Inflammatory Type Focal Cerebral Arteriopathy of the Posterior Circulation in Children: A Comparative Cohort Study.

BACKGROUND: Inflammatory type focal cerebral arteriopathy (FCA-i) in the anterior circulation (AC) is well characterized, and the focal cerebral arteriopathy severity score (FCASS) reflects the severity of the disease. We identified cases of FCA-i in the posterior circulation (PC) and adapted the FCASS to describe these cases. METHODS: In this comparative cohort study, patients from the Swiss NeuroPaediatric Stroke Registry with ischemic stroke due to FCA-i between January 2000 and December 2018 were analyzed. A comparison between PC and AC cases regarding pediatric National Institutes of Health Stroke Scale score and pediatric stroke outcome measure and FCASS was performed. We estimated infarct size by the modified pediatric Alberta Stroke Program Early Computed Tomography Score in children with AC stroke and the adapted Bernese posterior diffusion-weighted imaging score in the PC. RESULTS: Thirty-five children with a median age of 6.3 (interquartile range, 2.7-8.2 [95% CI, 0.9-15.6]; 20 male; 57.1%) years with FCA-i were identified. The total incidence rate was 0.15/100 000/year (95% CI, 0.11-0.21). Six had PC-FCA-i. Time to final FCASS was longer in the PC compared with AC; the evolution of FCASS did not differ. Initial pediatric National Institutes of Health Stroke Scale score was higher in children with FCA-i in the PC with a median of 10.0 (interquartile range, 5.75-21.0) compared with 4.5 (interquartile range, 2.0-8.0) in those with AC-FCA-i. Different from the anterior cases, PC infarct volume did not correlate with higher discharge, maximum, or final FCASS scores (Pearson correlation coefficient [r], 0.25, 0.35, and 0.54). CONCLUSIONS: FCA-i also affects the PC. These cases should be included in future investigations into FCA-i. Although it did not correlate with clinical outcomes in our cohort, the modified FCASS may well serve as a marker for the evolution of the arteriopathy in posterior FCA-i.

Development of Collateral Vessels after Anterior Circulation Large Vessel Occlusion in Pediatric Arterial Ischemic Stroke Relates to Stroke Etiology: A Longitudinal Study.

BACKGROUND AND PURPOSE: The characteristics of large vessel occlusion (LVO) in the acute phase of pediatric arterial ischemic stroke and their natural history according to stroke etiology are poorly explored. This studied aimed at describing the prevalence and the radiological evolution of LVO in pediatric AIS. MATERIALS AND METHODS: This single-center retrospective study included consecutive non-neonate children with acute arterial ischemic stroke, intracranial proximal LVO in the anterior circulation (MCA, anterior cerebral artery, and/or ICA), and clinical and imaging follow-up for at least 18 months, during a 9-year period. RESULTS: Intracranial LVO was observed in 24.8% of patients with anterior circulation arterial ischemic stroke and adequate follow-up (n = 26/105), with a median age of 4.2 years (IQR 0.8-9), sex ratio 1.16. The main stroke etiology associated with LVO was unilateral focal cerebral arteriopathy (n = 12, 46%). During follow-up, a specific pattern of unilateral poststroke anastomotic bridge was observed in 8/26 patients, with the poststroke development of nonperforating collaterals forming a bridge in bypass of the LVO site with visible distal flow, within a median delay of 11 months. The development of unilateral poststroke anastomotic bridge was only observed in patients with unilateral focal cerebral arteriopathy. No patient with this pattern experienced stroke recurrence or further progressive vascular modifications. CONCLUSIONS: After stroke, the development of unilateral poststroke anastomotic bridge is specifically observed in children with focal cerebral arteriopathy, appearing in the first year after stroke. This clinical-radiologic pattern was not associated with stroke recurrence or arterial worsening, differentiating it from progressive intracranial arteriopathy, such as Moyamoya angiopathy.

Genetic Mechanisms of Migraine: Insights from Monogenic Migraine Mutations.

Migraine is a disabling neurological disorder burdening patients globally. Through the increasing development of preclinical and clinical experimental migraine models, advancing appreciation of the extended clinical phenotype, and functional neuroimaging studies, we can further our understanding of the neurobiological basis of this highly disabling condition. Despite increasing understanding of the molecular and chemical architecture of migraine mechanisms, many areas require further investigation. Research over the last three decades has suggested that migraine has a strong genetic basis, based on the positive family history in most patients, and this has steered exploration into possibly implicated genes. In recent times, human genome-wide association studies and rodent genetic migraine models have facilitated our understanding, but most migraine seems polygenic, with the monogenic migraine mutations being considerably rarer, so further large-scale studies are required to elucidate fully the genetic underpinnings of migraine and the translation of these to clinical practice. The monogenic migraine mutations cause severe aura phenotypes, amongst other symptoms, and offer valuable insights into the biology of aura and the relationship between migraine and other conditions, such as vascular disease and sleep disorders. This review will provide an outlook of what is known about some monogenic migraine mutations, including familial hemiplegic migraine, familial advanced sleep-phase syndrome, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL): A challenging diagnosis and a rare multiple sclerosis mimic.

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is an extremely rare hereditary cerebral small vessel disease caused by homozygous or compound heterozygous mutations in the gene coding for high-temperature requirement A serine peptidase 1 (HtrA1). Given the rare nature of the disease, delays in diagnosis and misdiagnosis are not uncommon. In this article, we reported the first case of CARASIL from Saudi Arabia with a novel homozygous variant c.1156C>T in exon 7 of the HTRA1 gene. The patient was initially misdiagnosed with primary progressive multiple sclerosis and treated with rituximab. CARASIL should be considered in the differential diagnosis of patients with suspected atypical progressive multiple sclerosis who have additional signs such as premature scalp alopecia and low back pain with diffuse white matter lesions in brain MRI. Genetic testing is important to confirm the diagnosis.

Tirofiban for Stroke without Large or Medium-Sized Vessel Occlusion.

BACKGROUND: The effects of the glycoprotein IIb/IIIa receptor inhibitor tirofiban in patients with acute ischemic stroke but who have no evidence of complete occlusion of large or medium-sized vessels have not been extensively studied. METHODS: In a multicenter trial in China, we enrolled patients with ischemic stroke without occlusion of large or medium-sized vessels and with a National Institutes of Health Stroke Scale score of 5 or more and at least one moderately to severely weak limb. Eligible patients had any of four clinical presentations: ineligible for thrombolysis or thrombectomy and within 24 hours after the patient was last known to be well; progression of stroke symptoms 24 to 96 hours after onset; early neurologic deterioration after thrombolysis; or thrombolysis with no improvement at 4 to 24 hours. Patients were assigned to receive intravenous tirofiban (plus oral placebo) or oral aspirin (100 mg per day, plus intravenous placebo) for 2 days; all patients then received oral aspirin until day 90. The primary efficacy end point was an excellent outcome, defined as a score of 0 or 1 on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) at 90 days. Secondary end points included functional independence at 90 days and a quality-of-life score. The primary safety end points were death and symptomatic intracranial hemorrhage. RESULTS: A total of 606 patients were assigned to the tirofiban group and 571 to the aspirin group. Most patients had small infarctions that were presumed to be atherosclerotic. The percentage of patients with a score of 0 or 1 on the modified Rankin scale at 90 days was 29.1% with tirofiban and 22.2% with aspirin (adjusted risk ratio, 1.26; 95% confidence interval, 1.04 to 1.53, P = 0.02). Results for secondary end points were generally not consistent with the results of the primary analysis. Mortality was similar in the two groups. The incidence of symptomatic intracranial hemorrhage was 1.0% in the tirofiban group and 0% in the aspirin group. CONCLUSIONS: In this trial involving heterogeneous groups of patients with stroke of recent onset or progression of stroke symptoms and nonoccluded large and medium-sized cerebral vessels, intravenous tirofiban was associated with a greater likelihood of an excellent outcome than low-dose aspirin. Incidences of intracranial hemorrhages were low but slightly higher with tirofiban. (Funded by the National Natural Science Foundation of China; RESCUE BT2 Chinese Clinical Trial Registry number, ChiCTR2000029502.).

Advances in the Diagnosis and Treatment of Pediatric Arterial Ischemic Stroke.

Though rare, stroke in infants and children is an important cause of mortality and chronic morbidity in the pediatric population. Neuroimaging advances and implementation of pediatric stroke care protocols have led to the ability to rapidly diagnose stroke and in many cases determine the stroke etiology. Though data on efficacy of hyperacute therapies, such as intravenous thrombolysis and mechanical thrombectomy, in pediatric stroke are limited, feasibility and safety data are mounting and support careful consideration of these treatments for childhood stroke. Recent therapeutic advances allow for targeted stroke prevention efforts in high-risk conditions, such as moyamoya, sickle cell disease, cardiac disease, and genetic disorders. Despite these exciting advances, important knowledge gaps persist, including optimal dosing and type of thrombolytic agents, inclusion criteria for mechanical thrombectomy, the role of immunomodulatory therapies for focal cerebral arteriopathy, optimal long-term antithrombotic strategies, the role of patent foramen ovale closure in pediatric stroke, and optimal rehabilitation strategies after stroke of the developing brain.

MR vessel wall enhancement in a pediatric focal cerebral arteriopathy.

BACKGROUND: Focal cerebral arteriopathy (FCA) is a common cause of childhood arterial ischemic stroke in previously healthy children. Although its mechanisms are poorly understood, recent studies have suggested inflammatory processes. Magnetic resonance vessel wall imaging (VWI) is a potential imaging biomarker of inflammation. CASE DESCRIPTION: We describe the case of a 7-year-old Japanese girl with right hemiplegia and dysarthria for 3 days. Brain MRI showed acute infarct in the left basal ganglia, and MRA and conventional cerebral angiogram detected vascular stenosis in the left distal internal carotid artery, left M1 and A1 segments. VWI revealed marked vessel wall enhancement and thickening in the left carotid artery, M1, and A2 segments. Based on imaging findings, she was diagnosed with acute ischemic stroke caused by FCA. Because VWI findings were thought to suggest vessel wall inflammation, high-dose steroid therapy was administered in addition to neuroprotective care and antithrombotic therapy. Although her clinical symptoms improved immediately, cerebral arteriopathy worsened on MRA a month after the onset. Subsequently, after 3 months of steroid therapy, vessel wall enhancement on VWI decreased, while arterial stenosis partially improved. At the follow-up 9 months after the onset, she had no recurrent stroke, her arteriopathy had stabilized. DISCUSSION: Definitive evidence of inflammatory mechanisms in FCA is limited, and appropriate management and treatment strategies for FCA are undefined. VWI attempts to demonstrate pathologic processes within the vessel wall, and reversible wall enhancement observed in our patient suggested the presence of inflammation. VWI would help in the evaluation of disease activity in FCA. CONCLUSION: VWI may contribute to the appropriate diagnosis and treatment for FCA to reflect active inflammation. Further work is needed to assess the utility of VWI in pediatric FCA.

Cerebral arteriopathy and ischemic stroke in a pediatric MYH11 patient.

OBJECTIVES: Mutations in the MYH11 gene result in smooth muscle cell dysfunction and are associated with familial thoracic aortic aneurysms and dissection. We describe a pediatric patient with a stroke and a pathogenic MYH11 IVS32G>A mutation, and a phenotype similar to ACTA2. METHODS: A proband girl with an acute ischemic stroke underwent genetic analysis and 7T high-resolution MRI. RESULTS: A 12-year-old girl presented with a right middle cerebral artery occlusion. She received thrombolysis and underwent mechanical thrombectomy. An extensive stroke work-up was negative. A three-generation pedigree showed a splice site mutation of MYH11 IVS32G>A of the proband and three more family members. A 7T-MRI showed "broomstick-like" straightening of distal arterial segments, a V-shaped anterior corpus callosum and a post-stroke cystic area of encephalomalacia. This vascular appearance and parenchymal abnormalities typically present in patients with an ACTA2 phenotype. 7T-MRI also demonstrated thickening of the right middle cerebral arterial wall. DISCUSSION: This case suggests that MYH11 patients may have a similar angiographic and brain parenchymal phenotype to patients with ACTA2 mutations. This is the first report of arterial wall thickening in a MYH11 stroke patient using 7T-MRI. Patients with MYH11 mutations may display a focal cerebral steno-occlusive arteriopathy that may lead to stroke.

When Recurrent Strokes, Back Pain, and Alopecia Constitute a Hereditary Cause of Small-Vessel Disease, CARASIL in an Arabic Woman.

INTRODUCTION: Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a rare autosomal recessive etiology of cerebral small-vessel disease. The bulk of CARASIL cases reported in the literature was from Japan and China. Herein, we report the first genetically confirmed case of CARASIL in the Arabic population. CASE PRESENTATION: We present the case of a 35-year-old Bahraini woman diagnosed with an acute ischemic stroke after experiencing right-sided weakness and slurred speech. She had complained of persistent headaches, decreased memory, hair loss, joint pain, and personality changes. CARASIL was suspected on her medical history and brain imaging results, and genetic testing confirmed the diagnosis. CONCLUSION: This case contributes to our understanding of CARASIL, which is an extremely rare disease. It adds to the growing data on disease reporting outside China and Japan. We also report the first case of CARASIL in an Arabic patient and describe magnetic resonance spectroscopy finding partially different from what has been reported before.

Characterization of Neuropsychological Outcomes in a Cohort of Pediatric Patients with Moyamoya Arteriopathy.

INTRODUCTION: Moyamoya arteriopathy is a severe, progressive cerebral arteriopathy that places affected children at high risk for stroke. Moyamoya has been associated with a range of neuropsychological deficits in adults, but data on many cognitive domains remain limited in the pediatric population and little is known about the neuropsychological profile of children with syndromic moyamoya. METHODS: This is a single-center, retrospective cohort study of children with moyamoya arteriopathy followed at our center who underwent neuropsychological testing between 2003 and 2021. Test scores were extracted from neuropsychological reports. Medical records were reviewed with attention to individual neuropsychological test results, medical comorbidities, presence of infarct(s) on neuroimaging, and history of clinical ischemic stroke. RESULTS: Of the 83 children with moyamoya followed at our center between 2003 and 2021, 13 had completed neuropsychological testing across multiple cognitive domains. Compared to age-based normative data, children in this sample had lower scores in overall intelligence (p = 0.003), global executive functioning (p = 0.005), and overall adaptive functioning (p = 0.015). There was no significant difference in overall intelligence between children with (n = 6) versus without (n = 7) a history of clinical stroke (p = 0.368), though children with any radiographic infarct scored lower in this domain (p = 0.032). CONCLUSION: In our cohort, children with moyamoya demonstrated impaired intelligence and executive functioning, even in the absence of clinical stroke. Neuropsychological evaluation should be considered standard of care for all children with moyamoya, even those without a history of clinical stroke.

Misery Perfusion and Tau Deposition in Atherosclerotic Major Cerebral Artery Disease: A 18F-Florzolotau Positron Emission Tomography Study.

BACKGROUND: Studies using animal models have shown that cerebral hypoperfusion causes hyperphosphorylation of tau protein, leading to neuronal damage. However, the relationship between hypoperfusion and tau deposition in humans is unclear. Hence, we aimed to determine whether cerebral hypoperfusion leading to decreased blood flow relative to metabolic demand [increased oxygen extraction fraction (OEF), misery perfusion] is associated with increased tau deposition in patients with atherosclerotic internal carotid artery or middle cerebral artery disease. METHODS: We prospectively evaluated the distribution of tau aggregate deposition using positron emission tomography and 18F-florzolotau (PMPBB3 [1-fluoro-3-((2-((1E,3E)-4-(6-(methylamino)pyridine-3-yl)buta-1,3-dien-1-yl)benzo[d]thiazol-6-yl)oxy)propan-2-ol)]) in 8 patients with atherosclerotic disease of the internal carotid artery or middle cerebral artery. The standardized uptake value ratio of 18F-florzolotau at 100 to 110 minutes after injection was calculated using the cerebellar cortex as a reference region and was correlated with OEF obtained from 15O-gas positron emission tomography in the middle cerebral artery distributions. RESULTS: Significant decreases in cerebral blood flow and cerebral metabolic rate of oxygen and increases in OEF were found in the hemisphere ipsilateral to the arterial lesion. 18F-florzolotau standardized uptake value ratio in this region was also greater than that in the contralateral hemisphere. In the ipsilateral hemisphere, 18F-florzolotau standardized uptake value ratio positively correlated with OEF values. CONCLUSIONS: This pilot study with a small sample size suggests that increases in OEF-misery perfusion-may be associated with increased tau aggregates deposition in atherosclerotic internal carotid artery or middle cerebral artery disease.

Cerebral Arteriopathies of Childhood - Current Approaches.

Up to more than half of previously healthy children presenting with their first arterial ischemic stroke have a cerebral arteriopathy. Cerebral arteriopathies during childhood can be congenital, reflecting abnormal vessel development, or acquired when caused by disruption of vascular homeostasis. Distinguishing different types of cerebral arteriopathies in children can be challenging but of great clinical value as they may dictate different disease and treatment courses, and clinical and radiologic outcomes. Furthermore, children with stroke due to a specific arteriopathy exhibit distinctive features when compared to those with stroke due to other causes or a different type of arteriopathy. These features become crucial in the management of pediatric stroke by choosing appropriate diagnostic and treatment strategies. The objective of this article is to provide the reader with a comprehensive up-to-date review of the classification, symptoms, diagnosis, treatment, and outcome of cerebral arteriopathies in children.

Neck-brain integrated ultrasound as a noninvasive screening tool to identify morphological features of middle cerebral artery disease.

BACKGROUND AND AIMS: Endovascular treatment is suitable for middle cerebral artery (MCA) with focal lesion. Therefore, accurate evaluation of the morphological features of MCA disease is critical. Ultrasonography is commonly used to screen for MCA lesions. However, there are few studies on lesion length. Using ultrasonography, we aimed to prospectively evaluate MCA disease with focal stenosis, long stenosis, focal occlusion, and long occlusion. METHODS: Patients with symptomatic MCA disease scheduled for digital subtraction angiography were enrolled. The ultrasonic parameters recorded included mean flow velocity at MCA (VMCA) and extracranial internal carotid artery (VICA), bilateral VMCA ratio, bilateral VICA ratio, and MCA flow continuity. RESULTS: A total of 278 MCAs were included. Compared to normal vessels, the bilateral VMCA ratio increased in the focal stenosis group and decreased in the long lesion and focal occlusion groups (all p < 0.05); the VICA and bilateral VICA ratio decreased in the long lesion group (all p < 0.01), and there was no significant difference in the focal lesion group (all p > 0.05). The optimal cut-offs were bilateral VMCA ratio <0.80 to predict long lesions and focal occlusions (sensitivity: 0.898, specificity: 0.975), and bilateral VICA ratio <0.84 to predict long lesions (sensitivity: 0.704, specificity: 0.879). The sensitivity and specificity to predict long occlusions were 96.7% and 94.8%, respectively, in the absence of MCA flow continuity. CONCLUSIONS: Neck-brain integrated ultrasound is an appropriate screening method for identifying MCA lesions with different morphologies. Endovascular treatment might not be recommended when bilateral VICA ratio <0.84 in patients with MCA lesions.

[Coronary CT angiography derived fractional flow reserve: the consideration and practice of functional evaluation for cerebral arterial diseases].

Cerebrovascular disease is a significant global public health concern, despite the diagnosis and treatment of stroke has made great progress in recent years, however, its mainly guided by anatomical indicators, which still needs to be further improved, and there is an urgent need to explore a more accurate and comprehensive functional imaging assessment method. Rapid development of coronary CT angiography derived fractional flow reserve (CT-FFR) has become an important technique for noninvasive evaluation of coronary artery disease, and these successful application experiences inspiried neurologists to explore the functional evaluation technique of cerebral arteries and demonstrated broad application prospects. In this paper, by analyzing and comparing the coronary CT-FFR technology, the progress, existing problems and possible solutions of the functional evaluation for cerebral arterial stenosis are discussed from the aspects of coronary CT-FFR study, cerebral artery functional evaluation study, and the comparison and consideration of cerebral arterial and coronary CT-FFR.

Clinical improvement of a toddler with COVID-19 focal cerebral arteriopathy possibly due to intra-arterial nimodipine.

Pediatric stroke is considered an infrequent complication of COVID-19. Focal cerebral arteriopathy (FCA) is one of the most common causes of arterial ischemic stroke in a previously healthy child. The present report describes a toddler with FCA most likely induced by SARS-CoV-2 infection who showed significant clinical improvement that may be related to injection of intra-arterial nimodipine. To our knowledge, this is the first reported use of nimodipine in this setting.

Neuronal Alterations in Secondary Thalamic Degeneration Due to Cerebral Infarction: A 11C-Flumazenil Positron Emission Tomography Study.

BACKGROUND: Studies using animal experiments have shown secondary neuronal degeneration in the thalamus after cerebral infarction. Neuroimaging studies in humans have revealed changes in imaging parameters in the thalamus, remote to the infarction. However, few studies have directly demonstrated neuronal changes in the thalamus in vivo. The purpose of this study was to determine whether secondary thalamic neuronal damage may manifest as a decrease in central benzodiazepine receptors in patients with cerebral infarction and internal carotid artery or middle cerebral artery disease. METHODS: We retrospectively analyzed the data of 140 patients with unilateral cerebral infarction ipsilateral to internal carotid artery or middle cerebral artery disease. All patients had quantitative measurements of 11C-flumazenil binding potential (FMZ-BP), cerebral blood flow, and cerebral metabolic rate of oxygen using positron emission tomography in the chronic stage. Region of interest analysis was performed using NeuroFlexer-an automated region of interest analysis software using NEUROSTAT. RESULTS: In the thalamus ipsilateral to the infarcts, the values of FMZ-BP, cerebral blood flow, and cerebral metabolic rate of oxygen were significantly lower than those in the contralateral thalamus. Significant correlations were found between the ipsilateral-to-contralateral ratio of FMZ-BP and the ipsilateral-to-contralateral ratio of cerebral blood flow or cerebral metabolic rate of oxygen in the thalamus. Patients with corona radiata infarcts and striatocapsular infarcts had significantly decreased ipsilateral-to-contralateral FMZ-BP ratio in the thalamus compared with those without. The ipsilateral-to-contralateral ratio of FMZ-BP in the thalamus was significantly correlated with the ipsilateral-to-contralateral cerebral metabolic rate of oxygen ratio in the frontal cortex and showed a significant negative correlation with the number of perseverative errors on the Wisconsin Card Sorting Test. CONCLUSIONS: Secondary thalamic neuronal damage may manifest as a decrease in central benzodiazepine receptors in patients with cerebral infarction and internal carotid artery or middle cerebral artery disease, which may be associated with frontal lobe dysfunction.

Characteristics of Moyamoya Syndrome in Pediatric Patients With Neurofibromatosis Type 1.

BACKGROUND: Moyamoya syndrome (MMS) is a progressive cerebral arteriopathy with increased incidence in children with neurofibromatosis type 1 (NF1). Despite the potential for significant neurological morbidity including stroke, little is known about the natural history, and no guidelines exist for screening and management of NF1-associated MMS. METHODS: We identified 152 literature cases of children aged ≤18 years with NF1-associated MMS. A meta-analysis was performed evaluating clinical and neuroimaging findings and patient outcomes. Data from 19 patients with NF1-associated MMS from our center treated from January 1995 to July 2020 were abstracted via chart review and similarly analyzed for clinical and neuroimaging features. RESULTS: Meta-analysis of literature cases showed a median age of MMS diagnosis of 6 years (interquartile range 3 to 10.8 years). Optic pathway gliomas were more common in patients with MMS (42%) compared with historical prevalence. Stroke or transient ischemic attack (TIA) was present at diagnosis in 46%. TIA and stroke were more common in patients with bilateral versus unilateral MMS (62% vs 34%, P = 0.001) and in children aged <4 years versus those aged ≥4 years (61% vs 40%, P = 0.02). Compared with the literature cases, our cohort was more frequently asymptomatic (42% vs 25%) and less likely to present with TIA or stroke (32% vs 46%) at diagnosis. CONCLUSIONS: These data suggest there is an aggressive form of MMS in children with NF1 <4 years of age. Therefore, early screening should be considered to facilitate early detection and treatment of cerebral arteriopathy.