intravenous methylprednisolone. METHODS: The home administration of intravenous methylprednisolone was coordinated by four MS networks in France; patients with MS with a relapse were referred by their neurologists, and treatment was administered by a local nurse. We analyzed the safety and efficiency of this approach and estimated the related cost savings. Patients completed a patient satisfaction questionnaire. RESULTS: Eight hundred and seven patients received intravenous methylprednisolone at home. The mean disease duration was 10.3 +/- 7.9 years. Treatment was often prescribed by community-based neurologists. The delay between prescription and treatment was 2.8 +/- 0.5 days if treatment was initiated at home and 1.9 +/- 3.0 days if treatment was initiated in hospital (the subsequent two injections were always administered at home). Home treatment was well tolerated; three serious side effects requiring hospital transfer were observed (anxiety, thoracic oppression, and arrhythmia), which were fully reversible. Overall, 93.8% of patients were satisfied with the treatment approach, and 98% wished to receive future treatment courses at home. The overall cost savings of home-based treatment versus hospital-based treatment were evaluated at EUR1,091,482. CONCLUSION: Safety data, patient satisfaction, and economic considerations support home-based treatment of MS relapses with intravenous methylprednisolone, provided strict patient selection criteria are observed and the process is coordinated and closely monitored by an MS network.

[Social handicap at the onset of the multiple sclerosis]. / Handicap social des formes précoces de sclérose en plaques.

Multiple sclerosis is the most frequent cause of handicap in young adults. Because of the young age of patients, the chronic relapsing course, the multifocal consequences of lesions, and the frequent progressive chronic course, multiple sclerosis has multiple consequences including individuals, familial, social and professional, that induces, in the early stage, a wide social handicap overflowing consequences of the neurological deficit. Since the onset of the disease, social events are very frequent: jobless and decrease of salaries (50% of the cases), divorce (10%), daily help (12%).

[Immunoablation and autologous hematopoietic stem cell transplantation (AHSCT) in multiple sclerosis]. / Intensification thérapeutique et autogreffe de cellules souches hématopoïétiques pour le traitement de la sclérose en plaques.

Numerous pathophysiological arguments supporting immunosuppression for multiple sclerosis have been collected during recent years. The relevance of intense immunosuppression, in terms of clinical benefit and early or late risk, remains a matter of discussion. Immunoablation followed by autologous hematopoietic stem cell transplantation (AHSCT) in multiple sclerosis uses intense immunosuppression, followed by reinjection of AHSC, a rescue procedure for the induced aplasia. This method targets disappearance of the immune disorder, and thus, in theory, the interruption of the disease course. Use of AHSCT to treat several types of autoimmune diseases has been performed with contrasted results. In multiple sclerosis, the experience has been gained over the past 10 years through short series of patients treated at a late stage of their disease. This article highlights the recent data of this particular treatment option in multiple sclerosis as well as the therapeutic aims that should be investigated in further trials.