Cerebral Arteriopathy Research Articles

Evolution of Extracranial Internal Carotid Artery Disease in Children With Sickle Cell Anemia.

Cerebral arteriopathy in patients with sickle cell anemia mainly affects the intracranial anterior circulation. However, the extracranial internal carotid artery (eICA) can also be stenosed and responsible for ischemic lesions. In children with sickle cell anemia, we perform routine annual Doppler ultrasound assessment of the eICA and magnetic resonance imaging with 3-dimensional time-of-flight magnetic resonance angiography of the Willis circle and neck arteries in those with abnormal velocity. Our aim was to report the evolution of eICA stenoses from 2011 to the present as a function of therapy in a retrospective case-series study. We hypothesized that chronic transfusion (CTT) would be more effective than hydroxyurea and simple observation on the evolution of eICA stenosis. Eligibility criteria were a history of eICA velocity ≥160 cm/s with a minimum Doppler and magnetic resonance imaging follow-up of 1 year. eICAs were graded for stenosis according to NASCET (The North American Symptomatic Carotid Endarterectomy Trial). Magnetic resonance imaging was investigated for ischemic lesions. Treatment with hydroxyurea and CTT were obtained from the chart review. Fifty-four patients were included. Eight patients had a stroke history. The median (range) follow-up was 4.7 years (1.1-9.2 years). On the first neck magnetic resonance angiography, stenosis was present in 48/54 (89%) patients. Kinking was found in 39/54 (72%) patients. On the last neck magnetic resonance angiography, the proportion of patients with eICA stenosis decreased to 39/54 (72%). ICA occlusion occurred in 5 patients despite CTT. Three patients had carotid webs without intracranial stenosis. The proportion of patients with improvement in stenosis score was 8% with no treatment intensification, 20% with hydroxyurea, and 48% with CTT (P=0.016). The mean (SD) change per year in stenosis score was 0.40 (0.60) without intensification, 0.20 (0.53) with hydroxyurea, and -0.18 (0.55) with CTT (P=0.006). Ischemic lesions were present initially in 46% of patients, and the incidence of progressive ischemic lesions was 2.5 events/100 patient-years. Cox regression analysis showed that the initial score for eICA stenosis was a significant predictive factor for the risk of new silent cerebral infarct events. Our study reinforces the need to assess cervical arteries for better prevention of cerebral ischemia and encourage initiation of CTT in sickle cell anemia children with eICA stenosis.

International Prevalence and Mechanisms of SARS-CoV-2 in Childhood Arterial Ischemic Stroke During the COVID-19 Pandemic.

Background:Data from the early pandemic revealed that 0.62% of children hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had an acute arterial ischemic stroke (AIS). In a larger cohort from June 2020 to December 2020, we sought to determine whether our initial point estimate was stable as the pandemic continued and to understand radiographic and laboratory data that may clarify mechanisms of pediatric AIS in the setting of SARS-CoV-2.Methods:We surveyed international sites with pediatric stroke expertise to determine numbers of hospitalized SARS-CoV-2 patients <18 years, numbers of incident AIS cases among children (29 days to <18 years), frequency of SARS-CoV-2 testing for children with AIS, and numbers of childhood AIS cases positive for SARS-CoV-2 June 1 to December 31, 2020. Two stroke neurologists with 1 neuroradiologist determined whether SARS-CoV-2 was the main stroke risk factor, contributory, or incidental.Results:Sixty-one centers from 21 countries provided AIS data. Forty-eight centers (78.7%) provided SARS-CoV-2 hospitalization data. SARS-CoV-2 testing was performed in 335/373 acute AIS cases (89.8%) compared with 99/166 (59.6%) in March to May 2020, P<0.0001. Twenty-three of 335 AIS cases tested (6.9%) were positive for SARS-CoV-2 compared with 6/99 tested (6.1%) in March to May 2020, P=0.78. Of the 22 of 23 AIS cases with SARS-CoV-2 in whom we could collect additional data, SARS-CoV-2 was the main stroke risk factor in 6 (3 with arteritis/vasculitis, 3 with focal cerebral arteriopathy), a contributory factor in 13, and incidental in 3. Elevated inflammatory markers were common, occurring in 17 (77.3%). From centers with SARS-CoV-2 hospitalization data, of 7231 pediatric patients hospitalized with SARS-CoV-2, 23 had AIS (0.32%) compared with 6/971 (0.62%) from March to May 2020, P=0.14.Conclusions:The risk of AIS among children hospitalized with SARS-CoV-2 appeared stable compared with our earlier estimate. Among children in whom SARS-CoV-2 was considered the main stroke risk factor, inflammatory arteriopathies were the stroke mechanism.

Carotid artery dissection in Hutchinson-Gilford Progeria: a case report

BackgroundStrokes in the paediatric age group have their own epidemiology and aetiology and are frequently misdiagnosed. As in the adult population, they present some risk factors that must be identified. Cerebral arteriopathies as a cause of paediatric ischaemic stroke present a very diverse aetiology and morphology.In this article we report a paediatric stroke in a patient who was diagnosed during his first months of life of Hutchinson-Gilford´s Progeria (HGP). This is a rare genetic condition caused by mutations in the LMNA gene, producing an aberrant lamin A protein. The disease leads to premature aging, and cardiovascular complications are the first cause of morbidity and mortality in these patients.Case presentationWe report the case of a 5-year-old patient with HGP (missense mutation—de novo—c.1822G > A in heterozygosis, LMNA gene). The patient was diagnosed during his first year of life and presented distinct phenotypical features. No other relevant comorbidities were present.He was admitted to the emergency department for right hemiparesis with at least 4 h of evolution, with inability to open the hand and slight decrease in the level of consciousness (pedNIHSS 5–6). Cranial-CT and angio-CT showed findings indicative of left carotid dissection. Consensus was reached on conservative medical management with anticoagulation and antiplatelet therapy. In the first few days, the patient had a favourable evolution with resolution of the right lower limb hemiparesis and, one month after discharge, of the hand paresis.ConclusionsThe clinical manifestations, the vascular phenotype of the genetic mutation and the location of the radiological signs on a specific vascular morphology are indicative of carotid dissection. Spontaneous dissections occur under a predisposing risk factor or disease and are an exceptional finding in patients with HGP.

Triple bypass for multisystem smooth muscle dysfunction syndrome due to Arg179His ACTA2 mutation

Missense mutations in the smooth muscle-specific isoform of the alpha-actin (ACTA2) gene, which encodes smooth muscle actin, congenitally cause systemic smooth muscle dysfunction, leading to multiple systemic smooth muscle dysfunction syndrome. This disease is often diagnosed through the development of congenital mydriasis, patent ductus arteriosus, or thoracic aortic aneurysm at a young age. Some patients develop cerebrovascular lesions, also known as ACTA2 cerebral arteriopathy, which cause ischemic stroke and require surgical revascularization. However, an effective and safe treatment has not yet been established owing to the rarity of the disease. Furthermore, most reports of this disease involve children, with only a few reports on adults and few detailed reports on treatment outcomes published to date. We report a 46-year-old woman with ACTA2 cerebral arteriopathy caused by Arg179His, the most common mutation in this disease; she is the oldest patient reported with this disease to the best of our knowledge. The patient was diagnosed with multiple systemic smooth muscle dysfunction syndrome and ACTA2 cerebral arteriopathy after experiencing a stroke in the right cingulate gyrus. She underwent direct triple bypass with three anastomoses of the right superficial temporal artery to the middle and anterior cerebral arteries. She developed an ischemic stroke as a postoperative complication.The efficacy and safety of this procedure have not been clearly confirmed owing to the frailty of the donor superficial temporal artery and the poor development of collateral circulation; however, direct bypass should be considered a treatment option for patients experiencing progressive multiple strokes.

Recanalization treatment for pediatric acute ischemic stroke: a nationwide french registry

There's to date no solid evidence that revascularization strategies improve functional outcome in children. In this study of consecutive children with AIS stroke patients treated with intravenous thrombolysis (IVT) and, or endovascular treatment (EVT) we aimed to provide up to date estimates of revascularization strategies’ safety and efficacy profiles in the pediatric population. The French KIDCLOT multicentric nationwide retrospective study (NCT03887143) collected data of consecutive children aged >28 days and <18 years old with acute ischemic stroke who had a recanalization treatment between January 1rst 2015 and May 31rst 2018. Overall, 68children from 30 participating centers were analyzed including 24 girls (35.3%), with a mean age at stroke onset of 10.1 ± 5.7 years old. IVT was administered in 44 patients (64.7%) and EVT was performed in 40 children (58.8%). Mean pedNIHSS at admission was 13.1 ± 6.1 overall and was higher in patients treated with MT (15.6 ± 6.2 vs 10.6 ± 6, p<0.01). Mean time from stroke onset to imaging was higher in patients treated with MT (286.5 ± 244.2 vs 189 ± 97.6, p=0.03). AIS was due to an anterior circulation occlusion in 57 children (83.8%). Median [IQR] admission ASPECTS score was 8 [7–9] and did not differ significantly between patients treated with or without MT. Main stroke etiologies were cardio-embolic (30.9%), focal cerebral arteriopathy (FCA, 25%). Mean time from onset to IVT was 201.7 ± 73 overall and was higher in patients treated with MT (231,8±52,6 vs 174,6±76,2 p=0,02). In MT patients, the rate of successful reperfusion (≥mTICI 2b) was 80% (32/40). Persistent proximal arterial stenosis on final DSA images was significantly more frequent in FCA cases (p<0,01). Death was observed in 3 patients (4.4%), all within the first week. Mean pedNIHSS improvement at 24 hours was 4.2 ± 6.9 overall, slightly but not significantly better in the MT group (5.1 ± 7 vs 3.4 ± 6.9 p=0.34). In the MT group, one patient suffered of intracranial arterial perforation, and one other of embol in a new territory. ICH and SICH were observed in four and one patients respectively, all in the MT group. The median mRS score at 3 months was 2 (IQR, 0-3) and further improved to 1 (IQR, 0-2) after 12 months, not different between MT and no-MT group. This study provides encouraging safety data in a population of AIS children treated with either IVT, EVT or both. One-year neurological outcome was good in three quarter of the study sample. EVT is feasible with rates of successful revascularization and procedural duration of similar magnitude to those found in adult populations (references 1 to 5)

Impact of Brain MRI Markers on Major and Mild Vascular Cognitive Impairment in CADASIL

Background: Cognitive impairment is the second most common clinical manifestation in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). However, understanding of cognitive impairment in CADASIL has been hampered by lack of consensus on diagnosis of vascular cognitive impairment (VCI). We used vascular impairment of cognition classification consensus study principles (VICCCS-1) and protocols (VICCCS-2) to assess the cognitive impairment in CADASIL. We also evaluated the impact of MRI markers on major and mild VCI in CADASIL.Methods: We prospectively recruited 64 patients who underwent standardized brain MRI and detailed neuropsychological test. MRI analysis included number of lacunes, number of cerebral microbleeds (CMB), normalized volume of white-matter hyperintensities (nWMH), and brain parenchymal fraction (BPF). BPF has been used to measure brain atrophy. The patients were divided into three groups: those with normal cognition (CADASIL-NC, n=14), those with mild VCI (CADASIL-mild VCI, n=38), and those with major VCI (CADASIL-major VCI, n=11).Results: The three groups differed according to age, with the major VCI group being older. The major VCI group had more lacunes, more CMB, more extensive white matter lesions and lower BPF than NC group. There were no significant differences between NC and mild VCI groups in BPF. BPF and age were the independent predictors of major VCI. There was a tendency that women were at higher risk for mild VCI, though it did not reach statistical significance. Women were older than men, but had lower number of lacunes in mild VCI.Conclusions: These findings suggest that brain atrophy and age are the main predictors of major VCI in CADASIL.

CADASIL in the Differential Diagnosis of Atypical Parkinsonism. Case Report

Autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease caused by mutations in the NOTCH3 gene. The clinical spectrum includes migraine, transient ischemic attacks and/or recurrent strokes, and cognitive impairment. The presence of signs and symptoms of Parkinsonism are poorly described in the phenotype of this disease. This case report was approved by the Ethics Committee of Universidade Metropolitana de Santos. Case Report: The present case refers to a 59-year-old female patient presenting with recurrent transient ischemic attacks, chronic migraine, depression and bilateral akinetic-rigid parkinsonism. Brain MRI showed diffuse and confluent lesions. The genetic study showed a de novo heterozygous pathogenic variant in the NOTCH3 gene. Symptomatic treatment with multiprofessional rehabilitation was instituted with partial improvement of symptoms.

Abstract WP176: Compared To Catheter Angiogram MRA Is A Moderate Predictor Of Suzuki Grade In Children With Moyamoya

Introduction: Moyamoya is a progressive cerebral arteriopathy affecting the arteries in the circle of Willis. Suzuki grade for moyamoya using catheter angiogram has been gold standard for the evaluation of moyamoya both in children and adults. Suzuki grade evaluates the amount of stenosis and collateral formation in the cerebral arteries. Magnetic resonance angiography (MRA) non-luminal imaging can overestimate stenosis and underestimate collaterals. With greater use of MRA for diagnosis and follow-up, it is important to understand MRA staging is truly comparable to catheter angiogram. Methods: Study neurologist and interventional radiologist reviewed both catheter angiograms and MRAs without clinical information. The modified Suzuki stage was used to evaluate the MRA. Median time from MRA to catheter angiogram was calculated. Cohen’s Kappa was used to compare modalities of Suzuki grade based on catheter angiogram to modified Suzuki grade by MRA on the same patients. Results: A total of 29 patients with moyamoya were reviewed. Median time between MRA and catheter angiogram was 2.4 months with interquartile range from 0.6-5.3 months. Unweighted Cohen’s Kappa was 0.34 (p&lt;0.0001) which is considered fair correlation. When we calculated a weighted Cohen’s Kappa it improved but only to 0.49 (p&lt;0.0001) which is moderate correlation. Conclusion: Using Cohen’s kappa to compare two methods of evaluating cerebral artery stenosis in children with moyamoya, we demonstrated that there is only moderate correlation between catheter angiogram Suzuki staging compared to modified Suzuki staging with MRA. In conclusion, we suggest caution in the reliance of MRA for diagnosis and follow-up of children with moyamoya. We recommend consideration catheter angiograms at time of diagnosis and with surgical planning.

Abstract 63: Recanalization Treatments In Pediatric Stroke: Safety And Efficacy Data Issued From The French KidClot Study

Background: Safety and efficacy of recanalization treatments, i.e. intravenous thrombolysis (IVT) and/or mechanical thrombectomy (MT), have to be refined in pediatric stroke. Methods: The French KIDCLOT multisourcing nationwide retrospective study (NCT03887143) collected data of consecutive children aged &gt;28 days and &lt;18 years old with acute arterial ischemic stroke who had a recanalization treatment, during a 41 month-period. Results: 68 patients, 44 boys (64.7%), median age at stroke onset 11.5 years old, were included. Pre-stroke mRS was 0 for 89.7%. Main stroke etiologies were cardio-embolic (30.9%), focal cerebral arteriopathy (FCA, 25%), cervical (carotid/vertebral) arteriopathy (13.2%), and thrombotic (11.8%). 70 pediatric procedures were recorded: IVT alone (n=31), MT alone (n=23), combined IVT and MT (n=14), and DSA without recanalization treatment (n=4). Median stroke onset to first recanalization treatment delay was shorter in adult stroke units than in pediatric wards (188 vs. 264 minutes respectively, p=0.0087). An early complication was reported for 6 procedures, including two significant intracranial hemorrhages. After MT, cardio-embolic stroke patients achieved good arterial recanalization more frequently than FCA patients (88.9% vs 33.3%). Although high initial severity markers (median NIHSScore=13.5, decreased consciousness in 52.2%, decompressive craniectomy in 17.1%), outcome was relatively good in the 65/68 survivors (median mRS=1 and PSOM=1.2 at 12 month-follow-up). Conclusions: This study provides encouraging safety data despite severe stroke presentations. It suggests potential ways to improve recanalization treatments efficacy in children: reducing management delays in pediatric wards and optimizing etiological orientation since the hyperacute phase, as cardio-embolic strokes seem to display a better recanalization rate profile.

Proteomic profiling in cerebral amyloid angiopathy reveals an overlap with CADASIL highlighting accumulation of HTRA1 and its substrates

Cerebral amyloid angiopathy (CAA) is an age-related condition and a major cause of intracerebral hemorrhage and cognitive decline that shows close links with Alzheimer's disease (AD). CAA is characterized by the aggregation of amyloid-β (Aβ) peptides and formation of Aβ deposits in the brain vasculature resulting in a disruption of the angioarchitecture. Capillaries are a critical site of Aβ pathology in CAA type 1 and become dysfunctional during disease progression. Here, applying an advanced protocol for the isolation of parenchymal microvessels from post-mortem brain tissue combined with liquid chromatography tandem mass spectrometry (LC–MS/MS), we determined the proteomes of CAA type 1 cases (n = 12) including a patient with hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), and of AD cases without microvascular amyloid pathology (n = 13) in comparison to neurologically healthy controls (n = 12). ELISA measurements revealed microvascular Aβ1-40 levels to be exclusively enriched in CAA samples (mean: > 3000-fold compared to controls). The proteomic profile of CAA type 1 was characterized by massive enrichment of multiple predominantly secreted proteins and showed significant overlap with the recently reported brain microvascular proteome of patients with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary cerebral small vessel disease (SVD) characterized by the aggregation of the Notch3 extracellular domain. We found this overlap to be largely attributable to the accumulation of high-temperature requirement protein A1 (HTRA1), a serine protease with an established role in the brain vasculature, and several of its substrates. Notably, this signature was not present in AD cases. We further show that HTRA1 co-localizes with Aβ deposits in brain capillaries from CAA type 1 patients indicating a pathologic recruitment process. Together, these findings suggest a central role of HTRA1-dependent protein homeostasis in the CAA microvasculature and a molecular connection between multiple types of brain microvascular disease.

COVID-19 and a Mysterious Case of Transient Cerebral Arteriopathy.

COVID-19 and a Mysterious Case of Transient Cerebral Arteriopathy.

Monogenic Causes of Strokes.

Strokes are the main cause of death and long-term disability worldwide. A stroke is a heterogeneous multi-factorial condition, caused by a combination of environmental and genetic factors. Monogenic disorders account for about 1% to 5% of all stroke cases. The most common single-gene diseases connected with strokes are cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) Fabry disease, mitochondrial myopathy, encephalopathy, lactacidosis, and stroke (MELAS) and a lot of single-gene diseases associated particularly with cerebral small-vessel disease, such as COL4A1 syndrome, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), and Hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS). In this article the clinical phenotype for the most important single-gene disorders associated with strokes are presented. The monogenic causes of a stroke are rare, but early diagnosis is important in order to provide appropriate therapy when available.

Candesartan prevents arteriopathy progression in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy model.

Cerebral small vessel disease (CSVD) causes dementia and gait disturbance due to arteriopathy. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a hereditary form of CSVD caused by loss of high-temperature requirement A1 (HTRA1) serine protease activity. In CARASIL, arteriopathy causes intimal thickening, smooth muscle cell (SMC) degeneration, elastic lamina splitting, and vasodilation. The molecular mechanisms were proposed to involve the accumulation of matrisome proteins as substrates or abnormalities in transforming growth factor β (TGF-β) signaling. Here, we show that HTRA1-/- mice exhibited features of CARASIL-associated arteriopathy: intimal thickening, abnormal elastic lamina, and vasodilation. In addition, the mice exhibited reduced distensibility of the cerebral arteries and blood flow in the cerebral cortex. In the thickened intima, matrisome proteins, including the hub protein fibronectin (FN) and latent TGF-β binding protein 4 (LTBP-4), which are substrates of HTRA1, accumulated. Candesartan treatment alleviated matrisome protein accumulation and normalized the vascular distensibility and cerebral blood flow. Furthermore, candesartan reduced the mRNA expression of Fn1, Ltbp-4, and Adamtsl2, which are involved in forming the extracellular matrix network. Our results indicate that these accumulated matrisome proteins may be potential therapeutic targets for arteriopathy in CARASIL.

Clinical and Molecular Genetic Findings of Cerebral Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

Clinical and Molecular Genetic Findings of Cerebral Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

Automated Perfusion-Diffusion Magnetic Resonance Imaging in Childhood Arterial Ischemic Stroke.

Recent studies using automated perfusion imaging software have identified adults most likely to benefit from reperfusion therapies in extended time windows. The time course of penumbral tissue is poorly characterized in childhood arterial ischemic stroke (AIS). We explore the feasibility of using automated perfusion-diffusion imaging software to characterize penumbra in childhood AIS. An observational cohort study of children with acute unilateral AIS presenting to our institution. Diffusion-weighted imaging and dynamic susceptibility contrast perfusion magnetic resonance imaging performed within 72 hours of symptom onset were necessary for inclusion. Perfusion-diffusion mismatch was estimated using RAPID software. Ischemic core was defined as apparent diffusion coefficient <620×10−6 mm2/s and hypoperfusion as Tmax >6 seconds. Favorable mismatch profile was defined as core volume <70 mL, mismatch volume ≥15 mL, and a mismatch ratio ≥1.8. Twenty-nine children (median 8 years old, interquartile range, 4.4–14.6) were included (26 unilateral middle cerebral artery and 3 unilateral cerebellar infarcts). Median Pediatric National Institutes of Health Stroke Scale was 4 (interquartile range, 3–11). Most cases had cryptogenic (n=11) or focal cerebral arteriopathy (n=9) causes. Median time-to-imaging =13.7 hours (interquartile range, 7.5–25.3). RAPID detected an ischemic core in 19 (66%) patients. In the remaining cases, the mean apparent diffusion coefficient values were mostly higher than the threshold as the majority of these presentations were delayed (median >21 hours) and infarct volumes were small (<3.5 mL). Overall, 3 children, imaged at 3.75, 11, and 23.5 hours had favorable mismatch profiles. This study demonstrates it is feasible to rapidly assess perfusion-diffusion mismatch in childhood AIS using automated software. Favorable mismatch profiles, using adult-based parameters, persisted beyond the standard 4.5 hours window for thrombolysis, suggesting potential therapeutic benefit of RAPID use. Further work is required to determine the utility of perfusion-based imaging to guide clinical decision making, whether adult thresholds require modification in childhood AIS, and to investigate the effect of time-delay and cause on mismatch characteristics.

Carasil and htra1: an early adulthood syndrome

Cerebral Autosomal Recessive Arteriopathy Subcortical Infracts Leukoencephalopathy (CARASIL), is an autosomal recessive disorder inherited by two copies of an abnormal gene from some trait, one from each parent. Person with this disorder may have a change in deep white matter in brain; and this disorder can be characterized by damage to small blood vessels in brain. Increasing muscle tone, slurred speech, stiff movement of legs, gait disturbance, spondylosis, sparse hair are the major symptoms. But the ultimate cause of this disorder can lead to loss of memory, cognitive impairment. This disorder can be caused in early adulthood i.e., between 20-40 years of age. CARASIL has first reported in Japan, later occurred in China and Caucasian population. A neurological disorder named Binswanger’s disease (BD) and chronic immunological disorder multiple sclerosis are main different alternation of this disease. Mutation requires the high temperature resultant, A serine peptidase 1 causes CARASIL, so it is a serine protease.&#x0D; Serine protease HTRA1 is an enzyme that in humans is encoded by HTRA1 gene. HTRA1 protein is composed of four distinct protein domains. This is located on the long (q) arm of chromosome 10 in a region known as 10q26. This protein is a secreted enzyme that is proposed to regulate the availability of insulin like growth factors (IGF) by cleaving IGF binding proteins. HTRA1 enzyme helps breakdown many other kinds of proteins in this space surrounding cells (extracellular matrix). This is attached to protein in Transforming Growth Factor Beta (TGF-beta) and slows down their ability to send chemical signals. Variant known as rs11200638 is found in an area of gene called promoter region which starts the production HTRA1 enzyme. It is unclear how of polymorphism in the HTRA1 gene might be an age-related macular degeneration.&#x0D; So at last, we can conclude that CARASIL is related to brain inherited from the abnormal genes caused to small arteries and to the specific area of deep brain in higher function; tissue loss due to lack of oxygen where small arteries get blocked destruction to myelin an oily substance covers and protects the nerve fibers in CNS.

CARASIL - A Review of Patients from India.

Cerebral small vessel disease (CSVD) is a well-known cause of vascular dementia. Though a majority of these cases are sporadic, familial monogenic causes are being frequently identified as well. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a rare autosomal recessive CSVD, caused by mutation in HTRA 1 gene on chromosome 10q (10q25.3-q26.2) in homozygous or compound heterozygous form. Indian literature has been quite scant with very few case reports of CARASIL, and only three familial cases were confirmed with mutational analysis. Testing facilities of HTRA 1 genetic mutation are now more widely available in India than before, and should be encouraged for appropriate patients. This would help in diagnosing, prognosticating and avoiding unnecessary further investigations and medications for these patients. We herein review the Indian scenario and our previously reported experiences of this disorder, while adding a case from north India with a befitting clinical history, family history, neuroimaging and documented HTRA1 genetic mutation.

Progression of central nervous system disease from pediatric to young adulthood in sickle cell anemia.

Silent cerebral infarcts and arteriopathy are common and progressive in individuals with sickle cell anemia. However, most data describing brain lesions in sickle cell anemia are cross-sectional or derive from pediatric cohorts with short follow-up. We investigated the progression of silent cerebral infarct and cerebral vessel stenosis on brain MRI and MRA, respectively, by describing the incidence of new or worsening lesions over a period of up to 25 years among young adults with sickle cell anemia and explored risk factors for progression. Forty-four adults with sickle cell anemia (HbSS or HbSβ0thalassemia), exposed to chronic transfusions (n = 12) or hydroxyurea (n = 32), median age 19.2 years (range 18.0-31.5), received a screening brain MRI/MRA and their results were compared with a clinical exam performed during childhood and adolescence. We used exact log-rank test to compare MRI and MRA progression among any two groups. The hazard ratio (HR) and 95% confidence interval (CI) were calculated from Cox regression analyses. Progression of MRI and MRA occurred in 12 (27%) and 4 (9%) young adults, respectively, relative to their pediatric exams. MRI progression risk was high among participants with abnormal pediatric exams (HR: 11.6, 95% CI: 2.5-54.7) and conditional or abnormal transcranial Doppler ultrasound velocities (HR: 3.9, 95% CI: 1.0-15.1). Among individuals treated with hydroxyurea, high fetal hemoglobin measured in childhood was associated with lower hazard of MRI progression (HR: 0.86, 95% CI: 0.76-0.98). MRA progression occurred more frequently among those with prior stroke (HR: 8.6, 95% CI: 1.2-64), abnormal pediatric exam (P = 0.00084), and elevated transcranial Doppler ultrasound velocities (P = 0.004). Brain MRI/MRA imaging in pediatrics can identify high-risk patients for CNS disease progression in young adulthood, prompting consideration for early aggressive treatments.

Viral mimetic triggers cerebral arteriopathy in juvenile brain via neutrophil elastase and NETosis

Stroke is among the top ten causes of death in children but has received disproportionally little attention. Cerebral arteriopathies account for up to 80% of childhood arterial ischemic stroke (CAIS) cases and are strongly predictive of CAIS recurrence and poorer outcomes. The underlying mechanisms of sensitization of neurovasculature by viral infection are undefined. In the first age-appropriate model for childhood arteriopathy—by administration of viral mimetic TLR3-agonist Polyinosinic:polycytidylic acid (Poly-IC) in juvenile mice—we identified a key role of the TLR3-neutrophil axis in disrupting the structural-functional integrity of the blood-brain barrier (BBB) and distorting the developing neurovascular architecture and vascular networks. First, using an array of in-vivo/post-vivo vascular imaging, genetic, enzymatic and pharmacological approaches, we report marked Poly-IC-mediated extravascular leakage of albumin (66kDa) and of a small molecule DiI (∼934Da) and disrupted tight junctions. Poly-IC also enhanced the neuroinflammatory milieu, promoted neutrophil recruitment, profoundly upregulated neutrophil elastase (NE), and induced neutrophil extracellular trap formation (NETosis). Finally, we show that functional BBB disturbances, NETosis and neuroinflammation are markedly attenuated by pharmacological inhibition of NE (Sivelestat). Altogether, these data reveal NE/NETosis as a novel therapeutic target for viral-induced cerebral arteriopathies in children.

Increased extracellular fluid is associated with white matter fiber degeneration in CADASIL: in vivo evidence from diffusion magnetic resonance imaging

BackgroundWhite matter hyperintensities (WMHs) are one of the hallmarks of cerebral small vessel disease (CSVD), but the pathological mechanisms underlying WMHs remain unclear. Recent studies suggest that extracellular fluid (ECF) is increased in brain regions with WMHs. It has been hypothesized that ECF accumulation may have detrimental effects on white matter microstructure. To test this hypothesis, we used cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) as a unique CSVD model to investigate the relationships between ECF and fiber microstructural changes in WMHs.MethodsThirty-eight CADASIL patients underwent 3.0 T MRI with multi-model sequences. Parameters of free water (FW) and apparent fiber density (AFD) obtained from diffusion-weighted imaging (b = 0 and 1000 s/mm2) were respectively used to quantify the ECF and fiber density. WMHs were split into four subregions with four levels of FW using quartiles (FWq1 to FWq4) for each participant. We analyzed the relationships between FW and AFD in each subregion of WMHs. Additionally, we tested whether FW of WMHs were associated with other accompanied CSVD imaging markers including lacunes and microbleeds.ResultsWe found an inverse correlation between FW and AFD in WMHs. Subregions of WMHs with high-level of FW (FWq3 and FWq4) were accompanied with decreased AFD and with changes in FW-corrected diffusion tensor imaging parameters. Furthermore, FW was also independently associated with lacunes and microbleeds.ConclusionsOur study demonstrated that increased ECF was associated with WM degeneration and the occurrence of lacunes and microbleeds, providing important new insights into the role of ECF in CADASIL pathology. Improving ECF drainage might become a therapeutic strategy in future.