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Background and ObjectivesSeizure incidence rates related to familial cerebral cavernous malformation (FCCM) are not well described, especially for children. To measure the seizure incidence rate, examine seizure predictors, and characterize epilepsy severity, we studied a cohort of children and adults with FCCM enrolled in the Brain Vascular Malformation Consortium (BVMC).MethodsSeizure data were collected from participants with FCCM in the BVMC at enrollment and during follow-up. We estimated seizure probability by age and tested whether cerebral cavernous malformation (CCM) counts or genotype were associated with earlier seizure onset.ResultsThe study cohort included 479 FCCM cases. Median age at enrollment was 42.5 years (interquartile range 22.5–55.0) and 19% were children (CCM1 (Common Hispanic Mutation) (88%), another CCM1 mutation (5%), CCM2 mutations (5%), and CCM3 mutations (2%). Prior to or during the study, 202 (42%) had a seizure. The cumulative incidence of a childhood seizure was 20.3% (95% confidence interval [CI] 17.0–23.4) and by age 80 years was 60.4% (95% CI 54.2–65.7). More total CCMs (hazard ratio [HR] 1.24 per SD unit increase, 95% CI 1.1–1.4) or more large CCMs (HR 1.5 per SD unit increase, 95% CI 1.2–1.9) than expected for age and sex increased seizure risk. A CCM3 mutation also increased risk compared to other mutations (HR 3.11, 95% CI 1.15–8.45). Individuals with a seizure prior to enrollment had increased hospitalization rates during follow-up (incidence rate ratio 10.9, 95% CI 2.41–49.32) compared to patients without a seizure history.DiscussionIndividuals with FCCM have a high seizure incidence and those with more CCMs or CCM3 genotype are at greater risk. Seizures increase health care utilization in FCCM.

Cerebrovascular malformations occur in both sporadic and inherited patterns. This paper reviews imaging and clinical features of cerebrovascular malformations with a genetic basis. Genetic diseases such as familial cerebral cavernous malformations and hereditary hemorrhagic telangiectasia often have manifestations in bone, skin, eyes, and visceral organs, which should be recognized. Genetic and molecular mechanisms underlying the inherited disorders are becoming better understood, and treatments are likely to follow. An interaction between the intestinal microbiome and formation of cerebral cavernous malformations has emerged, with possible treatment implications. Two-hit mechanisms are involved in these disorders, and additional triggering mechanisms are part of the development of malformations. Hereditary hemorrhagic telangiectasia encompasses a variety of vascular malformations, with widely varying risks, and a more recently recognized association with cortical malformations. Somatic mutations are implicated in the genesis of some sporadic malformations, which means that discoveries related to inherited disorders may aid treatment of sporadic cases. This paper summarizes the current state of knowledge of these conditions, salient features regarding mechanisms of development, and treatment prospects.

BACKGROUND AND PURPOSE: Cavernous malformations occur most often in the brain but can occur in the spinal cord. Small studies of patients with familial cerebral cavernous malformations suggested a prevalence of spinal cord cavernous malformations of 20%–42%. We aimed to review our familial cohort and prospectively estimate the prevalence of spinal cord cavernous malformations. MATERIALS AND METHODS: We initially reviewed our familial cerebral cavernous malformations cohort for spinal cord cavernous malformations and reviewed clinical spine MR imaging examinations for sequence sensitivity. We then prospectively performed research MR imaging of the spinal cord in 29 patients from the familial cohort to estimate the prevalence. RESULTS: Gradient-based sequences identified the most spinal cord cavernous malformations on clinical MR images, forming the basis for developing our screening MR imaging. Screening spinal cord MR imaging demonstrated a prevalence of 72.4%, and a positive correlation with patient age and number of cerebral cavernous malformations. CONCLUSIONS: Spinal cord cavernous malformations occur commonly in the familial cerebral cavernous malformation population. Gradient-based sequences are the most sensitive and should be used when spinal cord cavernous malformations are suspected. This study establishes the prevalence in the familial population at around 70% and supports the idea that this condition is a progressive systemic disease that affects the entire central nervous system.

Background To investigate whether common variants in EPHB4 and RASA1 are associated with cerebral cavernous malformation (CCM) disease severity phenotypes, including intracranial hemorrhage (ICH), total and large lesion counts. Methods Familial CCM cases enrolled in the Brain Vascular Malformation Consortium were included (n = 338). Total lesions and large lesions (≥5 mm) were counted on MRI; clinical history of ICH at enrollment was assessed by medical records. Samples were genotyped on the Affymetrix Axiom Genome‐Wide LAT1 Human Array. We tested the association of seven common variants (three in EPHB4 and four in RASA1) using multivariable logistic regression for ICH (odds ratio, OR) and multivariable linear regression for total and large lesion counts (proportional increase, PI), adjusting for age, sex, and three principal components. Significance was based on Bonferroni adjustment for multiple comparisons (0.05/7 variants = 0.007). Results EPHB4 variants were not significantly associated with CCM severity phenotypes. One RASA1 intronic variant (rs72783711 A>C) was significantly associated with ICH (OR = 1.82, 95% CI = 1.21–2.37, p = 0.004) and nominally associated with large lesion count (PI = 1.17, 95% CI = 1.03–1.32, p = 0.02). Conclusion A common RASA1 variant may be associated with ICH and large lesion count in familial CCM. EPHB4 variants were not associated with any of the three CCM severity phenotypes., We investigated whether common variants in EPHB4 and RASA1 are associated with familial cerebral cavernous malformation (CCM) disease severity phenotypes, including intracranial hemorrhage (ICH), total and large lesion counts. EPHB4 variants were not associated with any of the three CCM severity phenotypes. However, an intronic RASA1 variant was significantly associated with ICH and large lesion count in familial CCM, suggesting that the Ras‐Erk pathway may play a role in CCM disease severity.

Purpose This study aimed to characterize mood and quality of life and to examine the associations of these areas with subjective cognitive concerns and attitudes toward genetic testing for the Common Hispanic Mutation, a gene that has been associated with increased risk for CCM1. Method Fifty-four adults with previous genetic testing for the Common Hispanic Mutation completed a mail survey that included assessments of the above identified areas. Results Self-reported depressive symptoms and quality of life did not differ between those with positive and negative genetic test results. The negative group expressed a more favorable attitude toward genetic testing (p < 0.001). There was a trend toward more subjective cognitive concerns in the positive group (p = 0.06). Using generalized linear regression, more subjective cognitive concerns were associated with poorer quality of life and more depressive symptoms (p < 0.001). Poorer attitude toward genetic testing was also associated with poorer quality of life (p < 0.05). Conclusions Subjective cognitive concerns and negative attitudes toward genetic testing may influence emotional well-being after genetic testing for the Common Hispanic Mutation. Additional research is needed that uses objective neuropsychological measures to understand the associations of subjective cognitive concerns, emotional well-being, and cognitive test performance in individuals with CCM1. There is also a need for research that focuses on protective factors and resiliency following genetic testing for CCM1 and the development of mental health interventions to preempt psychosocial difficulties.

Familial cerebral cavernous malformations due to the common Hispanic mutation (FCCM1-CHM) is an endemic condition among the Hispanic population of the Southwestern United States associated with significant morbidity and mortality. Cutaneous vascular malformations (CVMs) can be found in individuals with FCCM1-CHM, but their morphology, prevalence, and association with cerebral cavernous malformations (CCMs) has not been well characterized. A cross-sectional study of 140 individuals with confirmed FCCM1-CHM was performed with statistical analyses of CVM, CCM, and patient characteristics. We then compared these findings to other cohorts with Familial cerebral cavernous malformations (FCCM) due to other mutations. We observed a higher overall prevalence and a different predominant morphological subtype of CVM compared to previous FCCM cohorts. While the number of CVMs was not a reliable indicator of the number of CCMs present, each person with one or more CVMs had evidence of central nervous system (CNS) disease. Awareness of the morphology of these cutaneous lesions can aid in the diagnosis of individuals with FCCM-CHM in Hispanic patients or those with family history of CCM.

Background: Familial cerebral cavernous malformations (FCCM) is an autosomal dominant disease caused by mutations in three genes: CCM1 , CCM2 , or CCM3 . FCCM patients typically present with multiple brain CCMs that can increase in number and size over time, and can cause intracranial hemorrhage (ICH) and other disabling symptoms, e.g., seizures, headaches, and deficits. Rates and predictors of ICH events in FCCM are not well described. The purpose of this study was to estimate ICH event rates and predictors in a cohort of FCCM patients followed prospectively. Methods: We collected baseline and follow-up data in 316 FCCM patients enrolled from 4 sites in the Brain Vascular Malformation Consortium CCM Project, including age, sex, race, CCM gene, CCM symptoms, and CCM burden (total and large CCMs>5mm) at baseline. We initially recruited CCM1 patients with the Common Hispanic Mutation (CHM), and later expanded to include other genetic types. We performed Kaplan-Meier survival analysis to estimate ICH event rates after enrollment, censoring at date of first treatment, death or last follow-up, out to 10 years. Cox regression analysis was performed to estimate hazard ratios (HR) of predictors, adjusting for age, sex, and family. Results: The majority of patients were female (63%) and of Hispanic ethnicity (83%). CCM gene mutation was known for 82%; 98% had CCM1 mutations (94% with CHM), 1% CCM2 , and 1% CCM3 . At enrollment, mean age was 39±20 years (range: 1-85), 32% had a history of ICH event, 38% had seizures, and 60% had headaches. Mean number of total and large CCMs was 55±103 and 4±7, respectively. Mean follow-up was 4.1±2.7 years. During 1285 person-years (PY) of follow-up, there were 31 ICH events for a rate of 2.4 per 100 PY (95% CI: 1.7-3.4) overall, 4.0 (2.5-6.6) in prior ICH patients, and 1.6 (1.0-2.8) in patients without prior ICH (HR=2.4, 95% CI: 1.2-4.9). ICH-free survival was not statistically significantly different by sex (HR=1.2, 95% CI: 0.6-2.8), age (HR=1.0 per decade, 0.8-1.2), total lesions (HR=1.2 per doubling, 0.9-1.5), or large lesions (HR=1.3 per doubling, 1.0-1.7). Conclusions: FCCM patients with prior history of ICH events are at higher risk for re-hemorrhage during follow-up. Additional studies are needed to identify predictors of ICH risk in FCCM.

This is a review of imaging techniques used to evaluate cerebral cavernous malformations (CCMs) and imaging findings associated with CCMs. This chapter includes discussion of computed tomography and magnetic resonance imaging sequences, appearance of CCMs and associated hemorrhage and key features to evaluate on imaging studies.

OBJECTIVE. The purpose of this study was to investigate whether MRI-typical and MRI-atypical intraosseous vascular malformations are associated with familial cerebral cavernous malformation (FCCM). MATERIALS AND METHODS. In a retrospective matched case-control study, two radiologists reviewed the spinal imaging, both CT and MRI, of 22 patients with FCCM seen between 2006 and 2017 and of age- and sex-matched control subjects for MRI-typical and MRI-atypical intraosseous vascular malformations. Quantitative analysis of lesions identified included vertebral level, size, and number of lesions. Pathologic samples from two lesions were analyzed for histologic and immunohistochemical features. Whether the presence of typical, atypical, and total intraosseous vascular malformations differed between patients and control subjects was tested. For patients with complete spinal imaging, whether intraosseous vascular malformations were associated with age, sex, brain lesion count, and spinal lesion count was also tested. RESULTS. MRI-atypical intraosseous vertebral malformations were more commonly present in patients with FCCM (p = 0.003). Sixteen lesions were found in nine patients and none in the control group. The numbers of MRI-typical intraosseous vascular malformations were similar between patients and control subjects (p = 0.480). Age was associated with typical intraosseous vascular malformations (p = 0.027), though not with atypical malformations. MRI-atypical malformations were larger (mean diameter double) than MRI-typical malformations (p = 0.023). Histologic analysis of two lesions from different patients with pathologic collapse revealed the same histologic features consistent with combined capillary-venous malformations. CONCLUSION. Vertebral capillary-venous malformations (MRI-atypical intraosseous vascular malformations) are common in patients with FCCM and may have a more aggressive clinical course than MRI-typical malformations.

Objective This study assessed the convergent validity of the NIHTB-CB in a sample of children and adolescents with CCM-1 and non-affected relatives. Method Twenty-two participants with CCM-1 and 7 non-affected relatives completed the NIHTB-CB and traditional neuropsychological measures. The following domains were assessed: memory (NIHTB-CB Picture Sequencing Memory and Child and Adolescent Memory Profile- Screening Index), word reading (NIHTB-CB Oral Reading and Wide Range Achievement Test-4th Word Reading [WRAT-4 WR]),processing speed (NIHTB-CB Pattern Comparison and Symbol Digit Modalities Test), and attention/working memory (NIHTB-CB List Sorting and Digit Span). Results The non-affected group scored higher than the CCM-1 group on WRAT-4 WR (t = 2.68, p = .02) and NIHTB-CB Oral Reading (t = 2.18, p = .05). The groups did not differ on the other measures (p > .05). Pearson’s correlations ranged from .45 for memory to .81 for word reading, demonstrating adequate construct validity for memory, processing speed, and attention/working memory and good to very good for word reading. The NIHTB-CB was more likely to identify participants as impaired for memory (17.2% vs 6.9%) and processing speed (62.1% vs. 3.4%). The traditional attention/working memory measure was more likely to identify participants as impaired (27.6% vs 3.4%). Impairment rates were similar for the word reading measures. Conclusions Of the domains considered, convergent validity was best established for word reading. Although correlations were adequate, rates of impairment differed for memory, processing speed, and attention/working memory, suggesting that caution is warranted when comparing the NIHTB-CB to traditional measures in these areas.

Noonan syndrome (NS) is an autosomal dominant developmental disorder caused by mutations in the RAS-MAPK signaling pathway that is well known for its relationship with oncogenesis. An 8.1-fold increased risk of cancer in Noonan syndrome has been reported, including childhood leukemia and solid tumors. The same study found a patient with a dysembryoplastic neuroepithelial tumor (DNET) and suggested that DNET tumors are associated with NS. Herein we report an 8-year-old boy with genetically confirmed NS and a DNET. Literature review identified eight other reports, supporting the association between NS and DNETs. The review also ascertained 13 non-DNET brain tumors in individuals with NS, bringing to 22 the total number of NS patients with brain tumors. Tumor growth while receiving growth hormone (GH) occurred in our patient and one other patient. It is unknown whether the development or progression of tumors is augmented by GH therapy, however there is concern based on epidemiological, animal and in vitro studies. This issue was addressed in a 2015 Pediatric Endocrine Society report noting there is not enough data available to assess the safety of GH therapy in children with neoplasia-predisposition syndromes. The authors recommend that GH use in children with such disorders, including NS, be undertaken with appropriate surveillance for malignancies. Our case report and literature review underscore the association of NS with CNS tumors, particularly DNET, and call attention to the recommendation that clinicians treating NS patients with GH do so with awareness of the possibility of increased neoplasia risk.

Background: Patient-reported quality of life (QoL) using standardized tools have been proposed as outcome measures in clinical trials. The NeuroQoL scale has been evaluated in patients with common neurological disorders (e.g., ischemic stroke, epilepsy, ALS, and Parkinson’s), but has not been applied to familial cerebral cavernous malformation (FCCM). FCCM is typically characterized by multiple brain lesions that can cause clinical symptoms (hemorrhages, seizures, headaches, neurological deficits) and affect QoL. The purpose of this study was to summarize NeuroQoL domain scores in FCCM patients. Methods: NeuroQoL short forms covering 12 QoL domains (Figure) were completed by 50 FCCM adults enrolled in the Brain Vascular Malformation Consortium CCM Project. Raw scores summing responses in each domain were converted to T-scores, which are standardized to general (8 domains) or clinical (4 domains) reference populations with mean of 50 and standard deviation of 10. One-sample t-tests were used to determine whether mean T-scores were significantly different from 50 (p Results: We observed significant differences between FCCM and the reference populations on several domains (Figure). Compared to the general reference population, FCCM patients were more likely to have higher positive affect (56, p Conclusion: FCCM patients differed from the reference populations on several NeuroQoL domains, including positive affect, depression, stigma, fatigue and social satisfaction. Further studies are needed to understand the effect of clinical symptoms on NeuroQoL domains in FCCM.

Background and purposeFamilial cerebral cavernous malformations, an autosomal dominant disorder, result in excess morbidity and mortality in affected patients. The disorder is most prevalent in the Southwest United States, where the affected families are most often carriers of the CCM1-KRIT1 Common Hispanic Mutation. The brain and spinal cord parenchyma in these individuals is usually affected by multiple cavernous malformations. Previous studies have shown abnormalities of endothelial cell junctions and the blood-brain barrier in cerebral cavernous malformations. Endothelial cell abnormalities have also been described in pathologic studies of white matter hyperintensities. We compared the prevalence of white matter hyperintensities in a population with known familial cerebral cavernous malformations.Materials and methodsWe examined 191 subjects with familial cerebral cavernous malformations who were enrolled into an institutional review board-approved study. All carry the same Common Hispanic Mutation in the CCM1 gene. Each subject underwent 3T MR imaging, including gradient recalled-echo, SWI, and FLAIR sequences. The number of cavernous malformations and the number of nonhemorrhagic white matter hyperintensities were counted. Subjects older than 60 years of age were excluded due to the high prevalence of white matter lesions in this population, and children younger than 6 were excluded due to potential sedation requirements. Logistic regression analysis was performed to determine the prevalence of abnormal white matter hyperintensities in those with familial cerebral cavernous malformations compared with healthy controls or those with sporadic cerebral cavernous malformation within the familial cerebral cavernous malformations group; it was also performed to evaluate the associations between abnormal white matter hyperintensities and age, sex, headaches, thyroid disease, diabetes, hypertension, hyperlipidemia, seizure history, or modified Rankin Scale score.ResultsFamilial CCM1 carriers have a higher prevalence of abnormal white matter hyperintensities (15.4%) compared with both control populations (2.1% and 2.5%, respectively) (P < .05). Logistic regression showed no statistical association with sex, headaches, hyperlipidemia, hypertension, thyroid disease, seizure history, number of cerebral cavernous malformations, or modified Rankin Scale score among those with familial cerebral cavernous malformation. An expected correlation with age was shown.ConclusionsFamilial CCM1 carriers have not only an increased number of cerebral cavernous malformations but also an increased number of white matter T2 hyperintensities, spatially distinct from cerebral cavernous malformations, which exceeded that of a healthy population. Clinical findings did not explain the association with abnormal white matter hyperintensities in the familial cerebral cavernous malformation population. To our knowledge, these relationships have not been previously reported. This finding suggests an additional manifestation of endothelial abnormalities in this population.

Cerebral cavernous malformations (CCMs) are a cause of stroke and seizure for which no effective medical therapies yet exist. CCMs arise from the loss of an adaptor complex that negatively regulates MEKK3-KLF2/4 signalling in brain endothelial cells, but upstream activators of this disease pathway have yet to be identified. Here we identify endothelial Toll-like receptor 4 (TLR4) and the gut microbiome as critical stimulants of CCM formation. Activation of TLR4 by Gram-negative bacteria or lipopolysaccharide accelerates CCM formation, and genetic or pharmacologic blockade of TLR4 signalling prevents CCM formation in mice. Polymorphisms that increase expression of the TLR4 gene or the gene encoding its co-receptor CD14 are associated with higher CCM lesion burden in humans. Germ-free mice are protected from CCM formation, and a single course of antibiotics permanently alters CCM susceptibility in mice. These studies identify unexpected roles for the microbiome and innate immune signalling in the pathogenesis of a cerebrovascular disease, as well as strategies for its treatment.

BackgroundDespite many publications about cerebral cavernous malformations (CCMs), controversy remains regarding diagnostic and management strategies.ObjectiveTo develop guidelines for CCM management.MethodsThe Angioma Alliance ( www.angioma.org ), the patient support group in the United States advocating on behalf of patients and research in CCM, convened a multidisciplinary writing group comprising expert CCM clinicians to help summarize the existing literature related to the clinical care of CCM, focusing on 5 topics: (1) epidemiology and natural history, (2) genetic testing and counseling, (3) diagnostic criteria and radiology standards, (4) neurosurgical considerations, and (5) neurological considerations. The group reviewed literature, rated evidence, developed recommendations, and established consensus, controversies, and knowledge gaps according to a prespecified protocol.ResultsOf 1270 publications published between January 1, 1983 and September 31, 2014, we selected 98 based on methodological criteria, and identified 38 additional recent or relevant publications. Topic authors used these publications to summarize current knowledge and arrive at 23 consensus management recommendations, which we rated by class (size of effect) and level (estimate of certainty) according to the American Heart Association/American Stroke Association criteria. No recommendation was levelA (because of the absence of randomized controlled trials), 11 (48%) were levelB, and 12 (52%) were levelC. Recommendations were classI in 8 (35%), classII in 10 (43%), and classIII in 5 (22%).ConclusionCurrent evidence supports recommendations for the management of CCM, but their generally low levels and classes mandate further research to better inform clinical practice and update these recommendations. The complete recommendations document, including the criteria for selecting reference citations, a more detailed justification of the respective recommendations, and a summary of controversies and knowledge gaps, was similarly peer reviewed and is available on line www.angioma.org/CCMGuidelines .

Purpose To determine if adrenal calcifications seen at computed tomography (CT) are associated with familial cerebral cavernous malformations (fCCMs) in carriers of the CCM1 Common Hispanic Mutation. Materials and Methods This study was approved by the institutional review board. The authors retrospectively reviewed abdominal CT scans in 38 patients with fCCM, 38 unaffected age- and sex-matched control subjects, and 13 patients with sporadic, nonfamilial cerebral cavernous malformation (CCM). The size, number, and laterality of calcifications and the morphologic characteristics of the adrenal gland were recorded. Brain lesion count was recorded from brain magnetic resonance (MR) imaging in patients with fCCM. The prevalence of adrenal calcifications in patients with fCCM was compared with that in unaffected control subjects and those with sporadic CCM by using the Fisher exact test. Additional analyses were performed to determine whether age and brain lesion count were associated with adrenal findings in patients with fCCM. Results Small focal calcifications (SFCs) (≤5 mm) were seen in one or both adrenal glands in 19 of the 38 patients with fCCM (50%), compared with 0 of the 38 unaffected control subjects (P < .001) and 0 of the 13 subjects with sporadic CCM (P = .001). Adrenal calcifications in patients with fCCM were more frequently left sided, with 17 of 19 patients having more SFCs in the left adrenal gland than the right adrenal gland and 50 of the 61 observed SFCs (82%) found in the left adrenal gland. No subjects had SFCs on the right side only. In patients with fCCM, the presence of SFCs showed a positive correlation with age (P < .001) and number of brain lesions (P < .001). Conclusion Adrenal calcifications identified on CT scans are common in patients with fCCM and may be a clinically silent manifestation of disease. © RSNA, 2017.

Objectives Extraglottic airway devices (EADs) are now commonly placed for airway management of critically ill or injured patients, particularly by emergency medical services providers in the out-of-hospital setting. Recent literature has suggested that EADs may cause decreased cerebral blood flow due to compression of the arteries of the neck by the devices’ inflated cuffs. Methods The authors identified a cohort of 17 patients presumed to be hemodynamically stable with EADs in place who underwent radiographic imaging of the neck. These studies were reviewed by a neuroradiologist to determine if mechanical compression of the carotid arteries was present. Results None of the 17 cases reviewed had radiographically evident mechanical compression of the carotid artery. Conclusions Until further studies are performed in which cerebral perfusion is evaluated prospectively in both hemodynamically stable and unstable human subjects, there is insufficicent evidence to recommend against the use of extraglottic airways in the emergency setting on the basis of carotid artery compression.

The aim of this study is to quantitatively evaluate the behavior of CNS cavernous malformations (CCMs) using a dynamic contrast-enhanced MRI (DCEMRI) technique sensitive for slow transfer rates of gadolinium. The prospective study was approved by the institutional review board and was HIPPA compliant. Written informed consent was obtained from 14 subjects with familial CCMs (4 men and 10 women, ages 22-76 years, mean 48.1 years). Following routine anatomic MRI of the brain, DCEMRI was performed for six slices, using T1 mapping with partial inversion recovery (TAPIR) to calculate T1 values, following administration of 0.025 mmol/kg gadolinium DTPA. The transfer rate (Ki) was calculated using the Patlak model, and Ki within CCMs was compared to normal-appearing white matter as well as to 17 normal control subjects previously studied. All subjects had typical MRI appearance of CCMs. Thirty-nine CCMs were studied using DCEMRI. Ki was low or normal in 12 lesions and elevated from 1.4 to 12 times higher than background in the remaining 27 lesions. Ki ranged from 2.1E-6 to 9.63E-4 min(-1), mean 3.55E-4. Normal-appearing white matter in the CCM patients had a mean Ki of 1.57E-4, not statistically different from mean WM Ki of 1.47E-4 in controls. TAPIR-based DCEMRI technique permits quantifiable assessment of CCMs in vivo and reveals considerable differences not seen with conventional MRI. Potential applications include correlation with biologic behavior such as lesion growth or hemorrage, and measurement of drug effects.

Object Fenestration of the lamina terminalis (FLT) during aneurysm surgery for subarachnoid hemorrhage can, in theory, improve CSF circulation from the lateral and third ventricles to the cortical subarachnoid space, which may, in turn, decrease the incidence of hydrocephalus and vasospasm. However, the actual effects of FLT on CSF circulation have been difficult to determine, due to confounding factors. In addition, it is unclear whether the lamina terminalis remains functionally patent when the brain resumes its normal position. The goal of this study was to assess the functional patency of the fenestrated lamina terminalis in patients who underwent surgery for ruptured aneurysms. Methods This prospective study included 15 patients who underwent surgical clipping of ruptured anterior circulation aneurysms, with FLT performed during surgery. On postoperative Day 1, the external ventricular drain of each patient was closed, and 1 ml of Omnipaque 300, an iodine based contrast agent, was injected intraventricularly, accompanied by cranial maneuvering designed to position the contrast agent adjacent to the lamina terminalis. Three to 5 minutes after cranial maneuvering, the flow of contrast agent into the basal cisterns was assessed with CT imaging. Flow was verified by an increase in Hounsfield units in a prespecified “region of interest” within the basal cisterns on the CT scan. This procedure was performed using a standardized protocol designed in consultation with the Department of Radiology and approved by the institutional review board. One patient who underwent endoscopic third ventriculostomy was recruited as a positive control to validate the technique, and 1 patient who underwent aneurysm clipping but not FLT was recruited as a negative control. Results Seventeen patients consented to study participation. In the 15 patients who underwent aneurysm clipping and FLT, and the negative control patient who underwent aneurysm clipping but not FLT, the contrast agent followed the normal ventricular pathway from the lateral ventricles into the fourth ventricle, and did not appear in the basal cisterns. In the positive control patient, the contrast agent robustly and immediately filled the basal cisterns. Conclusions Fenestration of the lamina terminalis did not result in functional patency of the lamina terminalis when performed as part of surgical clipping for ruptured aneurysms.

Familial cerebral cavernous malformations are autosomal dominant conditions that can result in significant morbidity. A two-hit mechanism is accepted as likely responsible for formation of these malformations. We present two patients with this disease who received therapeutic radiation and developed very high numbers of malformations within the radiation ports, supporting radiation as an accelerator of lesion formation and suggesting implications for risks of radiation in this disease.

Objective Magnetic resonance imaging (MRI) often demonstrates brain lesions in neuropsychiatric systemic lupus erythematosus (NPSLE). The present study compared postmortem histopathology with premortem MRI in NPSLE. Methods Two hundred subjects with NPSLE were studied prospectively with MRI over a 10-year period during which 22 subjects died. In 14 subjects, a brain autopsy with histopathology, that permitted direct comparison with premortem MRI, was successfully obtained. Surface anatomy was used to determine the approximate location of individual lesions. Results Premortem MRI findings in fatal NPSLE were small focal white matter lesions (100%), cortical atrophy (64%), ventricular dilation (57%), cerebral edema (50%), diffuse white matter abnormalities (43%), focal atrophy (36%), cerebral infarction (29%), acute leukoencephalopathy (25%), intracranial hemorrhage (21%), and calcifications (7%). Microscopic findings in fatal NPSLE included global ischemic changes (57%), parenchymal edema (50%), microhemorrhages (43%), glial hyperplasia (43%), diffuse neuronal/axonal loss (36%), resolved cerebral infarction (33%), microthomboemboli (29%), blood vessel remodeling (29%), acute cerebral infarction (14%), acute macrohemorrhages (14%), and resolved intracranial hemorrhages (7%). Cortical atrophy and ventricular dilation seen by MRI accurately predicted brain mass at autopsy (r = −0.72, P = 0.01, and r = −0.77, P = 0.01, respectively). Cerebral autopsy findings, including infarction, cerebral edema, intracranial hemorrhage, calcifications, cysts, and focal atrophy, were also predicted accurately by premortem MRI. Conclusion Brain lesions in NPSLE detected by MRI accurately represent serious underlying cerebrovascular and parenchymal brain injury on pathology.

To explore the effects of commonly encountered pathology on auditory recognition strategies in elderly participants, magnetoencephalographic (MEG) brain activation patterns and performance were examined in 30 elderly [18 controls and 12 elderly with mild cognitive impairment (MCI) or probable Alzheimer's disease (AD)]. It was predicted that participants with known pathology would reveal different networks of brain activation, compared to healthy elderly, which should correlate with poorer performance. Participants heard a list of words representing common objects, twice. After 20 minutes a list of new and old words was presented and participants judged whether each word was heard earlier. MEG responses were analyzed using a semiautomated source modeling procedure. A cluster analysis using all subjects' MEG sources revealed three dominant patterns of activity which correlated with IQ and task performance. The highest performing group revealed activity in premotor, anterior temporal, and superior parietal lobes with little contribution from prefrontal cortex. Performance and brain activation patterns were also compared for individuals with or without abnormalities such as white matter hyperintensities and/or volume reduction evidenced on their MRIs. Memory performance and activation patterns for individuals with white matter hyperintensities resembled the group of MCI/AD patients. These results emphasize the following: (1) general pathology correlates with cognitive decline and (2) full characterization of the health of elderly participants is important in studies of normal aging since random samples from the elderly population are apt to include individuals with subclinical pathology that can affect cognitive performance.

As a part of a larger study of normal aging and Alzheimer’s disease (AD), which included patients with mild cognitive impairment (MCI), we investigated the response to median nerve stimulation in primary and secondary somatosensory areas. We hypothesized that the somatosensory response would be relatively spared given the reported late involvement of sensory areas in the progression of AD. We applied brief pulses of electric current to left and right median nerves to test the somato-sensory response in normal elderly (NE), MCI, and AD. MEG responses were measured and were analyzed with a semi-automated source localization algorithm to characterize source locations and timecourses. We found an overall difference in the amplitude of the response of the primary somatosensory source (SI) based on diagnosis. Across the first three peaks of the SI response, the MCI patients exhibited a larger amplitude response than the NE and AD groups (P < 0.03). Additional relationships between neuropsychological measures and SI amplitude were also determined. There was no significant difference in amplitude for the contralateral secondary somatosensory source across diagnostic category. These results suggest that somatosensory cortex is affected early in the progression of AD and may have some consequence on behavioral and functional measures.

BACKGROUND AND PURPOSE: CCMs are commonly associated with DVAs, but the incidence of association in familial CCM is unknown. The presence of a DVA significantly complicates surgical management of a CCM because of the risk of compromised venous drainage. In this investigation, we compared the incidence of a DVA in the presence of a CCM in sporadic and familial CCM cases comprising predominantly familial CCM with the Southwestern US common Hispanic mutation (or Q455X mutation) of CCM1 . MATERIALS AND METHODS: Retrospective review was performed of 112 patients identified with CCM. MR imaging review included the presence or absence of a DVA and number, location, size, and signal-intensity characteristics of CCMs. Record review included patient and family history and documented genetic mutations. Statistical analysis was performed by using the Fisher exact and 2-sample t tests. RESULTS: Eighty-one cases were familial, 18 were sporadic, and 13 were indeterminate. There were a total of 2212 CCMs: 2176, 21, and 15 in the familial, sporadic, and indeterminate groups, respectively. There was a close association of CCM and DVA (an apparent combined vascular lesion) in 8 of 18 (44%) sporadic cases and only 1 possible such association in the familial cases. The difference was highly statistically significant ( P < .0001). CONCLUSIONS: Familial CCMs are unlikely to be associated with DVAs, and sporadic CCMs have a high rate of association with DVA. This difference in imaging features of familial and sporadic CCMs suggests the possibility of a different developmental mechanism. CCM : cerebral cavernous malformation DVA : developmental venous anomaly FLAIR : fluid-attenuated inversion recovery FSE : fast spin-echo GR : gradient recall SE : spin-echo SWI : susceptibility-weighted imaging

Background Familial Cerebral Cavernous Malformation type 1 (CCM1) is an autosomal dominant disease caused by mutations in the Krev Interaction Trapped 1 (KRIT1/CCM1) gene, and characterized by multiple brain lesions. CCM lesions manifest across a range of different phenotypes, including wide differences in lesion number, size and susceptibility to intracerebral hemorrhage (ICH). Oxidative stress plays an important role in cerebrovascular disease pathogenesis, raising the possibility that inter-individual variability in genes related to oxidative stress may contribute to the phenotypic differences observed in CCM1 disease. Here, we investigated whether candidate oxidative stress-related cytochrome P450 (CYP) and matrix metalloproteinase (MMP) genetic markers grouped by superfamilies, families or genes, or analyzed individually influence the severity of CCM1 disease. Methods Clinical assessment and cerebral susceptibility-weighted magnetic resonance imaging (SWI) were performed to determine total and large (≥5 mm in diameter) lesion counts as well as ICH in 188 Hispanic CCM1 patients harboring the founder KRIT1/CCM1 ‘common Hispanic mutation’ (CCM1–CHM). Samples were genotyped on the Affymetrix Axiom Genome-Wide LAT1 Human Array. We analyzed 1,122 genetic markers (both single nucleotide polymorphisms (SNPs) and insertion/deletions) grouped by CYP and MMP superfamily, family or gene for association with total or large lesion count and ICH adjusted for age at enrollment and gender. Genetic markers bearing the associations were then analyzed individually. Results The CYP superfamily showed a trend toward association with total lesion count (P=0.057) and large lesion count (P=0.088) in contrast to the MMP superfamily. The CYP4 and CYP8 families were associated with either large lesion count or total lesion count (P=0.014), and two other families (CYP46 and the MMP Stromelysins) were associated with ICH (P=0.011 and 0.007, respectively). CYP4F12 rs11085971, CYP8A1 rs5628, CYP46A1 rs10151332, and MMP3 rs117153070 single SNPs, mainly bearing the above-mentioned associations, were also individually associated with CCM1 disease severity. Conclusions Overall, our candidate oxidative stress-related genetic markers set approach outlined CYP and MMP families and identified suggestive SNPs that may impact the severity of CCM1 disease, including the development of numerous and large CCM lesions and ICH. These novel genetic risk factors of prognostic value could serve as early objective predictors of disease outcome and might ultimately provide better options for disease prevention and treatment., Graphical abstract, Highlights • Inter-individual variability in oxidative stress-related genes may impact CCM1 disease severity. • CYP4 and CYP8 families were associated with either large lesion or total lesion count, while CYP46 and MMP Stromelysin families were associated with ICH. • Single SNPs in CYP4F8, CYP4F11, CYP4F12, CYP8A1, CYP19A1, CYP27A1, CYP27B1, CYP46A1 and CYP51A1 genes showed significant associations with at least one disease severity phenotype. • A single SNP in the MMP3 gene was strongly associated with ICH. • CYP and MMP SNPs associated with CCM1 disease severity could serve as early objective predictors of disease susceptibility and outcome.

Infectious agents have been investigated, developed, and used by both governments and terrorist groups as weapons of mass destruction. CNS infections, though traditionally considered less often than respiratory diseases in this scenario, may be very important. Viruses responsible for encephalitides can be highly infectious in aerosol form. CNS involvement in anthrax is ominous but should change treatment. Brucellosis, plague, Q fever, and other bacteria can uncommonly manifest with meningoencephalitis and other findings. Emerging diseases may also pose threats. We review infectious agents of particular concern for purposes of biowarfare with respect to CNS manifestations and imaging features.

Neuroimaging studies of healthy aging often reveal differences in neural activation patterns between young and elderly groups for episodic memory tasks, even though there are no differences in behavioral performance. One explanation typically offered is that the elderly compensate for their memory deficiencies through the recruitment of additional prefrontal regions. The present study of healthy aging compared magnetoencephalographic (MEG) time-courses localized to specific cortical regions in two groups of subjects (20-29 years and >or=65 years) during a visual delayed-match-to-sample (DMS) task. MR morphometrics and neuropsychological test results were also examined with the hope of providing insight into the nature of the age-related differences. The behavioral results indicated no differences in performance between young and elderly groups. Although there was a main effect of age on the latency of the initial peak in primary/secondary visual cortex, these longer latencies were not correlated with the performance of elderly on the DMS task. The lateral occipital gyrus (LOG) revealed qualitatively different patterns of activity for the two age groups corroborated by neuropsychological test results. Morphometric results for the young versus elderly groups revealed less white (WM) and gray matter (GM) volumes in the frontal lobes of the elderly. When a group of middle-aged subjects (33-43 years) was included in the morphometric analyses, the middle-aged subjects revealed statistically greater WM volumes in frontal and parietal cortex suggesting immature WM tracts in the young. Perhaps our elderly utilized a different strategy compared to the young due to the different brain maturation levels of these groups.

Congenital fibrosis of the extraocular muscles type 1 (CFEOM1; OMIM #135700) is an autosomal dominant strabismus disorder associated with defects of the oculomotor nerve. We show that individuals with CFEOM1 harbor heterozygous missense mutations in a kinesin motor protein encoded by KIF21A. We identified six different mutations in 44 of 45 probands. The primary mutational hotspots are in the stalk domain, highlighting an important new role for KIF21A and its stalk in the formation of the oculomotor axis.

Objective To investigate neurometabolite concentrations in right prefrontal white matter in children with attention-deficit/hyperactivity disorder (ADHD) and relations of neurometabolites with attention skill and frontal anatomy. Method Single voxel proton magnetic resonance spectroscopy (1H-MRS), quantitative morphometric analysis of left and right dorsolateral frontal volumes, and assessment of attentional problems with the Conners Continuous Performance Test were undertaken in 23 children (17 male) with ADHD (with no comorbid learning disabilities) and 24 matched controls (16 male). Results No overall group differences were found for any neurometabolite. However, a group by sex interaction was noted for N-acetylaspartate, such that girls with ADHD had especially low concentrations. Morphological analyses revealed smaller right (but not left) dorsolateral volumes in children with ADHD, and in the ADHD group this volume correlated with neurometabolite concentrations. In the ADHD group Continuous Performance Test performance was related to both dorsolateral volume and the creatine-phosphocreatine peak from 1H-MRS. Conclusions These results add to a growing body of evidence suggesting sex-specific neurobiological differences in ADHD and draw attention to relationships between neurochemistry, neuroanatomy, and performance in children with ADHD. Study limitations include small sample size and clinical heterogeneity among the children with ADHD.

Reduced frontal N -acetylaspartate (NAA) has been repeatedly found in chronic schizophrenia and suggests neuronal loss or dysfunction. However, the potential confounding effect of antipsychotic drugs on NAA has not been resolved. The few studies of antipsychotic-naive patients are inconclusive. A recent report suggests that antipsychotic drugs may increase NAA in the dorsolateral prefrontal cortex (DLPFC). We studied 10 minimally treated (less than 3 weeks lifetime exposure) schizophrenia patients and 10 normal controls with single-voxel proton magnetic resonance spectroscopy ( 1 H-MRS) of the left frontal and occipital lobes. Concentrations of NAA, Cho, and Cre were determined and corrected for the proportion of cerebrospinal fluid (CSF) in the voxel. Patients were treated in a randomized-controlled double-blind design with either haloperidol or quetiapine. 1 H-MRS was repeated within a year. There were no differences in frontal or occipital NAA between patients and controls at baseline. However, frontal NAA was reduced in the schizophrenia group within the first year of treatment. Patients had a clear clinical response to treatment but changes in frontal NAA were not correlated with symptom improvement. The well-described reduced frontal NAA in schizophrenia may not be a trait of the illness but may represent medication effect or progression of the disease.

Objective: Previous proton magnetic resonance spectroscopy (1H-MRS) studies in posttraumatic stress disorder (PTSD) report decreased hippocampal N-acetylaspartate (NAA), an indicator of neuronal integrity. However, other areas of the brain need to be explored. The objective of this study was to investigate the specificity of hippocampal NAA concentration changes in PTSD by also examining a control region, the occipital white matter (OWM). Methods: Eight patients with PTSD and 5 control subjects underwent single-voxel 1H-MRS of the hippocampi and bilateral OWM. Absolute neurometabolite concentrations were determined. Preliminary Results: Trends toward reduced left hippocampal NAA and creatine (Cre) were found in the PTSD group. PTSD subjects also had reduced bilateral OWM Cre. Conclusions: The preliminary results of our study in civilians with PTSD replicate previous MRS studies and are consistent with decreased hippocampal neuronal integrity without effects in the OWM. Replication of our findings is needed.

OBJECTIVE: Proton magnetic resonance spectroscopy (1H-MRS) studies of medicated patients with schizophrenia suggest high choline levels in the caudate nucleus. However, assessments of antipsychotic-naive patients are needed. METHOD: The authors studied 11 antipsychotic-naive schizophrenia patients and 11 normal comparison subjects with single-voxel 1H-MRS of the left caudate nucleus. Concentrations of N-acetylaspartate, choline, and creatine were determined and corrected for the proportion of cerebrospinal fluid in the voxel. RESULTS: The patients with schizophrenia had significantly higher levels of choline than the comparison subjects, while the other two metabolites did not differ between groups. CONCLUSIONS: High caudate choline levels in schizophrenia are not secondary to antipsychotic treatment.

Familial cerebral cavernous malformation type 1 (CCM1) is an autosomal dominant disease caused by mutations in the Krev Interaction Trapped 1 (KRIT1/CCM1) gene, and characterized by multiple brain lesions that often result in intracerebral hemorrhage (ICH), seizures, and neurological deficits. Carriers of the same genetic mutation can present with variable symptoms and severity of disease, suggesting the influence of modifier factors. Evidence is emerging that inflammation and immune response play a role in the pathogenesis of CCM. The purpose of this study was to investigate whether common variants in inflammatory and immune response genes influence the severity of familial CCM1 disease, as manifested by ICH and greater brain lesion count.Hispanic CCM1 patients (n=188) harboring the founder Q455X 'common Hispanic mutation' (CHM) in the KRIT1 gene were analyzed at baseline. Participants were enrolled between June 2010 and March 2014 either through the Brain Vascular Malformation Consortium (BVMC) study or through the Angioma Alliance organization. Clinical assessment and cerebral susceptibility-weighted magnetic resonance imaging were performed to determine ICH as well as total and large (≥5 mm in diameter) lesion counts. Samples were genotyped on the Affymetrix Axiom Genome-Wide LAT1 Human Array. We analyzed 830 variants in 56 inflammatory and immune response genes for association with ICH and residuals of log-transformed total or large lesion count adjusted for age at enrollment and gender. Variants were analyzed individually or grouped by sub-pathways or whole pathways.At baseline, 30.3% of CCM1-CHM subjects had ICH, with a mean ± standard deviation (SD) of 60.1±115.0 (range 0-713) for total lesions and 4.9±8.7 (range 0-104) for large lesions. The heritability estimates explained by all autosomal variants were 0.20 (SE=0.31), 0.81 (SE=0.17), and 0.48 (SE=0.19), for ICH, total lesion count, and large lesion count, respectively. TGFBR2 rs9823731 was significantly associated with ICH as well as with the total and large lesion counts (p≤0.017). Further, IL-4 rs9327638, CD14 rs778588, IL-6R rs114660934 and MSR1 rs62489577 were associated with two markers of disease severity. Finally, the whole pathway was associated with total lesion count (p=0.005) with TLR-4 rs10759930, CD14 rs778588, IL-6R rs114660934 and IGH rs57767447 mainly bearing this association. Eicosanoid signaling, extracellular pattern recognition, and immune response sub-pathways were also associated with the total lesion count.These results suggest that polymorphisms in inflammatory and immune response pathways contribute to variability in CCM1 disease severity and might be used as predictors of disease severity. In particular, TGFBR2 rs9823731 was associated with all three markers of CCM1 disease severity tested, suggesting that TGFBR2 might be a key participant in the mechanism underlying CCM1 disease severity and phenotype variability. However, further longitudinal studies in larger sample sizes are needed to confirm these findings.

Balamuthia mandrillaris is a free-living amoeba that can cause granulomatous amebic encephalitis (GAE). We report a case in an individual with a history of alcohol abuse, cocaine use, and ditch water exposure. This is the first reported case of GAE due to B mandrillaris in New Mexico.

Hydranencephaly is a condition in which cerebral hemispheres are absent and reduced to fluid-filled sacs in a normal skull. Numerous causes have been proposed. We report a male infant with hydranencephaly and congenital vascular malformations (port wine stains, generalized nevus flammeus, anomalous retinal vessels, and absent internal carotid flow). Magnetic resonance imaging of the brain showed absence of most of the cerebrum except for small portions of the occipital cortex and thalami. Magnetic resonance angiography showed flow within the vertebral and basilar arteries without internal carotid intracranial flow above the internal carotid petrous and cavernous portion. This is a report of cutaneous and retinal malformations associated with hydranencephaly. Vascular malformations of larger vessels (e.g., webbing of the carotid arteries and an absent internal carotid arterial system) have been observed in other infants with hydranencephaly, and are proposed to lead to brain destruction. The case reported herein supports the role of primary vascular malformations in the development of some cases of hydranencephaly.

Gerstmann syndrome (GS) comprises four interlaced neuropsychological symptoms including finger agnosia, right-left confusion, agraphia, and acalculia. While GS is commonly associated with focal lesions to the region of the left angular gyrus, it has also been associated with numerous diffuse etiologies including atrophy, alcoholism, carbon monoxide poisoning, lead intoxication and anaphylactic shock. Thus, a vigorous debate has emerged as to whether GS represents a syndrome arising from general brain decline or a distinct and localizing lesion. We report a right-handed patient who developed neuropsychological dysfunction secondary to systemic lupus erythematosus (SLE). Neuropsychological evaluation found the patient to exhibit symptoms consistent with the GS tetrad, as well as general cognitive decline. Magnetic resonance imaging revealed a distinct focal lesion of the left parieto-occipital white matter underlying the angular gyrus as well as diffuse atrophy. (1)H-magnetic resonance spectroscopy revealed substantial metabolic derangement in a voxel placed within the visible lesion, although substantial metabolic derangement was observed in regions remote from the focal pathology. Thus, GS in this first case in SLE would appear to comprise a focal neurological tetrad of disorders within a more general pattern of cognitive decline and metabolic derangement.

Object. Confirmation of cervical spine stability is difficult to obtain in the comatose or obtunded trauma patient. Concurrent therapies such as endotracheal intubation and the application of rigid cervical collars diminish the utility of plain radiographs. Bony as well as supportive soft-tissue structures must be evaluated before the cervical spine can be determined to be uninjured. Although major injuries to extradural soft-tissue structures in the awake trauma patient are frequently excluded by physical examination, when the patient is obtunded the physical examination may be unreliable. Therefore, an enhanced diagnostic method for the evaluation of soft-tissue injury is desirable. The authors conducted a study in which magnetic resonance (MR) imaging was used as such a method to assess posttraumatic spinal stability in the comatose or obtunded patient. Methods. Early, limited (sagittal T1- and T2-weighted) MR imaging was performed posttruama in 121 patients to assess soft-tissue injury. In all patients the mechanism of injury potentially could be associated with cervical spine instability, and each patient was endotracheally intubated because of head injury or severe multisystem injuries. All patients underwent imaging studies within 48 hours of injury and were either treated or cleared and spinal precautions were discontinued. Patients were excluded from this study if they had an obvious cervical spine injury identified on the initial radiographic studies or if they were determined to be too medically unstable to undergo MR imaging within the acute period ( Thirty-one (25.6%) of the 121 patients were found to have sustained significant injury to the paravertebral ligamentous structures, the disc interspace, or the bony cervical spine. These injuries were undetected by plain radiography. The other 90 patients (74.4%) were determined within 48 hours not to have sustained a soft-tissue injury. Eight patients (6.6%) ultimately underwent surgery to treat the cervical spine injury, and MR imaging was the first test that identified the injury in each of these patients. There were no complications related to imaging procedures. Conclusions. Sagittal T1- and T2-weighted MR imaging appears to be a safe, reliable method for evaluating the cervical spine for nonapparent injury in comatose or obtunded trauma patients. In the early postinjury period, nursing and medical care are thereby facilitated for patients in whom occult injury to the spine is ruled out and for whom those attendant precautions are unnecessary.