EMA’s final opinion confirms restrictions on use of linear gadolinium agents in body scans

Recommendations conclude EMA’s scientific review of gadolinium deposition in brain and other tissues

The European Medicines Agency (EMA) has concluded its review of gadolinium contrast agents, confirming recommendations to restrict the use of some linear gadolinium agents used in MRI body scans and suspend the authorisations of others.

The recommendations – confirmed by EMA’s Committee for Medicinal Products for Human Use (CHMP) – follow a review that found that gadolinium deposition occurs in brain tissues following use of gadolinium contrast agents.

There is currently no evidence that gadolinium deposition in the brain has caused any harm to patients; however EMA has recommended restrictions for some intravenous linear agents in order to prevent any risks that could potentially be associated with gadolinium brain deposition.

The intravenous linear agents gadoxetic acid and gadobenic acid can continue to be used for liver scans because they are taken up in the liver and meet an important diagnostic need. In addition, gadopentetic acid given intra-articularly (into the joint) can continue to be used for joint scans because the dose of gadolinium used for joint injections is very low.

All other intravenous linear products (gadodiamide, gadopentetic acid and gadoversetamide) should be suspended in the EU.

Another class of gadolinium agents known as macrocyclic agents (gadobutrol, gadoteric acid and gadoteridol) are more stable and have a lower propensity to release gadolinium than linear agents. These products can continue to be used in their current indications but in the lowest doses that enhance images sufficiently and only when unenhanced body scans are not suitable.

The suspensions or restrictions on linear agents can be lifted if the companies concerned provide evidence of new benefits in an identified patient group that outweigh the risk of brain deposition or if the companies can modify their products so they do not release gadolinium significantly or cause its retention in tissues.

EMA’s scientific review of gadolinium deposition in brain and other tissues is now concluded. The final recommendations will be sent to the European Commission, which will issue a final legally binding decision applicable in all EU Member States

Matrix metalloproteinase 9 is decreased in natalizumab-treated multiple sclerosis patients at risk for progressive multifocal leukoencephalopathy

Abstract

Objective

To identify biomarkers associated with the development of progressive multifocal leukoencephalopathy (PML) in multiple sclerosis (MS) patients treated with natalizumab (NTZ).

Methods

Relapsing–remitting MS patients who developed PML under NTZ therapy (pre-PML) and non-PML NTZ-treated patients (NTZ-ctr) were included in the study. Cryopreserved peripheral blood mononuclear cells and serum samples collected at baseline, at 1- and 2-year treated time points, and during PML were analyzed for gene expression by RNA sequencing and for serum protein levels by Luminex and enzyme-linked immunosorbent assays, respectively.

Results

Among top differentially expressed genes in the RNA sequencing between pre-PML and NTZ-ctr patients, pathway analysis revealed a high representation of genes belonging to the following categories: proangiogenic factors (MMP9, VEGFA), chemokines (CXCL1, CXCL5, IL8, CCL2), cytokines (IL1B, IFNG), and plasminogen- and coagulation-related molecules (SERPINB2, PLAU, PLAUR, TFPI, THBD). Serum protein levels for these candidates were measured in a 2-step manner in a screening cohort and a validation cohort of pre-PML and NTZ-ctr patients. Only matrix metalloproteinase 9 (MMP9) was validated; in pre-PML patients, MMP9 protein levels were significantly reduced at baseline compared with NTZ-ctr patients, and levels remained lower at later time points during NTZ treatment.

Interpretation

The results from this study suggest that the proangiogenic factor MMP9 may play a role as a biomarker associated with the development of PML in MS patients treated with NTZ. 

Ann Neurol 2017.

ER stress and the unfolded protein response in neurodegeneration

The clinical manifestation of neurodegenerative diseases is initiated by the selective alteration in the functionality of distinct neuronal populations. The pathology of many neurodegenerative diseases includes accumulation of misfolded proteins in the brain. In physiological conditions, the proteostasis network maintains normal protein folding, trafficking and degradation; alterations in this network — particularly disturbances to the function of endoplasmic reticulum (ER) — are thought to contribute to abnormal protein aggregation. ER stress triggers a signalling reaction known as the unfolded protein response (UPR), which induces adaptive programmes that improve protein folding and promote quality control mechanisms and degradative pathways or can activate apoptosis when damage is irreversible. In this Review, we discuss the latest advances in defining the functional contribution of ER stress to brain diseases, including novel evidence that relates the UPR to synaptic function, which has implications for cognition and memory. A complex concept is emerging wherein the consequences of ER stress can differ drastically depending on the disease context and the UPR signalling pathway that is altered. Strategies to target specific components of the UPR using small molecules and gene therapy are in development, and promise interesting avenues for future interventions to delay or stop neurodegeneration.

Nature Review Neurology 2017

Stroke in women — from evidence to inequalities

Abstract

Stroke is the second largest cause of disability-adjusted life-years lost worldwide. The prevalence of stroke in women is predicted to rise rapidly, owing to the increasing average age of the global female population. Vascular risk factors differ between women and men in terms of prevalence, and evidence increasingly supports the clinical importance of sex differences in stroke. The influence of some risk factors for stroke — including diabetes mellitus and atrial fibrillation — are stronger in women, and hypertensive disorders of pregnancy also affect the risk of stroke decades after pregnancy. However, in an era of evidence-based medicine, women are notably under-represented in clinical trials — despite governmental actions highlighting the need to include both men and women in clinical trials — resulting in a reduced generalizability of study results to women. The aim of this Review is to highlight new insights into specificities of stroke in women, to plan future research priorities, and to influence public health policies to decrease the worldwide burden of stroke in women.

Nature Reviews Neurology 2017

Large Perivascular Spaces Visible on Magnetic Resonance Imaging, Cerebral Small Vessel Disease Progression, and Risk of Dementia The Age, Gene/Environment Susceptibility–Reykjavik Study

Abstract

Importance  With advancing age, an increased visibility of perivascular spaces (PVSs) on magnetic resonance imaging (MRI) is hypothesized to represent impaired drainage of interstitial fluid from the brain and may reflect underlying cerebral small vessel disease (SVD). However, whether large perivascular spaces (L-PVSs) (>3 mm in diameter) visible on MRI are associated with SVD and cognitive deterioration in older individuals is unknown.

Objective  To examine whether L-PVSs are associated with the progression of the established MRI markers of SVD, cognitive decline, and increased risk of dementia.

Design, Setting, and Participants  The prospective, population-based Age, Gene/Environment Susceptibility–Reykjavik Study assessed L-PVSs at baseline (September 1, 2002, through February 28, 2006) on MRI studies of the brain in 2612 participants. Participants returned for additional MRI from April 1, 2007, through September 30, 2011, and underwent neuropsychological testing at the 2 time points a mean (SD) of 5.2 (0.2) years apart. Data analysis was conducted from August 1, 2016, to May 4, 2017.

Exposures  The presence, number, and location of L-PVSs.

Main Outcomes and Measures  Incident subcortical infarcts, cerebral microbleeds, and progression of white matter hyperintensities detected on MRI; cognitive decline defined as composite score changes between baseline and follow-up in the domains of memory, information processing speed, and executive function; and adjudicated incident dementia cases diagnosed according to international guidelines.

Results  Of the 2612 study patients (mean [SD] age, 74.6 [4.8] years; 1542 [59.0%] female), 424 had L-PVSs and 2188 did not. The prevalence of L-PVSs was 16.2% (median number of L-PVSs, 1; range, 1-17). After adjusting for age, sex, and interval between baseline and follow-up scanning, the presence of L-PVSs was significantly associated with an increased risk of incident subcortical infarcts (adjusted risk ratio, 2.54; 95% CI, 1.76-3.68) and microbleeds (adjusted risk ratio, 1.43; 95% CI, 1.18-1.72) and a greater 5-year progression of white matter hyperintensity volume. The presence of L-PVSs was also associated with a steeper decline in information processing speed and more than quadrupled the risk of vascular dementia. All associations persisted when further adjusted for genetic and cerebrovascular risk factors. The associations with cognitive outcomes were independent of educational level, depression, and other SVD MRI markers.

Conclusions and Relevance  Large PVSs are an MRI marker of SVD and associated with the pathogenesis of vascular-related cognitive impairment in older individuals. Large PVSs should be included in assessments of vascular cognitive impairment in the older population and as potential targets for interventions.

JAMA Neurology 2017

Prevalence of Intracranial Aneurysm in Women With Fibromuscular Dysplasia A Report From the US Registry for Fibromuscular Dysplasia

Abstract

Importance  The prevalence of intracranial aneurysm in patients with fibromuscular dysplasia (FMD) is uncertain.

Objective  To examine the prevalence of intracranial aneurysm in women diagnosed with FMD.

Design, Setting, and Participants  This cross-sectional study included 669 women with intracranial imaging registered in the US Registry for Fibromuscular Dysplasia, an observational disease-based registry of patients with FMD confirmed by vascular imaging and currently enrolling at 14 participating US academic centers. Registry enrollment began in 2008, and data were abstracted in September 2015. Patients younger than 18 years at the time of FMD diagnosis were excluded. Imaging reports of all patients with reported internal carotid, vertebral, or suspected intracranial artery aneurysms were reviewed. Only saccular or broad-based aneurysms 2 mm or larger in greatest dimension were included. Extradural aneurysms in the internal carotid artery were included; fusiform aneurysms, infundibulae, and vascular segments with uncertainty were excluded.

Main Outcomes and Measures  Percentage of women with FMD with intracranial imaging who had an intracranial aneurysm.

Results  Of 1112 female patients in the registry, 669 (60.2%) had undergone intracranial imaging at the time of enrollment (mean [SD] age at enrollment, 55.6 [10.9] years). Of the 669 patients included in the analysis, 86 (12.9%; 95% CI, 10.3%-15.9%) had at least 1 intracranial aneurysm. Of these 86 patients, 25 (53.8%) had more than 1 intracranial aneurysm. Intracranial aneurysms 5 mm or larger occurred in 32 of 74 patients (43.2%), and 24 of 128 intracranial aneurysms (18.8%) were in the posterior communicating or posterior arteries. The presence of intracranial aneurysm did not vary with location of extracranial FMD involvement. A history of smoking was significantly associated with intracranial aneurysm: 42 of 78 patients with intracranial aneurysm (53.8%) had a smoking history vs 163 of 564 patients without intracranial aneurysm (28.9%; P < .001).

Conclusions and Relevance  The prevalence of intracranial aneurysm in women diagnosed with FMD is significantly higher than reported in the general population. Although the clinical benefit of screening for intracranial aneurysm in patients with FMD has yet to be proven, these data lend support to the recommendation that all patients with FMD undergo intracranial imaging if not already performed.

JAMA Neurology 2017

Early detection of consciousness in patients with acute severe traumatic brain injury

Abstract

Patients with acute severe traumatic brain injury may recover consciousness before self-expression. Without behavioural evidence of consciousness at the bedside, clinicians may render an inaccurate prognosis, increasing the likelihood of withholding life-sustaining therapies or denying rehabilitative services. Task-based functional magnetic resonance imaging and electroencephalography techniques have revealed covert consciousness in the chronic setting, but these techniques have not been tested in the intensive care unit. We prospectively enrolled 16 patients admitted to the intensive care unit for acute severe traumatic brain injury to test two hypotheses: (i) in patients who lack behavioural evidence of language expression and comprehension, functional magnetic resonance imaging and electroencephalography detect command-following during a motor imagery task (i.e. cognitive motor dissociation) and association cortex responses during language and music stimuli (i.e. higher-order cortex motor dissociation); and (ii) early responses to these paradigms are associated with better 6-month outcomes on the Glasgow Outcome Scale-Extended. Patients underwent functional magnetic resonance imaging on post-injury Day 9.2 ± 5.0 and electroencephalography on Day 9.8 ± 4.6. At the time of imaging, behavioural evaluation with the Coma Recovery Scale-Revised indicated coma (n = 2), vegetative state (n = 3), minimally conscious state without language (n = 3), minimally conscious state with language (n = 4) or post-traumatic confusional state (n = 4). Cognitive motor dissociation was identified in four patients, including three whose behavioural diagnosis suggested a vegetative state. Higher-order cortex motor dissociation was identified in two additional patients. Complete absence of responses to language, music and motor imagery was only observed in coma patients. In patients with behavioural evidence of language function, responses to language and music were more frequently observed than responses to motor imagery (62.5–80% versus 33.3–42.9%). Similarly, in 16 matched healthy subjects, responses to language and music were more frequently observed than responses to motor imagery (87.5–100% versus 68.8–75.0%). Except for one patient who died in the intensive care unit, all patients with cognitive motor dissociation and higher-order cortex motor dissociation recovered beyond a confusional state by 6 months. However, 6-month outcomes were not associated with early functional magnetic resonance imaging and electroencephalography responses for the entire cohort. These observations suggest that functional magnetic resonance imaging and electroencephalography can detect command-following and higher-order cortical function in patients with acute severe traumatic brain injury. Early detection of covert consciousness and cortical responses in the intensive care unit could alter time-sensitive decisions about withholding life-sustaining therapies.

Brain 2017

Long-term antithrombotic treatment in intracranial hemorrhage survivors with atrial fibrillation

ABSTRACT

Objective: To perform a systematic review and meta-analysis of studies reporting recurrent intracranial hemorrhage (ICH) and ischemic stroke (IS) in ICH survivors with atrial fibrillation (AF) during long-term follow-up.

Methods: A comprehensive literature search including MEDLINE, EMBASE, Cochrane library, clinical trials registry was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. We considered studies capturing outcome events (ICH recurrence and IS) for ≥3 months and treatment exposure to vitamin K antagonists (VKAs), antiplatelet agents (APAs), or no antithrombotic medication (no-ATM). Corresponding authors provided aggregate data for IS and ICH recurrence rate between 6 weeks after the event and 1 year of follow-up for each treatment exposure. Meta-analyses of pooled rate ratios (RRs) were conducted with the inverse variance method.

Results: Seventeen articles met inclusion criteria. Seven observational studies enrolling 2,452 patients were included in the meta-analysis. Pooled RR estimates for IS were lower for VKAs compared to APAs (RR = 0.45, 95% confidence interval [CI] 0.27–0.74, p = 0.002) and no-ATM (RR = 0.47, 95% CI 0.29–0.77, p = 0.002). Pooled RR estimates for ICH recurrence were not significantly increased across treatment groups (VKA vs APA: RR = 1.34, 95% CI 0.79–2.30, p = 0.28; VKA vs no-ATM: RR = 0.93, 95% CI 0.45–1.90, p = 0.84).

Conclusions: In observational studies, anticoagulation with VKA is associated with a lower rate of IS than APA or no-ATM without increasing ICH recurrence significantly. A randomized controlled trial is needed to determine the net clinical benefit of anticoagulation in ICH survivors with AF.

Neurology 2017

Cardiovascular health in young adulthood and structural brain MRI in midlife The CARDIA study

ABSTRACT

Objective: To examine the association between the American Heart Association (AHA) Life's Simple 7 (LS7) metric and brain structure.

Methods: We determined cardiovascular health (CVH) according to the AHA LS7, assigning 0, 1, or 2 points for meeting poor, intermediate, or ideal criteria for the 7 components (range 0–14) at baseline (aged 18–30 years in 1985–1986) and year 25 follow-up examination for 518 participants of the Coronary Artery Risk Development in Young Adults (CARDIA) brain MRI substudy. Visit-based CVH score and average score was assessed in relation to percent of intracranial volume of normal tissue of the whole brain, gray matter, and white matter, and abnormal tissue volume of white matter at year 25 using multivariable linear, logistic, and quantile regression, after adjustment for age, sex, race, field center, educational attainment, and alcohol consumption.

Results: Mean percentage of whole brain volume, normal gray matter, and normal white matter was 81.3% (±2.5), 42.9% (±2.0), and 38.4% (±2.0). Greater CVH score at baseline (per each additional point at year 0: 0.1%, 95% confidence limits 0.01–0.3; p < 0.05) and average CVH score were associated with greater percentage of whole brain volume (per each additional point in average score: 0.2%, 95% confidence limits 0.04–0.3; p < 0.05). Visit-based or average CVH score was not significantly associated with normal gray or white matter volume or abnormal white matter volume.

Conclusions: Maintaining ideal levels of cardiovascular health, determined by the LS7, in young adulthood is associated with greater whole brain volume in middle age but not regional differences in structure.

Neurology 2017

Biological age is better than chronological as predictor of 3-month outcome in ischemic stroke

ABSTRACT

Objective: To analyze the effect of age-related DNA methylation changes in multiple cytosine-phosphate-guanine (CpG) sites (biological age [b-age]) on patient outcomes at 3 months after an ischemic stroke.

Methods: We included 511 patients with first-ever acute ischemic stroke assessed at Hospital del Mar (Barcelona, Spain) as the discovery cohort. Demographic and clinical data, including chronological age (c-age), vascular risk factors, initial stroke severity, recanalization treatment, and previous and 3-month modified Rankin Scale (p-mRS and 3-mRS, respectively) were registered. B-age was estimated with an algorithm, based on DNA methylation in 71 CpGs. Bivariate analysis determined variables associated with 3-mRS for inclusion in ordinal multivariate analysis.

Results: After ordinal regressions for 3-month ischemic stroke outcome (3-mRS), b-age was associated with outcome (odds ratio 1.04 [95% confidence interval 1.01–1.07]), nullifying c-age. Stepwise regression kept b-age, basal NIH Stroke Scale, sex, p-mRS, and recanalization treatment as better explanatory variables, instead of c-age. These results were successfully replicated in an independent cohort.

Conclusions: B-age, estimated by DNA methylation, is an independent predictor of ischemic stroke outcome regardless of chronological years.

Neurology 2017

Early and lethal neurodegeneration with myasthenic and myopathic features A new ALG14-CDG

ABSTRACT

Objective: To describe the presentation and identify the cause of a new clinical phenotype, characterized by early severe neurodegeneration with myopathic and myasthenic features.

Methods: This case study of 5 patients from 3 families includes clinical phenotype, serial MRI, electrophysiologic testing, muscle biopsy, and full autopsy. Genetic workup included whole exome sequencing and segregation analysis of the likely causal mutation.

Results: All 5 patients showed severe muscular hypotonia, progressive cerebral atrophy, and therapy-refractory epilepsy. Three patients had congenital contractures. All patients died during their first year of life. In 2 of our patients, electrophysiologic testing showed abnormal decrement, but treatment with pyridostigmine led only to temporary improvement. Causative mutations in ALG14 were identified in all patients. The mutation c.220 G>A (p.Asp74Asn) was homozygous in 2 patients and heterozygous in the other 3 patients. Additional heterozygous mutations were c.422T>G (p.Val141Gly) and c.326G>A (p.Arg109Gln). In all cases, parents were found to be heterozygous carriers. None of the identified variants has been described previously.

Conclusions: We report a genetic syndrome combining myasthenic features and severe neurodegeneration with therapy-refractory epilepsy. The underlying cause is a glycosylation defect due to mutations in ALG14. These cases broaden the phenotypic spectrum associated with ALG14 congenital disorders of glycosylation as previously only isolated myasthenia has been described.

Neurology 2017

Motor speech signature of behavioral variant frontotemporal dementia Refining the phenotype

ABSTRACT

Objective: To provide a comprehensive description of motor speech function in behavioral variant frontotemporal dementia (bvFTD).

Methods: Forty-eight individuals (24 bvFTD and 24 age- and sex-matched healthy controls) provided speech samples. These varied in complexity and thus cognitive demand. Their language was assessed using the Progressive Aphasia Language Scale and verbal fluency tasks. Speech was analyzed perceptually to describe the nature of deficits and acoustically to quantify differences between patients with bvFTD and healthy controls. Cortical thickness and subcortical volume derived from MRI scans were correlated with speech outcomes in patients with bvFTD.

Results: Speech of affected individuals was significantly different from that of healthy controls. The speech signature of patients with bvFTD is characterized by a reduced rate (75%) and accuracy (65%) on alternating syllable production tasks, and prosodic deficits including reduced speech rate (45%), prolonged intervals (54%), and use of short phrases (41%). Groups differed on acoustic measures derived from the reading, unprepared monologue, and diadochokinetic tasks but not the days of the week or sustained vowel tasks. Variability of silence length was associated with cortical thickness of the inferior frontal gyrus and insula and speech rate with the precentral gyrus.

Conclusions: One in 8 patients presented with moderate speech timing deficits with a further two-thirds rated as mild or subclinical. Subtle but measurable deficits in prosody are common in bvFTD and should be considered during disease management. Language function correlated with speech timing measures derived from the unprepared monologue only.

Neurology 2017

Effects of exercise on fitness and health of adults with spinal cord injury A systematic review

ABSTRACT

Objective: To synthesize and appraise research testing the effects of exercise interventions on fitness, cardiometabolic health, and bone health among adults with spinal cord injury (SCI).

Methods: Electronic databases were searched (1980–2016). Included studies employed exercise interventions for a period ≥2 weeks, involved adults with acute or chronic SCI, and measured fitness (cardiorespiratory fitness, power output, or muscle strength), cardiometabolic health (body composition or cardiovascular risk factors), or bone health outcomes. Evidence was synthesized and appraised using Grading of Recommendations Assessment, Development, and Evaluation (GRADE).

Results: A total of 211 studies met the inclusion criteria (22 acute, 189 chronic). For chronic SCI, GRADE confidence ratings were moderate to high for evidence showing exercise can improve all of the reviewed outcomes except bone health. For acute SCI, GRADE ratings were very low for all outcomes. For chronic SCI, there was low to moderate confidence in the evidence showing that 2–3 sessions/week of upper body aerobic exercise at a moderate to vigorous intensity for 20–40 minutes, plus upper body strength exercise (3 sets of 10 repetitions at 50%–80% 1-repetition maximum for all large muscle groups), can improve cardiorespiratory fitness, power output, and muscle strength. For chronic SCI, there was low to moderate confidence in the evidence showing that 3–5 sessions per week of upper body aerobic exercise at a moderate to vigorous intensity for 20–44 minutes can improve cardiorespiratory fitness, muscle strength, body composition, and cardiovascular risk.

Conclusions: Exercise improves fitness and cardiometabolic health of adults with chronic SCI. The evidence on effective exercise types, frequencies, intensities, and durations should be used to formulate exercise guidelines for adults with SCI.

Neurology 2017

Profile of neonatal epilepsies Characteristics of a prospective US cohort

ABSTRACT

Objective: Although individual neonatal epilepsy syndromes are rare, as a group they represent a sizable subgroup of neonatal seizure etiologies. We evaluated the profile of neonatal epilepsies in a prospective cohort of newborns with seizures.

Methods: Consecutive newborns with seizures were enrolled in the Neonatal Seizure Registry (an association of 7 US children's hospitals). Treatment and diagnostic testing were at the clinicians' discretion. Neonates with seizures related to epileptic encephalopathies (without structural brain abnormalities), brain malformations, or benign familial epilepsies were included in this analysis.

Results: Among 611 consecutive newborns with seizures, 79 (13%) had epilepsy (35 epileptic encephalopathy, 32 congenital brain malformations, 11 benign familial neonatal epilepsy [BFNE], 1 benign neonatal seizures). Twenty-nine (83%) with epileptic encephalopathy had genetic testing and 24/29 (83%) had a genetic etiology. Pathogenic or likely pathogenic KCNQ2 variants (n = 10) were the most commonly identified etiology of epileptic encephalopathy. Among 23 neonates with brain malformations who had genetic testing, 7 had putative genetic etiologies. Six infants with BFNE had genetic testing; 3 had pathogenic KCNQ2 variants and 1 had a pathogenic KCNQ3 variant. Comorbid illnesses that predisposed to acute symptomatic seizures occurred in 3/35 neonates with epileptic encephalopathy vs 10/32 with brain malformations (p = 0.03). Death or discharge to hospice were more common among newborns with brain malformations (11/32) than those with epileptic encephalopathy (3/35, p = 0.01).

Conclusions: Neonatal epilepsy is often due to identifiable genetic causes. Genetic testing is now warranted for newborns with epilepsy in order to guide management and inform discussions of prognosis.

Neurology 2017

Autoantibodies in chronic inflammatory neuropathies: diagnostic and therapeutic implications

The chronic inflammatory neuropathies (CINs) are rare, very disabling autoimmune disorders that generally respond well to immune therapies such as intravenous immunoglobulin (IVIg). The most common forms of CIN are chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), multifocal motor neuropathy, and polyneuropathy associated with monoclonal gammopathy of unknown significance. The field of CIN has undergone a major advance with the identification of IgG4 autoantibodies directed against paranodal proteins in patients with CIDP. Although these autoantibodies are only found in a small subset of patients with CIDP, they can be used to guide therapeutic decision-making, as these patients have a poor response to IVIg. These observations provide proof of concept that identifying the target antigens in tissue-specific antibody-mediated autoimmune diseases is important, not only to understand their underlying pathogenic mechanisms, but also to correctly diagnose and treat affected patients. This state-of-the-art Review focuses on the role of autoantibodies against nodes of Ranvier in CIDP, a clinically relevant emerging field of research. The role of autoantibodies in other immune-mediated neuropathies, including other forms of CIN, primary autoimmune neuropathies, neoplasms, and systemic diseases that resemble CIN, are also discussed.

Nature Reviews Neurology 2017

A clinicopathological approach to the diagnosis of dementia

The most definitive classification systems for dementia are based on the underlying pathology which, in turn, is categorized largely according to the observed accumulation of abnormal protein aggregates in neurons and glia. These aggregates perturb molecular processes, cellular functions and, ultimately, cell survival, with ensuing disruption of large-scale neural networks subserving cognitive, behavioural and sensorimotor functions. The functional domains affected and the evolution of deficits in these domains over time serve as footprints that the clinician can trace back with various levels of certainty to the underlying neuropathology. The process of phenotyping and syndromic classification has substantially improved over decades of careful clinicopathological correlation, and through the discovery of in vivo biomarkers of disease. Here, we present an overview of the salient features of the most common dementia subtypes — Alzheimer disease, vascular dementia, frontotemporal dementia and related syndromes, Lewy body dementias, and prion diseases — with an emphasis on neuropathology, relevant epidemiology, risk factors, and signature signs and symptoms.

Nature Reviews Neurology 2017

Secular Trends of Amyotrophic Lateral Sclerosis The Piemonte and Valle d’Aosta Register

Abstract

Importance  This study reports the long-term epidemiologic trends of amyotrophic lateral sclerosis (ALS) based on a prospective register.

Objective  To examine the 20-year epidemiologic trends of ALS in the Piemonte and Valle d’Aosta regions of Italy.

Design, Setting, and Participants  The Piemonte and Valle d’Aosta Register for ALS (PARALS) is an epidemiologic prospective register that covers 2 Italian regions (population of 4 476 931 inhabitants according to the 2011 census) from January 1, 1995, through December 31, 2014. Case ascertainment is based on multiple sources (neurologic departments, hospital discharge archives, and mortality records). Incidence rates are age and sex standardized for the Italian population of the 2011 census. Age-period-cohort (APC) analysis was performed using a Poisson regression model.

Main Outcomes and Measures  The primary study outcomes were long-term incidence and prevalence rates of ALS using a prospective design and their determinants.

Results  During the study period, a total of 2702 patients (mean [SD] age at onset, 65.7 [11.1] years; 1246 [46.1%] female and 1456 [53.9%] male) received a diagnosis of ALS between 1995 and 2014, corresponding to a crude annual incidence rate of 3.03 per 100 000 population (95% CI, 2.85-3.23) and an adjusted incidence rate of 2.78 per 100 000 population (95% CI, 2.57-2.96). The age-adjusted incidence rate increased in the 2 decades of the study (1995-2004: 2.66; 95% CI, 2.50-2.83; 2005-2014: 2.89; 95% CI, 2.71-3.07; P = .04), mostly in women. The adjusted rate ratio of men to women decreased from 1.27:1 (1995-2004) to 1.17:1 (2005-2014). The analysis of deviance for the APC regression models indicated that the drift variable is relevant in explaining the variation of ALS incidence rates over time in the overall population (change in deviance, 4.6553; P = .03) and in women (change in deviance, 3.8821; P = .05) but not in men (change in deviance, 0.77215; P = .38). A total of 479 patients with ALS were alive and had not undergone tracheostomy at the prevalence day (December 31, 2014), corresponding to a crude prevalence rate of 10.54 per 100 000 population (95% CI, 9.64-11.52).

Conclusions and Relevance  During the 1995 to 2014 period, the crude and adjusted incidences of ALS increased in Piemonte and Valle d’Aosta, mostly in women. The APC model revealed that the increase of ALS incidence is attributable to a birth cohort effect in women, with a peak in the 1930 cohort. The different increase of ALS incidence in men and women points to an effect of exogenous factors with a differential effect on the 2 sexes, acting on a genetic background.

JAMA Neurology 2017