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Amyotrophic lateral sclerosis (ALS) is one of the most severe motor neuron (MN) disorders in adults. Phenotype of ALS patients is highly variable and may be influenced by modulators of energy metabolism. Recent works have implicated the liver X receptors α and β (LXRs), either in the propagation process of ALS or in the maintenance of MN survival. LXRs are nuclear receptors activated by oxysterols, modulating cholesterol levels, a suspected modulator of ALS severity. In a cohort of 438 ALS patients and 330 healthy controls, the influence of LXR genes on ALS risk and phenotype was studied using single nucleotide polymorphisms (SNPs). The two LXRα SNPs rs2279238 and rs7120118 were shown to be associated with age at onset in ALS patients. Consistently, homozygotes were twice more correlated than were heterozygotes to delayed onset. The onset was thus delayed by 3.9 years for rs2279238 C/T carriers and 7.8 years for T/T carriers. Similar results were obtained for rs7120118 (+2.1 years and +6.7 years for T/C and C/C genotypes, respectively). The LXRβ SNP rs2695121 was also shown to be associated with a 30% increase of ALS duration (p = 0.0055, FDR = 0.044). The tested genotypes were not associated with ALS risk. These findings add further evidence to the suspected implication of LXR genes in the disease process of ALS and might open new perspectives in ALS therapeutics.

Background: Chronic cluster headache (CH) is a rare, highly disabling primary headache condition. As NMDA receptors are possibly overactive in CH, NMDA receptor antagonists, such as ketamine, could be of interest in patients with intractable CH., Case Reports: Two Caucasian males, 28 and 45 years-old, with chronic intractable CH, received a single ketamine infusion (0.5 mg/kg over 2 h) combined with magnesium sulfate (3000 mg over 30 min) in an outpatient setting. This treatment led to a complete relief from symptoms (attack frequency and pain intensity) for one patient and partial relief (50%) for the other patient, for 6 weeks in both cases., Conclusion: The NMDA receptor is a potential target for the treatment of chronic CH. Randomized, placebo-controlled studies are warranted to establish both safety and efficacy of such treatment., (© 2017 American Headache Society.)

Objective: To describe the clinico-radiologic outcome of MS patients with natalizumab-related progressive multifocal leukoencephalopathy (Nz-PML) surviving and receiving disease-modifying therapy (DMT)., Methods: We describe clinical and radiologic evolution of Nz-PML survivors in an observational retrospective multicenter cohort to clarify the effect of different subsequent MS DMT strategies. Twenty-three patients from 11 centers were analyzed. Outcomes were (1) clinical efficacy of post-PML MS DMT, (2) radiologic efficacy of post-PML MS DMT, (3) radiologic evolution of PML lesion, and (4) disability progression., Results: There was no clinical worsening of PML symptoms with a stability of Expanded Disability Status Scale at the last follow-up. No relapse was reported with fingolimod and dimethyl fumarate. No radiologic worsening of Nz-PML lesion was observed at the end of the follow-up., Conclusion: In this large cohort of patients with Nz-PML, MS therapies given after Nz discontinuation were not associated with PML worsening. A larger cohort with longer follow-up will be necessary to confirm this therapeutic strategy.

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., (© The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex (M1) at high frequency (>5 Hz) induces analgesic effects, probably by activating pain modulation systems. A new rTMS paradigm--theta burst stimulation (TBS)--consists of bursts of three pulses at 50 Hz repeated five times per second. Like high frequency rTMS, both intermittent and prolonged continuous TBS (iTBS and pcTBS) lead to a facilitation of cortical excitability., Objectives: (1) to evaluate the analgesic effects of neuronavigated iTBS and pcTBS, comparing them with those of classical high frequency rTMS (10 Hz) over the left M1, (2) to elucidate the role of conditioned pain modulation (CPM) in the antinociceptive effect of rTMS and (3) to investigate possible correlations between analgesia and cortical excitability., Methods: Fourteen healthy volunteers participated in four experimental sessions, carried out in a random order (iTBS, pcTBS, 10 Hz rTMS or sham). Cold pain threshold, CPM and cortical excitability measurements were carried out before and after rTMS., Results: We found that the analgesic effects of 10 Hz rTMS and pcTBS were significantly superior to those of sham rTMS. Moreover, pcTBS was significantly more effective than 10 Hz rTMS (P = 0.026). Analgesia did not seem to be driven by changes in CPM or cortical excitability., Conclusion: Prolonged cTBS has considerable clinical potential, as it has a shorter treatment duration (by a factor 8) and stronger analgesic effects than the classical high frequency protocol. Studies in patients are required to confirm the potential of this new stimulation paradigm for clinical applications., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Established in 2003, the multiple sclerosis (MS) regional hospital network in the Auvergne area of France links not only neurologists but also many other specialists (e.g., urologists, ophthalmologists) and more than 400 other allied healthcare professionals (including physiotherapists, nurses, occupational therapists) involved in the care of patients with MS. This multidisciplinary network aims to improve quality of care for an estimated 1600 + MS patients in the Auvergne region through numerous training courses and medical support programs. The initiative is supported by the regional regulatory authority and receives public funding from the Auvergne regional state health insurance office. The Auvergne MS network has facilitated improvements in quality of care by coordinating patient care in the proximal vicinity of the patient's home and has provided useful information about MS epidemiology (incidence and prevalence) in the region. Using a multidisciplinary approach, the Auvergne MS network has explored other avenues of domiciliary-based care to seek improvements in the patient-centered management of MS. These include: access to high-dose methylprednisolone in the home, ensuring appropriate supervision and support; participation in national clinical research programs coordinated from hospital centers of excellence; provision of multidisciplinary clinic services where healthcare professionals across different disciplines can attend to the patient on the same day in the same center of care; development of individual and group-based cognitive therapy programs; educational programs focusing on the management of fatigue and cognitive impairment associated with MS; and educational programs focusing on optimal use of immunomodulating agents in MS patients.

Fabry disease, rare X-linked disorder with deficient activity of alpha-galactosidase A, leads to a multiple organ failure caused by a progressive accumulation of the substrat globotriasocylceramide in cells. Peripheral nerve involvement, neuropathic pain and chronic acroparesthesiae, are the most frequently reported signs and often revealing the disease. They are secondary to the small nerve fibres (fibres 5), that explained the normality of electroneuromyography. Cochleovestibular and autonomic nervous system involvement appear later in the illness, aseptic meningitis are rare. Cerebrovascular events (stroke, transient ischaemic attack) are reported in 25% of patients, increasing with age. Affecting essentially the posterior circulation, their etiologies have to be clarified. MRI shows numerous silent lesions, increasing with age, mainly in small perforant arteries and pulvinar calcifications, due to on increase in cerebral perfusion with an impaired cerebral autoregulation, secondary to the glycosphingolipid storage in vascular endothelial cells. Enzyme replacement therapy could improve cerebral regional blood flow disturbances and painful neuropathy