BACKGROUND:The incidence of aneurysmal subarachnoid haemorrhage declined between 1980 and 2010, which coincided with a decline in smoking and prevalence of hypertension. We aimed to investigate whether the decrease in subarachnoid haemorrhage incidence is paralleled by declines in unruptured intracranial aneurysm (UIA) prevalence. METHODS:For this systematic review and meta-analysis, we searched Embase, PubMed, and Web of Science for articles published in any language from Jan 1, 2011 to Dec 31, 2025, and reassessed 68 articles published before March 1, 2011 from a 2011 systematic review and meta-analysis. Articles were eligible for inclusion if they used a cross-sectional or case-control design and provided the crude number of participants and those with UIA. We only included studies reporting numbers of UIA separately from ruptured aneurysms and with ten or more patients. Summary data were independently extracted by JD with AZ or CB and conflicts were resolved by GJER. The primary outcome was proportion of participants with UIA. Relative to a hypothetical reference population (mean age 50 years, 50% women, and no comorbidities), age and/or sex-adjusted prevalence ratios (PRs) for regions, comorbidities, and risk ratios (RRs) for female sex, smoking, and hypertension were estimated using generalised linear mixed models. A time trend analysis was done by binomial meta regression using the mid-year of data acquisition. We assessed the certainty of evidence using GRADE. The study was registered with PROSPERO, number CRD420261296728. FINDINGS:Our search screened 4708 studies. 67 reassessed and 95 newly identified articles, reporting on 316 131 participants and 11 822 people with UIAs, were included in our meta-analysis. In the reference population, the estimated prevalence of UIAs was 3·9% (95% CI 3·0-5·1). The prevalence of UIAs in individuals with atherosclerosis was 5·5% (4·7-6·4; 2229 of 40970 participants) and the adjusted PR was 1·3 (95% CI 0·8-2·0) compared with the reference population. For positive family history of aneurysmal subarachnoid haemorrhage (aSAH) or UIA, the UIA prevalence was 7·9% (5·6-11·1; 412 of 4252 participants) and the adjusted PR was 2·4 (0·5-11·2). For connective-tissue disorder, the UIA prevalence was 10·3% (6·5-16·0; 94 of 879 participants) and the adjusted PR was 3·9 (2·0-7·6). For autosomal dominant polycystic kidney disease (ADPKD), the UIA prevalence was 12·8% (9·2-17·6; 293 of 1990 participants) and the adjusted PR was 4·4 (1·5-12·6). RRs were for current smoking 1·4 (1·2-1·6; 798 of 27911 participants), for having hypertension 1·6 (1·5-1·7, 4043 of 83053 participants), and for female sex 1·9 (1·8-2·0; 3415 of 65020 women and 2122 of 76130 men). In studies on healthy individuals with MR angiography or CT angiography as imaging modality, the prevalence in 2016-2022 was 6·6% (6·3-6·8; 2904 of 41191 participants). The adjusted PR was 1·8 (1·1-2·8) for 2016-2022 versus 2002-2015. Prevalence of UIAs of 5 mm or larger was 0·7% (0·6-0·8) in 2002-2015 and 1·4% (1·0-1·9) in 2016-2022. The UIA prevalence did not differ between countries. τ2 showed significant heterogeneity between studies. The certainty of the evidence ranged from very low to moderate. INTERPRETATION:Prevalence of UIA is increasing, particularly over the past two decades. This increase is only in part explained by improved detection of small UIAs and an ageing population, and other factors-such as environmental-are likely involved. Alongside patients with ADPKD and a positive family history of aSAH, patients with connective-tissue disorders had a higher prevalence of UIA than the reference population. Our findings warrant further investigation into the potential benefit of personalised screening and management strategies in groups at high risk for having UIAs. FUNDING:None.
BACKGROUND:The clinical potential of orexin 2 receptor (OX2R) agonism for improving measures of wakefulness and cataplexy in patients with narcolepsy type 1 has been described in a phase 2 study. Here, we aimed to evaluate the safety, tolerability, and efficacy of alixorexton, another oral OX2R agonist, in narcolepsy type 1. METHODS:In this randomised, double-blind, placebo-controlled, phase 2 trial, adult participants (aged 18-70 years) with narcolepsy type 1 were recruited from 46 hospitals and private research centres across the USA, Europe, and Australia. Participants were centrally randomly assigned (1:1:1:1) in blocks of four via an interactive response technology system stratified by region and baseline weekly cataplexy rate (WCR) to receive 4 mg, 6 mg, or 8 mg tablets of alixorexton or placebo once daily for 6 weeks, followed by an optional 7-week open-label extension. Participants had narcolepsy type 1, diagnosed per the International Classification of Sleep Disorders, Third Edition, and confirmed by overnight polysomnography and the Multiple Sleep Latency Test or cerebrospinal hypocretin-1 concentrations. The sponsor, assessors, investigators, and participants were masked during the randomised double-blind treatment period. Efficacy and safety assessments were conducted in participants who received at least one dose of study drug. The primary endpoint was change from baseline to week 6 in mean sleep latency (MSL) on the Maintenance of Wakefulness Test (MWT). Safety endpoints included treatment-emergent adverse events. This trial was registered with ClinicalTrials.gov (NCT06358950) and is completed. FINDINGS:Between May 24, 2024, and May 5, 2025, 153 individuals were screened and 92 participants were randomly assigned to receive alixorexton 4 mg (n=23), 6 mg (n=22), 8 mg (n=24), or placebo (n=23). Mean age was 33·5 years (SD 12·1), 57 (62%) were women, and 35 (38%) were men. At week 6, the observed MSL on the MWT was 2·3 min (SD 2·7) for placebo, 24·0 min (8·7) for alixorexton 4 mg, 25·9 min (9·4) for 6 mg, and 28·2 min (11·4) for 8 mg. Alixorexton improved MSL on the MWT, with a least-squares mean placebo-corrected change from baseline of 22·2 min (95% CI 17·2-27·2) for alixorexton 4 mg, 24·1 min (19·0-29·1) for 6 mg, and 26·0 min (21·0-31·0) for 8 mg (adjusted p=0·0099 for 4 mg, adjusted p<0·0001 for 6 mg and 8 mg). Treatment-emergent adverse events occurring in at least 5% of participants given alixorexton and more frequently than those given placebo up to week 6 were pollakiuria (38 [55%]), insomnia (19 [28%]), salivary hypersecretion (17 [25%]), micturition urgency (ten [14%]), blurred vision (ten [14%]), and hyperhidrosis (five [7%]). INTERPRETATION:In this phase 2 trial, once-daily oral alixorexton provided clinically meaningful improvements at 6 weeks for participants with narcolepsy type 1, including in wakefulness, excessive daytime sleepiness, and cataplexy. The treatment was generally well tolerated, with adverse events consistent with the known on-target effects of OX2R agonists. Together, these findings support the further phase 3 evaluation of alixorexton as a potential therapeutic option for people with narcolepsy type 1. FUNDING:Alkermes.
Bradycardia due to cardiac conduction abnormalities is prevalent in patients with dementia with Lewy bodies possibly due to autonomic dysfunction and neurodegeneration. Cholinesterase inhibitors remain the most effective treatment for cognitive and neuropsychiatric symptoms in patients with dementia with Lewy bodies, but are often withheld due to concerns of potentially worsening cardiac risk. Randomised clinical trials and meta-analysis evidence support a favourable cardiac safety profile for cholinesterase inhibitors in dementia with Lewy bodies. Emerging evidence challenges the conventional avoidance of cholinesterase inhibitors in patients who have dementia with Lewy bodies and cardiac abnormalities, and suggests that these patients can also be treated with cholinesterase inhibitors without increasing the risk of major cardiovascular events. Integrating available evidence with a pragmatic, expert-informed approach, and cardiac screening and monitoring, can enable patients with dementia with Lewy bodies and cardiac abnormalities to benefit from cholinesterase inhibitors.
BACKGROUND:Poor fetal growth is a major cause of perinatal morbidity and mortality and predisposes individuals to chronic diseases in adulthood. Antiseizure medication use in pregnancy has been linked with poor fetal growth, but this association has received little attention and its multifaceted aspects remain unclear. We investigated the risk of poor fetal growth in infants exposed prenatally to antiseizure monotherapy versus polytherapy, across different antiseizure monotherapies, and across common antiseizure medication combinations. METHODS:This prospective, observational, longitudinal cohort study was based on singleton livebirths of women (aged 14-55 years at conception) with epilepsy on antiseizure medication and enrolled at any point in pregnancy into the International Registry of Antiepileptic Drugs and Pregnancy (EURAP) between June 20, 1999, and Nov 15, 2023. Follow-up data were acquired after each trimester and at delivery. Multivariable models were used to assess the association of antiseizure medication exposures with different fetal growth indicators: birthweight centile (primary outcome); small for gestational age (SGA; birthweight <10th centile for gestational age); severe SGA (birthweight <3rd centile); and low birthweight (<2500 g). Models were adjusted for a wide range of clinical and demographic factors that could influence the association between antiseizure medication exposure and poor fetal growth. FINDINGS:The primary outcome analysis included 15 893 offspring prenatally exposed to antiseizure medications (12 911 exposed to monotherapy and 2982 to polytherapy). The other analyses were limited to one offspring per mother and included 13 728 offspring (11 142 exposed to monotherapy and 2586 to polytherapy). Compared with offspring exposed to monotherapy, those exposed to polytherapy had a lower birthweight centile (adjusted unstandardised model coefficient [b] -2·74 [95% CI -4·22 to -1·26]) and an approximately 50% higher risk of SGA (adjusted odds ratio [OR] 1·48 [95% CI 1·29 to 1·70]), severe SGA (1·49 [1·22 to 1·83]), and low birthweight (1·50 [1·15 to 1·95]). Birthweight centile decreased with increasing number of concomitant antiseizure medications (adjusted b -14·18 [95% CI -24·07 to -4·29] with four antiseizure medications [n=48] relative to monotherapy). Among monotherapies, birthweight centile was lower (in decreasing order) with topiramate (adjusted b -11·93 [95% CI -16·72 to -7·15], n=248), phenobarbital (-8·08 [-11·89 to -4·26], n=431), oxcarbazepine (-5·10 [-8·24 to -1·96], n=557), carbamazepine (-3·15 [-5·01 to -1·28], n= 2797), valproic acid (-2·54 [-4·50 to -0·58], n=1829), and levetiracetam (-2·51 [-4·38 to -0·63], n=1809) compared with lamotrigine (n=4672). Offspring exposed to carbamazepine and levetiracetam in combination (n=173) had a lower birthweight centile (adjusted b -6·27 [95% CI -12·03 to -0·50]) than those exposed to lamotrigine monotherapy. No differences in birthweight centile were found between offspring exposed to lamotrigine monotherapy and those exposed to lamotrigine in combination with either levetiracetam (adjusted b 0·19 [95% CI -2·67 to 3·06], n=470) or valproic acid (0·11 [-3·59 to 3·82], n=258). INTERPRETATION:In addition to congenital malformations and neurodevelopmental effects, poor fetal growth should be regarded as an important adverse outcome of prenatal antiseizure medication exposure. Risk varies across individual antiseizure monotherapies and specific antiseizure combinations and increases with the number of concomitant antiseizure medications. These findings have important implications for preconception counselling and management, including risk prediction and individualised treatment selection. FUNDING:Brain Australia, Neurological Foundation of New Zealand, Norman Beischer Medical Research Foundation, Weary Dunlop Medical Research Foundation.
BACKGROUND:Vanishing white matter is a neurodegenerative disease with onset mostly in children aged 1-6 years that causes early death and has no effective therapy. The disease is caused by a genetic defect affecting eukaryotic initiation factor 2B, a key regulator of the integrated stress response. The α2-adrenergic antihypertensive drug guanabenz inhibits this stress response and has shown benefit in a mouse model of the disease. We aimed to assess the safety, tolerability, and efficacy of guanabenz in young children with vanishing white matter. METHODS:This single-arm, phase 1/2 trial was conducted at the Amsterdam University Medical Center, Amsterdam, Netherlands, with international recruitment. Eligible patients had a diagnosis of vanishing white matter, confirmed by MRI and genetic testing; were aged 6 years or younger at disease onset; had a disease duration of 8 years or less; and were still able to walk at least ten steps with, at most, the light support of one hand. Oral guanabenz was started at a dose of 0·15 mg/kg per day and titrated over approximately 6 weeks to the maximum tolerated dose, with an optimum (target) dose of 2 mg/kg per day. Trial duration was 4 years with minimum follow-up of 1 year. The primary safety objective was to evaluate the safety and tolerability of guanabenz in the intention-to-treat population, defined as all patients for whom informed consent was provided and who received at least their first dose of guanabenz. The primary efficacy outcome was the time to loss of walking with support. Patients were matched (1:2, without replacement) to untreated historical controls from the Vanishing White Matter Registry, on the basis of a similar age of onset and similar disability at the same disease duration as the patient. Groups were compared using Kaplan-Meier curves, log-rank tests, and hazard ratios (HRs) estimated using Cox proportional hazards models with treatment group and year of onset as covariates. The study was registered with the EU Clinical Trials Register (2017-001438-25) and the EU Clinical Trials Information System (2023-503320-89-00). FINDINGS:Between May 31, 2021 and May 31, 2024, 33 patients were screened, found eligible, and enrolled, of whom 31 completed the trial. The median age of patients was 5·4 years (IQR 3·6-7·9), the median age of disease onset was 3·1 years (IQR 2·1-4·5), and the median treatment duration was 3·1 years (IQR 2·4-3·6). 63 serious adverse events were reported in 25 (76%) of 33 patients. 30 (48%) of these 63 events were judged likely or very likely to be related to guanabenz, of which 28 were classified as suspected unexpected serious adverse reactions. 24 of these reactions were hallucinations, occurring in 18 (55%) of 33 patients; these occurred intermittently, occurred mostly within the first 4 months of treatment, and mostly resolved within 4 months after the first event. The remaining four reactions-three of constipation of unexpected severity and one of transient hypotension with sedation-each required brief hospital admission and resolved. After the initial 4-6 months, guanabenz was well tolerated and no patients discontinued the study because of side-effects. After titration, four small dose reductions were applied, but there were no dose interruptions. No life-threatening events or deaths occurred. The 33 patients treated with guanabenz had a significantly lower risk of losing the ability to walk with support than the 66 historical controls (HR 0·33 [95% CI 0·16-0·69]; log-rank p=0·0061). INTERPRETATION:Guanabenz treatment had an acceptable and manageable safety profile and, after the initial phase, was well tolerated in children with vanishing white matter. Treated patients with disease onset at age 6 years or younger, who were still ambulant at baseline, had a significantly lower risk of losing the ability to walk with support than did matched historical controls, although this was a non-randomised comparison. The disease-modifying effect of guanabenz should be confirmed in a long-term extension study. FUNDING:ZonMw, Nederlandse Hersenstichting, European Leukodystrophy Association, and the VWM Families Foundation.
Chronic subdural haematoma is associated with increased frailty, comorbidities including dementia, and a higher risk of mortality compared to age-matched controls, with incidence rising as populations age. Burr holes have long been considered the mainstay of surgical treatment for chronic subdural haematoma, but novel therapies are seeking to expand treatment beyond surgical burr hole drainage. Since 2020, several high-quality clinical trials have helped refine operative strategies, provided robust evidence against the routine use of steroids, and investigated minimally invasive treatment with middle meningeal artery embolisation. One treatment approach does not fit all patients, and stratification using risk factors for poor outcome might prove crucial in maximising benefit from adjuvant therapies such as middle meningeal artery embolisation. Results of further trials of middle meningeal artery embolisation and drug trials are awaited, and increased recognition of the need for multispecialist care should also help to improve outcomes for patients with chronic subdural haematoma in the future.
