Identification of Novel Risk Loci and Causal Insights for Sporadic Creutzfeldt-Jakob Disease

The first evidence of statistically robust genetic associations in sporadic human prion disease that implicate intracellular trafficking and sphingolipid metabolism as molecular causal mechanisms.

source: The Lancet

Summary

Identification of Novel Risk Loci and Causal Insights for Sporadic Creutzfeldt-Jakob Disease: A Genome-Wide Association Study

[Posted 16/Oct/2020]

AUDIENCE: Neurology, Internal Medicine, Geriatric

KEY FINDINGS: Study presents the first evidence of statistically robust genetic associations in sporadic human prion disease that implicate intracellular trafficking and sphingolipid metabolism as molecular causal mechanisms. Risk SNPs in STX6 are shared with progressive supranuclear palsy, a neurodegenerative disease associated with misfolding of protein tau, indicating that sCJD might share the same causal mechanisms as prion-like disorders.

BACKGROUND: Human prion diseases are rare and usually rapidly fatal neurodegenerative disorders, the most common being sporadic Creutzfeldt-Jakob disease (sCJD). Variants in the PRNP gene that encodes prion protein are strong risk factors for sCJD but, although the condition has similar heritability to other neurodegenerative disorders, no other genetic risk loci have been confirmed. We aimed to discover new genetic risk factors for sCJD, and their causal mechanisms.

DETAILS: A genome-wide association study was conducted of sCJD in European ancestry populations (patients diagnosed with probable or definite sCJD identified at national CJD referral centres) with a two-stage study design using genotyping arrays and exome sequencing. Conditional, transcriptional, and histological analyses of implicated genes and proteins in brain tissues, and tests of the effects of risk variants on clinical phenotypes, were done using deep longitudinal clinical cohort data. Control data from healthy individuals were obtained from publicly available datasets matched for country. Samples from 5208 cases were obtained between 1990 and 2014. Found 41 genome-wide significant single nucleotide polymorphisms (SNPs) and independently replicated findings at three loci associated with sCJD risk; within PRNP (rs1799990; additive model odds ratio [OR] 1.23 [95% CI 1.17-1.30], p=2.68 × 10-15; heterozygous model p=1.01 × 10-135), STX6 (rs3747957; OR 1.16 [1.10-1.22], p=9.74 × 10-9), and GAL3ST1 (rs2267161; OR 1.18 [1.12-1.25], p=8.60 × 10-10). Follow-up analyses showed that associations at PRNP and GAL3ST1 are likely to be caused by common variants that alter the protein sequence, whereas risk variants in STX6 are associated with increased expression of the major transcripts in disease-relevant brain regions.

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FUNDING: Medical Research Council and the UK National Institute of Health Research in part through the Biomedical Research Centre at University College London Hospitals National Health Service Foundation Trust.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Source: The Lancet Published October 01, 2020. DOI: https://doi.org/10.1016/S1474-4422(20)30273-8


Association of Ideal Cardiovascular Health at Age 50 With Incidence of Dementia

Adherence to the Life Simple 7 ideal cardiovascular health recommendations in midlife was associated with a lower risk of dementia later in life.

source: BMJ

Summary

Association of Ideal Cardiovascular Health at Age 50 With Incidence of Dementia: 25 Year Follow-Up of Whitehall II Cohort Study

[Posted 06/Oct/2020]

AUDIENCE: Neurology, Internal Medicine, Geriatric

KEY FINDINGS: Adherence to the Life Simple 7 ideal cardiovascular health recommendations in midlife was associated with a lower risk of dementia later in life.

BACKGROUND: To examine the association between the Life Simple 7 cardiovascular health score at age 50 and incidence of dementia.

DETAILS: 7899 participants with data on the cardiovascular health score at age 50 were included. The cardiovascular health score included four behavioural (smoking, diet, physical activity, body mass index) and three biological (fasting glucose, blood cholesterol, blood pressure) metrics, coded on a three point scale (0, 1, 2). The cardiovascular health score was the sum of seven metrics (score range 0-14) and was categorised into poor (scores 0-6), intermediate (7-11), and optimal (12-14) cardiovascular health. Main outcome measure was Incident dementia, identified through linkage to hospital, mental health services, and mortality registers until 2017. 347 incident cases of dementia were recorded over a median follow-up of 24.7 years. Compared with an incidence rate of dementia of 3.2 (95% confidence interval 2.5 to 4.0) per 1000 person years among the group with poor cardiovascular health, the absolute rate differences per 1000 person years were -1.5 (95% confidence interval -2.3 to -0.7) for the group with intermediate cardiovascular health and -1.9 (-2.8 to -1.1) for the group with optimal cardiovascular health. Higher cardiovascular health score was associated with a lower risk of dementia (hazard ratio 0.89 (0.85 to 0.95) per 1 point increment in the cardiovascular health score). Similar associations with dementia were observed for the behavioural and biological subscales (hazard ratios per 1 point increment in the subscores 0.87 (0.81 to 0.93) and 0.91 (0.83 to 1.00), respectively). The association between cardiovascular health at age 50 and dementia was also seen in people who remained free of cardiovascular disease over the follow-up (hazard ratio 0.89 (0.84 to 0.95) per 1 point increment in the cardiovascular health score).

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Source: Sabia, S., Fayosse, A., Dumurgier, J., Schnitzler, A., Empana, J. P., Ebmeier, K. P., … Singh-Manoux, A. (2019). Association of ideal cardiovascular health at age 50 with incidence of dementia: 25 Year follow-up of Whitehall II cohort study. The BMJ, 366. https://doi.org/10.1136/bmj.l4414

Published: Aug 2020


Paternal Exposure to Antiepileptic Drugs and Offspring Outcomes

Paternal antiepileptic drugs use during conception is not associated with adverse outcomes in the offspring.

source: J Neurol Neurosurg Psychiatry

Summary

Paternal Exposure to Antiepileptic Drugs and Offspring Outcomes: A Nationwide Population-Based Cohort Study in Sweden

[Posted 01/Oct/2020]

AUDIENCE: Neurology, Internal Medicine

KEY FINDINGS: Paternal AED use during conception is not associated with adverse outcomes in the offspring.

BACKGROUND: To investigate the association between paternal use of antiepileptic drugs (AEDs) and adverse neurodevelopmental outcomes and major congenital malformations (MCM) in the offspring.

DETAILS: Using nationwide Swedish registries, 1,144,795 births to 741,726 fathers without epilepsy and 4,544 births to 2,955 fathers with epilepsy were included. Of these, 2,087 (45.9%) were born to fathers with epilepsy who had dispensed an AED during the conception period. Children who had both parents with epilepsy were excluded. The incidence rate of MCM, autism spectrum disorder, attention deficit hyperactivity disorder (ADHD) and intellectual disability in offspring was analysed. Offspring of fathers exposed to AEDs did not show an increased risk of MCM (adjusted OR 0.9, 95% CI 0.7 to 1.2), autism (adjusted HR (aHR) 0.9, 95% CI 0.5 to 1.7), ADHD (aHR 1.1, 95% CI 0.7 to 1.9) or intellectual disability (aHR 1.3, 95% CI 0.6 to 2.8) compared with offsspring of fathers with epilepsy not exposed to AEDs. Among offspring of fathers with epilepsy who used valproate in monotherapy during conception, rates of autism (2.9/1000 child-years) and intellectual disability (1.4/1000 child-years) were slightly higher compared with the offspring of fathers with epilepsy who did not use AEDs during conception (2.1/1000 child-years autism, 0.9/1000 child-years intellectual disability), but in the propensity-score adjusted analyses, no statistically significant increased risk of adverse outcomes was found.

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Source: Tomson, T., Muraca, G., & Razaz, N. (2020). Paternal exposure to antiepileptic drugs and offspring outcomes: A nationwide population-based cohort study in Sweden. Journal of Neurology, Neurosurgery and Psychiatry, 91(9), 907-913. https://doi.org/10.1136/jnnp-2020-323028

Published: Aug 2020


Apathy, But not Depression, Predicts All-Cause Dementia in Cerebral SVD

Apathy, but not depression, may be a prodromal symptom of dementia in small vessel disease (SVD), and may be useful in identifying at-risk individuals.

source: J Neurol Neurosurg Psychiatry

Summary

Apathy, But not Depression, Predicts All-Cause Dementia in Cerebral Small Vessel Disease

[Posted 10/Sep/2020]

AUDIENCE: Neurology, Internal Medicine

KEY FINDINGS: Apathy, but not depression, may be a prodromal symptom of dementia in SVD, and may be useful in identifying at-risk individuals.

BACKGROUND: To determine whether apathy or depression predicts all-cause dementia in small vessel disease (SVD) patients.

DETAILS: Analyses used two prospective cohort studies of SVD: St. George’s Cognition and Neuroimaging in Stroke (SCANS; n=121) and Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort (RUN DMC; n=352). Multivariate Cox regressions were used to predict dementia using baseline apathy and depression scores in both datasets. Change in apathy and depression was used to predict dementia in a subset of 104 participants with longitudinal data from SCANS. All models were controlled for age, education and cognitive function. Baseline apathy scores predicted dementia in SCANS (HR 1.49, 95% CI 1.05 to 2.11, p=0.024) and RUN DMC (HR 1.05, 95% CI 1.01 to 1.09, p=0.007). Increasing apathy was associated with dementia in SCANS (HR 1.53, 95% CI 1.08 to 2.17, p=0.017). In contrast, baseline depression and change in depression did not predict dementia in either dataset. Including apathy in predictive models of dementia improved model fit.

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Copyright © 2020 BMJ Publishing Group Ltd. All rights reserved.

Source: J Neurol Neurosurg Psychiatry Published August 14, 2020. http://dx.doi.org/10.1136/jnnp-2020-323092.


Efficacy and Safety of Adjunctive Lacosamide in the Treatment of Primary Generalised Tonic-Clonic Seizures

Lacosamide was efficacious and generally safe as adjunctive treatment for uncontrolled primary generalised tonic-clonic seizures (PGTCS) in patients with idiopathic generalised epilepsy (IGE)

source: J Neurol Neurosurg Psychiatry

Summary

Efficacy and Safety of Adjunctive Lacosamide in the Treatment of Primary Generalised Tonic-Clonic Seizures: a Double-Blind, Randomised, Placebo-Controlled Trial

[Posted 25/Aug/2020]

AUDIENCE: Neurology, Internal Medicine

KEY FINDINGS: Lacosamide was efficacious and generally safe as adjunctive treatment for uncontrolled PGTCS in patients with IGE.

BACKGROUND: Objective of this trial is to evaluate efficacy and safety of lacosamide (up to 12 mg/kg/day or 400 mg/day) as adjunctive treatment for uncontrolled primary generalised tonic-clonic seizures (PGTCS) in patients (>=4 years) with idiopathic generalised epilepsy (IGE).

DETAILS: Phase 3, double-blind, randomised, placebo-controlled trial (SP0982; NCT02408523) in patients with IGE and PGTCS taking 1–3 concomitant antiepileptic drugs. Primary outcome was time to second PGTCS during 24-week treatment. 242 patients were randomised and received >=1 dose of trial medication (lacosamide/placebo: n=121/n=121). Patients (mean age: 27.7 years; 58.7% female) had a history of generalised-onset seizures (tonic-clonic 99.6%; myoclonic 38.8%; absence 37.2%). Median treatment duration with lacosamide/placebo was 143/65 days. Risk of developing a second PGTCS during 24-week treatment was significantly lower with lacosamide than placebo (Kaplan-Meier survival estimates 55.27%/33.37%; HR 0.540, 95% CI 0.377 to 0.774; p<0.001; n=118/n=121). Median time to second PGTCS could not be estimated for lacosamide (>50% of patients did not experience a second PGTCS) and was 77.0 days for placebo. Kaplan-Meier estimated freedom from PGTCS at end of the 24-week treatment period (day 166) for lacosamide/placebo was 31.3%/17.2% (difference 14.1%; p=0.011). More patients on lacosamide than placebo had >=50% (68.1%/46.3%) or >=75% (57.1%/36.4%) reduction from baseline in PGTCS frequency/28 days, or observed freedom from PGTCS during treatment (27.5%/13.2%) (n=119/n=121). 96/121 (79.3%) patients on lacosamide had treatment-emergent adverse events (placebo 79/121 (65.3%)), most commonly dizziness (23.1%), somnolence (16.5%), headache (14.0%). No patients died during the trial.

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Copyright © 2020 BMJ Publishing Group Ltd. All rights reserved.

Source: J Neurol Neurosurg Psychiatry Published August 18, 2020. doi: http://dx.doi.org/10.1136/jnnp-2020-323524.


FDA Approves Targeted Treatment for Rare DMD Mutation

FDA granted accelerated approval to Viltepso (viltolarsen) injection for the treatment of Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the DMD gene that is amenable to exon 53 skipping.

source: FDA

Summary

FDA Approves Targeted Treatment for Rare Duchenne Muscular Dystrophy Mutation

[Posted 13/Aug/2020]

AUDIENCE: Neurology, Genetic, Internal Medicine

Today, the U.S. Food and Drug Administration granted accelerated approval to Viltepso (viltolarsen) injection for the treatment of Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the DMD gene that is amenable to exon 53 skipping. This is the second FDA-approved targeted treatment for patients with this type of mutation. Approximately 8% of patients with DMD have a mutation that is amenable to exon 53 skipping.

“The FDA is committed to fostering drug development for serious neurological disorders like Duchenne muscular dystrophy,” said Billy Dunn, M.D., director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research. “Today’s approval of Viltepso provides an important treatment option for Duchenne muscular dystrophy patients with this confirmed mutation.”

DMD is a rare genetic disorder characterized by progressive muscle deterioration and weakness. It is the most common type of muscular dystrophy. DMD is caused by mutations in the DMD gene that results in an absence of dystrophin, a protein that helps keep muscle cells intact. The first symptoms are usually seen between three and five years of age and worsen over time. DMD occurs in approximately one out of every 3,600 male infants worldwide; in rare cases, it can affect females.

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Viltepso was evaluated in two clinical studies with a total of 32 patients, all of whom were male and had genetically confirmed DMD. The increase in dystrophin production was established in one of those two studies, a study that included 16 DMD patients, with 8 patients receiving Viltepso at the recommended dose. In the study, dystrophin levels increased, on average, from 0.6% of normal at baseline to 5.9% of normal at week 25.

The FDA concluded that the applicant’s data demonstrated an increase in dystrophin production that is reasonably likely to predict clinical benefit in patients with DMD who have a confirmed mutation of the dystrophin gene amenable to exon 53 skipping. A clinical benefit of the drug has not been established. In making this decision, the FDA considered the potential risks associated with the drug, the life-threatening and debilitating nature of the disease, and the lack of available therapies.

As part of the accelerated approval process, the FDA is requiring the company to conduct a clinical trial to confirm the drug’s clinical benefit. The ongoing study is designed to assess whether Viltepso improves the time to stand for DMD patients with this confirmed mutation. If the trial fails to verify clinical benefit, the FDA may initiate proceedings to withdraw approval of the drug.

The most common side effects observed in DMD patients (pooled from the two studies) treated with 80 mg/kg once a week were: Upper respiratory tract infection, injection site reaction, cough and fever.

Although kidney toxicity was not observed in the Viltepso clinical studies, the clinical experience with Viltepso is limited, and kidney toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides. Kidney function should be monitored in patients taking Viltepso.

Viltepso was approved under the FDA’s accelerated approval pathway, which provides for the approval of drugs that treat serious or life-threatening diseases and generally offer a meaningful advantage over existing treatments. Approval under this pathway can be based on adequate and well-controlled studies showing the drug has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit to patients (i.e., how patients feel or function or whether they survive). This pathway provides earlier patient access to promising new drugs while the company conducts clinical trials to verify the predicted clinical benefit.

The FDA granted this application Priority Review designation.

The FDA is granting the approval to NS Pharma, Inc.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Source: FDA

Published: August 12, 2020.


FDA Approves Oral Treatment for Spinal Muscular Atrophy

FDA pproved Evrysdi (risdiplam) to treat patients two months of age and older with spinal muscular atrophy (SMA), a rare and often fatal genetic disease affecting muscle strength and movement.

source: FDA

Summary

FDA Approves Oral Treatment for Spinal Muscular Atrophy

[Posted 11/Aug/2020]

AUDIENCE: Neurology, Orthopedic, Pediatric

The U.S. Food and Drug Administration today approved Evrysdi (risdiplam) to treat patients two months of age and older with spinal muscular atrophy (SMA), a rare and often fatal genetic disease affecting muscle strength and movement. This is the second drug and the first oral drug approved to treat this disease.

“Evrysdi is the first drug for this disease that can be taken orally, providing an important treatment option for patients with SMA, following the approval of the first treatment for this devastating disease less than four years ago,” said Billy Dunn, M.D., director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research.

SMA is a hereditary disease that causes weakness and muscle wasting because patients lose lower motor neurons (nerve cells) that control movement. Evrysdi contains a survival of motor neuron 2-directed RNA splicing modifier. The efficacy of Evrysdi for the treatment of patients with infantile-onset and later-onset SMA was evaluated in two clinical studies. The infantile-onset SMA study included 21 patients who had an average age of 6.7 months when the study began. In that open-label study, efficacy was established based on the ability to sit without support for at least five seconds and survival without permanent ventilation. After 12 months of treatment, 41% of patients were able to sit independently for more than five seconds, a meaningful difference from the natural progression of the disease because almost all untreated infants with infantile-onset SMA cannot sit independently. After 23 or more months of treatment, 81% of patients were alive without permanent ventilation, which is a noticeable improvement from typical disease progression without treatment.

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Patients with later-onset SMA were evaluated in a second randomized, placebo-controlled study. The study included 180 patients with SMA aged two to 25 years. The primary endpoint was the change from baseline in MFM32 (a test of motor function) total score at the one-year mark. Patients on Evrysdi saw an average 1.36 increase in their score at the one-year mark, compared to a 0.19 decrease in patients on placebo (inactive treatment).

The most common side effects of Evrysdi include fever, diarrhea, rash, ulcers of the mouth area, joint pain (arthralgia) and urinary tract infections. Patients with infantile-onset SMA had similar side effects as individuals with later-onset SMA. Additional side effects for the infantile-onset population include upper respiratory tract infection, pneumonia, constipation and vomiting. Patients should avoid taking Evrysdi together with drugs that are multidrug and toxin extrusion substrates because Evrysdi may increase plasma concentrations of these drugs.

The FDA granted this application fast track designation and priority review. The drug also received orphan drug designation, which provides incentives to assist and encourage drug development for rare diseases. The application was awarded a Rare Pediatric Disease Priority Review Voucher.

The FDA granted this approval of Evrysdi to Genentech, Inc.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Source: FDA

Published: August 07, 2020.


New Insights in Post-Traumatic Headache With Cluster Headache Phenotype

This largest series of PTH-CH defines it as a unique entity with specific evolutive profile. Patients with PTH-CH are more likely to suffer from the chronic variant, have marked autonomic features, be intractable to treatment and have associated chronic migraine compared with primary CH.

source: J Neurol Neurosurg Psychiatry

Summary

New Insights In Post-Traumatic Headache With Cluster Headache Phenotype: A Cohort Study

[Posted 21/Jul/2020]

AUDIENCE: Neurology, Internal Medicine, Psychiatry

KEY FINDINGS: This largest series of PTH-CH defines it as a unique entity with specific evolutive profile. Patients with PTH-CH are more likely to suffer from the chronic variant, have marked autonomic features, be intractable to treatment and have associated chronic migraine compared with primary CH.

BACKGROUND: To define the characteristics of post-traumatic headache with cluster headache phenotype (PTH-CH) and to compare these characteristics with primary CH.

DETAILS: A retrospective study was conducted of patients seen between 2007 and 2017 in a headache centre and diagnosed with PTH-CH that developed within 7 days of head trauma. A control cohort included 553 patients with primary CH without any history of trauma who attended the headache clinic during the same period. Data including demographics, attack characteristics and response to treatments were recorded.Twenty-six patients with PTH-CH were identified. Multivariate analysis revealed significant associations between PTH-CH and family history of CH (OR 3.32, 95% CI 1.31 to 8.63), chronic form (OR 3.29, 95% CI 1.70 to 6.49), parietal (OR 14.82, 95% CI 6.32 to 37.39) or temporal (OR 2.04, 95% CI 1.10 to 3.84) location of pain, and presence of prominent cranial autonomic features during attacks (miosis OR 11.24, 95% CI 3.21 to 41.34; eyelid oedema OR 5.79, 95% CI 2.57 to 13.82; rhinorrhoea OR 2.65, 95% CI 1.26 to 5.86; facial sweating OR 2.53, 95% CI 1.33 to 4.93). Patients with PTH-CH were at a higher risk of being intractable to acute (OR 12.34, 95% CI 2.51 to 64.73) and preventive (OR 16.98, 95% CI 6.88 to 45.52) treatments and of suffering from associated chronic migraine (OR 10.35, 95% CI 3.96 to 28.82).

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Source: Grangeon, L., O’Connor, E., Chan, C.-K., Akijian, L., Pham Ngoc, T. M., & Matharu, M. S. (2020). New insights in post-traumatic headache with cluster headache phenotype: a cohort study. Journal of Neurology, Neurosurgery & Psychiatry, 91(6), 572–579. https://doi.org/10.1136/jnnp-2019-322725

Published: June 2020


Long-term Safety and Effectiveness of Natalizumab Treatment in Clinical Practice

Since the TOP 5-year interim analysis (December 2012), cohort size (6148 vs 4821), median exposure (3.3 vs 1.8 years) and median follow-up time (62 vs 26 months) have increased.

source: J Neurol Neurosurg Psychiatry

Summary

Long-term Safety and Effectiveness of Natalizumab Treatment in Clinical Practice: 10 Years of Real-World Data from the Tysabri Observational Program (TOP)

[Posted 08/Jul/2020]

AUDIENCE: Neurology, Internal Medicine, Psychiatry

KEY FINDINGS: Since the TOP 5-year interim analysis (December 2012), cohort size (6148 vs 4821), median exposure (3.3 vs 1.8 years) and median follow-up time (62 vs 26 months) have increased. This 10-year interim analysis further supports the robust real-world effectiveness and well-established safety profile of natalizumab.

BACKGROUND: The Tysabri Observational Programme (TOP), which began >10 years ago, is an open-label, multinational, prospective observational study evaluating the long-term safety and effectiveness of natalizumab in relapsing-remitting multiple sclerosis

DETAILS: These data provide a 10-year interim analysis of safety and effectiveness in TOP. Annualised relapse rates (ARRs) and disability progression/improvement were analysed using the Poisson model and the Kaplan-Meier method, respectively. Analyses included patients on natalizumab and those who discontinued natalizumab but remained in TOP. As of November 2017, TOP included 6148 patients. Overall, 829 patients (13.5%) experienced >=1 serious adverse event (SAE), with infection the most common (4.1%). Fifty-three patients (0.9%) had confirmed progressive multifocal leukoencephalopathy. SAE data were consistent with natalizumab’s known safety profile; no new safety signals were identified. A total of 3210 patients (52.2%) discontinued natalizumab; 2117 (34.4%) withdrew from TOP. Median time on natalizumab was 3.3 (range 0–11.6) years; median follow-up time was 5.2 (range 0–10.8) years. The on-natalizumab ARR was 0.15, a 92.5% reduction from the year before initiation. Ten-year cumulative probabilities of disability worsening and improvement were 27.8% and 33.1%, respectively. On-natalizumab ARRs were similar between patients who discontinued or remained on natalizumab, suggesting limited attrition bias.

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TRIAL REGISTRATION NUMBER: NCT00493298.

Copyright © 2020 BMJ Publishing Group Ltd. All rights reserved.

Source: J Neurol Neurosurg Psychiatry Published March 31, 2020. http://dx.doi.org/10.1136/jnnp-2019-322326.


Ten-Year Risks of Recurrent Stroke, Disability, Dementia and Cost in Relation to Site of Primary Intracerebral Haemorrhage

Compared with non-lobar ICH, the substantially higher 10-year risks of recurrent stroke, dementia and lower QALYs after lobar ICH highlight the need for more effective prevention for this patient group.

source: J Neurol Neurosurg Psychiatry

Summary

Ten-Year Risks of Recurrent Stroke, Disability, Dementia and Cost in Relation to Site of Primary Intracerebral Haemorrhage: Population-Based Study

[Posted 01/Jul/2020]

AUDIENCE: Neurology, Internal Medicine, Emergency Medicine

KEY FINDINGS: Compared with non-lobar ICH, the substantially higher 10-year risks of recurrent stroke, dementia and lower QALYs after lobar ICH highlight the need for more effective prevention for this patient group.

BACKGROUND: Patients with primary intracerebral haemorrhage (ICH) are at increased long-term risks of recurrent stroke and other comorbidities. However, available estimates come predominantly from hospital-based studies with relatively short follow-up. Moreover, there are also uncertainties about the influence of ICH location on risks of recurrent stroke, disability, dementia and quality of life.

DETAILS: In a population-based study (Oxford Vascular Study/2002-2018) of patients with a first ICH with follow-up to 10 years, we determined the long-term risks of recurrent stroke, disability, quality of life, dementia and hospital care costs stratified by haematoma location.Of 255 cases with primary ICH (mean/SD age 75.5/13.1), 109 (42.7%) had lobar ICH, 144 (56.5%) non-lobar ICH and 2 (0.8%) had uncertain location. Annual rates of recurrent ICH were higher after lobar versus non-lobar ICH (lobar=4.0%, 2.7-7.2 vs 1.1%, 0.3-2.8; p=0.02). Moreover, cumulative rate of dementia was also higher for lobar versus non-lobar ICH (n/% lobar=20/36.4% vs 16/20.8%, p=0.047), and there was a higher proportion of disability at 5 years in survivors (15/60.0% vs 9/31.0%, p=0.03). The 10-year quality-adjusted life years (QALYs) were also lower after lobar versus non-lobar ICH (2.9 vs 3.8 for non-lobar, p=0.04). Overall, the mean 10-year censor-adjusted costs were £19,292, with over 80% of costs due to inpatient hospital admission costs, which did not vary by haematoma location (p=0.90).

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Source: Li, L., Luengo-Fernandez, R., Zuurbier, S. M., Beddows, N. C., Lavallee, P., Silver, L. E., … Rothwell, P. M. (2020). Ten-year risks of recurrent stroke, disability, dementia and cost in relation to site of primary intracerebral haemorrhage: Population-based study. Journal of Neurology, Neurosurgery and Psychiatry, 91(6), 580-585. https://doi.org/10.1136/jnnp-2019-322663

Published: May 2020


FDA Approves New Therapy for Dravet Syndrome

Fintepla (fenfluramine), a Schedule IV controlled substance approved by FDA for the treatment of seizures associated with Dravet syndrome in patients age 2 and older.

source: FDA

Summary

FDA Approves New Therapy for Dravet Syndrome

[Posted 30/Jun/2020]

AUDIENCE: Neurology, Pediatric, Internal Medicine, Family Medicine

The U.S. Food and Drug Administration today approved Fintepla (fenfluramine), a Schedule IV controlled substance, for the treatment of seizures associated with Dravet syndrome in patients age 2 and older. Dravet syndrome is a life-threatening, rare and chronic form of epilepsy. It is often characterized by severe and unrelenting seizures despite medical treatment.

“Dravet syndrome is a debilitating disease that takes a tremendous toll on both patients and their families,” said Billy Dunn, M.D., director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research. “Fintepla offers an additional effective treatment option for the treatment of seizures associated with Dravet syndrome. The FDA will continue to work with companies on drug development for Dravet syndrome and other types of epilepsy.”

The effectiveness of Fintepla for the treatment of seizures associated with Dravet syndrome was demonstrated in two clinical studies in 202 subjects between ages 2 and 18. The studies measured the change from baseline in the frequency of convulsive seizures. In both studies, subjects treated with Fintepla had significantly greater reductions in the frequency of convulsive seizures during the trials than subjects who received placebo (inactive treatment). These reductions were seen within 3-4 weeks, and remained generally consistent over the 14- to 15-week treatment periods.

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Fintepla labeling includes a boxed warning stating the drug is associated with valvular heart disease (VHD) and pulmonary arterial hypertension (PAH). Because of these risks, patients must have cardiac monitoring using echocardiograms performed before treatment, every six months during treatment, and once three to six months after treatment is discontinued. If the echocardiogram shows signs of VHD, PAH, or other cardiac abnormalities, health care professionals must consider the benefits and risks of continuing treatment with Fintepla for the patient.

Because of the risks of VHD and PAH, Fintepla is available only through a restricted drug distribution program, under a risk evaluation and mitigation strategy (REMS). The Fintepla REMS requires health care professionals who prescribe Fintepla and pharmacies that dispense Fintepla to be specially certified in the Fintepla REMS and that patients be enrolled in the REMS. As part of the REMS requirements, prescribers and patients must adhere to the required cardiac monitoring with echocardiograms to receive Fintepla.

The most common adverse reactions in clinical studies were decreased appetite; drowsiness, sedation and lethargy; diarrhea; constipation; abnormal echocardiogram; fatigue or lack of energy; ataxia (lack of coordination), balance disorder, gait disturbance (trouble with walking); increased blood pressure; drooling, salivary hypersecretion (saliva overproduction); pyrexia (fever); upper respiratory tract infection; vomiting; decreased weight; risk of falls; and status epilepticus.

The FDA granted this application Priority Review. Fintepla received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted approval of Fintepla to Zogenix, Inc.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Source: FDA

Published: June 25, 2020.


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