Second cistron in CACNA1A gene encodes a transcription factor mediating cerebellar development and SCA6.

The CACNA1A gene, encoding the voltage-gated calcium channel subunit α1A, is involved in pre- and postsynaptic Ca(2+) signaling, gene expression, and several genetic neurological disorders. We found that CACNA1A coordinates gene expression using a bicistronic mRNA bearing a cryptic internal ribosomal entry site (IRES). The first cistron encodes the well-characterized α1A subunit. The second expresses a transcription factor, α1ACT, which coordinates expression of a program of genes involved in neural and Purkinje cell development. α1ACT also contains the polyglutamine (polyQ) tract that, when expanded, causes spinocerebellar ataxia type 6 (SCA6). When expressed as an independent polypeptide, α1ACT-bearing an expanded polyQ tract-lacks transcription factor function and neurite outgrowth properties, causes cell death in culture, and leads to ataxia and cerebellar atrophy in transgenic mice. Suppression of CACNA1A IRES function in SCA6 may be a potential therapeutic strategy.

Risk factors associated with in-hospital complications for pediatric sickle-cell disease-associated moyamoya syndrome: a nationwide cross-sectional study.

PURPOSE: Sickle-cell disease-associated moyamoya syndrome (SCD-MMS) carries a high risk for recurrent strokes and cerebrovascular morbidity in children. However, few data are available about complications that occur in children hospitalized with SCD-MMS. The purpose of this analysis was to determine the risk factors for in-hospital complications in pediatric SCD-MMS admissions, and thus aid physicians in optimizing future treatment plans. METHODS: A national database of pediatric hospital admissions was examined across the years 2003-2019. ICD-9 and ICD-10 diagnosis codes were analyzed to identify discharges with a primary diagnosis of SCD-MMS and identify in-hospital complications, defined as complication-associated diagnostic codes logged during the same admission. Patient demographics, comorbidities, and hospital characteristics were examined using univariate and multivariate logistic regression analyses to determine associations with in-hospital complications. RESULTS: In total, 274 admissions with a primary diagnosis of SCD-MMS were identified. During 64 (23.4%) admissions, transfusion therapy was given, and in 86 admissions (31.4%), surgical revascularization was performed. In 10 admissions (3.6%), a total of 11 in-hospital complications were identified. After multivariate regression, both comorbid chronic lung disease (adjusted OR 5.3 [1.1, 26.9], P = 0.04) and surgical revascularization (adjusted OR 10.2 [2.0, 52.4], P = 0.006) were associated with development of complications. CONCLUSIONS: In this nationwide database of pediatric SCD-MMS hospitalizations, comorbid chronic lung disease and surgical revascularization were associated with development of in-hospital complications. Patients with comorbid chronic lung disease or who are admitted for revascularization may warrant closer monitoring and greater medical optimization during the hospitalization.

Repeat Catheter Angiography in Patients with Aneurysmal-Pattern Angiographically Negative Subarachnoid Hemorrhage.

BACKGROUND: A significant proportion of patients with subarachnoid hemorrhage have a normal cerebral angiogram. Patients with angiographically negative subarachnoid hemorrhage (anSAH) with either perimesencephalic- (panSAH) or aneurysmal-pattern hemorrhage (aanSAH, also known as diffuse anSAH) have an excellent prognosis, but only if underlying vascular abnormalities are completely excluded. The rate of occult aneurysms in patients with aanSAH varies widely across studies. The purpose of this study was to quantify the value of repeat DSA in these patients. METHODS: We reviewed the records of all patients initially diagnosed with aanSAH after a screening DSA at a single tertiary neurovascular referral center from January 2006-April 2018. Patients with panSAH and traumatic SAH were excluded. We also performed a systematic review and meta-analysis of positive second DSAs in previously published case series of patients with aanSAH who underwent two serial DSAs. For meta-analysis, PubMed Central, MEDLINE and Cochrane Library databases were searched for pertinent studies up to November 2019. The rate of aneurysm detection on repeat angiography was extracted from each study. Pooled rates for positive second angiogram were calculated as untransformed proportions in a binary random-effects model meta-analysis. Inter-study heterogeneity was calculated using an I2 statistic. RESULTS: Three of 27 patients (11.1%) with aanSAH and at least two DSAs were subsequently found to have a cerebral aneurysm in our institutional dataset. Twenty-six studies in our systematic review met inclusion criteria, and the pooled rate of positive second angiogram was 10.4% (95% CI 7.3%-13.5%, P < 0.001). Substantial inter-study heterogeneity was observed in the meta-analysis (I2 = 61.7%, P < 0.001). CONCLUSIONS: One in 10 patients with aanSAH has an occult ruptured aneurysm. A second-look DSA should be strongly considered in these cases.

Location-based treatment of intracranial aneurysms in moyamoya disease: a systematic review and descriptive analysis.

We conducted a systematic review of the literature to evaluate the efficacy of various treatment modalities for intracranial aneurysms (IA) in patients with moyamoya disease (MMD) based on anatomical location of IA. A comprehensive review of studies documenting single cases or series of MMD patients with concomitant IA was conducted. Aneurysms were classified into two primary anatomical categories: those of the Circle of Willis (CoW) and those of peripheral "moyamoya" collateral vessels. Conservative, endovascular, and open surgical treatment modalities and their outcomes between each anatomical subgroup were descriptively compared. A total of 124 studies consisting of 275 patients with 313 IA were included. Of all IA, 59.6% were located on CoW vessels, 33.7% on peripheral vessels, and 6.7% in "other" locations. Of all CoW IA, 87.2% treated with endovascular techniques had no or minimal deficit at follow-up as compared with 56.7% of those treated with open surgery. Ninety-five percent of patients with peripheral aneurysms treated with endovascular therapy had no or minimal deficit, in contrast to open surgery (69.6%). Of peripheral IA treated conservatively with or without revascularization, 65.7% had spontaneous resolution as compared with 12.0% IA of the CoW. Our results support the use of endovascular techniques for direct treatment of both CoW and peripheral IA. Aneurysms of peripheral vessels respond well to indirect treatment through surgical revascularization as opposed to CoW aneurysms. The quality of evidence is limited due to heterogeneity of included studies and IA management in MMD patients should be considered in a case-specific manne.

High prevalence of pro-thrombotic conditions in adult patients with moyamoya disease and moyamoya syndrome: a single center study.

BACKGROUND: Moyamoya Disease (MMD) and moyamoya Syndrome (MMS) have been reported to be associated with pro-thrombotic states in some patients. To date, however, such reports have been limited to case reports or small case series. We sought to determine the prevalence of pro-thrombotic states among a large cohort of both MMD and MMS patients. METHODS: We retrospectively reviewed the medical records of all adult patients who were diagnosed with MMD or MMS from our institution. In addition to basic demographic and clinical data, the presence of certain pro-thrombotic conditions was noted. The presence of such conditions was determined based on review of clinical diagnoses and laboratory reports. The length of follow-up and the presence of interval ischemic events were obtained. RESULTS: Out of a total of 180 patients diagnosed with MMD or MMS, 33 were found to have a concomitant pro-thrombotic condition (18.3%). Of 147 patients with MMD, 23 were found to have a pro-thrombotic condition (15.6%). There were 10 out of 33 total patients (30.3%) in the MMS cohort that had a concomitant pro-thrombotic condition. There were no differences in specific pro-thrombotic conditions between MMD and MMS cohorts. There were no differences in future ischemic events between moyamoya patients with pro-thrombotic tendencies compared to those without (13.3% versus 23.7%, respectively, P = 0.32), and this was also true for patients who underwent revascularization procedures (22.6% versus 29.4%, P = 0.76). There was also no difference in prevalence of revascularization graft occlusion between moyamoya patients with pro-thrombotic tendencies and those without at follow-up (1.2% versus 5.9%, P = 0.31). CONCLUSIONS: It is likely that both MMD and MMS are associated with or predispose to pro-thrombotic conditions in adult patients, although the clinical and surgical significance is uncertain. Further study is needed in order to further elucidate and characterize this potential association.

Symptomatic developmental venous anomalies.

Cerebral developmental venous anomalies (DVAs) are variations of venous vascular anatomy related to an underdevelopment of either the superficial or deep venous emissary system, resulting in a dilated transmedullary vein fed by multiple smaller venous radicles responsible for drainage of normal brain parenchyma. While typically benign and found incidentally on imaging studies, DVAs can rarely be symptomatic. The radiographic appearance of DVAs, as well as their symptomatic manifestations, is diverse. Herein, we will discuss the pathophysiology of symptomatic DVAs while providing illustrative case examples depicting each of their pathogenic mechanisms.

How I do it: surgical clip reconstruction of a large, partially thrombosed, ruptured middle cerebral artery aneurysm.

BACKGROUND: Ruptured large and partially thrombosed aneurysms are challenging lesions to treat successfully. METHODS: We describe the surgical treatment of a large, ruptured partially thrombosed middle cerebral artery (MCA) aneurysm. Once the Sylvian fissure is dissected, temporary clips are placed, and the clot is evacuated with simple microsuction and ultrasonic aspiration. The aneurysm is then carefully clip reconstructed to avoid compromise of the parent vessels. CONCLUSION: In cases of surgical clipping of large, thrombosed aneurysms, it is important to be aware of a few, but critically important, pitfalls to ensure successful outcome.

Racial and Ethnic Disparities in the Utilization of Thrombectomy for Acute Stroke.

Background and Purpose- Racial and ethnic disparities in the access to mechanical thrombectomy (MT) for treatment of acute ischemic stroke (AIS) secondary to large vessel occlusion have been previously described. The effect of recent randomized trials validating MT as an effective therapy for AIS secondary to large vessel occlusion on such disparities has not been investigated. Methods- Information on admissions for AIS to endovascular centers occurring between January 2016 and September 2018 was obtained from a national database. The number of patients receiving IV-tPA (intravenous tissue-type plasminogen activator) and MT at each institution was determined, and patient demographics were characterized according to age, sex, race/ethnicity, and insurance status. Comparisons of patients who did and did not undergo MT and between patients of different racial and ethnic backgrounds were performed. Demographic variables independently associated with the utilization of MT were identified using multivariate linear regression analysis. Results- There were 206 853 admissions to 173 endovascular centers during the time period of interest. The overall utilization of MT was 8.4%. The utilization of MT for black/Hispanic patients was lower than that among white/non-Hispanic patients (7.0% versus 9.8%; P<0.001). Black/Hispanic patients were also less likely to receive IV-tPA (16.2% versus 20.5%; P<0.001) and to be admitted to the endovascular center after transfer from a different hospital (20.0% versus 30.1%; P<0.001). On multivariate linear regression analysis, increasing institutional proportions of patients with female sex (ß=-0.601; P<0.001), insurance with Medicaid or uninsured status (ß=-0.153; P=0.029), and black/Hispanic race/ethnicity (ß=-0.062; P=0.046) were independently associated with lower institutional utilization of MT. Conclusions- Despite the mainstream acceptance of MT for the treatment of AIS secondary to large vessel occlusion, racial and ethnic disparities in the utilization of MT persist.

Clinical presentation, natural history and outcomes of intramedullary spinal cord cavernous malformations.

OBJECTIVE: There is a paucity of literature investigating the clinical course of patients with spinal intramedullary cavernous malformations (ISCMs). We present a large case series of ISCMs to describe clinical presentation, natural history and outcomes of both surgical and conservative management. METHODS: We retrospectively reviewed the clinical course of patients diagnosed with ISCMs at our institution between 1995 and 2016. Haemorrhage was defined as clinical worsening in tandem with imaging changes visualised on follow-up MRI. Outcomes assessed included neurological status and annual haemorrhage rates. RESULTS: A total of 107 patients met inclusion criteria. Follow-up data were available for 85 patients. While 21 (24.7%) patients underwent immediate surgical resection, 64 (75.3%) were initially managed conservatively. Among this latter group, 16 (25.0%) suffered a haemorrhage during follow-up and 11 (17.2%) required surgical resection due to interval bleeding or neurological worsening. The overall annual risk of haemorrhage was 5.5% per person year. The rate among patients who were symptomatic and asymptomatic on presentation was 9.5% and 0.8%, respectively. Median time to haemorrhage was 2.3 years (0.1-12.3). Univariate analysis identified higher ISCM size (p=0.024), history of prior haemorrhage (p=0.013) and presence of symptoms (p=0.003) as risk factors for subsequent haemorrhage. Multivariable proportional hazards analysis revealed presence of symptoms to be independently associated with haemorrhage during follow-up (HR 9.39, CI 1.86 to 170.8, p=0.013). CONCLUSION: Large, symptomatic ISCMs appear to be at increased risk for subsequent haemorrhage. Surgery may be considered in such lesions to prevent rebleeding and subsequent neurological worsening.

Nuances of transarterial and transvenous embolization of a large tentorial arteriovenous fistula.

An 80-year-old female presented with a long history of severe pulsatile tinnitus, vertigo, and decreased hearing. She was found to have a large right-sided tentorial arteriovenous fistula (AVF) with enlarged deep draining veins, including the vein of Rosenthal. The patient underwent Onyx embolization of the fistula via a combined transarterial and transvenous approach resulting in complete obliteration of the fistula. Her symptoms improved immediately after the procedure and at 6-months' follow-up she was clinically asymptomatic with no evidence of residual fistula on neuroimaging. Transvenous embolization of AVF is at times necessary when transarterial access is not possible.The video can be found here: https://youtu.be/uOMHY7eaOoQ.

Contemporary and emerging magnetic resonance imaging methods for evaluation of moyamoya disease.

Numerous recent technological advances offer the potential to substantially enhance the MRI evaluation of moyamoya disease (MMD). These include high-resolution volumetric imaging, high-resolution vessel wall characterization, improved cerebral angiographic and perfusion techniques, high-field imaging, fast scanning methods, and artificial intelligence. This review discusses the current state-of-the-art MRI applications in these realms, emphasizing key imaging findings, clinical utility, and areas that will benefit from further investigation. Although these techniques may apply to imaging of a wide array of neurovascular or other neurological conditions, consideration of their application to MMD is useful given the comprehensive multidimensional MRI assessment used to evaluate MMD. These MRI techniques span from basic cross-sectional to advanced functional sequences, both qualitative and quantitative.The aim of this review was to provide a comprehensive summary and analysis of current key relevant literature of advanced MRI techniques for the evaluation of MMD with image-rich case examples. These imaging methods can aid clinical characterization, help direct treatment, assist in the evaluation of treatment response, and potentially improve the understanding of the pathophysiology of MMD.

The Effect of Epidural Steroid Injections on Bone Mineral Density and Vertebral Fracture Risk: A Systematic Review and Critical Appraisal of Current Literature.

Objective: The aim of this paper is to review the available literature investigating the effect of epidural steroid injections (ESIs) on bone mineral density (BMD) and vertebral fracture risk. Study design: Systematic review of current literature. Methods: The sources of the data were PubMed, Embase, Cochrane, and Scopus. Papers included in the review were original research articles in peer-reviewed journals. Results: A total of 7,233 patients (eight studies) with a mean age ranging between 49 and 74 years and an average follow-up between six and 60 months were studied. Steroids that were used included triamcinolone, dexamethasone, and methylprednisolone (MP), with a mean number of injections ranging from one to 14.7 and an average cumulative dose in MP equivalents between 80 and 8,130 mg. Epidural steroids were associated with significantly decreased BMD in four out of six included studies, and with increased risk of vertebral fracture in one out of two included studies. Significant reductions in BMD were associated with a cumulative MP dose of 200 mg over a one-year period and 400 mg over three years, but not in doses of less than 200 mg of MP equivalents for postmenopausal women and at least 3 g for healthy men. The risk of osteopenia and osteoporosis was lower in patients who were receiving anti-osteoporotic medication during the treatment course. Conclusions: ESIs should be recommended with caution, especially in patients at risk for osteoporotic fractures, such as women of postmenopausal age. Anti-osteoporotic medication might be considered prior to ESI.

Transfer to High-Volume Centers Associated With Reduced Mortality After Endovascular Treatment of Acute Stroke.

BACKGROUND AND PURPOSE: Some have argued that it may be beneficial to expand the availability of endovascular revascularization services to lower-volume hospitals to minimize the morbidity associated with transfer to larger endovascular centers. We compared the outcomes after revascularization of patients directly admitted to a low-volume center and those transferred to a high-volume center. METHODS: We searched a national database of hospital-reported outcomes for patients who underwent endovascular revascularization for acute ischemic stroke. Hospitals were categorized as low, medium, or high procedural volume hospitals. Outcomes of inpatient admissions were collected and compared on the basis of admission source and hospital procedural volume. RESULTS: A total of 118 institutions with 8533 patients were included. Mortality rate (14.9% versus 18.6%; P=0.049) and mortality index (1.1 versus 1.6; P=0.048) were significantly lower among directly admitted relative to transferred patients. For all patients, there were significant differences in institutional mortality rate (low: 19.7%, medium: 14.9%, high: 9.8%; P=0.003) and mortality index (low: 1.5, medium: 1.1, high: 0.8; P=0.004) between low-, medium-, and high-volume hospitals. For transferred patients to high-volume centers, both mortality rate (high: 10.0% versus low: 20.4%; P=0.005) and mortality index (high: 0.8 versus low: 1.5; P=0.034) were significantly lower than that observed for directly admitted patients to low-volume hospitals. CONCLUSIONS: We report a beneficial effect of treatment at high-volume hospitals in spite of the detrimental effects of transfer. These findings argue for the centralization of care.

Investigation into drivers of cost of stenting for carotid stenosis.

OBJECTIVE: We aimed to identify factors associated with cost of carotid artery stenting (CAS). METHODS: Patient and hospital characteristics affecting cost of admission for CAS were identified using the Vizient national database of hospital-reported outcomes. Patients who underwent CAS for either asymptomatic or symptomatic carotid stenosis were identified using surgical Medicare Severity-Diagnosis Related Groups and appropriate International Classification of Diseases, Ninth Revision and Tenth Revision codes. RESULTS: There were 166 hospitals that reported outcomes from 7369 inpatient admissions for CAS. Each institution reported a mean value for cost related to patient care per admission for CAS; the average cost across all reporting institutions was $12,834.14 (standard error of the mean [SEM], 492.88). Institutions in the lowest 25th percentile with respect to frequency of intensive care unit admission after CAS had lower cost of admission than institutions above the 75th percentile ($10,971.30 [SEM, 460.67] vs $14,992.90 [964.29]; P = .002), without any differences in incidence of stroke during admission (2.2% [SEM, 0.3] vs 2.0% [0.4]; P = .877) or 30-day readmission (1.9% [SEM, 0.4] vs 2.5 [0.6]; P = .329). Admissions for patients with symptomatic stenosis were more expensive than those with asymptomatic stenosis ($20,462.10 [SEM, 819.93] vs $11,285.20 [347.11]; P < .001). Obesity was also associated with greater costs of admission ($14,176.20 [SEM, 597.13] vs $12,287.10 [395.73]; P < .001). CONCLUSIONS: Admission to an intensive care unit, symptomatic stenosis, and obesity were associated with increased costs in patients undergoing CAS. These data may aid in identifying opportunities to improve the cost-effectiveness of this procedure.

Diabetes and Back Pain: Markers of Diabetes Disease Progression Are Associated With Chronic Back Pain.

IN BRIEF Diabetes has been associated with the incidence of back pain. However, the relationship between markers of diabetes progression and back pain has not been studied. The objective of this study was to correlate clinical and laboratory measures of diabetes disease severity to the presence of back pain to provide insight into the relationship between these conditions. Findings showed that markers of diabetes disease progression were associated with the presence of back pain, suggesting that uncontrolled diabetes may contribute to the development of chronic back pain.

Muscarinic acetylcholine receptor activation blocks long-term potentiation at cerebellar parallel fiber-Purkinje cell synapses via cannabinoid signaling.

Muscarinic acetylcholine receptors (mAChRs) are known to modulate synaptic plasticity in various brain areas. A signaling pathway triggered by mAChR activation is the production and release of endocannabinoids that bind to type 1 cannabinoid receptors (CB1R) located on synaptic terminals. Using whole-cell patch-clamp recordings from rat cerebellar slices, we have demonstrated that the muscarinic agonist oxotremorine-m (oxo-m) blocks the induction of presynaptic long-term potentiation (LTP) at parallel fiber (PF)-Purkinje cell synapses in a CB1R-dependent manner. Under control conditions, LTP was induced by delivering 120 PF stimuli at 8 Hz. In contrast, no LTP was observed when oxo-m was present during tetanization. PF-LTP was restored when the CB1R antagonist N-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide (AM251) was coapplied with oxo-m. Furthermore, the suppressive effect of oxo-m on PF-LTP was abrogated by the GDP analog GDP-ß-S (applied intracellularly), the phospholipase C inhibitor U-73122, and the diacylglycerol lipase inhibitor tetrahydrolipstatin (THL), suggesting that cannabinoid synthesis results from the activation of Gq-coupled mAChRs present on Purkinje cells. The oxo-m-mediated suppression of LTP was also prevented in the presence of the M3 receptor antagonist DAU 5884, and was absent in M1/M3 receptor double-KO mice, identifying M3 receptors as primary oxo-m targets. Our findings allow for the possibility that cholinergic signaling in the cerebellum--which may result from long-term depression (LTD)-related disinhibition of cholinergic neurons in the vestibular nuclei--suppresses presynaptic LTP to prevent an up-regulation of transmitter release that opposes the reduction of postsynaptic responsiveness. This modulatory capacity of mAChR signaling could promote the functional penetrance of LTD.