French validation of the Quality of life in Essential Tremor Questionnaire (QUEST) and the Essential Tremor Embarrassment Assessment (ETEA).

Two scales have been developed and validated in English to evaluate the impact of tremor on daily life, namely Quality of life in Essential Tremor Questionnaire (QUEST) and Essential Tremor Embarrassment Assessment (ETEA). The psychometric properties of the French version of these two scales were assessed for 117 patients with head tremor. Both scales showed excellent acceptability, very good internal consistency (Cronbach's alpha coefficient>0.8) and reproducibility (Lin concordance coefficient>0.8), satisfactory external validity and satisfactory sensitivity to change. In conclusion, the French versions of QUEST and ETEA are comprehensive, valid and reliable instruments for assessing patients with head tremor.

123I-FP-CIT SPECT imaging in blepharospasm.

INTRODUCTION: Blepharospasm is a focal dystonia characterized by involuntary cocontraction of the eyelid protractors, causing spasmodic closure of the eyelids. Apraxia of eyelid opening is caused by an inability to initiate lid opening without paralytic abnormality. Some studies suggest that patients with either pure blepharospasm or blepharospasm associated with apraxia of eyelid opening are more prone to developing Parkinson's disease. METHODS: In our study, 123I-FP-CIT (DAT) SPECT was performed in 24 patients with either pure blepharospasm or blepharospasm associated with apraxia of eyelid opening and no signs of parkinsonism to identify dopaminergic dysfunction. RESULTS: DAT-SPECT was abnormal in 11 (46%) cases (five patients with isolated blepharospasm and six patients with blepharospasm associated with apraxia of eyelid opening) whose mean disease duration was 11 years. CONCLUSION: Our study revealed presynaptic dopaminergic dysfunction, as determined by 123I-FP-CIT or DAT-SPECT, in nearly half of our blepharospasm patients (with or without apraxia of eyelid opening). Thus, the presence of blepharospasm might be an early sign of a parkinsonian syndrome.

Chitinase 3-like proteins as diagnostic and prognostic biomarkers of multiple sclerosis.

BACKGROUND: Despite sensitivity of MRI to diagnose multiple sclerosis (MS), prognostic biomarkers are still needed for optimized treatment. OBJECTIVE: The objective of this paper is to identify cerebrospinal fluid (CSF) diagnostic biomarkers of MS using quantitative proteomics and to analyze their expression at different disease stages. METHODS: We conducted differential analysis of the CSF proteome from control and relapsing-remitting MS (RRMS) patients followed by verification by ELISA of candidate biomarkers in CSF and serum in control, clinically isolated syndrome (CIS), RRMS and progressive MS (PMS) patients. RESULTS: Twenty-two of the 527 quantified proteins exhibited different abundances in control and RRMS CSF. These include chitinase 3-like protein 1 (CHI3L1) and 2 (CHI3L2), which showed a strong expression in brain of MS patients, especially in astrocytes and microglial cells from white matter plaques. CSF and serum CHI3L1 levels increased with the disease stage and CIS patients with high CSF (>189 ng/ml) and serum (>33 ng/ml) CHI3L1 converted more rapidly to RRMS (log rank test, p < 0.05 and p < 0.001, respectively). In contrast, CSF CHI3L2 levels were lower in PMS than in RRMS patients. Accordingly, CSF CHI3L1/CHI3L2 ratio accurately discriminated PMS from RRMS. CONCLUSIONS: CSF CHI3L1 and CHI3L2 and serum CHI3L1 might help to define MS disease stage and have a prognostic value in CIS.

A prospective observational post-marketing study of natalizumab-treated multiple sclerosis patients: clinical, radiological and biological features and adverse events. The BIONAT cohort.

BACKGROUND AND PURPOSE: BIONAT is a French multicentric phase IV study of natalizumab (NTZ)-treated relapsing-remitting multiple sclerosis (MS) patients. The purpose of this study was to collect clinical, radiological and biological data on 1204 patients starting NTZ, and to evaluate the clinical/radiological response to NTZ after 2 years of treatment. METHODS: Patients starting NTZ at 18 French MS centres since June 2007 were included. Good response to NTZ was defined by the absence of clinical and radiological activity. Data analysed in this first report on the BIONAT study focus on patients who started NTZ at least 2 years ago (n = 793; BIONAT2Y ). RESULTS: NTZ was discontinued in 17.78% of BIONAT2Y. The proportion of patients without combined disease activity was 45.59% during the first two successive years of treatment. Systematic dosage of anti-NTZantibodies (Abs) detected only two supplementary patients with anti-NTZ Abs compared with strict application of recommendations. A significant decrease of IgG,M concentrations at 2 years of treatment was found. CONCLUSIONS: The efficacy of NTZ therapy on relapsing-remitting MS in a real life setting is confirmed in the BIONAT cohort. The next step will be the identification of biomarkers predicting response to NTZ therapy and adverse events.

[Cerebrotendinous xanthomatosis: a multicentric retrospective study of 15 adults, clinical and paraclinical typical and atypical aspects]. / Étude rétrospective multicentrique de 15 cas adultes de xanthomatose cérébrotendineuse : aspects cliniques et paracliniques typiques et atypiques.

INTRODUCTION: Cerebrotendinous xanthomatosis, a metabolic leukodystrophy with an autosomal recessive inheritance, is secondary to deficiency of sterol 27-hydroxylase, an enzyme involved in cholesterol catabolism. Classical symptoms include clinical or infraclinical xanthomas affecting the skin and tendons, early cataracts, neurological signs and diarrhea. Brain imaging reveals involvement of the dentate nuclei and periventricular white matter hyperintensities. The diagnosis is based on an increased cholestanol level in serum, confirmed by the presence of a mutation in the CYP27A1 gene. Treatment is based on chenodeoxycholic acid. METHOD: We report a retrospective multicentric study of 15 cases of cerebrotendinous xanthomatosis diagnosed in French adults. Clinical, molecular and MRI findings were recorded in all patients. RESULTS: The average age at diagnosis was 39years (range 27-65). Disease onset occurred in childhood in 73% of patients and in adulthood in 27%. All patients with a pediatric onset were diagnosed during adulthood (age range 28-65years). Clinical symptoms variably associated cerebellar syndrome, pyramidal syndrome, cognitive decline, epilepsy, neuropathy (sought in 10 of our patients, present in forms in 8), psychiatric disorders, cataract and xanthomas. One patient had an atypical presentation: monoparesis associated with xanthomas. Brain MRI was abnormal in all: findings consisted in T2-weighted hyperintensity of the dentate nuclei (47%), periventricular leuoencephalopathy (73%) which preferentially involved the posterior cerebral part (60%), leucoencephalopathy with a vascular pattern (7%), hyperintensity of the cortico-spinal tracts (53%), globi pallidi, corpus callosum and cerebral atrophy (33%). Serum cholestanol was elevated in 93% of patients. The most frequent mutation was 1183C>T (n=5/15). Under treatment with chenodeoxycholic acid, eight patients improved initially, followed by stabilization in five of them, and worsening in the others. Four patients died. CONCLUSION: Patients with the xanthoma-neurological disorder association should be tested for cerebrotendinous xanthomatosis. The disease often begins in childhood with a diagnostic delay but also in adulthood. Involvement of the dentate nuclei is specific but not sensitive and the supratentorial leucoencephalopathy is not specific but with an antero-posterior gradient. A vascular distribution and involvement of the corpus callosum are possible. Serum cholestanol assay is very reliable: an elevated level provides the diagnosis, which must nevertheless be confirmed by molecular biology.

I123-FP-CIT single-photon emission tomography in patients with long-standing mixed tremor.

BACKGROUND AND PURPOSE: Essential tremor is an abnormal movement characterized by postural and/or kinetic tremor. In some essential tremor patients, rest tremor (RT) is observed but it is not clear if this RT is a feature of essential tremor or a symptom of Parkinson's disease (PD). I123-FP-CIT single-photon emission tomography is used to distinguish essential tremor and PD. OBJECTIVES: To analyse I123-FP-CIT single-photon emission tomography in a larger series of patients with mixed tremor (i.e. action tremor associated with RT) without PD criteria. METHODS: We studied 33 consecutives patients (18 men and 15 women) with mixed tremor, clinically and by neuroimaging in all cases. RESULTS: I123-FP-CIT single-photon emission tomography was abnormal in 25 of our patients (75.7%) with mixed tremor, and we noted a reduced uptake mostly in the putamen. In our patients with abnormal imaging, RT was unilateral in 52%. In 15 of these 25 patients, putaminal reduced uptake was bilateral and symmetrical. In the other 10 patients, putaminal reduced uptake was asymmetrical or unilateral. In these 10 cases, six had a unilateral RT corresponding to (crossed) predominant reduced uptake in three cases. In our patients with normal imaging, RT was unilateral in 87.5%. CONCLUSIONS: This study shows that mixed tremor is a heterogeneous entity. The majority of patients with mixed tremor showed nigrostriatal dysfunction on I123-FP-CIT single-photon emission tomography, suggesting that mixed tremor may be a parkinsonian syndrome rather than a clinical variant of essential tremor.

[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.

GQ1b ganglioside antibody-related disorders: a case with a complex phenotype.

We described an overlap syndrome associating Miller Fisher syndrome (MFS) and acute inflammatory demyelinating polyradiculoneuropathy (AIDP). Furthermore, the patient presented unusual neurological manifestations including headache, T10 sensory level, urinary urgency, and gadolinium enhancement of the spinal roots. One year follow-up was characterized by clinical recovery and persistent high rates of anti-GQ1b, -GD1b and -GT1b antibodies. Our case suggests broad phenotype of persistent antigangliosides antibodies.

[Retinal atrophy using optical coherence tomography (OCT) in 15 patients with multiple sclerosis and comparison with healthy subjects]. / Etude de la perte axonale optique en tomographie en cohérence optique (OCT) chez 15 patients atteints de sclérose en plaques et comparaison avec une population de témoins appariés.

INTRODUCTION: Multiple sclerosis is a common disabling progressive neurological disorder. Axonal loss is thought to be a likely cause of persistent disability after a multiple sclerosis relapse. Retinal nerve fiber layer (RNFL) imaging by optical coherence tomography (OCT) seems to be a non-invasive way of detecting optical axonal loss following optic neuritis. OBJECTIVE: To determine whether multiple sclerosis affects retinal nerve fiber layer measurements obtained with optical coherence tomography (OCT3-Carl Zeiss Meditec, Dublin, California, USA). MATERIAL AND METHODS: Diagnosis of MS was based on the MacDonald criteria. The cohort was divided into two groups based on their clinical course (multiple sclerosis with [n=8; 16 eyes] or without [n=7; 14 eyes] optic neuritis antecedents). The disease-free controls were matched for age and gender (n=15; 30 eyes). Retinal nerve fiber layer thickness was measured using optical coherence tomography (OCT; fastRNFL and RNFL thickness software protocol). Visual acuity, visual field, color vision were also noted. RESULTS: There were highly significant reductions (p<0.001) of retinal nerve fiber layer thickness in affected patients (with or without optic neuritis antecedents) compared with control eyes (fastRNFL and RNFL procedures). Visual acuity, visual field and color vision were globally less altered than OCT. There were no significant relationships among RNFL thickness and visual acuity, visual field, or color vision. CONCLUSION: This study has demonstrated the anatomic changes of the retinal nerve fiber layer of patients with multiple sclerosis with optic neuritis antecedents. Thus axonal loss following optic neuritis can be detected with OCT. But the retinal nerve fiber layer of patients without optic neuritis is also thinner than disease-free controls so that chronic optic axonal loss can be frequent in multiple sclerosis. Additionally, OCT was more sensitive than the common ophthalmological explorations to detect optical nerve impairment during multiple sclerosis. Finally, we demonstrated that two procedures fastRNFL and RNFL could be used to detect optic nerve impairment.

[Ma2 antibody and multiple mononeuropathies]. / Mononeuropathie multiple et anticorps anti-Ma2.

Anti-Ma2 antibodies belong to a family of onconeuronal antibodies that target proteins expressed in brain, testis and several tumors. Previously observed in patients presenting with limbic encephalitis, they seem to be associated with several other paraneoplastic syndromes. We report the case of a 73-year-old woman presenting sensory and motor neuropathy associated with non-small-cell lung cancer who had Ma2-antibodies.

Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia: An MRI Study of 16 French Cases.

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia is an autosomal dominant leukoencephalopathy related to CSF1R gene mutations. A growing number of clinicoradiologic phenotypes have been described. In this study, we analyzed brain imaging findings in 16 patients with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia to refine radiologic diagnostic clues. T2/FLAIR white matter hyperintensities were present in all patients with frontal or frontoparietal predilection, with asymmetric distribution in more than one-third. Brain atrophy and callosal involvement were almost constant, and corticospinal tract involvement was frequent. Moreover, deep white matter hyperintense dots on DWI and deep punctate calcifications on CT were often found. Conversely, deep gray matter nuclei, external capsules, and brain stem were rarely involved. Our series emphasized the great variability of MR imaging findings seen in adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. A complete imaging screening including DWI, T2*, and CT is mandatory to accurately assess patients with suspected inherited adult-onset leukoencephalopathy.

[Writer's cramp secondary to spinocerebellar ataxia type 7]. / Une crampe de l'écrivain associée à une ataxie spinocérébelleuse de type 7.

Spinocerebellar ataxia type 7 (SCA 7) is a rare autosomal dominant neurodegenerative disorder (ADCA) caused by expansion of a highly unstable CAG repeat. Clinical features including progressive cerebellar, retinal degeneration and pyramidal signs. We report a patient with SCA 7 diagnosis revealed by progressive cerebellar ataxia and writer's cramp.

[Devic disease associated with isolated spinal cord atrophy]. / Maladie de devic associée à une atrophie médullaire.

Devic disease is a rare entity characterized by bilateral optic neuritis and transverse myelitis. Recently, recognition of antibody activity (Anti NMO) led to broaden the clinical and MR phenotype spectrum of this disease. This report is about a patient with spinal cord atrophy and bilateral optic neuritis, occurring more than 8 years after symptom onset.

[Influence of acute aggravations on the development of long-term handicap in relapsing remitting multiple sclerosis: a clinical study in 99 patients]. / Influence des poussées sur la survenue d'un handicap au long cours dans la sclérose en plaques de forme rémittente: étude observationnelle de 99 patients.

INTRODUCTION: Rate of relapse occurring during the first 5 years of MS-RR is a prognosis factor of occurrence of disability or secondary progressive (SP) phase. Progressive phase, related to chronic axonal loss, is mainly considered as the principal factor of disability progression. Influence of acute relapses during the relapsing-remitting phase on disability development is not known as a prognosis factor. OBJECTIVES: To determine the influence of the exacerbations among patients with RR-MS after the second clinical event on the disability occurrence. METHODS: Diagnosis of multiple sclerosis was established according to Poser's classification. Disability measurement was made with the use of the Expanded Disability Status Scale (EDSS). The patients included in the study were classified as clinically definite RR-MS, with an EDSS score500 m. The study began at the time of the second clinical event and ended when an EDSS score of 4.0 was reached or when a SP phase was beginning or at the last follow-up visit date if these two stages were not reached. The primary outcome measure was the comparison of the risk and the average time to reach an EDSS>or=4.0 or a SP form according to the annual exacerbation rate (AER) using Kaplan-Meier survival curve. RESULTS: Among the 238 ms patients of the database, 136 patients were classified as having a definite RR-MS. Among these 136 patients, 99 patients could be included in the study according to the inclusion criteria. The median follow up of the patients since the first clinical event was 9.8 years (range 4 to 44). The average EDSS score was 0.7 at the beginning of the study and 2.3 at the end. 20.2p.cent of patients (n=20) reached an EDSS score of 4.0 or a SP-MS. The median AER was 0.4 and the average 0.62 (range 0 to 6.1). The time to reach the primary end point for 25p.cent of the population was 17.8 years in group with an AER<0.4 (group A) and 6.9 years in group with an AER>0.4 (group B) (logrank; p<0.0001). The relative risk for patients of the group B compared to group A to reach an EDSS of 4.0 or a SP form was 8.01 (IC-95p.cent: 2.74-23.46; p=0.0001). CONCLUSIONS: In spite of a limited number of patients, this study gives evidence that a high rate of acute exacerbations in RR-MS patients after the second clinical event may be an independent predictive factor of long-term residual disability progression. High relapse rate leads to a more frequent and faster SP or EDSS>4.0 occurrence.

[Adult leukoencephalopathy caused by alpha-mannosidosis deficiency]. / Leucoencéphalopathie de l'adulte associée à un déficit en alpha-mannosidase.

Adult leukoencephalopathy caused by alpha-mannosidosis deficiency (MIM248500) is a recessive inherited lysosomal storage disease associated with decreased activity of alpha-mannosidase. This enzyme degrades oligosaccharides and glycoproteins in neural and visceral tissues. There are two different disease phenotypes, type-I or severe infantile phenotype and type 2, which progresses more slowly and is compatible with survival into adulthood. We report the case of a 51-year-old man with gait disorders beginning at the age of 40 years associated with leukoencephalopathy due to alpha-mannosidosis deficiency.