Brachial and subclavian arteries aneurysms due to tuberous sclerosis complex mechanisms - case report and literature review.

INTRODUCTION: Tuberous sclerosis complex (TSC) is a rare autosomal dominant condition characterized by cutaneous, cerebral, and other multiorgan involvement. Aneurysms due to TSC pathogenic mechanism are rarely present, mainly aortic, renal, or intracranial and very few associated with peripheral circulation. A TSC patient, aged 31 years, who developed brachial and subclavian arteries aneurysms is presented. The question of a random association of the aneurysms with TSC versus aneurysms within pathogenic released mammalian target of rapamycin (mTOR) pathway effect was raised. CASE PRESENTATION: Patient's file, available from the age of six months, was analyzed for demonstration of the TSC diagnosis. Patient was examined, and cerebral magnetic resonance imaging (MRI) was repeated. Surgery and angiographic reports and images were reviewed. Pathology of the aneurysmal wall available from surgery was reexamined and special stainings and immunohistochemistry markers were applied. Genetic characterization of the patient was performed. Definite TSC was diagnosed based on major criteria [ungual fibromas, shagreen patch, cortical tubers, subependymal nodules (SENs), subependymal giant cell astrocytoma (SEGA)], minor criteria (confetti skin lesions, dental enamel pits, gingival fibromas), genetic result showing heterozygous variant in exon 8 of TSC1 gene (c.733C>T-p.Arg245*). Pathology analysis revealed markedly thickened aneurysmal wall due to smooth muscle cells (SMCs) proliferation in media and neoformation vessels with similar characteristics in the aneurysmal wall. DISCUSSIONS AND CONCLUSIONS: This is a rare case with aneurysms related to TSC, with an exceptional peripheral localization. Pathology exam is the key investigation in demonstrating the TSC-related pathogenic mechanism. A literature review showed 73 TSC cases presenting aneurysms published until now.

The gain of function SCN1A disorder spectrum: novel epilepsy phenotypes and therapeutic implications.

Brain voltage-gated sodium channel NaV1.1 (SCN1A) loss-of-function variants cause the severe epilepsy Dravet syndrome, as well as milder phenotypes associated with genetic epilepsy with febrile seizures plus. Gain of function SCN1A variants are associated with familial hemiplegic migraine type 3. Novel SCN1A-related phenotypes have been described including early infantile developmental and epileptic encephalopathy with movement disorder, and more recently neonatal presentations with arthrogryposis. Here we describe the clinical, genetic and functional evaluation of affected individuals. Thirty-five patients were ascertained via an international collaborative network using a structured clinical questionnaire and from the literature. We performed whole-cell voltage-clamp electrophysiological recordings comparing sodium channels containing wild-type versus variant NaV1.1 subunits. Findings were related to Dravet syndrome and familial hemiplegic migraine type 3 variants. We identified three distinct clinical presentations differing by age at onset and presence of arthrogryposis and/or movement disorder. The most severely affected infants (n = 13) presented with congenital arthrogryposis, neonatal onset epilepsy in the first 3 days of life, tonic seizures and apnoeas, accompanied by a significant movement disorder and profound intellectual disability. Twenty-one patients presented later, between 2 weeks and 3 months of age, with a severe early infantile developmental and epileptic encephalopathy and a movement disorder. One patient presented after 3 months with developmental and epileptic encephalopathy only. Associated SCN1A variants cluster in regions of channel inactivation associated with gain of function, different to Dravet syndrome variants (odds ratio = 17.8; confidence interval = 5.4-69.3; P = 1.3 × 10-7). Functional studies of both epilepsy and familial hemiplegic migraine type 3 variants reveal alterations of gating properties in keeping with neuronal hyperexcitability. While epilepsy variants result in a moderate increase in action current amplitude consistent with mild gain of function, familial hemiplegic migraine type 3 variants induce a larger effect on gating properties, in particular the increase of persistent current, resulting in a large increase of action current amplitude, consistent with stronger gain of function. Clinically, 13 out of 16 (81%) gain of function variants were associated with a reduction in seizures in response to sodium channel blocker treatment (carbamazepine, oxcarbazepine, phenytoin, lamotrigine or lacosamide) without evidence of symptom exacerbation. Our study expands the spectrum of gain of function SCN1A-related epilepsy phenotypes, defines key clinical features, provides novel insights into the underlying disease mechanisms between SCN1A-related epilepsy and familial hemiplegic migraine type 3, and identifies sodium channel blockers as potentially efficacious therapies. Gain of function disease should be considered in early onset epilepsies with a pathogenic SCN1A variant and non-Dravet syndrome phenotype.

Societal Cost of Ischemic Stroke in Romania: Results from a Retrospective County-Level Study.

BACKGROUND: Health policies in transitioning health systems are rarely informed by the economic burden of disease due to scanty access to data. This study aimed to estimate direct and indirect costs for first-ever acute ischemic stroke (AIS) during the first year for patients residing in Cluj, Romania, and hospitalized in 2019 at the County Emergency Hospital (CEH). METHODS: The study was conducted using a mixed, retrospective costing methodology from a societal perspective to measure the cost of first-ever AIS in the first year after onset. Patient pathways for AIS were reconstructed to aid in mapping inpatient and outpatient cost items. We used anonymized administrative and clinical data at the hospital level and publicly available databases. RESULTS: The average cost per patient in the first year after stroke onset was RON 25,297.83 (EUR 5226.82), out of which 80.87% were direct costs. The total cost in Cluj, Romania in 2019 was RON 17,455,502.7 (EUR 3,606,505.8). CONCLUSIONS: Our costing exercise uncovered shortcomings of stroke management in Romania, particularly related to acute care and neurorehabilitation service provision. Romania spends significantly less on healthcare than other countries (5.5% of GDP vs. 9.8% European Union average), exposing stroke survivors to a disproportionately high risk for preventable and treatable post-stroke disability.