Cerebral arteriopathies of childhood and stroke - A focus on systemic arteriopathies and pediatric fibromuscular dysplasia (FMD).

Systemic vascular involvement in children with cerebral arteriopathies is increasingly recognized and often highly morbid. Fibromuscular dysplasia (FMD) represents a cerebral arteriopathy with systemic involvement, commonly affecting the renal and carotid arteries. In adults, FMD diagnosis and classification typically relies on angiographic features, like the 'string-of-beads' appearance, following exclusion of other diseases. Pediatric FMD (pFMD) is considered equivalent to adult FMD although robust evidence for similarities is lacking. We conducted a comprehensive literature review on pFMD and revealed inherent differences between pediatric and adult-onset FMD across various domains including epidemiology, natural history, histopathophysiology, clinical, and radiological features. Although focal arterial lesions are often described in children with FMD, the radiological appearance of 'string-of-beads' is highly nonspecific in children. Furthermore, children predominantly exhibit intimal-type fibroplasia, common in other childhood monogenic arteriopathies. Our findings lend support to the notion that pFMD broadly reflects an undefined heterogenous group of monogenic systemic medium-or-large vessel steno-occlusive arteriopathies rather than a single entity. Recognizing the challenges in categorizing complex morphologies of cerebral arteriopathy using current classifications, we propose a novel term for describing children with cerebral and systemic vascular involvement: 'cerebral and systemic arteriopathy of childhood' (CSA-c). This term aims to streamline patient categorization and, when coupled with advanced vascular imaging and high-throughput genomics, will enhance our comprehension of etiology, and accelerate mechanism-targeted therapeutic developments. Lastly, in light of the high morbidity in children with cerebral and systemic arteriopathies, we suggest that investigating for systemic vascular involvement is important in children with cerebral arteriopathies.

Occlusive Disease and Upright Activity in Acute Ischemic Stroke.

The impact of out-of-bed upright activity on outcomes in ischemic stroke patients with severe extra- and intracranial stenosis or occlusion is unknown. Using ultrasound findings from a cohort recruited to A Very Early Rehabilitation Trial (AVERT) which compared higher dose very early mobilisation (VEM) to usual care (UC), we aimed to explore the association between occlusive disease and 3-month outcomes and occlusive disease-by-mobilisation treatment interactions. Participants with ischemic stroke, with carotid and transcranial Doppler ultrasounds performed ≤1 week after admission, were included in this single centre substudy in Melbourne, Australia. Reports were retrospectively reviewed to determine the degree of stenosis or presence of occlusion in the relevant arterial territory. Stenosis ≥70% extracranial or ≥50% intracranial were classified as severe or occlusion. Overall, 19% (n = 36/191) had occlusive disease in the affected circulation. About 40% (n = 14/36) with occlusive disease and 51% (n = 79/155) without had a 3-month favourable outcome (mRS 0-2) (adjusted OR0.53, CI0.17-1.67). Fourteen percent (n = 5) with occlusive disease and 4% (n = 6) without died by 3 months (adjusted OR2.52, CI0.6-10.7). Fifty percent (n = 11/22) of UC (adjusted OR0.86, CI0.23-3.2) and 21% (n = 3/14) of VEM participants (adjusted OR0.16, CI0.01-2.7) with occlusive disease had a favourable outcome. Almost 30% (n = 4) VEM participants with occlusive disease died (adjusted OR3.99, CI0.69-22.9) compared to 5% (n = 1) UC participants with occlusive disease (adjusted OR0.45, CI0.02-8.6), however numbers were small. No stenosis-by-treatment interactions were found. High quality prospective studies are needed to help guide decision making about when patients with occlusive disease should commence upright activity in acute stroke.

MRI Vessel Wall Enhancement and Other Imaging Biomarkers in Pediatric Focal Cerebral Arteriopathy-Inflammatory Subtype.

Background and Purpose- Focal cerebral arteriopathy-inflammatory type (FCA-i) is a common cause of pediatric arterial ischemic stroke characterized angiographically by unifocal and unilateral stenosis/irregularity of the large anterior circulation arteries with a presumed inflammatory cause. Arterial vessel wall enhancement (VWE) on vessel wall magnetic resonance imaging is a potential biomarker of inflammation that may improve diagnosis, guide treatment, and predict outcomes in patients with FCA-i. We hypothesized that patients with FCA-i with more severe or extensive VWE would have worse arteriopathy, larger infarcts, worse clinical outcome, and increased risk for infarct progression/recurrence. Methods- Pediatric patients with arterial ischemic stroke, classified as FCA-i, and who underwent vessel wall imaging were retrospectively identified at our institution. Clinical data were reviewed and the Pediatric Stroke Outcome Measure at 1 year was determined as the primary clinical end point. Neuroimaging studies were assessed for infarct size, arteriopathy severity (Focal Cerebral Arteriopathy Severity Score), and VWE. Results- Nine cases of FCA-i with vessel wall imaging were evaluated, and there was a strong correlation between clinical outcome at 1-year with initial infarct volume (Spearman correlation coefficient rho=0.84; P<0.01) and arteriopathy severity (Focal Cerebral Arteriopathy Severity Score; rho=0.85; P<0.01). Patients with infarct progression/recurrence had worse Focal Cerebral Arteriopathy Severity Score at presentation compared with those without progression/recurrence (median [IQR]; 9.0 [8.0-11.8] and 5.0 [4.0-7.0], respectively; P<0.05). On the contrary, measures of VWE were not correlated with arteriopathy severity, infarct size, clinical outcome, or risk of infarct progression/recurrence. Moreover, not all patients with FCA-i demonstrated VWE. Conclusions- VWE may not be a reliable biomarker for the diagnosis or assessment of FCA-i, and future work is needed to assess the utility of vessel wall imaging in pediatric arterial ischemic stroke and FCA-i.

Focal cerebral arteriopathy and childhood stroke.

PURPOSE OF REVIEW: Focal cerebral arteriopathy (FCA) is one of the most common causes of arterial ischaemic stroke in a previously healthy child. Distinguishing between different subtypes of arteriopathy is challenging and has significant management implications. RECENT FINDINGS: Recent studies have helped to define the subtypes of focal cerebral arteriopathies and improved understanding of their clinical and radiological features. In addition, they have reported new evidence for the association between viral infection and inflammation in the pathogenesis of FCA and proposed new radiological, serum and cerebrospinal fluid biomarkers to guide diagnosis and management. There is limited evidence to guide treatment of FCA but a role for steroids and antiviral therapies have been reported. SUMMARY: Despite the recent advances there is a limited knowledge of the pathophysiology and outcomes following FCA. Research priorities include the identification of biomarkers to improve accuracy of initial diagnosis and predict progression, and interventional trials to determine best treatments to reduce stroke recurrence risk.

Review on the Diagnosis and Treatment of Reversible Cerebral Vasoconstriction Syndrome in Children and Adolescents.

Reversible cerebral vasoconstriction syndrome (RCVS) is a clinical-radiologic diagnosis that affects children and adolescents, but it is much more frequently reported in adults. Clinically, patients present with severe and commonly recurrent thunderclap headaches. Typical precipitating triggers include vasoactive substances, serotonergic agents, and the postpartum period. There may be associated neurologic complications at presentation or in the weeks following, such as convexity subarachnoid hemorrhage, stroke, cerebral edema, cervical artery dissection (CeAD), and seizures. Angiographically, the cerebral arteries demonstrate segmental vasoconstriction and dilation, although imaging early in the clinical course may be normal. Work-up is performed to exclude intracranial disorders such as vasculitis, subarachnoid hemorrhage due to ruptured aneurysm, meningitis, and intracranial venous sinus thrombosis. Within 1 month of initial symptom onset, clinical symptoms such as severe headache have ceased, and within 3 months, the cerebral vasoconstriction is much improved or resolved. Management involves avoidance of precipitating triggers and potentially short-term pharmacotherapy with calcium channel blockers for patients with associated neurologic complications. Steroids are not recommended and may worsen the clinical outcome. Prognosis is excellent in the large majority of patients, and only 5% of patients experience a recurrence of RCVS.

Selective neuronal damage and blood pressure in atherosclerotic major cerebral artery disease.

OBJECTIVE: In patients with atherosclerotic major cerebral artery disease, low blood pressure might impair cerebral perfusion, thereby exacerbate the risk of selective neuronal damage. The purpose of this retrospective study was to determine whether low blood pressure at follow-up is associated with increased selective neuronal damage. METHODS: We retrospectively analysed data from 76 medically treated patients with atherosclerotic internal carotid artery or middle cerebral artery disease with no ischaemic episodes on a follow-up of 6 months or more. All patients had measurements of the distribution of central benzodiazepine receptors twice using positron emission tomography and 11C-flumazenil. Using three-dimensional stereotactic surface projections, we quantified abnormal decreases in the benzodiazepine receptors of the cerebral cortex within the middle cerebral artery distribution and correlated these changes in the benzodiazepine receptors index with blood pressure values at follow-up examinations. RESULTS: The changes in the benzodiazepine receptor index during follow-up (mean 27±21 months) were negatively correlated with systolic blood pressure at follow-up. The relationship between changes in benzodiazepine receptor index and systolic blood pressure was different among patients with and without decreased cerebral blood flow at baseline (interaction, p<0.005). Larger increases in benzodiazepine receptor index (neuronal damage) were observed at lower systolic blood pressure levels in patients with decreased cerebral blood flow than in patients without such decreases. CONCLUSION: In patients without ischaemic stroke episodes at follow-up but with decreased cerebral blood flow due to arterial disease, low systolic blood pressure at follow-up may be associated with increased selective neuronal damage.

Arterial stiffness and total cerebral small vessel disease score in community-dwelling older adults: Results from the Atahualpa Project.

Information on the association between arterial stiffness and cerebral small vessel disease (cSVD) is limited and confined to white and Asian populations. More regional information is needed to confirm this association in different ethnic groups. Using the Atahualpa Project cohort, we aimed to assess whether the aortic pulse wave velocity (PWV) is associated with the total cSVD score, as well as with each of the neuroimaging signatures of cSVD, in a population of Amerindians living in rural Ecuador. Atahualpa residents aged ⩾ 60 years were offered a brain magnetic resonance imaging scan (MRI) and aortic PWV determination. An ordinal logistic regression model, adjusted for demographics and cardiovascular risk factors, was constructed to predict the total cSVD score by levels of aortic PWV. The association between the neuroimaging signatures of cSVD and the aortic PWV was assessed by adjusted logistic regression models. Of 437 candidates, 303 (69%) underwent a brain MRI and aortic PWV determinations. The total cSVD score was 0 points in 65% of individuals, 1 point in 18%, 2 points in 11%, and 3-4 points in 6%. The mean aortic PWV was 10.4 ± 1.8 m/s, which increased from 9.8 ± 1.2 to 12.3 ± 1.8 m/s in individuals with a cSVD score of 0 and 3-4, respectively ( p < 0.001). An ordinal logistic regression model showed significant association between the PWV and the cSVD score. A change of one unit of the aortic PWV increased the odds of having a higher total cSVD score by 1.73 (95% CI: 1.28-2.35; p < 0.001). In addition, individual neuroimaging signatures of cSVD, with the exception of lacunar infarcts, were associated with the aortic PWV. This study shows a significant association between the aortic PWV and total cSVD score and most of its individual components in older Amerindians.

A Follow-up Study of Cerebral Microbleeds in Patients Who Received Stents for Symptomatic Cerebral Artery Stenosis.

BACKGROUND: The aims of this study were to explore (i) the dynamic changes in cerebral microbleeds (CMBs) in patients with symptomatic cerebral artery stenosis who received endovascular stent-assisted angioplasty and (ii) the risk factors associated with the new incidence of CMBs as well as whether CMBs increased the risk of vascular events in these patients. METHODS: Clinical information and magnetic resonance images were collected on admission and 3 months after endovascular stent-assisted angioplasty. Based on susceptibility-weighted imaging, the patients were divided into groups with or without newly developed CMBs, and between-group differences in risk factors were compared. We also compared whether CMBs increased the risk of vascular events among those patients. RESULTS: Seventy-three patients completed the relevant follow-up examinations. After an average follow-up period of 109 days, 7 (9.6%) patients showed new CMBs. A univariate analysis showed that the number of lacunar infarcts and the increase in systolic blood pressure were higher in patients with new CMBs than in those without new CMBs, and these differences were significant (P = 0.034, P = 0.001). Increased systolic blood pressure was an independent risk factor for developing new CMBs (P = 0.017). CONCLUSIONS: CMBs may be a continuously progressing cerebral small-vessel disease. The newly developed CMBs in patients with intracranial and/or extracranial stents were associated with increased systolic blood pressure but not with the number of baseline CMBs.

The Thunderclap Headache: Approach and Management in the Emergency Department.

BACKGROUND: A thunderclap headache (TCH) is a severe headache reaching at least 7 (out of 10) in intensity within 1 min of onset, and can be the presenting symptom of several conditions with potential for significant morbidity and mortality. OBJECTIVE OF THE REVIEW: This narrative review evaluates the various conditions that may present with TCH and proposes a diagnostic algorithm for patients with TCH. DISCUSSION: TCH is a symptom associated with several significant diseases. The most common diagnosed condition is subarachnoid hemorrhage (SAH). Other diagnoses include reversible cerebral vasoconstriction syndrome, cerebral venous thrombosis, cervical artery dissection, posterior reversible encephalopathy syndrome, spontaneous intracranial hypotension, and several others. Patients with TCH require history and physical examination, with a focus on the neurologic system, evaluating for these conditions, including SAH. Further testing often includes head computed tomography (CT) without contrast, CT angiography of the head and neck, and lumbar puncture. Evaluation must take into account history, examination, and the presence of any red flags or signs suggestive of a specific etiology. An algorithm is provided for guidance within this review incorporating these modalities. Management focuses on the specific diagnosis. If testing is negative for a serious condition and the patient improves, discharge home may be appropriate with follow-up. CONCLUSIONS: Patients presenting with TCH require diagnostic evaluation. History and examination are vital in assessing for risk factors for various conditions. Focused testing can assist with diagnosis, with management tailored to the specific diagnosis.

A Clinical Paradigm for Classifying Neurologic Symptoms to Screen for Emergent Large Vessel Occlusions.

BACKGROUND: With newly-extended treatment windows for endovascular therapy in emergent large vessel occlusions, it is increasingly important to identify thrombectomy-eligible patients without overwhelming resources dedicated to acute stroke care. We devised a simple paradigm to classify patient's presenting neurologic symptoms to screen for large vessel occlusions. METHODS: We reviewed the presenting symptoms, imaging findings, and final diagnoses of consecutive emergency department stroke alert cases. Patients were classified based on their neurologic exams as focal objective, focal subjective, or nonfocal. Outcomes of final diagnoses of acute ischemic stroke and large vessel occlusions were compared across groups. Comparisons were made to other large vessel occlusion prediction scales. RESULTS: Of 521 patients, 342 (65.6%) were categorized as focal objective, 142 (27.2%) as focal subjective, and 37 (7.1%) as nonfocal. Ischemic stroke and large vessel occlusions were diagnosed in 114 (21.9%) and 27 (5.2%) of patients, respectively. Classification as focal objective significantly predicted stroke (odds ratio 3.77; 95% confidence interval 2.17-6.55) and captured all large vessel occlusions (P = .0001). The focal objective categorization was the only tool which achieved 100% sensitivity for large vessel occlusions (with a specificity of 36%) compared to other large vessel occlusion prediction tools. CONCLUSIONS: Patients who presented as stroke alerts without focal neurologic symptoms were unlikely to have large vessel occlusions. With high sensitivity, classifying patients' neurologic exams into focal objective versus subjective or nonfocal categories may serve as a useful tool to screen for large vessel occlusions and prevent unnecessary emergent workup in patients unlikely to be endovascular candidates.

Management of Intracranial Stenotic Disease in Cancer Patients Treated With Vasotoxic Agents.

OBJECTIVE: To summarize the characteristics of and therapeutic options for cancer patients whose treatments may be vasotoxic and cause intracranial arterial stenotic disease and stroke. METHODS: We describe 3 patients with symptomatic cerebrovascular pathology that were being actively treated for cancer. RESULTS: Two of the patients were being treated with tyrosine kinase inhibitors (TKIs); and the third was being treated with 2 monoclonal antibodies, one of which was targeting an endothelial growth factor. These agents have been associated with vascular adverse events. Surgical revascularization was done in the first 2 patients, as they were suffering from cerebral ischemia. The third patient had suffered a significant brain hemorrhage, and therapeutic options were limited. In the first 2 patients, treatments also included antiplatelet agents and stopping/changing the TKI. In one of these patients we demonstrated regression of arterial stenosis after changing the TKI. CONCLUSIONS: Possibilities for treatment in this population, beyond the usual medical and surgical administrations, may include stopping or changing cancer drugs that may be related to the development of arterial pathology. Collaboration with oncologists is essential in this subset of patients. While aware of the potential for vascular toxicity, oncologists are often not fully appreciative of the fact that their therapeutic agents can cause stroke.

Reversible Cerebral Vasoconstriction Syndrome after Administering Etanercept during Puerperium.

Our objective is to clarify relationship between reversible cerebral vasoconstriction syndrome and administrating etanercept during puerperium. Several lines of evidence have suggested tumor necrosis factor (TNF) as a mediator of vascular dysfunction associated with estrogen deficiency. A 32-year-old woman resumed etanercept (25 mg/week), a TNF inhibitor, which had been discontinued during pregnancy, because of the deterioration of rheumatoid arthritis. She was admitted to our hospital with upper right quadrant blindness and mild right hemiparesis accompanied by pulsating left occipital pain, which had appeared 4 hours after restarting etanercept (25 mg/week). Magnetic resonance imaging and angiography revealed acute left hippocampal infarction with multiple segmental stenoses of the main intracranial arteries. Reversible cerebral vasoconstriction syndrome was diagnosed based on improvement of the multiple stenoses on magnetic resonance angiography on hospital day 17. A causal relationship was considered to exist between TNF inhibition by etanercept and multiple cerebral vasoconstrictions with brain infarct in this puerperant.

Long-Term Effects on Preventing Stroke after Endovascular Treatment or Bypass Surgery for Intracranial Arterial Stenosis.

BACKGROUND: Intracranial arterial stenosis (ICAS) is an important cause of ischemic stroke worldwide due to its higher risk of recurrence with medical therapy. Although some large randomized studies failed to show the superiority of surgical treatment compared with medical therapy, the results of medical therapy are not sufficient. There are patients who still benefit from surgical treatment. This retrospective analysis aimed to evaluate the long-term efficacy of surgical therapy with percutaneous transluminal angioplasty and/or stenting (PTA/PTAS) or extracranial-intracranial (EC/IC) bypass surgery for patients with ICAS. METHODS: Between October 2005 and December 2016, 55 ICAS patients were treated with PTA/PTAS or EC-IC bypass surgery. Their electronic medical records were retrospectively reviewed and analyzed. The primary outcome was all adverse events beyond 30 days after a revascularization procedure. RESULTS: We performed 21 cases (35%) of PTA, 4 cases (7%) of PTAS, and 34 cases (58%) of EC-IC bypass surgery and the median follow-up duration was 66 months (range 1-144 months). The occurrence rate of the primary outcome was 10.2% and only 1 patient (1.8%) experienced ipsilateral disabling ischemic stroke beyond 30 days. The long-term functional independent survival rate was 83.6%. CONCLUSIONS: We demonstrated a long-term favorable outcome of combined surgical intervention for ICAS patients with PTA/PTAS and EC-IC bypass surgery, and the result was better than previously reported outcomes of medical therapy. Additional multicenter studies are required to draw firm conclusions on the efficacy of reduction of recurrent stroke in patients with ICAS.

Design, Application and Infield Validation of a Pre-Hospital Emergent Large Vessel Occlusion Screening Tool: Ventura Emergent Large Vessel Occlusion Score.

BACKGROUND: The outcome of endovascular treatment for emergent large vessel occlusion (ELVO) is dependent on timely recanalization. To identify ELVO in the field, we present a simplified score, which has been applied and validated in the field by emergency medical services (EMS). Methods and Analysis: Ventura ELVO Scale (VES) comprise of 4 components: Eye Deviation, Aphasia, Neglect, and Obtundation with score range 0-4. The score of greater than or equal to 1 will be considered as ELVO positive. A positive VES along with positive Cincinnati scale prompts ELVO activation. EMS then notify to neurointervention protocol at the receiving stroke center. The performance of VES was evaluated retrospectively. For statistical analysis, SAS version 9.4 was used and Fisher's modelling was used for the comparative analysis. RESULTS: Total 184 patients were included in the final analysis, 62 (33.7%) patients were called VES positive from the field. Out of 62, 36 (58%) patients had ELVO. The mean NIHSS on arrival was 16 in VES positive and 5 in VES negative patients. VES was 94.7% sensitive and 82.4% specific while the PPV and NPV of VES were 58.1% and 98.4%, respectively. It showed 84.9% accuracy. CONCLUSIONS: VES is an effective and simplified prehospital screening tool for detection of ELVO in the field. Its implementation can beat the target door to groin time to improve outcomes and in future it can be used for rerouting of ELVO patients to comprehensive stroke center.

Focal Cerebral Arteriopathy of Childhood: Novel Severity Score and Natural History.

Background and Purpose- Focal cerebral arteriopathy (FCA)-a common cause of arterial ischemic stroke in previously healthy children-often progresses over days to weeks, increasing the risk of recurrent stroke. We developed a novel severity scoring system designed to quantify FCA progression and correlate with clinical outcomes. Methods- The VIPS study (Vascular Effects of Infection in Pediatric Stroke) prospectively enrolled 355 children with arterial ischemic stroke (2010-2014), including 41 with centrally confirmed FCA. Two neuroradiologists independently reviewed FCA cerebrovascular imaging, assigning a graded severity score of zero (no involvement) to 4 (occlusion) to individual arterial segments. The FCA severity score (FCASS) was the unweighted sum. In an iterative process, we modeled scores derived from different combinations of arterial segments to identify the model that optimized correlation with clinical outcome, simplicity, and reliability. Results- The optimal FCASS summed scores from 5 arterial segments: supraclinoid internal carotid artery, A1, A2, M1, and M2. The median (interquartile range) baseline FCASS was 4 (2-6). Of 33 children with follow-up imaging, the maximum FCASS (at any time point) was 7 (5-9). Twenty-four (73%) had FCA progression on follow-up with their maximum FCASS at a median of 8 (5-35.5) days poststroke; their median FCASS increase was 4 (2.5-6). FCASS did not correlate with recurrent arterial ischemic stroke. Maximum (but not baseline) FCASS correlated with 1-year pediatric stroke outcome measures ( P=0.037). Conclusions- Our novel scoring system for FCA severity correlates with neurological outcomes in the VIPS cohort and provides a tool for FCA treatment trials under development.

Blood-brain barrier breakdown in reversible cerebral vasoconstriction syndrome: Implications for pathophysiology and diagnosis.

OBJECTIVE: Diagnosis of reversible cerebral vasoconstriction syndrome (RCVS) is currently based on luminographic findings of vasoconstriction. In addition to vasoconstriction, the blood-brain barrier (BBB) breakdown has been postulated as a central mechanism of RCVS. Our aim was to document BBB breakdown in patients with RCVS and its role for the pathophysiology-based diagnosis of RCVS. METHODS: We prospectively recruited 72 consecutive patients with thunderclap headache who did not have aneurysmal subarachnoid hemorrhage from April 2015 to July 2016 at the Samsung Medical Center. Based on the International Classification of Headache Disorders-3 beta criteria and neuroimaging, patients were classified as having RCVS (n = 41; "definite" in 29 imaging-proven patients and "probable" in 12 imaging-negative patients), other secondary causes (n = 7), and thunderclap headache of undetermined cause (n = 24). BBB breakdown was evaluated using contrast-enhanced fluid-attenuated inversion recovery magnetic resonance imaging. RESULTS: BBB breakdown was documented in 20 (69.0%) patients with definite RCVS, 3 (25.0%) patients with probable RCVS, and none with other secondary causes. BBB breakdown was present in RCVS patients with (n = 4) and without (n = 19) concomitant posterior reversible encephalopathy syndrome. In patients with RCVS, the extent of BBB breakdown was independently associated with neurological complications (multivariate odds ratio = 1.48 per 1 territorial increase, 95% confidence interval = 1.04-2.12, adjusted p = 0.032). Three (12.5%) patients with thunderclap headache of undetermined cause were newly classified as having RCVS by the presence of BBB breakdown. INTERPRETATION: This is the first study to show BBB breakdown in patients with RCVS. This finding might broaden our understanding of the pathophysiology and clinical spectrum of RCVS. Ann Neurol 2017;81:454-466.

ACTA2 Cerebral Arteriopathy: Not Just a Puff of Smoke.

BACKGROUND: Missense mutations in the gene that codes for smooth muscle actin, ACTA2, cause diffuse smooth muscle dysfunction and a distinct cerebral arteriopathy collectively known as multisystemic smooth muscle dysfunction syndrome (MSMDS). Until recently, ACTA2 cerebral arteriopathy was considered to be a variant of moyamoya disease. However, recent basic science and clinical data have demonstrated that the cerebral arteriopathy caused by mutant ACTA2 exhibits genetic loci, histopathology, neurological sequelae, and radiographic findings unique from moyamoya disease. We conducted a literature review to provide insight into the history, clinical significance, and neurosurgical management of this recently described novel cerebral arteriopathy. SUMMARY: We performed a literature search using PubMed with the key words "ACTA2 mutation," "ACTA2 cerebral arteriopathy," and "multisystemic smooth muscle dysfunction syndrome." Case reports with confirmed ACTA2 mutations and cerebral arteriopathy were included in our review. Our literature search revealed 15 articles (58 cases) of confirmed ACTA2 cerebral arteriopathy. Distinctive features of this arteriopathy included an aberrant internal carotid circulation with dilatation of the proximal segments, occlusive disease at the distal segments, and dolichoectasia. As such, mutant ACTA2 predisposed patients to ischemic strokes as children. Direct and indirect cerebral revascularization procedures are the mainstay treatment options with varying degrees of success. Key Messages: ACTA2 cerebral arteriopathy is a recently described novel cerebrovascular disease seen in patients with MSMDS. Patients currently diagnosed with moyamoya disease who also have dysfunction of smooth muscle organs may benefit from reevaluation by a medical geneticist and ACTA2 genotyping.

Influence of cerebrovascular reactivity on outcome of the patients with ≥50% symptomatic unilateral middle cerebral artery stenosis.

Purpose/aim of the study: Cerebrovascular reactivity (CVR) reflects the vasodilatory reserve of cerebral resistance vessels, which is an important marker for assessing cerebrovascular disease. The present study is to investigate whether CVR impairment increases adverse long-term outcome risk of patients with ≥ 50% symptomatic unilateral middle cerebral artery (MCA) stenosis (ischemic stroke (IS) or transient ischemic attack (TIA)). MATERIAL AND METHODS: Digital subtraction angiography (DSA) was used to assess the degree of stenosis, and perfusion CT and 5% CO2 inhalation were adopted to evaluate CVR. Patients with ≥ 50% symptomatic unilateral MCA stenosis were assigned to non-CVR impairment group and CVR impairment group according to CVR status. The long-term follow-up endpoint was composite of any IS ( in the territory of the studied MCA) or death within 12 months. RESULTS: Seventy-three patients with ≥ 50% symptomatic unilateral MCA stenosis, involving 31 non-CVR impairment cases and 42 CVR impairment cases, were included in the present study. Finally, IS occurred in six CVR impairment patients, and no endpoint happened in the non-CVR impairment group. Therefore, the annual rate of IS was 14.29% in the CVR impairment group and 0% in the non-CVR impairment group (P = 0.035). Besides, further Kaplan-Meier analysis found CVR impairment was closely associated with the IS risk (Kaplan-Meier Log-rank 4.719, P = 0.030). CONCLUSIONS: Our results showed that for patients with ≥ 50% symptomatic unilateral MCA stenosis, there was significant difference between non-CVR impairment cases and CVR impairment cases in the annual rate of IS. It suggests that CVR impairment increases the risk of adverse long-term outcomes.

Increased Left Ventricular Filling Pressure and Arterial Occlusion in Stroke Related to Atrial Fibrillation.

BACKGROUND: We investigated whether left ventricular filling pressure is associated with arterial occlusion in patients with ischemic stroke related to atrial fibrillation (AF). METHODS: Ninety-nine patients with AF-related stroke were included. Left ventricular filling pressure was assessed by E (early mitral inflow velocity)/e' (early diastolic velocity of the mitral valve annulus velocity) ratio based on tissue Doppler echocardiography. Arterial occlusion was evaluated by computed tomography or magnetic resonance angiography. In addition, the presence of a hyperdense middle cerebral artery sign (HMCAS) on noncontrast brain computed tomography, a marker of acute thrombus burden, was assessed. Multiple logistic regression was used to evaluate the association of E/e' with arterial occlusion and the HMCAS. RESULTS: The mean age was 73.2 (±10.2), and 56% were men. Thirty-six (36.4%) patients had arterial occlusion on imaging. E/e' ratios were independently associated with arterial occlusion with an odds ratio of 1.24 (per 1 increase, 95% confidence interval 1.11-1.38). The receiver operating characteristics curve demonstrated that E/e' ratios have an excellent discriminatory capacity in predicting arterial occlusion with an area under the curve of .77 (P < .001). In addition, E/e' ratios were higher in patients with HMCAS than in those without (19.1 versus 14.0, P < .001). CONCLUSION: E/e' ratios were associated with arterial occlusion in AF-related stroke and may play a role in identifying patients at high risk of severe stroke.

Impact of vessel wall lesions and vascular stenoses on cerebrovascular reactivity in patients with intracranial stenotic disease.

PURPOSE: To compare cerebrovascular reactivity (CVR) and CVR lagtimes in flow territories perfused by vessels with vs. without proximal arterial wall disease and/or stenosis, separately in patients with atherosclerotic and nonatherosclerotic (moyamoya) intracranial stenosis. MATERIALS AND METHODS: Atherosclerotic and moyamoya patients with >50% intracranial stenosis and <70% cervical stenosis underwent angiography, vessel wall imaging (VWI), and CVR-weighted imaging (n = 36; vessel segments evaluated = 396). Angiography and VWI were evaluated for stenosis locations and vessel wall lesions. Maximum CVR and CVR lagtime were contrasted between vascular territories with and without proximal intracranial vessel wall lesions and stenosis, and a Wilcoxon rank-sum was test used to determine differences (criteria: corrected two-sided P < 0.05). RESULTS: CVR lagtime was prolonged in territories with vs. without a proximal vessel wall lesion or stenosis for both patient groups: moyamoya (CVR lagtime = 45.5 sec ± 14.2 sec vs. 35.7 sec ± 9.7 sec, P < 0.001) and atherosclerosis (CVR lagtime = 38.2 sec ± 9.1 sec vs. 35.0 sec ± 7.2 sec, P = 0.001). For reactivity, a significant decrease in maximum CVR in the moyamoya group only (maximum CVR = 9.8 ± 2.2 vs. 12.0 ± 2.4, P < 0.001) was observed. CONCLUSION: Arterial vessel wall lesions detected on noninvasive, noncontrast intracranial VWI in patients with intracranial stenosis correlate on average with tissue-level impairment on CVR-weighted imaging. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2017;46:1167-1176.