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Cladribine tablets (CladT) is a highly active oral disease-modifying therapy (DMT) for the management of relapsing multiple sclerosis (RMS). CladT acts as an immune reconstitution therapy, in that two short courses of treatment 1 year apart have been shown to suppress disease activity for a prolonged period in most patients, without need for continued DMT. Each course of CladT induces a profound reduction in B lymphocytes that recovers over months, and serious lymphopenia (Grade 3–4) is uncommon. Smaller reductions in levels of T lymphocytes occur slightly later: on average, these remain within the normal range and repopulate progressively. A larger effect occurs on CD8 vs. CD4 cells. Reactivation of latent or opportunistic infections (e.g. varicella zoster, tuberculosis) is mostly associated with very low lymphocyte counts (< 200/mm3). Screening and managing pre-existing infections, vaccinating non-exposed patients and delaying the 2nd year of treatment with CladT to allow lymphocytes to recover to > 800/mm3 (if necessary) are important for avoiding infections and higher-grade lymphopenia. There was no demonstrable or apparent effect of CladT on the efficacy of vaccinations, including against Covid-19. Adverse events consistent with drug-induced liver injury (DILI) represent a rare but potentially serious complication of CladT therapy in spontaneous adverse event reporting; patients should be screened for liver dysfunction before starting treatment. Ongoing hepatic monitoring is not required, but CladT must be withdrawn if signs and symptoms of DILI develop. There was a numerical imbalance for malignancies when comparing cladribine to placebo in the clinical programme, particularly in short-term data, but recent evidence shows that the risk of malignancy with CladT is similar to the background rate in the general population and to that with other DMTs. Overall, CladT is well tolerated with a favorable safety profile appropriate for the management of RMS. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "Expert Narrative Review of the Safety of Cladribine Tablets for the Management of Relapsing Multiple Sclerosis." The correction addresses errors in Table 1 of the article, specifically in the data for the second row under the column "Integrated safety analysis" and the sixth and seventh rows under the column "Post-approval cohort." The corrected data is provided in the notice. The original article has been corrected accordingly. [Extracted from the article]

Introduction: It is important to confirm the effectiveness and tolerability of disease-modifying treatments for relapsing–remitting multiple sclerosis (RRMS) in real-world treatment settings. This prospective observational cohort study (VIRGILE) was performed at the request of the French health authorities. The primary objective was to evaluate the effectiveness of fingolimod 0.5 mg in reducing the annualised relapse rate (ARR) in patients with RRMS. Methods: Participating neurologists enrolled all adult patients with RRMS starting fingolimod treatment between 2014 and 2016, who were followed for 3 years. Follow-up consultations took place at the investigator's discretion. The primary outcome measure was the change in ARR at month 24 after fingolimod initiation. Relapses and adverse events were documented at each consultation; disability assessment (EDSS) and magnetic resonance imagery were performed at the investigator's discretion. Results: Of 1055 eligible patients, 633 patients were assessable at month 36; 405 (64.0%) were treated continuously with fingolimod for 3 years. The ARR decreased from 0.92 ± 0.92 at inclusion to 0.31 ± 0.51 at month 24, a significant reduction of 0.58 [95% CI − 0.51 to − 0.65] relapses/year (p < 0.001). Since starting fingolimod, 461 patients (60.9%) remained relapse-free at month 24 and 366 patients (55.5%) at month 36. In multivariate analysis, no previous disease-modifying treatment, number of relapses in the previous year and lower EDSS score at inclusion were associated with a greater on-treatment reduction in ARR. The mean EDSS score remained stable over the course of the study. Sixty-one out of 289 (21.1%) patients presented new radiological signs of disease activity. Treatment-related serious adverse events were lymphopenia (N = 21), bradycardia (N = 19), elevated transaminases (N = 9) and macular oedema (N = 9). Conclusions: The effectiveness and tolerability of fingolimod in everyday clinical practice are consistent with findings of previous phase III studies. Our study highlights the utility of fingolimod for the long-term management of patients with multiple sclerosis. [ABSTRACT FROM AUTHOR]

We present the MRI of a 70-year-old patient showing unilateral subcortical extensive dilated perivascular spaces with surrounding fluid-attenuated inversion recovery hyperintensities associated with the presence of small cysts and tubular hypointensities in and near the superior sagittal sinus co-locating with draining cortical veins on gadolinium-enhanced T1-weighted imaging representing probably (dilated) spaces between pial sheath and cortical vein walls. These (peri)venous superior sagittal sinus cysts seem to represent either hydrops cause (by blocking interstitial fluid flow in perivenous subpial space, via meningeal lymphatics) or consequence (where cysts might have been formed due to subpial fluid flow obstruction by unknown cause). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Cladribine tablets (CladT) has been available for therapeutic use in France since March 2021 for the management of highly active relapsing multiple sclerosis (RMS). This high-efficacy disease-modifying therapy (DMT) acts as an immune reconstitution therapy. In contrast to most high-efficacy DMTs, which act via continuous immunosuppression, two short courses of oral treatment with CladT at the beginning of years 1 and 2 of treatment provide long-term control of MS disease activity in responders to treatment, without the need for any further pharmacological treatment for several years. Although the labelling for CladT does not provide guidance beyond the initial treatment courses, real-world data on the therapeutic use of CladT from registries of previous clinical trial participants and patients treated in routine practice indicate that MS disease activity is controlled for a period of years beyond this time for a substantial proportion of patients. Moreover, this clinical experience has provided useful information on how to initiate and manage treatment with CladT. In this article we, a group of expert neurologists from France, provide recommendations on the initiation of CladT in DMT-naïve patients, how to switch from existing DMTs to CladT for patients with continuing MS disease activity, how to manage patients during the first 2 years of treatment and finally, how to manage patients with or without MS disease activity in years 3, 4 and beyond after initiating treatment with CladT. We believe that optimisation of the use of CladT beyond its initial courses of treatment will maximise the benefits of this treatment, especially early in the course of MS when suppression of focal inflammation in the CNS is a clinical priority to limit MS disease progression. [ABSTRACT FROM AUTHOR]

The article discusses the characteristics of cortical lesions found in different disorders using magnetic resonance imaging (MRI). It mentions that the identification of cortical lesion depends on the exact localisation of signal changes. It outlines several radiological approach in determining different disorders which include fluid-attenuated inversion recover (FLAIR), diffusion-weighted imaging (DWI), and apparent diffusion coefficient (ADC).

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. [ABSTRACT FROM AUTHOR]

Background. Thalamic lesions are seen in a multitude of disorders including vascular diseases, metabolic disorders, inflammatory diseases, trauma, tumours, and infections. In some diseases, thalamic involvement is typical and sometimes isolated, while in other diseases thalamic lesions are observed only occasionally (often in the presence of other typical extrathalamic lesions). Summary. In this review, we will mainly discuss the MRI characteristics of thalamic lesions. Identification of the origin of the thalamic lesion depends on the exact localisation inside the thalamus, the presence of extrathalamic lesions, the signal changes on different MRI sequences, the evolution of the radiological abnormalities over time, the history and clinical state of the patient, and other radiological and nonradiological examinations. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To look for cerebral white matter MRI changes in patients with long-standing and disabling MS. Methods: We analyzed retrospectively brain MRIs (performed 10 or more years after symptom onset) of patients with MS diagnosis and expanded disability status scale of 6 or more. The following parameters were analyzed: total number of brain T2 hyperintensities; number of brainstem, cerebellar, corpus callosum, basal ganglia, and juxtacortical T2 hyperintensities; diffuse leukoencephalopathy score; total number of T1 hypointensities. Results: Eighty-four patients were included. The mean time between symptom onset and MRI was 20.2 years. Eight percent had less than 9 cerebral T2 hyperintensities. Posterior fossa, juxtacortical, and corpus callosum T2 hyperintensities, and T1 hypointensities lacked in respectively 19%, 12%, 47%, and 8%. Overall, normal MRI was not seen, 6% had abnormal MRI but did not meet Barkhof''s criteria, and the remaining 94% had MRI abnormalities fulfilling Barkhof''s criteria. Moderate or severe diffuse leukoencephalopathy was seen in 69%. Extensive diffuse leukoencephalopathy predominant to nodular lesions was seen in 5%. Conclusions: Despite long-standing and disabling MS, typical MRI abnormalities lacked in a minority of patients, and 6% did not fulfil Barkhof''s criteria. The majority showed moderate or severe diffuse leukoencephalopathy. [Copyright &y& Elsevier]

Background: Among the different types of pain related to Parkinson's disease (PD), parkinsonian central pain (PCP) is the most disabling. Objectives: We investigated the analgesic efficacy of two therapeutic strategies (opioid with oxycodone‐ prolonged‐release (PR) and higher dose of levodopa/benserazide) compared with placebo in patients with PCP. Methods: OXYDOPA was a randomized, double‐blind, double‐dummy, placebo‐controlled, multicenter parallel‐group trial run at 15 centers within the French NS‐Park network. PD patients with PCP (≥30 on the Visual Analogue Scale [VAS]) were randomly assigned to receive oxycodone‐PR (up to 40 mg/day), levodopa/benserazide (up to 200 mg/day) or matching placebo three times a day (tid) for 8 weeks at a stable dose, in add‐on to their current dopaminergic therapy. The primary endpoint was the change in average pain intensity over the previous week rated on VAS from baseline to week‐10 based on modified intention‐to‐treat analyses. Results: Between May 2016 and August 2020, 66 patients were randomized to oxycodone‐PR (n = 23), levodopa/benserazide (n = 20) or placebo (n = 23). The mean change in pain intensity was −17 ± 18.5 on oxycodone‐PR, −8.3 ± 11.1 on levodopa/benserazide, and −14.3 ± 18.9 in the placebo groups. The absolute difference versus placebo was −1.54 (97.5% confidence interval [CI], −17.0 to 13.90; P = 0.8) on oxycodone‐PR and +7.79 (97.5% CI, −4.99 to 20.58; P = 0.2) on levodopa/benserazide. Similar proportions of patients in each group experienced all‐cause adverse events. Those leading to study discontinuation were most frequently observed with oxycodone‐PR (39%) than levodopa/benserazide (5%) or placebo (15%). Conclusions: The present trial failed to demonstrate the superiority of oxycodone‐PR or a higher dose of levodopa in patients with PCP, while oxycodone‐PR was poorly tolerated. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Abstract: Camptocormia, due to paraspinal muscle weakness, is seen in several types of myopathy. Myofibrillar myopathies (MFM) are histopathologically characterized by desmin-positive protein aggregates and myofibrillar disintegration. Camptocormia can be seen in the late stages of the known MFM diseases. We present a case of MFM with progressive camptocormia since the age of 64, isolated for 6years, followed later by upper and lower limb weakness. Camptocormia has never been described as the presenting clinical sign of MFM. MFM joins the growing number of myopathies potentially presenting with camptocormia. [Copyright &y& Elsevier]

This study compares two methods to quantify the amplitude and frequency of head movements in patients with head tremor: one based on video-based motion analysis, and the other using a miniature wireless inertial magnetic motion unit (IMMU). Concomitant with the clinical assessment of head tremor severity, head linear displacements in the frontal plane and head angular displacements in three dimensions were obtained simultaneously in forty-nine patients using one video camera and an IMMU in three experimental conditions while sitting (at rest, counting backward, and with arms extended). Head tremor amplitude was quantified along/around each axis, and head tremor frequency was analyzed in the frequency and time-frequency domains. Correlation analysis investigated the association between the clinical severity of head tremor and head linear and angular displacements. Our results showed better sensitivity of the IMMU compared to a 2D video camera to detect changes of tremor amplitude according to examination conditions, and better agreement with clinical measures. The frequency of head tremor calculated from video data in the frequency domain was higher than that obtained using time-frequency analysis and those calculated from the IMMU data. This study provides strong experimental evidence in favor of using an IMMU to quantify the amplitude and time-frequency oscillatory features of head tremor, especially in medical conditions. [ABSTRACT FROM AUTHOR]

The number of ageing people with relapsing multiple sclerosis (RMS) is increasing. The efficacy of disease-modifying therapies (DMTs) for RMS declines with age. Also, older persons with MS may be more susceptible to infections, hospitalisations and malignancy. Aging people with MS have higher rates of comorbidities versus aged-matched controls, increasing the individual risk of disability. We review the therapeutic properties of cladribine tablets (CladT) in ageing people with RMS, with regard to their utility for allowing these individuals to cease continuous administration of a DMT (i.e. to act as an "exit therapy"). CladT is thought to be an immune reconstitution therapy, in that two short courses of oral treatment 1 year apart provide suppression of MS disease activity in responders that far outlasts the duration of treatment and post-treatment reductions in lymphocyte counts. Post hoc analyses, long-term follow-up of populations with RMS in randomised trials, and real-world evidence suggest that the efficacy of CladT is probably independent of age, although more data in the elderly are still needed. No clear adverse signals for lymphopenia or other adverse safety signals have emerged with increasing age, although immunosenescence in the setting of age-related "inflammaging" may predispose elderly patients to a higher risk of infections. Updating vaccination status is recommended, especially against pneumococci and herpes zoster for older patients, to minimise the risk of these infections. CladT may be a useful alternative treatment for ageing people with MS who often bear a burden of multiple comorbidities and polypharmacy and who are more exposed to the adverse effects of continuous immunosuppressive therapy. [ABSTRACT FROM AUTHOR]

Continuous subcutaneous apomorphine infusion (CSAI) is used to treat patients with Parkinson's disease (PD) who are experiencing motor fluctuations. However, the need to initiate this treatment during a hospital stay may restrict patients' access to it. To assess the feasibility and benefits of initiating CSAI in the patient's own home. A French prospective multicenter longitudinal observational study (APOKADO) among patients with PD who required subcutaneous apomorphine, comparing in-hospital versus home initiation. Clinical status was assessed according to the Hoehn and Yahr score), the Unified Parkinson's Disease Rating Scale Part III, and the Montreal Cognitive Assessment. We assessed patients' quality of life with the 8-item Parkinson's Disease Questionnaire, rated the improvement in their clinical status on the 7-point Clinical Global Impression–Improvement scale, recorded adverse events, and ran a cost–benefit analysis. 145 patients with motor fluctuations were included in 29 centers (office and hospital). Of these, 106 (74%) were initiated onto CSAI at home, and 38 (26%) in hospital. At inclusion, the two groups were comparable for all demographic and PD characteristics. After 6 months, quality of life, adverse events and early dropout rates were similarly rare-across the two groups. Patients in the home group improved more quickly their quality of life and became more autonomous in managing the device than those in the hospital group, and their care costed less. This study shows that home (versus in-hospital) initiation of CSAI is feasible, improves patients' quality of life more quickly, with the same level of tolerance. It is also less expensive. This finding should make it easier for patients to access this treatment in the future. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented regarding the case of a 62-year-old man diagnosed with amyotrophic lateral sclerosis characterized by laryngospasm.

Loss of function variants in CACNA1A cause a broad spectrum of neurological disorders, including episodic ataxia, congenital or progressive ataxias, epileptic manifestations or developmental delay. Variants located on the AG/GT consensus splice sites are usually considered as responsible of splicing defects, but exonic or intronic variants located outside of the consensus splice site can also lead to abnormal splicing. We investigated the putative consequences on splicing of 11 CACNA1A variants of unknown significance (VUS) identified in patients with episodic ataxia or congenital ataxia. In silico splice predictions were performed and RNA obtained from fibroblasts was analyzed by Sanger sequencing. The presence of abnormal transcripts was confirmed in 10/11 patients, nine of them were considered as deleterious and one remained of unknown significance. Targeted next‐generation RNA sequencing was done in a second step to compare the two methods. This method was successful to obtain the full cDNA sequence of CACNA1A. Despite the presence of several isoforms in the fibroblastic cells, it detected most of the abnormally spliced transcripts. In conclusion, RNA sequencing was efficient to confirm the pathogenicity of nine novel CACNA1A variants. Sanger or Next generation methods can be used depending on the facilities and organization of the laboratories. [ABSTRACT FROM AUTHOR]

Background: We recently demonstrated in a randomized controlled trial (APOMORPHEE, NCT02940912) that night‐time only subcutaneous apomorphine infusion improves sleep disturbances and insomnia in patients with advanced Parkinson's disease and moderate to severe insomnia. Objectives: To identify the best candidates for receiving night‐time only subcutaneous apomorphine infusion in routine care. Methods: In this post‐hoc analysis of APOMORPHEE, we compared the characteristics of patients according to whether they chose to continue night‐time only subcutaneous apomorphine infusion at the end of the study period or not. Results: Half of the patients (22/42) chose to continue the treatment. Off duration (day or night), painful Off dystonia, and insomnia severity at baseline were associated with night‐time only apomorphine continuation. Multivariate analysis retained only Off duration as an independent predictor of continuation. Conclusions: The best candidates for night‐time only apomorphine are patients with severe and prolonged Off periods (day or night) and severe insomnia. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Approved botulinum toxin A products require reconstitution. AbobotulinumtoxinA solution for injection is a ready-to-use liquid formulation of abobotulinumtoxinA.Objectives: 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.Methods: 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.Results: 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.Conclusions: 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background and purpose: In addition to combined central and peripheral demyelination, other immune diseases could involve both the central nervous system (CNS) and peripheral nervous system (PNS). Methods: 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. Results: 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). Conclusions: 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. [ABSTRACT FROM AUTHOR]

The article offers information on a 16-year-old man who manifested voluntary controlled ocular flutter. It states that the patient was referred to a neurological consultation due to peculiar eye movements. It was revealed that the patient's brain magnetic resonance imaging (MRI) was normal. Meanwhile, omnipause neuron dysfunction is the perceived cause of his ocular flutter. It adds that voluntary ocular flutter's pathophysiology is unclear.

Background: Insomnia is a frequent complaint of patients with Parkinson's disease, and it negatively affects quality of life. Drugs that improve both sleep and parkinsonism would be of major benefit to patients with Parkinson's disease-related insomnia. We aimed to test the safety and efficacy of subcutaneous night-time only apomorphine infusion in patients with Parkinson's disease and insomnia.Methods: We did a randomised, multicentre, double-blind, placebo-controlled, crossover trial in 11 expert centres in Parkinson's disease and sleep centres in France. Participants aged 35-90 years with fluctuating Parkinson's disease and moderate to severe insomnia (Insomnia Severity Index score ≥15) were randomly assigned to either first receive night-time subcutaneous apomorphine (up to 5 mg/h) or matching placebo. Randomisation was done using a computer-generated plan in blocks of four, stratified by centre. This first intervention was followed by a 14-night washout period, then crossover to the other intervention. The treatment periods consisted of a 10-night titration phase followed by a 7-night fixed-dose phase. The dose was adjusted during the titration phase on the basis of a daily telephone call assessing sleep quality and treatment tolerability. The primary efficacy endpoint was the difference in Parkinson's disease sleep scale (PDSS) scores from the beginning to the end of each treatment period. Analysis was done on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, NCT02940912.Findings: Between Jan 31, 2017, and Jan 29, 2021, 46 participants were enrolled. 25 (54%) patients were randomly assigned to receive apomorphine first and 21 (46%) patients to receive placebo first. Mean change in PDSS score was significantly greater with night-time apomorphine infusion (15·18 [SD 24·34]) compared with placebo (5·23 [21·52]; treatment effect 9·95 [95% CI 0·88-19·03]; p=0·041). Adverse events were reported in 25 (54%) participants during the apomorphine period and in 17 (37%) participants during the placebo period (p=0·16). Apomorphine was associated with more frequent dizziness than was placebo (seven [15%] vs 0; p=0·041).Interpretation: Subcutaneous night-time only apomorphine infusion improved sleep disturbances according to difference on PDSS score, with an overall safety profile consistent with previous studies in Parkinson's disease. This treatment might be useful to manage sleep disturbances in patients with advanced Parkinson's disease and moderate to severe insomnia.Funding: Orkyn and Aguettant Pharma.Translation: For the French translation of the abstract see Supplementary Materials section. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Sex steroids could explain the course of multiple sclerosis (MS) in pregnancy. Objective: To compare the annualized relapse rate (ARR) 12 weeks post-partum in women treated with nomegestrol acetate (NOMAc) and 17-beta-estradiol (E2) versus placebo. Methods: POPARTMUS is a randomized, proof-of-concept trial in women with MS, receiving oral NOMAc 10 mg/day and transdermal estradiol 75 µg/week, or placebo. Results: Recruitment was stopped prematurely due to slow inclusions (n = 202). No treatment effect was observed on ARR after 12 weeks (sex steroids = 0.90 (0.58–1.39), placebo = 0.97 (0.63–1.50) (p = 0.79)). Conclusion: POPARTMUS failed showing efficacy of a NOMAc–E2 combination in preventing post-partum relapses. [ABSTRACT FROM AUTHOR]

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. . [ABSTRACT FROM AUTHOR]

Levodopa (L‐dopa) remains the basis of pharmacological treatment of Parkinson's disease (PD). However, L‐dopa therapy is associated with the development of complications and presents major challenges in the long‐term treatment. Thus, other medications may be suggested to delay and/or reduce the doses of L‐dopa in order to prevent complications. The interpretation of treatment evolution reported in clinical trials on PD may be tricky, especially due to some variability in medications and dose regimens. Some authors have suggested a conversion factor to generate a total L‐dopa equivalent daily dose (LEDD), calculated as a sum of each parkinsonian medication. Therefore, LEDD provides an artificial summary of the total daily medication a patient is receiving, and to date, there is no report focusing on the clinical interpretation of this parameter. Thus, based on a 3‐year, multi‐center retrospective study assessing the impact of second‐line therapy initiation on LEDD in PD patients, the aim of our article was to discuss LEDD as a quantitative outcome to estimate the impact of second‐line therapies on medication regimens; and in the second part of the discussion, to provide a narrative review of the clinical outcomes associated with LEDD in the literature. [ABSTRACT FROM AUTHOR]

We compared SimoaTM and EllaTM immunoassays to assess serum neurofilament‐light chain levels in 203 multiple sclerosis patients from the OFSEP HD study. There was a strong correlation (ρ = 0.86, p < 0.0001) between both platforms. The EllaTM instrument overestimated values by 17%, but as the data were linear (p = 0.57), it was possible to apply a correction factor to EllaTM results. As for SimoaTM, serum neurofilament‐light chain levels measured by EllaTM were correlated with age and EDSS and were significantly higher in active multiple sclerosis, suggesting that these assays are equivalent and can be used in routine clinical practice. [ABSTRACT FROM AUTHOR]

Abstract: Myocardial infarction after rituximab or other monoclonal antibody therapies has been reported in rare cases, all in patients with classical cardiovascular risk factors or associated inflammatory or lymphoproliferative disorders. We report the case of a 52-year-old man, without classical cardiovascular risk factors or associated inflammatory or lymphoproliferative disorder, treated for seronegative myasthenia with rituximab infusions complicated by myocardial infarction. The exact origin of myocardial infarction after monoclonal antibody treatment is unclear. Myocardial infarction is a rare but possibly fatal complication of rituximab infusion, even occurring in relatively young patients, without classical risk factors and without associated inflammatory or lymphoproliferative disorder. [Copyright &y& Elsevier]

A letter to the editor is presented which discusses the case of an 87-year-old right-handed man with acute throwing movements on the left upper and lower limb wherein acute infarction of the subthalamic nucleus (STN) and signs of chronic ischaemic microangiopathy was detected through magnetic resonance imaging (MRI) of the brain.

Keywords: autoimmune; myoclonus; CASPR2; encephalomyelitis EN autoimmune myoclonus CASPR2 encephalomyelitis 1260 1262 3 11/05/21 20211101 NES 211101 An 86-year-old man presented with continuous movements of the abdominal wall (abdominal segmental myoclonus mimicking a belly dancer), gait unsteadiness, progressive cognitive deficit, episodic symptomatic hypotension, and diaphoresis for 2 months. Lower limb myoclonus while standing or walking has been earlier reported as a movement disorder phenotype in CASPR2 antibody-related encephalomyelitis.3,4 One patient with spinal myoclonus has been reported with clinical lower limb myoclonus associated with abdominal myoclonus only observed by electromyography.5 To the best of our knowledge, this is the first case of clinical abdominal myoclonus associated with CASPR2 antibodies. [Extracted from the article]

Objective: We aimed to identify timing distortions in production and perception of rhythmic events in patients with idiopathic REM sleep behavior disorder (iRBD) as early markers of Parkinson's disease (PD). Methods: Rhythmic skills, clinical characteristics, dysautonomia, depression, and olfaction were compared in 97 participants, including 21 participants with iRBD, 38 patients with PD, and 38 controls, matched for age, gender, and education level. Rhythmic disturbances can be easily detected with dedicated motor tasks via a tablet application. Rhythm production was tested in two conditions: to examine the ability to generate a spontaneous endogenous rhythm, tapping rate and variability in a finger tapping task without external stimulation was measured, while the ability to synchronize to an external rhythm was tested with finger tapping to external auditory cues. Rhythm perception was measured with a task, in which the participants had to detect a deviation from a regular rhythm. Participants with iRBD had dopamine transporter imaging. Results: Participants with iRBD and PD revealed impaired spontaneous rhythm production and poor rhythm perception compared to controls. Impaired rhythm production was correlated with olfaction deficits, dysautonomia, impaired non‐motor aspects of daily living, and dopamine uptake measures. Conclusions: Participants with iRBD show impaired rhythm production and perception; this impairment is correlated with other early markers for PD. Testing rhythmic skills with short and inexpensive tests may be promising for screening for potential future PD in iRBD patients. [ABSTRACT FROM AUTHOR]

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-naïve patient and one non-treatment-naïve 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The article offers information on a study related to association of Neuraxial analgesia (NA) with increased risk of post-partum relapses in Multiple Sclerosis (MS). Topics discussed include high risk of post-partum relapses in women who experienced relapses in year before and during pregnancy; data collection from Prevention of Post-Partum Relapses with Progestin and Estradiol in Multiple Sclerosis study; and the results showing no association in post-partum relapses in MS and NA.

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. [ABSTRACT FROM AUTHOR]

Vascular parkinsonism is a difficult clinical differential diagnosis in elderly subjects. We aimed at identifying morphometric markers in the brain of elderly patients with vascular parkinsonism (VP) compared with age-matched patients with Parkinson's disease (PD) and healthy controls. In this multicenter prospective study, 46 patients (80 ± 5 years old; male 32) with parkinsonism (32 PD and 14 VP) and 29 controls (mean age 78 ± 3 years; male 21) underwent brain MRI on a 3-T scanner including T1 MPRAGE and FLAIR sequences. Volumetric morphometry was obtained using Morphobox software and compared between patients and controls. Receiver operating characteristics curve analysis with computation of area under the curve (AUC) was used to compare diagnostic values. Caudate nucleus and white matter hyperintense lesions (WMHL) volumes appeared significantly higher in patients with VP. Normalized caudate volume of at least 0.67% and normalized WMHL of at least 1.11% identified patients with VP from patients with PD and controls with similar performances ( p > 0.25). Caudate nucleus and WMHL volumes were positively correlated ( ρ = 0.74, p < 0.0001), suggesting vascular disease related remodelling in elderly subjects. Caudate nucleus and WMHL MRI volumes might be used as additional markers to help identify patients with VP in the initial workup of elderly subjects with parkinsonian symptoms. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Therapeutic options are limited in secondary progressive multiple sclerosis (SPMS). Open-label studies suggested efficacy of monthly IV cyclophosphamide (CPM) without induction for delaying progression but no randomized trial was conducted so far. Objective: To compare CPM to methylprednisolone (MP) in SPMS. Methods: Randomized, double-blind clinical trial on two parallel groups. Patient with SPMS, with a documented worsening of the Expanded Disability Status Scale (EDSS) score during the last year and an EDSS score between 4·0 and 6·5 were recruited and received one intravenous infusion of treatment (CPM: 750 mg /m2 body surface area—MP: 1g) every four weeks for one year, and every eight weeks for the second year. The primary endpoint was the time to EDSS deterioration, when confirmed sixteen weeks later, analyzed using a Cox model. Results: Due to recruitment difficulties, the study was terminated prematurely after 138 patients were included (CPM, n = 72; MP, n = 66). In the CPM group, 33 patients stopped treatment prematurely, mainly due to tolerability, compared with 22 in the MP group. Primary endpoint: the hazard ratio for EDSS deterioration in the CPM in comparison with the MP group was 0.61 [95% CI: 0·31–1·22](p = 0·16). According to the secondary multistate model analysis, patients in the CPM group were 2.2 times more likely ([1·14–4.29]; p = 0.02) to discontinue treatment than those in the MP group and 2.7 times less likely (HR = 0.37, 95% CI: 0.17–0.84; p = 0.02) to experience disability progression when they did not stop treatment prematurely. Safety profile was as expected. Conclusion: Although the primary end-point was negative, secondary analysis suggested that CPM decreases the risk of progression in SPMS, but its use may be limited by low tolerability. Trial Registration: Clinicaltrials.gov [ABSTRACT FROM AUTHOR]

Abstract: β-Mannosidosis (OMIM 248510) is an inborn lysosomal storage disorder caused by deficiency of β-mannosidase activity. This enzyme is encoded by a single gene (MANBA), located on chromosome 4q22–25. This autosomal recessive disorder is characterized by a wide range of symptoms including mental retardation, behavioural problems, hearing loss, recurrent respiratory infections, angiokeratoma, facial dysmorphism, skeletal deformation, seizures, hypotonia, demyelinating polyneuropathy, and hepatosplenomegaly. The age of symptom onset is variable. We describe a 14-year clinical follow-up of a patient with β-mannosidase deficiency with symptoms of mental retardation, progressive spasticity and cerebellar ataxia, a clinical spectrum that so far has never been reported in β-mannosidosis. A novel mutation in the MANBA gene was found in our patient. Evoked potentials were in favour of a demyelinating pathology of the central nervous system. Serial MRI showed generalized cortical and subcortical atrophy in the absence of white matter changes suggesting an additional axonal pathophysiological component. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Adult-onset genetic leukoencephalopathies are rare and heterogeneous disorders. Ayrignac et al. identify 154 patients using an MRI pattern-based algorithm that focuses on the presence of vascular or cavitary lesions. They are able to verify the diagnosis genetically in 64% of cases, confirming the value of the MRI classification system.Inherited white matter diseases are rare and heterogeneous disorders usually encountered in infancy. Adult-onset forms are increasingly recognized. Our objectives were to determine relative frequencies of genetic leukoencephalopathies in a cohort of adult-onset patients and to evaluate the effectiveness of a systematic diagnostic approach. Inclusion criteria of this retrospective study were: (i) symmetrical involvement of white matter on the first available brain MRI; (ii) age of onset above 16 years. Patients with acquired diseases were excluded. Magnetic resonance imaging analysis identified three groups (vascular, cavitary and non-vascular/non-cavitary) in which distinct genetic and/or biochemical testing were realized. One hundred and fifty-four patients (male/female = 60/94) with adult-onset leukoencephalopathies were identified. Mean age of onset was 38.6 years. In the vascular group, 41/55 patients (75%) finally had a diagnosis [including CADASIL (cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy, n = 32) and COL4A1 mutation, n = 7]. In the cavitary group, 13/17 (76%) patients had a diagnosis of EIF2B-related disorder. In the third group (n = 82), a systematic biological screening allowed a diagnosis in 23 patients (28%) and oriented direct genetic screening identified 21 additional diseases (25.6%). Adult-onset genetic leukoencephalopathies are a rare but probably underestimated entity. Our study confirms the use of a magnetic resonance imaging-based classification with a final diagnosis rate of 64% (98/154) cases. [ABSTRACT FROM AUTHOR]

The article presents a study which confirms the reliability of potassium channel inward rectifying potassium channel 4.1 (Kir4.1) as markers of multiple sclerosis (MS). The study uses enzyme-linked immunosorbent assay (ELISA) and immunofluorescence to identify presence of anti-Kir4.1 antibodies in MS and other neurological diseases patients. Result confirms the prevalence of anti-Kir4.1 antibodies in MS patients.