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In addition to combined central and peripheral demyelination, other immune diseases could involve both the central nervous system (CNS) and peripheral nervous system (PNS).To identify immune-mediated diseases responsible for symptomatic combined central/peripheral nervous system involvement (ICCPs), we conducted a multicentric retrospective study and assessed clinical, electrophysiological, and radiological features of patients fulfilling our ICCP criteria.Thirty patients (20 males) were included and followed during a median of 79.5 months (interquartile range [IQR] = 43-145). The median age at onset was 51.5 years (IQR = 39-58). Patients were assigned to one of four groups: (i) monophasic disease with concomitant CNS/PNS involvement including anti-GQ1b syndrome (acute polyradiculoneuropathy + rhombencephalitis, n = 2), checkpoint inhibitor-related toxicities (acute polyradiculoneuropathy + encephalitis, n = 3), and anti-glial fibrillary acidic protein astrocytopathy (subacute polyradiculoneuropathy and meningoencephalomyelitis with linear gadolinium enhancements, n = 2); (ii) chronic course with concomitant CNS/PNS involvement including paraneoplastic syndromes (ganglionopathy/peripheral hyperexcitability + limbic encephalitis, n = 4); (iii) chronic course with sequential CNS/PNS involvement including POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) syndrome (polyradiculoneuropathy + strokes, n = 2), histiocytosis (polyradiculoneuropathy + lepto-/pachymeningitis, n = 1), and systemic vasculitis (multineuropathy + CNS vasculitis/pachymeningitis, n = 2); and (iv) chronic course with concomitant or sequential CNS/PNS involvement including combined central and peripheral demyelination (polyradiculoneuropathy + CNS demyelinating lesions, n = 10) and connective tissue diseases (ganglionopathy/radiculopathy/multineuropathy + limbic encephalitis/transverse myelitis/stroke, n = 4).We diagnosed nine ICCPs. The timing of central and peripheral manifestations and the disease course help determine the underlying immune disease. When antibody against neuroglial antigen is identified, CNS and PNS involvement is systematically concomitant, suggesting a common CNS/PNS antigen and a simultaneous disruption of blood-nerve and blood-brain barriers.

Multiple sclerosis (MS) is an inflammatory demyelinating disease often characterized by remission and relapse periods occurring at irregular intervals after an initial attack (clinically isolated syndrome) and followed by a gradual progression of disability. Clinical symptoms, magnetic resonance imaging and abnormalities in cerebrospinal fluid (CSF) immunoglobulin profile allow diagnosis with a good sensitivity. However, current biomarkers lack specificity or have poor individual prognostic value. To identify novel candidate biomarkers of MS, we analysed 1) the CSF proteome from symptomatic controls and patients with clinically isolated syndrome or remitting-relapsing multiple sclerosis (n=40), and 2) changes in oligodendrocyte secretome upon proinflammatory or pro-apoptotic treatment. Proteins exhibiting differences in abundance in both studies were combined with previously described MS biomarkers to build a list of 87 proteins that were quantified by parallel reaction monitoring (PRM) in CSF samples from a new cohort comprising symptomatic controls and MS patients at different disease stages (n=60). The eleven proteins that passed this qualification step were subjected to a new PRM assay from a larger cohort (n=158) comprising patients with MS at different disease stages or with other inflammatory or non-inflammatory neurological disorders. Collectively, these studies identified a biomarker signature of MS that might improve MS diagnosis and prognosis. These include the oligodendrocyte precursor cell proteoglycan Syndecan-1, which was more efficient than previously described biomarkers to discriminate MS from other inflammatory and non-inflammatory neurological disorders.

Background and aimsMultiple sclerosis (MS) is associated with osteoporosis, possibly due to neurological disability and decreased calcium intake. The objective of this study was to evaluate the efficacy of a personalized nutritional advice program by a dietitian compared to the delivery of a standard advice form to optimize dietary calcium intake in outpatients with MS.MethodsWe performed a randomized, controlled, parallel trial comparing the efficacy of a personalized dietary advice (PDA) program to standard advice form (SAF) to increase daily calcium intake in MS patients. The study population was composed by patients with relapsing-remitting MS aged 18–69 years old. PDA program consisted in dietary advice delivered by a dietitian at baseline, 1 month, and 3 months. Calcium and nutrient intake in patients from both groups was evaluated at baseline and 6 months using a dietary survey.ResultsOf the 194 patients screened for inclusion, 182 patients were included (79% female, median age of 42 years, and median EDSS of 2.0), and randomized to SAF (n = 92) or PDA (n = 90). At 6 months, median calcium intake increased by 241 mg/day in the PDA group and decreased by 120 mg/day in the SAF group (p < 0.0001). However, the median calcium intake was 947 mg/day in the SAF group and 778 mg/day in the PDA group at baseline (p = 0.0077), potentially favoring the effect of dietary advice. Complementary analyses focusing on patients with insufficient calcium intakes at baseline revealed comparable values in both groups (p = 0.69). Of those, patients included in the PDA group obtained significantly higher calcium intakes at 6 months than patients from the SAF group (p = 0.0086) independently of EDSS, PASAT, HADS and EQ-5D scores.ConclusionThis work shows the efficacy of dietary management based on personalized advice program over 3 months to durably increase calcium consumption in MS patients with insufficient calcium intake.Clinical trial registrationclinicaltrials.gov, identifier NCT02664623.

The treatment strategy in relapsing multiple sclerosis (RMS) is a complex decision requiring individualization of treatment sequences to maximize clinical outcomes. Current local and international guidelines do not provide specific recommendation on the use of immune reconstitution therapy (IRT) as alternative to continuous immunosuppression in the management of RMS. The objective of the program was to provide consensus-based expert opinion on the optimal use of IRT in the management of RMS. A Delphi method was performed from May 2022 to July 2022. Nineteen clinical assertions were developed by a scientific committee and sent to 14 French clinical experts in MS alongside published literature. Two consecutive reproducible anonymous votes were conducted. Consensus on recommendations was achieved when more than 75% of the respondents agreed or disagreed with the clinical assertions. After the second round, consensus was achieved amongst 16 out of 19 propositions: 13 clinical assertions had a 100% consensus, 3 clinical assertions a consensus above 75% and 3 without consensus. Expert-agreed consensus is provided on topics related to the benefit of the early use of IRT from immunological and clinical perspectives, profiles of patients who may benefit most from the IRT strategy (e.g. patients with family planning, patient preference and lifestyle requirements). These French expert consensuses provide up-to-date relevant guidance on the use of IRT in clinical practice. The current program reflects status of knowledge in 2022 and should be updated in timely manner when further clinical data in IRT become available.

Background In 2020 the coronavirus disease 19 (COVID-19) pandemic imposed a total and sudden lockdown. We aimed to investigate the consequences of the first COVID-19 lockdown (mid-March – mid-April 2020) on motor and non-motor symptoms (NMS) in a cohort of French people with Parkinson's disease (PwP). Methods PwP were enrolled either by an on-line survey sent from the national France Parkinson association (FP) to reach the French community of PwP or as part of outpatients' telemedicine visits followed by an hospital-based Parkinson Expert Center (PEC). All patients were evaluated using the same standardized questionnaire assessing motor and NMS (including a list of most disabling, new or worsened symptoms and Patient's Global Impression-Improvement scales [PGI-I]) psycho-social queries and quality of life. Results 2653 PwP were included: 441 (16.6%) in the PEC group and 2122 (83.4%) in the community-based group. Physiotherapy was interrupted among 88.6% of the patients. 40.9% referred a clinical modification of their symptoms. Based on the questionnaire, pain (9.3%), rigidity (9.1%) and tremor (8.5%) were the three most frequently new or worsened reported symptoms. Based on the PGI-I, the motor symptoms were the most affected domain, followed by pain and psychic state. PwP in community-based group tended to have more frequent worsening for motor symptoms, motor complications, pain and confusion than those of the PEC group. Conclusions The first COVID-19 lockdown had a negative impact on motor and NMS of PwP. Efforts should be allocated to avoid interruption of care, including physiotherapy and physical activities and implement telemedicine. .

Background Prolonged-release fampridine (PR-FAM) 10-mg tablet twice daily is the only approved pharmacological treatment for improvement of walking ability in adults with multiple sclerosis (MS). LIBERATE assessed the safety/effectiveness of PR-FAM in the real-world. Objectives The aim of this study was to collect additional safety data, including the incidence rate of seizures and other adverse events (AEs) of interest, from patients with MS taking PR-FAM in routine clinical practice (including patients aged ≥ 65 years and those with pre-existing cardiovascular risk factors). Other objectives included change over time in patient-reported evaluation of physical and psychological impact of MS while taking PR-FAM, and change over time in physician-reported assessment of walking ability in MS patients taking PR-FAM. Methods Patients with MS newly prescribed PR-FAM were recruited (201 sites, 13 countries). Demographic/safety data were collected at enrolment through 12 months. Physician-rated Clinical Global Impression of Improvement (CGI-I) scores for walking ability, and Multiple Sclerosis Impact Scale-29 (MSIS-29) were assessed. Results Safety analysis included 4646 patients with 3534.8 patient-years of exposure; median (range) age, 52.6 (21–85) years, 87.3% < 65 years, and 65.7% women. Treatment-emergent AEs (TEAEs) were reported in 2448 (52.7%) patients, and serious TEAEs were reported in 279 (6.0%) patients, of whom 37 (< 1%) experienced treatment-emergent serious AEs (TESAEs) considered related to PR-FAM. AEs of special interest (AESI) occurred in 1799 (38.7%) patients, and serious AESI in 128 (2.8%) patients. Seventeen (< 1%) patients experienced actual events of seizure. Overall, 1158 (24.9%) patients discontinued treatment due to lack of efficacy. At 12 months, a greater proportion of patients on-treatment had improvement from baseline in CGI-I for walking ability versus those who discontinued (61% vs. 11%; p < 0.001). MSIS-29 physical impact score improved significantly for patients on-treatment for 12 months versus those who discontinued (mean change, baseline to 12 months: − 9.99 vs. − 0.34 points; p < 0.001). Results were similar for MSIS-29 psychological impact. Conclusion No new safety concerns were identified in this real-world study, suggesting that routine risk-minimization measures are effective. CGI-I and MSIS-29 scores after 12 months treatment with PR-FAM treatment show clinical benefits consistent with those previously reported. Trial Registration ClinicalTrials.gov: NCT01480063. Supplementary Information The online version contains supplementary material available at 10.1007/s40263-021-00840-x.

A 74-year-old man presented with falls, dysphagia, and personality change. Examination showed axial parkinsonism (without response to levodopa), low pitched dysarthria, supranuclear vertical gaze palsy, decreased blinking, square-wave jerks, primitive reflexes, apathy, and decreased verbal fluency. Brain MRI showed dorsal midbrain and frontal …

Background Alzheimer disease (AD) is a common complex disorder with a high genetic component. Loss-of-function (LoF) SORL1 variants are one of the strongest AD genetic risk factors. Estimating their age-related penetrance is essential before putative use for genetic counseling or preventive trials. However, relative rarity and co-occurrence with the main AD risk factor, APOE-ε4, make such estimations difficult. Methods We proposed to estimate the age-related penetrance of SORL1-LoF variants through a survival framework by estimating the conditional instantaneous risk combining (i) a baseline for non-carriers of SORL1-LoF variants, stratified by APOE-ε4, derived from the Rotterdam study (N = 12,255), and (ii) an age-dependent proportional hazard effect for SORL1-LoF variants estimated from 27 extended pedigrees (including 307 relatives ≥ 40 years old, 45 of them having genotyping information) recruited from the French reference center for young Alzheimer patients. We embedded this model into an expectation-maximization algorithm to accommodate for missing genotypes. To correct for ascertainment bias, proband phenotypes were omitted. Then, we assessed if our penetrance curves were concordant with age distributions of APOE-ε4-stratified SORL1-LoF variant carriers detected among sequencing data of 13,007 cases and 10,182 controls from European and American case-control study consortia. Results SORL1-LoF variants penetrance curves reached 100% (95% confidence interval [99–100%]) by age 70 among APOE-ε4ε4 carriers only, compared with 56% [40–72%] and 37% [26–51%] in ε4 heterozygous carriers and ε4 non-carriers, respectively. These estimates were fully consistent with observed age distributions of SORL1-LoF variant carriers in case-control study data. Conclusions We conclude that SORL1-LoF variants should be interpreted in light of APOE genotypes for future clinical applications.

Background and ObjectivesTo evaluate the predictive value of serum neurofilament light chain (sNfL) and CSF NfL (cNfL) in patients with radiologically isolated syndrome (RIS) for evidence of disease activity (EDA) and clinical conversion (CC).MethodssNfL and cNfL were measured at RIS diagnosis by single-molecule array (Simoa). The risk of EDA and CC according to sNfL and cNfL was evaluated using the Kaplan-Meier analysis and multivariate Cox regression models including age, spinal cord (SC) or infratentorial lesions, oligoclonal bands, CSF chitinase 3–like protein 1, and CSF white blood cells.ResultsSixty-one patients with RIS were included. At diagnosis, sNfL and cNfL were correlated (Spearman r = 0.78,p< 0.001). During follow-up, 47 patients with RIS showed EDA and 36 patients showed CC (median time 12.6 months, 1–86). When compared with low levels, medium and high cNfL (>260 pg/mL) and sNfL (>5.0 pg/mL) levels were predictive of EDA (log rank,p< 0.01 andp= 0.02, respectively). Medium-high cNfL levels were predictive of CC (log rank,p< 0.01). In Cox regression models, cNfL and sNfL were independent factors of EDA, while SC lesions, cNfL, and sNfL were independent factors of CC.DiscussioncNfL >260 pg/mL and sNfL >5.0 pg/mL at diagnosis are independent predictive factors of EDA and CC in RIS. Although cNfL predicts disease activity better, sNfL is more accessible than cNfL and can be considered when a lumbar puncture is not performed.Classification of EvidenceThis study provides Class II evidence that in people with radiologic isolated syndrome (RIS), initial serum and CSF NfL levels are associated with subsequent evidence of disease activity or clinical conversion.

Immediate-release (IR) amantadine has been used for treatment of levodopa induced dyskinesia (LID). The immediate-release/extended-release (IR/ER) amantadine formulation OS320 (OSMOLEX ER®) contains an IR outer layer and ER core for once-daily dosing.Report individual and pooled results for the similarly designed double-blind, placebo-controlled ALLAY-LID I and II trials, assessing IR/ER-amantadine for LID.PD patients with LID were randomized to IR/ER-amantadine 193 mg, 258 mg, or placebo. Primary endpoint was Unified Dyskinesia Rating Scale (UDysRS) score change from baseline to Day 98. Secondary outcome was ON time without troublesome dyskinesia based on diaries. Exploratory outcomes were other diary states (including OFF), MDS-UPDRS Parts II + III and Fatigue Severity Scale.Overall, 222 individuals enrolled (N = 87 ALLAY-LID I, N = 135 ALLAY-LID II); both trials terminated early for sponsor's decision. While ALLAY-LID I did not meet its primary endpoint, a significant reduction in UDysRS scores versus placebo was observed in ALLAY-LID II for both 193 mg and 258 mg doses. In the pooled analysis, placebo-adjusted UDysRS score differences were -5.5 [-9.8, -1.2], p = 0.012 and -5.2 [-9.5, -0.9], p = 0.017, respectively. IR/ER-amantadine 258 mg significantly increased time spent ON without troublesome dyskinesia in ALLAY-LID II and pooled analysis. Reductions in ON time with dyskinesia supported the primary outcome. There was no effect on OFF time or other outcomes. Overall, 13.3% (193 mg), 18.7% (258 mg) and 11.1% (placebo) discontinued for adverse events, most commonly hallucinations (4.0%, 10.7%, and 1.4%, respectively).IR/ER-amantadine significantly reduced LID in ALLAY-LID II but not in ALLAY-LID I; post-hoc pooled data also indicated a positive treatment effect on LID.

Background and purpose Diagnostic criteria for adult onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) due to colony-stimulating factor 1 receptor (CSF1R) mutation have recently been proposed. Our objective was to assess their accuracy in an independent multicenter cohort. Methods We evaluated the sensitivity and specificity of the diagnostic criteria for ALSP (including the "probable" and "possible" definitions) in a national cohort of 22 patients with CSF1R mutation, and 59 patients with an alternative diagnosis of adult onset inherited leukoencephalopathy. Results Overall, the sensitivity of the diagnostic criteria for ALSP was 82%, including nine of 22 patients diagnosed as probable and nine of 22 diagnosed as possible. Twenty of the 59 CSF1R mutation-negative leukoencephalopathies fulfilled the diagnostic criteria, leading to a specificity of 66%. Conclusions Diagnostic criteria for ALSP have an overall limited sensitivity along with a modest specificity. We suggest that in patients suspected of genetic leukoencephalopathy, a comprehensive magnetic resonance imaging pattern-based approach is warranted, together with white matter gene panel or whole exome sequencing.

IF 10.292; International audience; The hereditary spastic paraplegias are an expanding and heterogeneous group of disorders characterized by spasticity in the lower limbs. Plasma biomarkers are needed to guide the genetic testing of spastic paraplegia. Spastic paraplegia type 5 (SPG5) is an autosomal recessive spastic paraplegia due to mutations in CYP7B1, which encodes a cytochrome P450 7α-hydroxylase implicated in cholesterol and bile acids metabolism. We developed a method based on ultra-performance liquid chromatography electrospray tandem mass spectrometry to validate two plasma 25-hydroxycholesterol (25-OHC) and 27-hydroxycholesterol (27-OHC) as diagnostic biomarkers in a cohort of 21 patients with SPG5. For 14 patients, SPG5 was initially suspected on the basis of genetic analysis, and then confirmed by increased plasma 25-OHC, 27-OHC and their ratio to total cholesterol. For seven patients, the diagnosis was initially based on elevated plasma oxysterol levels and confirmed by the identification of two causal CYP7B1 mutations. The receiver operating characteristic curves analysis showed that 25-OHC, 27-OHC and their ratio to total cholesterol discriminated between SPG5 patients and healthy controls with 100% sensitivity and specificity. Taking advantage of the robustness of these plasma oxysterols, we then conducted a phase II therapeutic trial in 12 patients and tested whether candidate molecules (atorvastatin, chenodeoxycholic acid and resveratrol) can lower plasma oxysterols and improve bile acids profile. The trial consisted of a three-period, three-treatment crossover study and the six different sequences of three treatments were randomized. Using a linear mixed effect regression model with a random intercept, we observed that atorvastatin decreased moderately plasma 27-OHC (∼30%, P < 0.001) but did not change 27-OHC to total cholesterol ratio or 25-OHC levels. We also found an abnormal bile acids profile in SPG5 patients, with significantly decreased total serum bile acids associated with a relative decrease of ursodeoxycholic and lithocholic acids compared to deoxycholic acid. Treatment with chenodeoxycholic acid restored bile acids profile in SPG5 patients. Therefore, the combination of atorvastatin and chenodeoxycholic acid may be worth considering for the treatment of SPG5 patients but the neurological benefit of these metabolic interventions remains to be evaluated in phase III therapeutic trials using clinical, imaging and/or electrophysiological outcome measures with sufficient effect sizes. Overall, our study indicates that plasma 25-OHC and 27-OHC are robust diagnostic biomarkers of SPG5 and shall be used as first-line investigations in any patient with unexplained spastic paraplegia.

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.

Autosomal dominant cerebellar ataxias have a marked heterogeneous genetic background, with mutations in 34 genes identified so far. This large amount of implicated genes accounts for heterogeneous clinical presentations, making genotype-phenotype correlations a major challenge in the field. While polyglutamine ataxias, linked to CAG repeat expansions in genes such as ATXN1, ATXN2, ATXN3, ATXN7, CACNA1A and TBP, have been extensively characterized in large cohorts, there is a need for comprehensive assessment of frequency and phenotype of more 'conventional' ataxias. After exclusion of CAG/polyglutamine expansions in spinocerebellar ataxia genes in 412 index cases with dominantly inherited cerebellar ataxias, we aimed to establish the relative frequencies of mutations in other genes, with an approach combining panel sequencing and TaqMan® polymerase chain reaction assay. We found relevant genetic variants in 59 patients (14.3%). The most frequently mutated were channel genes [CACNA1A (n = 16), KCND3 (n = 4), KCNC3 (n = 2) and KCNA1 (n = 2)]. Deletions in ITPR1 (n = 11) were followed by biallelic variants in SPG7 (n = 9). Variants in AFG3L2 (n = 7) came next in frequency, and variants were rarely found in STBN2 (n = 2), ELOVL5, FGF14, STUB1 and TTBK2 (n = 1 each). Interestingly, possible risk factor variants were detected in SPG7 and POLG. Clinical comparisons showed that ataxias due to channelopathies had a significantly earlier age at onset with an average of 24.6 years, versus 40.9 years for polyglutamine expansion spinocerebellar ataxias and 37.8 years for SPG7-related forms (P = 0.001). In contrast, disease duration was significantly longer in the former (20.5 years versus 9.3 and 13.7, P=0.001), though for similar functional stages, indicating slower progression of the disease. Of interest, intellectual deficiency was more frequent in channel spinocerebellar ataxias, while cognitive impairment in adulthood was similar among the three groups. Similar differences were found among a single gene group, comparing 23 patients with CACNA1A expansions (spinocerebellar ataxia 6) to 22 patients with CACNA1A point mutations, which had lower average age at onset (25.2 versus 47.3 years) with longer disease duration (18.7 versus 10.9), but lower severity indexes (0.39 versus 0.44), indicating slower progression of the disease. In conclusion, we identified relevant genetic variations in up to 15% of cases after exclusion of polyglutamine expansion spinocerebellar ataxias, and confirmed CACNA1A and SPG7 as major ataxia genes. We could delineate firm genotype-phenotype correlations that are important for genetic counselling and of possible prognostic value.

International audience; Simultaneous multiple intracerebral hemorrhage (SMICH) is defined as ICH in two or more discrete noncontiguous acute intraparenchymal locations on initial CT. About 5% of ICH patients present with SMICH. ICH/SMICH etiology is classically divided into disorders of primary or secondary origin. About half of primary SMICH cases are caused by cerebral amyloid angiopathy or hypertensive arteriopathy. In this review, we will discuss the radiological features associated with the different causes of primary and secondary ICH and SMICH. Due to its rarity and the associated high morbidity and mortality, we will focus in particular on SMICH.

Cerebrotendineous xanthomatosis (CTX) is an autosomal recessive disorder of bile acids synthesis. Patients may present with a variety of clinical manifestations: bilateral cataract and chronic diarrhea during childhood, then occurrence of neurological debilitating symptoms in adulthood (cognitive decline, motor disorders). Plasma cholestanol is used as a diagnostic marker of CTX, and to monitor the response to the treatment. Current treatment for CTX is chenodeoxycholic acid (CDCA), which was reported to improve and/or stabilize clinical status and decrease levels of plasma cholestanol. Rare published reports have also suggested a potential efficacy of cholic acid (CA) in patients with CTX. In this retrospective Franco-Belgian multicentric study, we collected data from 12 patients treated with CA, evaluating their clinical status, cholestanol levels and adverse effects during the treatment period. The population was divided in two subgroups: treatment-naive (who never had CDCA prior to CA) and non-treatment-naive patients (who had CDCA prior to CA introduction). We found that treatment with CA significantly and strongly reduced cholestanol levels in all patients. Additionally, 10 out of 12 patients clinically improved or stabilized with CA treatment. Worsening was noted in one treatment-naive patient and one non-treatment-naive patient, but both patients experienced similar outcomes with CDCA treatment as well. No adverse effects were reported from patients with CA treatment, whereas elevated transaminases were observed in some patients while they were treated with CDCA. In conclusion, these findings suggest that CA may be a suitable alternative treatment for CTX, especially in patients with side effects related to CDCA.

Pozadi: Již schvalene produkty botulotoxinu A vyžaduji rekonstituci. Tekutý abobotulotoxin A je již připraven k přimemu použiti. Cile: Cilem teto studie byl průkaz vyssi efektivity tekute formy abobotulotoxinu A proti placebu a non-inferioritni ucinnost abobotulotoxinu A v tekute formě proti abobotulotoxinu A dodavaneho v praskove formě u cervikalni dystonie. Metody: Jednalo se o fazi 3, multicentrickou, prospektivni, dvojitě zaslepenou, randomizovanou, aktivni a placebem kontrolovanou studii (N=369). Pacient s cervikalni dystonii byli randomizovani (3:3:1) pro abobotulinumtoxin A v tekute formě 500 U, pro abobotulinumtoxin A 500 U dodavaný v praskove formě a pro placebo. Nasledně po dvojitě zaslepene fazi pak nemocni dostavali tekutý abobotulinumtoxin A v otevřene fazi studie a to po dobu 4 cyklů. Primarni cilem byla změna v týdnu 4 hodnocena pomoci TWSTRS (Toronto Western Spasmodic Torticollis Rating Scale) skore. Sekundarni cile byly – změny proti bazalni navstěvě ci zakladně navstěvě cyklu (TWSTRS). Výsledky: V týdnu 4 byly oba hodnocene produkty superiorni proti placebu. Sniženi TWSTRS skore proti placebu - pro tekutou formu -12.5, pro klasickou -14.0 a pro placebo -3.9. Limit noninferiority (3 body dle TWSTRS) nebyl v týdnu 4 dosažen pro tekutou formu, ale byl dosažen ve vsech cyklech extencni faze. Bezpecnostni profil byl stejný u obou hodnocených preparatů – dysfagie a bolesti v mistě aplikace. Zavěr: I když nebylo dosaženo kriteriu non-inferiority, je tekuta preparat podobně ucinný jako klasický preparat, kdy se vytvaři aplikacni forma rozpustěnim suche praskove formy. Nově zkousený tekutý preparat je urcen pro chronickou lecbu a vyznacuje se zlepsenými – vyhovujicimi podminkami při připravě preparatu k aplikaci.

BACKGROUND AND PURPOSE: Patients with vascular parkinsonism have higher cognitive decline and more basal ganglia lesions. We aimed to evaluate the relationship of cognitive impairment with functional connectivity between the basal ganglia and cingulate cortex in vascular parkinsonism. MATERIALS AND METHODS: Thirty patients (8 with vascular parkinsonism and 22 with Parkinson disease) and 23 controls were enrolled. The Mattis Dementia Rating Scale and the Stroop Task were used to assess cognitive decline. MR imaging examinations included T1-MPRAGE, FLAIR, and resting-state fMRI sequences. MPRAGE was segmented to obtain basal ganglia and cingulate cortex volumes. FLAIR was segmented to obtain white matter hyperintensity lesion volume. Resting-state fMRI sequences were used to compare basal ganglia functional connectivity with the cingulate cortex between patients and controls. RESULTS: Patients with vascular parkinsonism exhibited impaired attention, resistance to interference, and inhibitory control and an increased number of errors on the Stroop Task. They also had higher caudate nucleus and white matter hyperintensity lesion volumes, which were positively correlated (ρ = 0.75, P < .0001). Caudate nucleus functional connectivity with the perigenual anterior cingulate cortex was increased in patients with vascular parkinsonism compared with controls and patients with Parkinson disease, and it was positively correlated with the caudate nucleus volume (ρ = 0.44, P = .016). Caudate nucleus functional connectivity with the posterior cingulate cortex was decreased in patients with vascular parkinsonism compared with controls and negatively correlated with the number of errors on the Stroop test (ρ = −0.51, P = .0003). CONCLUSIONS: In patients with vascular parkinsonism, cognitive decline could be related to changes of caudate nucleus functional connectivity with the cingulate cortex at resting-state, which may be induced by ischemia-related remodelling.

Memantine, an uncompetitive antagonist of N-methyl- d -aspartate (NMDA)-type glutamate receptors that was approved for the treatment of moderate to severe Alzheimer's disease, has been negatively evaluated for the treatment of cognitive disorders of multiple sclerosis, but these studies were conducted only during short-term administration and on a heterogeneous group of patients with different forms of the disease. In addition, many adverse reactions were observed in these patients. Aims The purpose of the “EMERITE” (NCT01074619) study was to examine the efficacy and safety of the long-term administration of memantine as a symptomatic treatment for cognitive disorders in patients with relapsing-remitting multiple sclerosis (RR-MS). Methods The study was supported by the French Ministry of Health and received additional support from Lundbeck. In this double-blind, placebo-controlled, parallel group, randomized trial, the participants were assigned to receive memantine (20 mg/day) or a placebo for 52 weeks. The participants included males and females, 18–60 years of age, with a diagnosis of RR-MS and presenting with a cognitive complaint and/or demonstrating moderate cognitive impairment. The data were collected in the Department of Neurology in 19 French centers. The primary outcome was the Paced Auditory Serial Addition Test (PASAT) score at week 52. Secondary measurements included additional neuropsychological tests and the annualized relapse rate. The scores were adjusted according to the baseline scores in the analysis. The safety was assessed by the number of adverse events. The random sequence was generated using the Excel software. At each center, only the pharmacist had access to the allocation sequence and could be asked to unblind the trial. Results Fifty patients were allocated to the memantine group, and 43 to the placebo group. The intent-to-treat (ITT) population included 31 patients in each group. After adjusting for the PASAT scores at baseline, the PASAT scores at the end point did not differ between the memantine and the placebo groups (p = 0.88). Adjusted mean score difference (memantine minus placebo), was − 0.40 (95% confidence interval: -5.5; + 4.7). No significant differences were observed for the secondary outcomes (short term memory and attention scores, EDSS, and relapse rate). The findings remained unchanged after multiple imputation of the missing values. Neurological and psychiatric adverse events were significantly higher in the memantine group than in the placebo group, and these parameters were higher than those reported in the product literature of memantine. Conclusions No differences between the placebo and memantine groups were observed. Nevertheless, the tolerability of memantine was significantly worse than expected.

Background Early manifestations of Multiple Sclerosis (MS) can be atypical and misleading, and several case report studies have highlighted that MS onset sometimes takes the form of a psychotic or manic episode. Methods All neurologists belonging to the French Multiple Sclerosis Observatory network were contacted by email and were asked to find patients with MS who presented with a history of psychiatric episode(s) near MS onset. Results Seventeen patients were selected that met the criteria of presenting with psychotic or manic symptoms either before the diagnosis of MS ( N =8), or at the time of the first neurological episode or shortly after ( N =9). Patients with a history of a psychiatric episode occurring before the first neurological episode were diagnosed on average 7 years later than patients with either a first neurological or a mixed (both neurological and psychiatric) episode. However, psychiatric symptoms in the first group and the first neurological symptoms of MS in the second group occurred at a similar age. Conclusion Based on this multiple case study, we question whether past psychotic or manic episode should be considered equivalent to a first manifestation of MS.

Background: Younger age, male sex and presence of spinal cord lesion(s) increase the risk of conversion from radiologically isolated syndrome (RIS) to relapsing-remitting multiple sclerosis (RRMS). Elevated cerebrospinal fluid (CSF) chitinase-3-like protein 1 (CHI3L1) levels predict conversion from clinically isolated syndrome (CIS) to RRMS. Objective: To evaluate the prognostic value of CSF CHI3L1 in RIS patients for conversion to RRMS. Methods: We compared CSF CHI3L1 concentrations in RIS, CIS, RRMS and symptomatic controls (SCs). We analysed the influence of epidemiological, radiological and CSF parameters on the risk of clinical event. Results: A total of 211 patients (71 RIS, 48 CIS, 50 RRMS and 42 SC) were included. CSF CHI3L1 levels were lower in RIS than in RRMS and higher in RIS with positive CSF versus negative CSF and SC. The presence of at least one spinal cord lesion was the only independent predictor of faster conversion to RRMS. Association of high CSF CHI3L1 levels, positive CSF (presence of oligoclonal bands and/or an elevated IgG index) or four Barkhof criteria with any spinal cord lesion showed a tendency for reduced mean conversion time. Conclusion: CSF CHI3L1 correlates with positive CSF but is not an independent predictor of the risk of conversion from RIS to RRMS.

Introduction: Mild ophthalmoparesis can be seen in oculopharyngeal muscular dystrophy (OPMD). Methods: Orthoptic analysis included assessment of phoria/tropia, eye excursion, saccades, pursuit, stereoacuity, and Hess–Lancaster screen test. Video-oculography included fixation, horizontal and vertical saccades, and pursuit. Results: Orthoptic abnormalities were: tropia (4 of 6); abnormal eye excursion (4 of 6, 78% involved lateral or superior rectus muscles); abnormal horizontal or vertical saccades (2 of 6); abnormal pursuit (0 of 6); abnormal stereoacuity (2 of 6); and pathological Hess–Lancaster screen (4 of 6). Video-oculographic abnormalities were present for: fixation (1 of 6); saccade latency (1 of 6); horizontal pursuit (3 of 6); and vertical pursuit (0 of 6). For horizontal saccades, mean velocity, peak velocity, and gain were pathological in 5 of 6, 5 of 6 (61% of pathological mean and peak velocities involved abducting eye movements), and 3 of 6, respectively. For vertical saccades, mean velocity, peak velocity, and gain were pathological in 4 of 6, 4 of 6 (53% involved upward movements), and 3 of 6, respectively. Conclusion: The data indicate preferential involvement of lateral and (to a lesser degree) superior rectus muscles in OPMD. Muscle Nerve 52: 554–558, 2015

International audience; OBJECTIVE:To assess the relationship between clinical pattern and cerebral glucose metabolism on [18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in Creutzfeldt-Jakob disease (CJD).METHODS:Predefined clinical signs (ataxia, visual, pyramidal, myoclonus, limb apraxia, limb dystonia, sensory, parkinsonism, and corticobasal syndrome [CBS]) and FDG-PET data were assessed in consecutive CJD patients. Two types of statistical parametric mapping (SPM) analyses, using stringent level of significance p < 0.001 and extent threshold of 100 voxels, were performed: one comparing CJD patients presenting specific sign against CJD patients without this specific sign (inter-CJD analysis), and one comparing CJD patients with specific sign against 18 healthy controls (CJD-control analysis).RESULTS:Fifteen CJD patients (11 probable and two histologically proven sporadic and two genetic CJD) were analyzed. CJD-control analysis of the entire CJD group showed lateralized frontal and parietal hypometabolism. When analyzing clinical CJD subgroups, inter-CJD analyses showed hypometabolism in more restricted areas than on CJD-control analyses. For CJD patients presenting with ataxia, visual signs and CBS (and CBS-associated signs), additional hypometabolic areas probably related to the specific signs were identified: pons and middle cerebellar peduncles in patients with ataxia; occipital cortex in patients with visual signs; and prerolandic and lateral parietal cortex in patients with CBS. For pyramidal signs, sensory loss, and parkinsonism, no abnormalities in brain areas typically involved in these signs were observed.CONCLUSION:In addition to lateralized frontal and parietal hypometabolism previously reported in CJD and observed here, hypometabolism in brain areas related to some specific signs (i.e. ataxia, visual signs, and CBS) is also seen.

Introduction Plantar flexion of toe dystonia is very painful and leads to difficulties in walking. The objective of this study was to investigate the effect of incobotulinum toxin A (Xeomin) in the treatment of this type of dystonia in parkinsonian patients, using a randomized, double blind, placebo-controlled trial. Methods 45 parkinsonian patients with painful dystonic plantar flexion of toes were injected either with incobotulinum toxin A (Btx group), or with placebo in two muscle targets: the Flexor digitorum longus and the Flexor digitorum brevis. Three groups were compared: the first group received placebo in the Flexor digitorum longus and 100UI of Btx in the Flexor digitorum brevis (n = 16); the second group received 100 UI of Btx in the Flexor digitorum longus and placebo in the Flexor digitorum brevis (n = 13); and the third group, 2 injections of placebo (n = 16). The patients were injected in the same way twice with an interval of 3 months. The primary endpoint was measured six weeks after injections with the Clinical Global Impression (CGI) of change. Dystonia severity and associated pain were also assessed. Results Mean CGI was improved in the Btx group compared to the placebo group (P = 0.039). A significant reduction of pain and dystonia severity were observed in patients treated with Btx compared to baseline but no improvement was noted when compared to placebo group. No difference of efficacy was highlighted between the two injection sites. Conclusions Btx injections are effective for improving clinical state of parkinsonian patients with plantar flexion of toe dystonia.

Resume Introduction La xanthomatose cerebrotendineuse, leucodystrophie metabolique de transmission autosomique recessive, est secondaire a un deficit en 27-sterol-hydroxylase, enzyme intervenant dans le catabolisme du cholesterol. Les symptomes classiquement revelateurs sont des xanthomes cutanes et tendineux (cliniques ou infracliniques), une cataracte precoce, une atteinte neurologique complexe et une diarrhee. L’imagerie cerebrale met en evidence une atteinte symetrique de la substance blanche et des noyaux denteles. Le diagnostic, suspecte sur une augmentation du cholestanol serique, est confirme par la presence d’une mutation dans le gene CYP27A1. Le traitement repose sur l’acide chenodesoxycholique. Methode Nous rapportons une serie multicentrique retrospective de 15 cas de xanthomatose cerebrotendineuse diagnostiques a l’âge adulte. Les donnees cliniques, moleculaires et IRM ont ete analysees pour chaque patient inclus. Resultats L’âge moyen de diagnostic etait de 39 ans (extremes : 27–65). Soixante-treize pour cent des patients debuterent leur maladie dans l’enfance et 27 % a l’âge adulte. Toutes les formes a debut pediatrique ont eu un diagnostic a l’âge adulte (âge moyen du diagnostic : 40 ans [extremes : 28–65]). Les symptomes cliniques associaient de maniere variable un syndrome cerebelleux, pyramidal, des troubles cognitifs, une epilepsie, une neuropathie (recherchee chez 10 de nos malades, presente chez 8 et de profil variable), des troubles psychiatriques, une cataracte et des xanthomes. Un patient avait une presentation atypique a savoir, une monoparesie associee a des xanthomes. L’IRM cerebrale, anormale chez tous nos malades, pouvait montrer une atteinte des noyaux denteles (47 %), une leucopathie periventriculaire (73 %) predominant dans les regions posterieures (60 %), une atteinte de la substance blanche de mecanisme vasculaire (7 %), une atteinte des faisceaux cortico-spinaux (53 %), des pallidums, du corps calleux ou une atrophie cortico-sous-corticale (33 %). Quatre-vingt-treize pour cent des patients avaient un taux de cholestanol serique eleve. La mutation la plus frequente etait 1183C>T, retrouvee chez 5 de nos 15 malades. Un traitement par acide chenodesoxycholique a permis une amelioration initiale chez 8 malades, suivie d’une stabilisation chez cinq d’entre eux, et d’une aggravation chez les trois autres. Quatre patients sont decedes des complications de la maladie. Conclusion Cette serie est la plus importante serie francaise rapportee a ce jour. Une xanthomatose cerebrotendineuse doit etre recherchee devant l’association de xanthomes (cliniques ou radiologiques) a un trouble neurologique. La maladie debute frequemment dans l’enfance mais de maniere aspecifique rendant compte du retard diagnostique. L’atteinte des noyaux denteles est tres evocatrice mais peu sensible. La leucopathie sus-tentorielle a souvent un gradient antero-posterieur. Une distribution vasculaire et une atteinte du corps calleux ne doivent pas faire exclure le diagnostic. Le dosage du cholestanol est tres fiable, son elevation permet de retenir le diagnostic, neanmoins celui-ci doit etre confirme par la biologie moleculaire.

Background: auto-antibodies against the potassium channel inward rectifying potassium channel 4.1 (Kir4.1) have previously been identified in 46% of patients with multiple sclerosis (MS). Objectives: to confirm these findings. Methods: we evaluated the presence of anti-Kir4.1 antibodies by enzyme-linked immunosorbent assay (ELISA) and immunofluorescence in 268 MS patients, 46 patients with other neurological diseases (OND) and 45 healthy controls. Results: anti-Kir4.1 antibodies were found in 7.5% of MS patients, 4.3% of OND patients and 4.4% of healthy controls. Immunofluorescence analysis did not identify any specific staining. Conclusions: we confirmed the presence of anti-Kir4.1 antibodies in MS patients, but at a much lower prevalence than previously reported.

Lesions of the corpus callosum (CC) are seen in a multitude of disorders including vascular diseases, metabolic disorders, tumours, demyelinating diseases, trauma and infections. In some diseases, CC involvement is typical and sometimes isolated, while in other diseases CC lesions are seen only occasionally in the presence of other typical extra-callosal abnormalities. In this review, we will mainly discuss the MRI characteristics of acquired lesions involving the CC. Identification of the origin of the CC lesion depends on the exact localisation of the lesion(s) inside the CC, presence of other lesions seen outside the CC, signal changes on different MRI sequences, evolution over time of the radiological abnormalities, history and clinical state of the patient, and other radiological and non-radiological examinations.

Background/Aims. Ocular motor disorders (OMDs) are a common feature of multiple sclerosis (MS). In clinical practice, if not reported by patients, OMDs are often underdiagnosed and their prevalence is underestimated.Methods. We studied 163 patients (125 women, 76.7%, 38 men, 23.3%; median age 45.0 years; median disease duration 10 years; median EDSS 3.5) with definite MS (n=150, 92%) or clinically isolated syndrome (n=13, 8%) who underwent a thorough clinical examination of eye movements. Data on localization of previous relapses, MS subtype, and MRI findings were collected and analyzed.Results. Overall, 111/163 (68.1%) patients showed at least one abnormality of eye movement. Most frequent OMDs were impaired smooth pursuit (42.3%), saccadic dysmetria (41.7%), unilateral internuclear ophthalmoplegia (14.7%), slowing of saccades (14.7%), skew deviation (13.5%), and gaze evoked nystagmus (13.5%). Patients with OMDs had more severe disability(P=0.0005)and showed more frequently infratentorial MRI lesions(P=0.004). Localization of previous relapses was not associated with presence of OMDs.Conclusion. OMDs are frequent in patients with stable (no relapses) MS. A precise bedside examination of eye motility can disclose abnormalities that imply the presence of subclinical MS lesions and may have a substantial impact on definition of the diagnosis and on management of MS patients.

Introduction La neuropathie ophtalmoplegique douloureuse (NOD), anciennement appelee migraine ophtalmoplegique fait partie integrante de la classification des cephalees : 13,9 -ICHD-3β. Observation Nous rapportons le cas d’une jeune femme de 26 ans qui presente depuis l’âge de 9 ans des episodes d’hemicrânie gauche associes a une ophtalmoplegie complete du nerf oculomoteur homolateral. A l’âge adulte, les crises se sont progressivement aggravees avec une atteinte oculomotrice de plus en plus severe et une recuperation partielle intercritique du nerf oculomoteur. Les IRM cerebro-orbitaires realisees sur une periode de 15 ans de suivi ont montre une prise de contraste persistante de la portion cysternale du nerf. Seuls les AINS et la corticotherapie pris des le debut de la crise ont permis de soulager efficacement la douleur mais n’etaient que partiellement efficaces sur l’ophtalmoplegie. Devant le caractere rapproche et severe des crises, nous avons mis en place un traitement immunosuppresseur. Discussion La NOD est une entite rare qui touche moins d’une personne sur un million. Le diagnostic de NOD repond a des criteres specifiques et incite a la prudence, une tumeur nerveuse doit toujours etre eliminee. La physiopathologie est encore mal connue, l’hypothese vasculaire est maintenant supplantee par l’hypothese inflammatoire en faveur d’une demyelinisation focale recurrente du nerf. Conclusion Aucun traitement de fond de la migraine n’a fait preuve de son efficacite, probablement en raison du mecanisme demyelinisant sous-jacent. En cas d’atteinte severe, un traitement immunosuppresseur pourrait etre considere.

Resume Introduction Les lesions cavitaires, definies par une degenerescence kystique de la substance blanche, ont ete decrites dans des atteintes hereditaires de la substance blanche (« leucodystrophies »). Cette atteinte est une des caracteristiques du childhood ataxia with central nervous system hypomyelination syndrome (CACH). Elles n’ont pas ete decrites dans la sclerose en plaques. Methodes Nous rapportons une serie retrospective multicentrique de 20 patients atteints de sclerose en plaques et presentant de larges lesions cavitaires. Les donnees cliniques, biologiques, electrophysiologiques, moleculaires et IRM ont ete collectees. Resultats Vingt patients ont ete inclus dans cette etude (6 hommes et 14 femmes). L’âge moyen au debut de la maladie etait de 37,6 ans (extremite 17–58 ans) et la duree moyenne d’evolution de 10 ans (extremite 2–20 ans). La moitie des patients (10/20) etait une forme primaire progressive. Le score EDSS moyen etait de 5,5 (extremite 2–8). Le score MMS moyen etait a 20/30. La recherche genetique de mutation du gene EIF2B codant pour le CACH syndrome a ete recherchee dans 7 cas et a toujours ete negative. Les lesions cavitaires etaient strictement supratentorielles et localisees au sein d’une leucopathie diffuse, avec une predominance posterieure chez la plupart des patients. Conclusion Les formes cavitaires de sclerose en plaques semblent representer un sous-groupe de patients caracterisee par une evolution clinique severe (forme primaire progressive, scores EDSS eleves et atteinte cognitive severe).

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.

Approved botulinum toxin A products require reconstitution. AbobotulinumtoxinA solution for injection is a ready-to-use liquid formulation of abobotulinumtoxinA.The objective of this study was to demonstrate the superior efficacy of abobotulinumtoxinA solution for injection to placebo and to test the noninferior efficacy of abobotulinumtoxinA solution for injection versus abobotulinumtoxinA (dry formulation) in cervical dystonia.This was a phase-3, multicenter, prospective, double-blind, randomized, active, and placebo-controlled study (N = 369). Patients with cervical dystonia were randomized (3:3:1) to abobotulinumtoxinA solution for injection 500 U, abobotulinumtoxinA 500 U, or placebo. Following the double-blind phase, patients received abobotulinumtoxinA solution for injection, open-label, for up to 4 cycles. The primary outcome was change from baseline at week 4 of the Toronto Western Spasmodic Torticollis Rating Scale total score. Secondary measures included change from baseline or cycle baseline in Toronto Western Spasmodic Torticollis Rating Scale scores.At week 4, both products were superior to placebo (Toronto Western Spasmodic Torticollis Rating Scale total score least square mean decrease from baseline, abobotulinumtoxinA solution for injection 500 U -12.5, abobotulinumtoxinA 500 U -14.0, placebo -3.9; P .0001 vs placebo). The noninferiority limit of 3 points in the Toronto Western Spasmodic Torticollis Rating Scale total score at week 4 was not met for abobotulinumtoxinA solution for injection versus abobotulinumtoxinA. Toronto Western Spasmodic Torticollis Rating Scale total score reductions were maintained for up to 4 cycles of abobotulinumtoxinA solution for injection open-label follow-up treatment. Safety profiles of abobotulinumtoxinA solution for injection and abobotulinumtoxinA were similar, with dysphagia and injection-site pain the most frequent drug-related adverse events.Although the predefined noninferiority criterion was not met, abobotulinumtoxinA solution for injection was similarly effective to freeze-dried abobotulinumtoxinA in reducing Toronto Western Spasmodic Torticollis Rating Scale total scores with a similar safety profile. AbobotulinumtoxinA solution for injection efficacy was maintained with chronic open-label treatment, and this novel formulation may add convenience as well as dosing accuracy to treatment with abobotulinumtoxinA. © 2016 International Parkinson and Movement Disorder Society.

Flashes of light or phosphenes are the sensation of light without light actually entering the eye. This phenomenon can be evoked by stimulation of the retina or the visual cortex of the brain and can appear unilaterally or bilaterally. From an ophthalmologic perspective, phosphenes can arise from photoreceptor induction by mechanical,1,2 inflammatory,3 or vascular4 stimuli. Therefore, it is necessary to determine the origin of phosphenes for further management. We encountered a patient who reported having phosphenes while moving his eyes laterally. We performed various ophthalmologic imaging studies to identify the origin of these phosphenes. Acknowledgment: The authors thank Florence Umuhoza, Lise Scandella, and Sarah Exbrayat for technical assistance and the patients for participation in the study.

According to the modified Boston criteria, cerebral amyloid angiopathy (CAA) can present with lobar hematoma (LH) or superficial siderosis (SS). Recently, decreased CSF β-amyloid peptide 40 and 42 (Aβ40; Aβ42) and increased total and phosphorylated tau (t-tau; p-tau) concentrations have been described in CAA presenting with LH. Our aim was to analyze CSF biomarkers as a diagnostic tool for CAA according to the modified Boston criteria. We prospectively included patients with possible or probable CAA according to the modified Boston criteria. CSF was analyzed for t-tau, p-tau, Aβ42, and Aβ40. Data were compared with AD patients (n = 42) and controls (n = 14). Thirteen CAA patients were included, nine presenting with LH and four with SS. T-tau and p-tau levels in CAA were higher than controls, but lower than in AD. Differences in t-tau and p-tau levels between CAA versus controls and AD were all significant apart of the CAA p-tau levels comparison with controls. Aβ42 levels in CAA were significantly lower than in controls, and slightly higher than in AD, though non-significantly. Aβ40 levels in CAA were non-significantly lower than in controls, and significantly lower than in AD. Combining the findings of our study and the earlier report, we confirm that patients with suspected CAA have significantly different values for t-tau, Aβ42, Aβ42/t-tau, and Aβ40. Especially Aβ40 levels seem to be of clinical interest to differentiate CAA from AD. CSF biomarkers have to be analyzed in a larger number of CAA patients, and compared to patients with other disorders causing LH or SS.

Objective: The purpose of our study was to assess the influence of pregnancy on the course of neuromyelitis optica (NMO) and the impact of epidural analgesia and breastfeeding on its activity in the postpartum period. Methods: We performed a retrospective study of patients with NMO diagnosed according to Wingerchuk criteria. We noted the number of relapses during the year before pregnancy (BP), during pregnancy (first trimester, second trimester, third trimester), and the year after (Y + 1: first trimester, second trimester [PP2], and third and fourth trimesters postpartum). Epidural analgesia and breastfeeding were recorded. Disability was evaluated with the Kurtzke Expanded Disability Status Scale (EDSS). The annualized relapse rate (ARR) was calculated. Results: We identified 124 patients (85 female) in the French NOMADMUS cohort on November 1, 2010. A total of 20 women (including 25 pregnancies) were informative with complete files. Comparisons between the ARR of each period and BP (1.0 ± 0.09) only showed an increased tendency for PP2 (0.8 ± 0.06, p = 0.07). Epidural analgesia and breastfeeding had no influence on the course of NMO. The EDSS score increased from 1.5 ± 1.7 BP to 2.6 ± 1.9 Y + 1 ( p = 0.027). Conclusion: This study shows that pregnancy influences the activity of NMO, a finding that justifies close medical monitoring. We found no evidence to suggest that either epidural analgesia or breastfeeding has an aggravating effect on NMO.

International audience

Introduction Le Teriflunomide (TRF) et le Dimethyl-Fumarate (DMF) sont deux traitements approuves de 1re ligne pour la forme remittente de sclerose en plaques (SEP). Cependant, a ce jour, il n’existe aucun essai randomise ni aucune etude observationnelle comparant leur efficacite relative. Objectif Le but de cette etude est de comparer le TRF et le DMF sur des criteres d’efficacite clinique et IRM a partir des donnees observationnelles des 34 centres issus de la cohorte francaise OFSEP. Methodes Les patients SEP inclus dans l’etude avaient une forme remittente de la maladie, etaient âges de 18 a 65 ans, avaient un score EDSS entre 0 et 5,5 a l’inclusion et une IRM dans l’annee precedant l’initiation du traitement. Les donnees ont ete collectees prospectivement a partir de 585 patients traites par TRF et 890 par DMF. Le critere de jugement principal etait la proportion de patients ayant fait au moins une poussee dans l’annee suivant l’initiation du traitement par TRF ou DMF. Trois criteres de jugement secondaires ont aussi ete etudies : la proportion de patients avec au moins une nouvelle lesion T2, la proportion de patients avec au moins une lesion prenant le gadolinium (gado+) et la proportion de patients avec une augmentation du score EDSS apres un an de traitement. L’analyse statistique etait basee sur des scores de propension (IPTW) et une regression logistique. Resultats La comparaison des deux groupes (TRF et DMF) a l’initiation du traitement montre que les patients traites par DMF avaient une duree de maladie plus courte, une proportion augmentee de patients ayant fait une poussee ou plus dans l’annee ou les deux annees precedant la mise en route du traitement et une augmentation du pourcentage de patients avec au moins une lesion gado+. Cependant apres ajustement sur ces facteurs confondant, apres un an de traitement la proportion de patients ayant fait au moins une poussee etait similaire dans le groupe TRF et DMF (20,1 % versus 20,4 %). De la meme facon l’analyse des criteres secondaires IRM et EDSS revelait une efficacite similaire entre les deux groupes apres un an de traitement. Interpretation En France, les neurologues choisissent preferentiellement le DMF comme traitement en premiere intention pour les patients ayant une forme plus active de maladie. Cependant, apres un an de traitement et apres correction pour les facteurs confondants, l’efficacite du DMF et du TRF est similaire en termes de prevention des poussees et de survenue de nouvelle lesion T2 ou de lesion gado+.

Introduction Les resultats globaux de l’etude PROTEC demontrent la reduction du taux annualise de poussees (TAP) et l’impact du dimethyle fumarate (DMF) sur les criteres evalues par les patients (CEP) dans le traitement de la sclerose en plaques recurrente-remittente (SEP-RR). Objectifs L’objectif etait de determiner l’efficacite clinique et l’impact sur les CEP du DMF sur une duree de 12 mois, dans le sous-groupe de patients francais de l’etude. Methodes PROTEC etait une etude de phase 4, internationale, multicentrique en ouvert, incluant 1105 patients adultes (≥ 18 ans) presentant une SEP-RR et naifs de traitement par DMF ou de traitement de seconde ligne. Les patients etaient traites par DMF 240 mg × 2/jour. Les poussees et la tolerance au traitement etaient evaluees a chaque visite (planifiee ou non). Les CEP des patients etaient evalues a l’inclusion et apres 3, 6 et 12 mois. Resultats Au total, 198 patients ont ete inclus en France (âge moyen [± ecart-type] : 40,0 [± 11,0] ans, % femmes : 76,8 %). Le TAP non ajuste pour les 12 mois avant et apres initiation du DMF etait respectivement de 0,62 (intervalle de confiance [IC] a 95 % : 0,52–0,72) et 0,22 (IC95 % : 0,15–0,31), avec un ratio de 0,36 (IC95 % : 0,25–0,51 ; p Discussion Un an apres l’initiation du DMF, huit patients sur dix (82,8 %) n’avaient pas presente de poussees et une diminution de 64 % du TAP a ete mise en evidence. Par ailleurs, une amelioration du score MSIS-29 (dimensions physique et psychologique), et des scores de satisfaction vis-a-vis du traitement, fatigue et depression ont ete observes. Conclusion A l’instar des resultats de la population totale de l’etude, le traitement par DMF est associe, dans le sous-groupe de patients francais, a une diminution du TAP et une amelioration de certains CEP a 12 mois. Informations complementaires L’etude a ete financee par Biogen.

Resume Introduction La sclerose en plaques (SEP) est une maladie neurologique chronique et souvent invalidante. Elle evolue par poussees ou sur un mode progressif. La classique dissociation axonomyelinique n’est plus a l’heure actuelle retenue en raison de l’atteinte axonale frequente et precoce. Le nerf optique peut, lui aussi, etre le siege d’une atrophie par perte axonale. Objectif Cette etude a pour objectif de determiner la perte axonale par la mesure de la couche des fibres retiniennes peripapillaires en tomographie en coherence optique (OCT) chez des patients atteints de SEP. Materiels et methodes Quinze patients atteints de SEP suivant les criteres de MacDonald ont ete inclus dans cette etude. Ils ont tous eu un examen neurologique et ophtalmologique, une IRM cerebrale et un examen OCT mesurant la perte axonale optique (procedure fastRNFL et RNFL). Deux sous-groupes ont ete etudies : patients avec antecedents de neuropathie optique inflammatoire (NOI) aigue ( n = 8 ; 16 yeux) ou indemnes de NOI ( n = 7 ; 14 yeux). Les resultats sont compares a une population temoin appariee. Resultats Il existe une difference tres significative ( p Conclusion L’OCT (procedure RNFL ou fastRNFL) apparait etre un examen sensible, reproductible et indolore de mesure de la perte axonale optique chez les patients atteints de SEP.

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.

Neuropathies optiques inflammatoires recidivantes Objectif : Evaluer les caracteristiques cliniques et paracliniques de patients presentant des neuropathies optiques isolees recidivantes. Patients et methode : Dans trois centres hospitaliers universitaires, Montpellier, Nimes et Strasbourg, entre octobre 2005 et septembre 2006, les dossiers de patients presentant des episodes de neuropathies optiques isolees corticosensibles evoluant par poussees, inclus prospectivement, ont ete analyses. Seuls les patients sans anomalie a l’imagerie par resonance magnetique de l’encephale ont ete inclus. Les parametres suivants ont ete releves : la date de la premiere poussee, l’âge, duree d’evolution, la corticodependance, l’atteinte uni- ou bilaterale, le nombre de poussees, l’acuite visuelle, l’epaisseur des fibres ganglionnaires, le bilan etiologique, l’existence et la nature d’un traitement de fond par immunosuppresseurs ou immunomodulateurs. Resultats : Sur la periode analysee, 13 patients (11 femmes, 2 hommes), âges de 17 a 54 ans ont ete inclus. Ils ont presente entre 2 et 6 poussees de neuropathies optiques sans signes d’evolution vers une sclerose en plaque. La duree mediane d’evolution a l’inclusion etait de 4 ans. Chez les patients non traites, l’acuite visuelle etait inversement correlee a la duree d’evolution (Spearman ; p = 0,0156), ce qui n’a pas ete observe chez les patients beneficiant d’un traitement de fond (Spearman ; p = 0,1032). Conclusion : La degradation de la fonction visuelle dans le temps observee dans cette etude retrospective de neuropathies optiques isolees recurrentes fait evoquer un mecanisme de perte axonale. Cette hypothese merite d’etre confirmee par une etude de cohorte multicentrique prospective avec evaluation de l’effet d’un traitement de fond sur la degradation fonctionnelle.

Resume Introduction La grande variabilite du pronostic de la sclerose en plaques de forme remittente (SEP-RR) et l’existence de traitements modifiant le cours de la maladie rendent necessaire la connaissance de marqueurs pronostiques. L’influence des poussees au-dela des premieres annees de la maladie sur la progression du handicap reste controversee. Methodes Il s’agit d’une etude longitudinale observationnelle de patients atteints de SEP-RR suivis dans le service de neurologie du CHU de Nimes. L’observation debutait apres la deuxieme poussee de la maladie et prenait fin lors du passage a une forme secondairement progressive (SP) ou a un score EDSS≥4,0. Les criteres de jugement analyses (courbe de survie, Kaplan-Meier) etaient le risque et le delai de survenue d’une forme SP ou d’un score EDSS≥4,0, en fonction du taux de poussees annuel median (TAP). Resultats 99 patients ont ete inclus. La mediane de la duree du suivi depuis les premiers symptomes etait de 9,8 ans (4 a 44 ans) et le TAP median de 0,4. 20,2 p. 100 des patients ont atteint le critere de jugement principal. L’analyse multivariee a montre que le groupe de patients ayant un TAP≥0,4 (n = 47) avait un risque 8 fois plus eleve de developper une forme SP ou un score EDSS de 4,0 (IC-95 p. 100 : 2,74-23,46 ; p = 0,0001), dans un delai plus court (25e percentile a 17,8 versus 6,9 ans, logrank ; p Conclusions Cette etude suggere qu’une frequence elevee de poussees au cours de la SEP-RR au-dela de la deuxieme poussee de la maladie est un facteur predictif independant de progression du handicap irreversible a long terme jusqu’a une forme SP ou un niveau de handicap relativement severe.

Background and objective: We explored which clinical and biochemical variables predict conversion from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS) in a large international cohort. Methods: Thirty-three centres provided serum samples from 1047 CIS cases with at least two years’ follow-up. Age, sex, clinical presentation, T2-hyperintense lesions, cerebrospinal fluid (CSF) oligoclonal bands (OCBs), CSF IgG index, CSF cell count, serum 25-hydroxyvitamin D3 (25-OH-D), cotinine and IgG titres against Epstein-Barr nuclear antigen 1 (EBNA-1) and cytomegalovirus were tested for association with risk of CDMS. Results: At median follow-up of 4.31 years, 623 CIS cases converted to CDMS. Predictors of conversion in multivariable analyses were OCB (HR = 2.18, 95% CI = 1.71–2.77, p < 0.001), number of T2 lesions (two to nine lesions vs 0/1 lesions: HR = 1.97, 95% CI = 1.52–2.55, p < 0.001; >9 lesions vs 0/1 lesions: HR = 2.74, 95% CI = 2.04–3.68, p < 0.001) and age at CIS (HR per year inversely increase = 0.98, 95% CI = 0.98–0.99, p < 0.001). Lower 25-OH-D levels were associated with CDMS in univariable analysis, but this was attenuated in the multivariable model. OCB positivity was associated with higher EBNA-1 IgG titres. Conclusions: We validated MRI lesion load, OCB and age at CIS as the strongest independent predictors of conversion to CDMS in this multicentre setting. A role for vitamin D is suggested but requires further investigation.