Breaking News: Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis

MATR3 is an RNA- and DNA-binding protein that interacts with TDP-43, a disease protein linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Using exome sequencing, we identified mutations in MATR3 in ALS kindreds. We also observed MATR3 pathology in ALS-affected spinal cords with and without MATR3 mutations. Our data provide more evidence supporting the role of aberrant RNA processing in motor neuron degeneration.

Nature Neuroscience 2014

Clinical, electrophysiological and molecular findings in early onset hereditary neuropathy with liability to pressure palsy

Introduction: The first episode of hereditary neuropathy with liability to pressure (HNPP) in childhood is rare.

Material and Methods: We analyzed retrospectively the data of 7 patients with a deletion in PMP22 and onset of symptoms before age 18 years. Direct sequencing of the LITAF gene was performed in patients and family members.

Results: Clinical presentations varied from mononeuropathies to brachial plexopathy, with recurrent episodes in 4 patients. Electrophysiological abnormalities characteristic for HNNP were found in most subjects. Analysis of the LITAF gene revealed an Ile92Val polymorphism in 6 of 7 (86%) probands and 5 of 7 (83%) family members, over 4 greater frequency than in the general population.

Conclusion: Clinical suspicion of HNPP even when nerve conduction study results do not fulfill HNPP criteria should indicate genetic testing. In our patients early-onset HNPP was associated frequently with Isoleucine 92valine LITAF polymorphism. 

Muscle & Nerve 2014

AHA/ASA Guideline on Palliative Care in Stroke

Background and Purpose—The purpose of this statement is to delineate basic expectations regarding primary palliative care competencies and skills to be considered, learned, and practiced by providers and healthcare services across hospitals and community settings when caring for patients and families with stroke.

Methods—Members of the writing group were appointed by the American Heart Association Stroke Council’s Scientific Statement Oversight Committee and the American Heart Association’s Manuscript Oversight Committee. Members were chosen to reflect the diversity and expertise of professional roles in delivering optimal palliative care. Writing group members were assigned topics relevant to their areas of expertise, reviewed the appropriate literature, and drafted manuscript content and recommendations in accordance with the American Heart Association’s framework for defining classes and level of evidence and recommendations.

Results—The palliative care needs of patients with serious or life-threatening stroke and their families are enormous: complex decision making, aligning treatment with goals, and symptom control. Primary palliative care should be available to all patients with serious or life-threatening stroke and their families throughout the entire course of illness. To optimally deliver primary palliative care, stroke systems of care and provider teams should (1) promote and practice patient- and family-centered care; (2) effectively estimate prognosis; (3) develop appropriate goals of care; (4) be familiar with the evidence for common stroke decisions with end-of-life implications; (5) assess and effectively manage emerging stroke symptoms; (6) possess experience with palliative treatments at the end of life; (7) assist with care coordination, including referral to a palliative care specialist or hospice if necessary; (8) provide the patient and family the opportunity for personal growth and make bereavement resources available if death is anticipated; and (9) actively participate in continuous quality improvement and research.

Conclusions—Addressing the palliative care needs of patients and families throughout the course of illness can complement existing practices and improve the quality of life of stroke patients, their families, and their care providers. There is an urgent need for further research in this area.

Stroke 2014

Patches of Disorganization in the Neocortex of Children with Autism

BACKGROUND

Autism involves early brain overgrowth and dysfunction, which is most strongly evident in the prefrontal cortex. As assessed on pathological analysis, an excess of neurons in the prefrontal cortex among children with autism signals a disturbance in prenatal development and may be concomitant with abnormal cell type and laminar development.

METHODS

To systematically examine neocortical architecture during the early years after the onset of autism, we used RNA in situ hybridization with a panel of layer- and cell-type–specific molecular markers to phenotype cortical microstructure. We assayed markers for neurons and glia, along with genes that have been implicated in the risk of autism, in prefrontal, temporal, and occipital neocortical tissue from postmortem samples obtained from children with autism and unaffected children between the ages of 2 and 15 years.

RESULTS

We observed focal patches of abnormal laminar cytoarchitecture and cortical disorganization of neurons, but not glia, in prefrontal and temporal cortical tissue from 10 of 11 children with autism and from 1 of 11 unaffected children. We observed heterogeneity between cases with respect to cell types that were most abnormal in the patches and the layers that were most affected by the pathological features. No cortical layer was uniformly spared, with the clearest signs of abnormal expression in layers 4 and 5. Three-dimensional reconstruction of layer markers confirmed the focal geometry and size of patches.

CONCLUSIONS

In this small, explorative study, we found focal disruption of cortical laminar architecture in the cortexes of a majority of young children with autism. Our data support a probable dysregulation of layer formation and layer-specific neuronal differentiation at prenatal developmental stages. (Funded by the Simons Foundation and others.)

NEJM 2014

A defect in the RNA-processing protein HNRPDL causes limb-girdle muscular dystrophy 1G (LGMD1G).

Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of genetically determined muscle disorders with a primary or predominant involvement of the pelvic or shoulder girdle musculature. More than 20 genes with autosomal recessive (LGMD2A to LGMD2Q) and autosomal dominant inheritance (LGMD1A to LGMD1H) have been mapped/identified to date. Mutations are known for six among the eight mapped autosomal dominant forms: LGMD1A (myotilin), LGMD1B (lamin A/C), LGMD1C (caveolin-3), LGMD1D (desmin), LGMD1E (DNAJB6), and more recently for LGMD1F (transportin-3). Our group previously mapped the LGMD1G gene at 4q21 in a Caucasian-Brazilian family. We now mapped a Uruguayan family with patients displaying a similar LGMD1G phenotype at the same locus. Whole genome sequencing identified, in both families, mutations in the HNRPDL gene. HNRPDL is a heterogeneous ribonucleoprotein (hnRNP) family member, which participates in mRNA biogenesis and metabolism. Functional studies performed in S. cerevisiae showed that the loss of HRP1 (yeast orthologue) had pronounced effects on both protein levels and cell localizations, and yeast proteome revealed dramatic reorganization of proteins involved in RNA processing pathways. In vivo analysis showed that hnrpdl is important for muscle development in zebrafish, causing a myopathic phenotype when knocked down. The present study presents a novel association between a muscular disorder and a RNA-related gene and reinforces the importance of RNA binding/processing proteins in muscle development and muscle disease. Understanding the role of these proteins in muscle might open new therapeutic approaches for muscular dystrophies

Hum Mol Genet 2014

JC Virus in CD34+ and CD19+ Cells in Patients With Multiple Sclerosis Treated With Natalizumab

Importance  Infection with JC virus (JCV) may lead to development of demyelinating progressive multifocal leukoencephalopathy in patients with multiple sclerosis (MS) who are treated with natalizumab.

Objective  To determine whether mononuclear cells in circulation from MS patients treated with natalizumab harbor JCV DNA.

Design, Setting, and Participants  In this prospective investigation, we enrolled 49 MS patients from the Clinical Center for Multiple Sclerosis at The University of Texas Southwestern Medical Center and 18 healthy volunteers. We drew 120-mL blood samples from 26 MS patients at baseline and at approximately 3-month intervals to 10 months during the course of natalizumab infusions. One blood sample was drawn from 23 MS patients receiving natalizumab for more than 24 months and from 18 healthy volunteers.

Interventions  Natalizumab treatment of MS.

Main Outcomes and Measures  The blood samples were separated using flow cytometry into CD34+, CD19+, and CD3+ cell subsets; DNA templates were prepared using quantitative polymerase chain reaction for JCV DNA identification. Plasma samples were tested for anti-JCV antibodies by enzyme-linked immunosorbent assays performed at the Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological and Communicative Diseases and Stroke.

Results  Thirteen of the 26 patients (50%) with baseline and follow-up blood samples had detectable viral DNA in at least 1 cell compartment at 1 or more points. Ten of the 23 patients (44%) receiving treatment for more than 24 months and 3 of the 18 healthy volunteers (17%) also had detectable viral DNA in 1 or more cell compartment. Fifteen of the 49 MS patients (31%) were confirmed to harbor JCV in CD34+ cells and 12 of 49 (24%) in CD19+ cells. Only 1 of 18 healthy volunteers were viremic in CD34+ cells and none in CD19+ cells. Nine patients and 1 healthy volunteer were viremic but had seronegative test results for JCV antibodies.

Conclusions and Relevance  JC virus DNA was detectable within cell compartments of natalizumab-treated MS patients after treatment inception and longer. JC virus DNA may harbor in CD34+ cells in bone marrow that mobilize into the peripheral circulation at high concentrations. Latently infected cells initiate differentiation to CD19+ cells that favors growth of JCV. These data link the mechanism of natalizumab treatment with progressive multifocal leukoencephalopathy.

JAMA Neurology 2o14

CLINICAL TRIAL A Randomized Clinical Trial of High-Dosage Coenzyme Q10 in Early Parkinson Disease No Evidence of Benefit

Importance  Coenzyme Q10 (CoQ10), an antioxidant that supports mitochondrial function, has been shown in preclinical Parkinson disease (PD) models to reduce the loss of dopamine neurons, and was safe and well tolerated in early-phase human studies. A previous phase II study suggested possible clinical benefit.

Objective  To examine whether CoQ10 could slow disease progression in early PD.

Design, Setting, and Participants  A phase III randomized, placebo-controlled, double-blind clinical trial at 67 North American sites consisting of participants 30 years of age or older who received a diagnosis of PD within 5 years and who had the following inclusion criteria: the presence of a rest tremor, bradykinesia, and rigidity; a modified Hoehn and Yahr stage of 2.5 or less; and no anticipated need for dopaminergic therapy within 3 months. Exclusion criteria included the use of any PD medication within 60 days, the use of any symptomatic PD medication for more than 90 days, atypical or drug-induced parkinsonism, a Unified Parkinson’s Disease Rating Scale (UPDRS) rest tremor score of 3 or greater for any limb, a Mini-Mental State Examination score of 25 or less, a history of stroke, the use of certain supplements, and substantial recent exposure to CoQ10. Of 696 participants screened, 78 were found to be ineligible, and 18 declined participation.

Interventions  The remaining 600 participants were randomly assigned to receive placebo, 1200 mg/d of CoQ10, or 2400 mg/d of CoQ10; all participants received 1200 IU/d of vitamin E.

Main Outcomes and Measures  Participants were observed for 16 months or until a disability requiring dopaminergic treatment. The prospectively defined primary outcome measure was the change in total UPDRS score (Parts I-III) from baseline to final visit. The study was powered to detect a 3-point difference between an active treatment and placebo.

Results  The baseline characteristics of the participants were well balanced, the mean age was 62.5 years, 66% of participants were male, and the mean baseline total UPDRS score was 22.7. A total of 267 participants required treatment (94 received placebo, 87 received 1200 mg/d of CoQ10, and 86 received 2400 mg/d of CoQ10), and 65 participants (29 who received placebo, 19 who received 1200 mg/d of CoQ10, and 17 who received 2400 mg/d of CoQ10) withdrew prematurely. Treatments were well tolerated with no safety concerns. The study was terminated after a prespecified futility criterion was reached. At study termination, both active treatment groups showed slight adverse trends relative to placebo. Adjusted mean changes (worsening) in total UPDRS scores from baseline to final visit were 6.9 points (placebo), 7.5 points (1200 mg/d of CoQ10; P = .49 relative to placebo), and 8.0 points (2400 mg/d of CoQ10; P = .21 relative to placebo).

Conclusions and Relevance  Coenzyme Q10 was safe and well tolerated in this population, but showed no evidence of clinical benefit.

JAMA Neurology 2014

Abnormal Functional Brain Connectivity and Personality Traits in Myotonic Dystrophy Type 1

Importance  Myotonic dystrophy type 1 (DM1), the most common muscular dystrophy observed in adults, is a genetic multisystem disorder affecting several other organs besides skeletal muscle, including the brain. Cognitive and personality abnormalities have been reported; however, no studies have investigated brain functional networks and their relationship with personality traits/disorders in patients with DM1.

Objective  To use resting-state functional magnetic resonance imaging to assess the potential relationship between personality traits/disorders and changes to functional connectivity within the default mode network (DMN) in patients with DM1.

Design, Setting, and Participants  We enrolled 27 patients with genetically confirmed DM1 and 16 matched healthy control individuals. Patients underwent personality assessment using clinical interview and Minnesota Multiphasic Personality Inventory-2 administration; all participants underwent resting-state functional magnetic resonance imaging. Investigations were conducted at the Istituto di Ricovero e Cura a Carattere Scientifico Santa Lucia Foundation, Catholic University of Sacred Heart, and Azienda Ospedaliera San Camillo Forlanini.

Intervention  Resting-state functional magnetic resonance imaging.

Main Outcomes and Measures  Measures of personality traits in patients and changes in functional connectivity within the DMN in patients and controls. Changes in functional connectivity and atypical personality traits in patients were correlated.

Results  We combined results obtained from the Minnesota Multiphasic Personality Inventory-2 and clinical interview to identify a continuum of atypical personality profiles ranging from schizotypal personality traits to paranoid personality disorder within our DM1 patients. We also demonstrated an increase in functional connectivity in the bilateral posterior cingulate and left parietal DMN nodes in DM1 patients compared with controls. Moreover, patients with DM1 showed strong associations between DMN functional connectivity and schizotypal-paranoid traits.

Conclusions and Relevance  Our findings provide novel biological evidence that DM1 is a clinical condition that also involves an alteration of functional connectivity of the brain. We speculate that these functional brain abnormalities, similarly to frank psychiatric disorders, may account for the atypical personality traits observed in patients with DM1.

JAMA Neurology 2014

Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial

Background

Secondary progressive multiple sclerosis, for which no satisfactory treatment presently exists, accounts for most of the disability in patients with multiple sclerosis. Simvastatin, which is widely used for treatment of vascular disease, with its excellent safety profile, has immunomodulatory and neuroprotective properties that could make it an appealing candidate drug for patients with secondary progressive multiple sclerosis.

Methods

We undertook a double-blind, controlled trial between Jan 28, 2008, and Nov 4, 2011, at three neuroscience centres in the UK. Patients aged 18—65 years with secondary progressive multiple sclerosis were randomly assigned (1:1), by a centralised web-based service with a block size of eight, to receive either 80 mg of simvastatin or placebo. Patients, treating physicians, and outcome assessors were masked to treatment allocation. The primary outcome was the annualised rate of whole-brain atrophy measured from serial volumetric MRI. Analyses were by intention to treat and per protocol. This trial is registered withClinicalTrials.gov, number NCT00647348.

Findings

140 participants were randomly assigned to receive either simvastatin (n=70) or placebo (n=70). The mean annualised atrophy rate was significantly lower in patients in the simvastatin group (0·288% per year [SD 0·521]) than in those in the placebo group (0·584% per year [0·498]). The adjusted difference in atrophy rate between groups was −0·254% per year (95% CI −0·422 to −0·087; p=0·003); a 43% reduction in annualised rate. Simvastatin was well tolerated, with no differences between the placebo and simvastatin groups in proportions of participants who had serious adverse events (14 [20%] vs nine [13%]).

Interpretation

High-dose simvastatin reduced the annualised rate of whole-brain atrophy compared with placebo, and was well tolerated and safe. These results support the advancement of this treatment to phase 3 testing.

Funding

The Moulton Foundation [charity number 1109891], Berkeley Foundation [268369], the Multiple Sclerosis Trials Collaboration [1113598], the Rosetrees Trust [298582] and a personal contribution from A Pidgley, UK National Institute of Health Research (NIHR) University College London Hospitals/UCL Biomedical Research Centres funding scheme.

Lancet 2014

Safety and efficacy of suvorexant during 1-year treatment of insomnia with subsequent abrupt treatment discontinuation: a phase 3 randomised, double-blind, placebo-controlled trial

Background

Suvorexant (MK-4305) is an orexin receptor antagonist shown to be efficacious for insomnia over 3 months. We aimed to assess its clinical profile during and after 1 year of treatment.

Methods

We did a randomised, placebo-controlled, parallel-group trial at 106 investigational centres in the Americas, Australia, Europe, and South Africa from December, 2009, to August, 2011. Patients aged 18 years or older with primary insomnia by DSM-IV-TR criteria were assigned using a computer-generated randomised allocation schedule to receive nightly suvorexant (40 mg for patients younger than 65 years, 30 mg for patients aged 65 years or older) or placebo at a 2:1 ratio for 1 year with a subsequent 2-month randomised discontinuation phase in which patients on suvorexant either continued suvorexant or were abruptly switched to placebo while patients on placebo remained on placebo. Treatment assignment was masked from patients and investigators. The primary objective was to assess the safety and tolerability of suvorexant for up to 1 year. Secondary objectives were to assess the efficacy of suvorexant for improving patient-reported subjective total sleep time (sTST) and time to sleep onset (sTSO) over the first month of treatment. Efficacy endpoints over the first month were assessed with a mixed model with terms for baseline value of the response variable, age, sex, region, treatment, time, and treatment by time interaction. This trial is registered with ClinicalTrials.gov, number NCT01021813.

Findings

322 (62%) of 522 patients randomly assigned to receive suvorexant and 162 (63%) of 259 assigned to receive placebo completed the 1-year phase. Over 1 year, 362 (69%) of 521 patients treated with suvorexant experienced any adverse events compared with 164 (64%) of 258 treated with placebo. Serious adverse events were recorded in 27 patients (5%) who received suvorexant and 17 (7%) who received placebo. The most common adverse event, somnolence, was reported for 69 patients (13%) who received suvorexant and seven (3%) who received placebo. At month 1, suvorexant (517 patients in the efficacy population) showed greater efficacy than placebo (254 in the efficacy population) in improving sTST (38·7 min vs 16·0 min; difference 22·7, 95% CI 16·4 to 29·0; p<0·0001) and sTSO (—18·0 min vs −8·4 min, difference −9·5, −14·6 to −4·5; p=0·0002).

Interpretation

Our findings show that suvorexant was generally safe and well tolerated over 1 year of nightly treatment in patients with insomnia, with efficacy noted for subjective measures of sleep onset and maintenance

Lancet Neurology 2014

Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial

Summary

Background

Fingolimod has shown reductions in clinical and MRI disease activity in patients with relapsing-remitting multiple sclerosis. We further assessed the efficacy and safety of fingolimod in such patients.

Methods

We did this placebo-controlled, double-blind phase 3 study predominantly in the USA (101 of 117 centres). Using a computer-generated sequence, we randomly allocated eligible patients—those aged 18—55 years with relapsing-remitting multiple sclerosis—to receive fingolimod 0·5 mg, fingolimod 1·25 mg, or placebo orally once daily (1:1:1; stratified by study centre). On Nov 12, 2009, all patients assigned to fingolimod 1·25 mg were switched to the 0·5 mg dose in a blinded manner after a review of data from other phase 3 trials and recommendation from the data and safety monitoring board, but were analysed as being in the 1·25 mg group in the primary outcome analysis. Our primary endpoint was annualised relapse rate at month 24, analysed by intention to treat. Secondary endpoints included percentage brain volume change (PBVC) from baseline and time-to-disability-progression confirmed at 3 months. This trial is registered with ClinicalTrilals.gov, number NCT00355134.

Findings

Between June 30, 2006, and March 4, 2009, we enrolled and randomly allocated 1083 patients: 370 to fingolimod 1·25 mg, 358 to fingolimod 0·5 mg, and 355 to placebo. Mean annualised relapse rate was 0·40 (95% CI 0·34—0·48) in patients given placebo and 0·21 (0·17—0·25) in patients given fingolimod 0·5 mg: rate ratio 0·52 (95% CI 0·40—0·66; p<0·0001), corresponding to a reduction of 48% with fingolimod 0·5 mg versus placebo. Mean PBVC was −0·86 (SD 1·22) for fingolimod 0·5 mg versus −1·28 (1·50) for placebo (treatment difference −0·41, 95% CI −0·62 to −0·20; p=0·0002). We recorded no statistically significant between-group difference in confirmed disability progression (hazard rate 0·83 with fingolimod 0·5 mg vs placebo; 95% CI 0·61—1·12; p=0·227). Fingolimod 0·5 mg caused more of the following adverse events versus placebo: lymphopenia (27 [8%] patients vs0 patients), increased alanine aminotransferase (29 [8%] vs six [2%]), herpes zoster infection (nine [3%] vs three [1%]), hypertension (32 [9%] vs 11 [3%]), first-dose bradycardia (five [1%] vs one [<0·5%]), and first-degree atrioventricular block (17 [5%] vs seven [2%]). 53 (15%) of 358 patients given fingolimod 0·5 mg and 45 (13%) of 355 patients given placebo had serious adverse events over 24 months, which included basal-cell carcinoma (ten [3%] patients vs two [1%] patients), macular oedema (three [1%] vs two [1%]), infections (11 [3%] vs four [1%]), and neoplasms (13 [4%] vs eight [2%]).

Interpretation

Our findings expand knowledge of the safety profile of fingolimod and strengthen evidence for its beneficial effects on relapse rates in patients with relapsing-remitting multiple sclerosis. We saw no effect of fingolimod on disability progression. Our findings substantiate the beneficial profile of fingolimod as a disease-modifying agent in the management of patients with relapsing-remitting multiple sclerosis.

Lancet Neurology 2014

Patients with ‘visual snow’ report continuous tiny dots in the entire visual field similar to the noise of an analogue television. As they frequently have migraine as a comorbidity with ophthalmological, neurological and radiological studies being normal, they are offered various diagnoses, including persistent migraine aura, post-hallucinogen flashback, or psychogenic disorder. Our aim was to study patients with ‘visual snow’ to characterize the phenotype. A three-step approach was followed: (i) a chart review of patients referred to us identified 22 patients with ‘visual snow’. Fifteen had additional visual symptoms, and 20 patients had comorbid migraine, five with aura; (ii) to identify systematically additional visual symptoms, an internet survey (n = 275) of self-assessed ‘visual snow’ subjects done by Eye On Vision Foundation was analysed. In two random samples from 235 complete data sets, the same eight additional visual symptoms were present in >33% of patients: palinopsia (trailing and afterimages), entoptic phenomena (floaters, blue field entoptic phenomenon, spontaneous photopsia, self-light of the eye), photophobia, and nyctalopia (impaired night vision); and (iii) a prospective semi-structured telephone interview in a further 142 patients identified 78 (41 female) with confirmed ‘visual snow’ and normal ophthalmological exams. Of these, 72 had at least three of the additional visual symptoms from step (ii). One-quarter of patients had ‘visual snow’ as long as they could remember, whereas for the others the mean age of onset was 21 ± 9 years. Thirty-two patients had constant visual symptoms, whereas the remainder experienced either progressive or stepwise worsening. Headache was the most frequent symptom associated with the beginning or a worsening of the visual disturbance (36%), whereas migraine aura (seven patients) and consumption of illicit drugs (five, no hallucinogens) were rare. Migraine (59%), migraine with aura (27%), anxiety and depression were common comorbidities over time. Eight patients had first degree relatives with visual snow. Clinical investigations were not contributory. Only a few treatment trials have been successful in individual patients. Our data suggest that ‘visual snow’ is a unique visual disturbance clinically distinct from migraine aura that can be disabling for patients. Migraine is a common concomitant although standard migraine treatments are often unhelpful. ‘Visual snow’ should be considered a distinct disorder and systematic studies of its clinical features, biology and treatment responses need to be commenced to begin to understand what has been an almost completely ignored problem.

Patients with ‘visual snow’ report continuous tiny dots in the entire visual field similar to the noise of an analogue television. As they frequently have migraine as a comorbidity with ophthalmological, neurological and radiological studies being normal, they are offered various diagnoses, including persistent migraine aura, post-hallucinogen flashback, or psychogenic disorder. Our aim was to study patients with ‘visual snow’ to characterize the phenotype. A three-step approach was followed: (i) a chart review of patients referred to us identified 22 patients with ‘visual snow’. Fifteen had additional visual symptoms, and 20 patients had comorbid migraine, five with aura; (ii) to identify systematically additional visual symptoms, an internet survey (n = 275) of self-assessed ‘visual snow’ subjects done by Eye On Vision Foundation was analysed. In two random samples from 235 complete data sets, the same eight additional visual symptoms were present in >33% of patients: palinopsia (trailing and afterimages), entoptic phenomena (floaters, blue field entoptic phenomenon, spontaneous photopsia, self-light of the eye), photophobia, and nyctalopia (impaired night vision); and (iii) a prospective semi-structured telephone interview in a further 142 patients identified 78 (41 female) with confirmed ‘visual snow’ and normal ophthalmological exams. Of these, 72 had at least three of the additional visual symptoms from step (ii). One-quarter of patients had ‘visual snow’ as long as they could remember, whereas for the others the mean age of onset was 21 ± 9 years. Thirty-two patients had constant visual symptoms, whereas the remainder experienced either progressive or stepwise worsening. Headache was the most frequent symptom associated with the beginning or a worsening of the visual disturbance (36%), whereas migraine aura (seven patients) and consumption of illicit drugs (five, no hallucinogens) were rare. Migraine (59%), migraine with aura (27%), anxiety and depression were common comorbidities over time. Eight patients had first degree relatives with visual snow. Clinical investigations were not contributory. Only a few treatment trials have been successful in individual patients. Our data suggest that ‘visual snow’ is a unique visual disturbance clinically distinct from migraine aura that can be disabling for patients. Migraine is a common concomitant although standard migraine treatments are often unhelpful. ‘Visual snow’ should be considered a distinct disorder and systematic studies of its clinical features, biology and treatment responses need to be commenced to begin to understand what has been an almost completely ignored problem.

Brain 2014

Summary of evidence-based guideline: Complementary and alternative medicine in multiple sclerosis

Objective: To develop evidence-based recommendations for complementary and alternative medicine (CAM) in multiple sclerosis (MS).

Methods: We searched the literature (1970–March 2011; March 2011−September 2013 MEDLINE search), classified articles, and linked recommendations to evidence.

Results and recommendations: Clinicians might offer oral cannabis extract for spasticity symptoms and pain (excluding central neuropathic pain) (Level A). Clinicians might offer tetrahydrocannabinol for spasticity symptoms and pain (excluding central neuropathic pain) (Level B). Clinicians should counsel patients that these agents are probably ineffective for objective spasticity (short-term)/tremor (Level B) and possibly effective for spasticity and pain (long-term) (Level C). Clinicians might offer Sativex oromucosal cannabinoid spray (nabiximols) for spasticity symptoms, pain, and urinary frequency (Level B). Clinicians should counsel patients that these agents are probably ineffective for objective spasticity/urinary incontinence (Level B). Clinicians might choose not to offer these agents for tremor (Level C). Clinicians might counsel patients that magnetic therapy is probably effective for fatigue and probably ineffective for depression (Level B); fish oil is probably ineffective for relapses, disability, fatigue, MRI lesions, and quality of life (QOL) (Level B); ginkgo biloba is ineffective for cognition (Level A) and possibly effective for fatigue (Level C); reflexology is possibly effective for paresthesia (Level C); Cari Loder regimen is possibly ineffective for disability, symptoms, depression, and fatigue (Level C); and bee sting therapy is possibly ineffective for relapses, disability, fatigue, lesion burden/volume, and health-related QOL (Level C). Cannabinoids may cause adverse effects. Clinicians should exercise caution regarding standardized vs nonstandardized cannabis extracts and overall CAM quality control/nonregulation. Safety/efficacy of other CAM/CAM interaction with MS disease-modifying therapies is unknown.

Neurology 2014

Late-onset Alzheimer disease genetic variants in posterior cortical atrophy and posterior AD

Objective: To investigate association of genetic risk factors for late-onset Alzheimer disease (LOAD) with risk of posterior cortical atrophy (PCA), a syndrome of visual impairment with predominant Alzheimer disease (AD) pathology in posterior cortical regions, and with risk of “posterior AD” neuropathology.

Methods: We assessed 81 participants with PCA diagnosed clinically and 54 with neuropathologic diagnosis of posterior AD vs 2,523 controls for association with 11 significant single nucleotide polymorphisms (SNPs) from published LOAD risk genome-wide association studies.

Results: There was highly significant association with APOE ε4 and increased risk of PCA (p = 0.0003, odds ratio [OR] = 3.17) and posterior AD (p = 1.11 × 10⁻¹⁷, OR = 6.43). No other locus was significant after corrections for multiple testing, although rs11136000 near CLU (p = 0.019, OR = 0.60) and rs744373 near BIN1 (p = 0.025, OR = 1. 63) associated nominally significantly with posterior AD, and rs3851179 at the PICALM locus had significant association with PCA (p = 0.0003, OR = 2.84). ABCA7 locus SNP rs3764650, which was also tested under the recessive model because of Hardy-Weinberg disequilibrium, also had nominally significant association with PCA risk. The direction of association at APOE, CLU, and BIN1 loci was the same for participants with PCA and posterior AD. The effects for all SNPs, except rs3851179, were consistent with those for LOAD risk.

Conclusions: We identified a significant effect for APOE and nominate CLU, BIN1, and ABCA7 as additional risk loci for PCA and posterior AD. Our findings suggest that at least some of the genetic risk factors for LOAD are shared with these atypical conditions and provide effect-size estimates for their future genetic studies.

Neurology 2014

Dorsal root ganglionopathy is responsible for the sensory impairment in CANVAS

Objective: To elucidate the neuropathology in cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS), a novel cerebellar ataxia comprised of the triad of cerebellar impairment, bilateral vestibular hypofunction, and a peripheral sensory deficit.

Method: Brain and spinal neuropathology in 2 patients with CANVAS, together with brain and otopathology in another patient with CANVAS, were examined postmortem.

Results: Spinal cord pathology demonstrated a marked dorsal root ganglionopathy with secondary tract degeneration. Cerebellar pathology showed loss of Purkinje cells, predominantly in the vermis.

Conclusion: The likely underlying sensory pathology in CANVAS is loss of neurons from the dorsal root and V, VII, and VIII cranial nerve ganglia—in other words, it is a “neuronopathy” rather than a “neuropathy.” Clinically, CANVAS is a differential diagnosis for both spinocerebellar ataxia type 3 (or Machado-Joseph disease) and Friedreich ataxia. In addition, there are 6 sets of sibling pairs, implying that CANVAS is likely to be a late-onset recessive or autosomal dominant with reduced penetrance disorder, and identification of the culprit gene is currently a target of investigation.

Neurology 2014

Seoul criteria for PiB(−) subcortical vascular dementia based on clinical and MRI variables

Objective: The purpose of this study was to propose new criteria for differentiating Pittsburgh compound B (PiB)-negative from PiB-positive subcortical vascular dementia (SVaD) using clinical and MRI variables.

Methods: We measured brain amyloid deposition using PiB-PET in 77 patients with SVaD. All patients met DSM-IVcriteria for vascular dementia and had severe white matter hyperintensities on MRI, defined as a cap or band ≥10 mm as well as a deep white matter lesion ≥25 mm. Eleven models were considered to differentiate PiB(−) from PiB(+) SVaD using 4 variables, including age, number of lacunes, medial temporal atrophy (MTA), and APOE ε4. The ideal cutoff values in each of the 11 models were selected using the highest Youden index.

Results: A total of 49 of 77 patients (63.6%) tested negative for PiB retention, while 28 (36.4%) tested positive for PiB retention. The ideal model for differentiating PiB(−) from PiB(+) SVaD was as follows: age ≤75 years, ≥5 lacunes, and MTA ≤3, which together yielded an accuracy of 67.5%.

Conclusion: When patients meet the DSM-IV criteria for vascular dementia and also have severe white matter hyperintensities, younger age, greater number of lacunes, and lesser MTA, these are predictive of a PiB(−) scan in patients with SVaD.

Classification of evidence: This study provides Class II evidence that the combination of younger age, greater number of lacunes, and lesser MTA identifies patients with SVaD at lower risk of Alzheimer disease pathology.

Neurology 2014

MS disease activity in RESTORE A randomized 24-week natalizumab treatment interruption study

Objective: Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE) was a randomized, partially placebo-controlled exploratory study evaluating multiple sclerosis (MS) disease activity during a 24-week interruption of natalizumab.

Methods: Eligible patients were relapse-free through the prior year on natalizumab and had no gadolinium-enhancing lesions on screening brain MRI. Patients were randomized 1:1:2 to continue natalizumab, to switch to placebo, or to receive alternative immunomodulatory therapy (other therapies: IM interferon β-1a [IM IFN-β-1a], glatiramer acetate [GA], or methylprednisolone [MP]). During the 24-week randomized treatment period, patients underwent clinical and MRI assessments every 4 weeks.

Results: Patients (n = 175) were randomized to natalizumab (n = 45), placebo (n = 42), or other therapies (n = 88: IM IFN-β-1a, n = 17; GA, n = 17; MP, n = 54). Of 167 patients evaluable for efficacy, 49 (29%) had MRI disease activity recurrence: 0/45 (0%) natalizumab, 19/41 (46%) placebo, 1/14 (7%) IM IFN-β-1a, 8/15 (53%) GA, and 21/52 (40%) MP. Relapse occurred in 4% of natalizumab patients and in 15%–29% of patients in the other treatment arms. MRI disease activity recurred starting at 12 weeks (n = 3 at week 12) while relapses were reported as early as 4–8 weeks (n = 2 in weeks 4–8) after the last natalizumab dose. Overall, 50/167 patients (30%), all in placebo or other-therapies groups, restarted natalizumab early because of disease activity.

Conclusions: MRI and clinical disease activity recurred in some patients during natalizumab interruption, despite use of other therapies.

Classification of evidence: This study provides Class II evidence that for patients with MS taking natalizumab who are relapse-free for 1 year, stopping natalizumab increases the risk of MS relapse or MRI disease activity as compared with continuing natalizumab.

Neurology 2014