Leslie Morrison

A Founder Mutation as a Cause of Cerebral Cavernous Malformation in Hispanic Americans

BACKGROUND Cerebral cavernous malformation is a vascular disease of the brain causing headaches, seizures, and cerebral hemorrhage. Familial and sporadic cases are recognized, and a gene causing familial disease has been mapped to chromosome 7. Hispanic Americans have a higher prevalence of cavernous malformation than do other ethnic groups, raising the possibility that affected persons in this population have inherited the same mutation from a common ancestor. METHODS We compared the segregation of genetic markers and clinical cases of cavernous malformation in Hispanic-American kindreds with familial disease; we also compared the alleles for markers linked to cavernous malformation in patients with familial and sporadic cases. RESULTS All kindreds with familial disease showed linkage of cavernous malformation to a short segment of chromosome 7 (odds supporting linkage, 4X10(10).1). Forty-seven affected members of 14 kindreds shared identical alleles for up to 15 markers linked to the cavernous-malformation gene, demonstrating that they had inherited the same mutation from a common ancestor. Ten patients with sporadic cases also shared these same alleles, indicating that they too had inherited the same mutation. Thirty-three asymptomatic carriers of the disease gene were identified, demonstrating the variability and age dependence of the development of symptoms and explaining the appearance of apparently sporadic cases. CONCLUSIONS Virtually all cases of familial and sporadic cavernous malformation among Hispanic Americans of Mexican descent are due to the inheritance of the same mutation from a common ancestor.

Use of tissue water as a concentration reference for proton spectroscopic imaging

A strategy for using tissue water as a concentration standard in 1H magnetic resonance spectroscopic imaging studies on the brain is presented, and the potential errors that may arise when the method is used are examined. The sensitivity of the method to errors in estimates of the different water compartment relaxation times is shown to be small at short echo times (TEs). Using data from healthy human subjects, it is shown that different image segmentation approaches that are commonly used to account for partial volume effects (SPM2, FSLs FAST, and K‐means) lead to different estimates of metabolite levels, particularly in gray matter (GM), owing primarily to variability in the estimates of the cerebrospinal fluid (CSF) fraction. While consistency does not necessarily validate a method, a multispectral segmentation approach using FAST yielded the lowest intersubject variability in the estimates of GM metabolites. The mean GM and white matter (WM) levels of N‐acetyl groups (NAc, primarily N‐acetylaspartate), choline (Ch), and creatine (Cr) obtained in these subjects using the described method with FAST multispectral segmentation are reported: GM [NAc] = 17.16 ± 1.19 mM; WM [NAc] = 14.26 ± 1.38 mM; GM [Ch] = 3.27 ± 0.47 mM; WM [Ch] = 2.65 ± 0.25 mM; GM [Cr] = 13.98 ± 1.20 mM; and WM [Cr] = 7.10 ± 0.67 mM. Magn Reson Med, 2006.

Practice Parameter: Pharmacologic treatment of spasticity in children and adolescents with cerebral palsy (an evidence-based review) Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society

Objective: To evaluate published evidence of efficacy and safety of pharmacologic treatments for childhood spasticity due to cerebral palsy. Methods: A multidisciplinary panel systematically reviewed relevant literature from 1966 to July 2008. Results: For localized/segmental spasticity, botulinum toxin type A is established as an effective treatment to reduce spasticity in the upper and lower extremities. There is conflicting evidence regarding functional improvement. Botulinum toxin type A was found to be generally safe in children with cerebral palsy; however, the Food and Drug Administration is presently investigating isolated cases of generalized weakness resulting in poor outcomes. No studies that met criteria are available on the use of phenol, alcohol, or botulinum toxin type B injections. For generalized spasticity, diazepam is probably effective in reducing spasticity, but there are insufficient data on its effect on motor function and its side-effect profile. Tizanidine is possibly effective, but there are insufficient data on its effect on function and its side-effect profile. There were insufficient data on the use of dantrolene, oral baclofen, and intrathecal baclofen, and toxicity was frequently reported. Recommendations: For localized/segmental spasticity that warrants treatment, botulinum toxin type A should be offered as an effective and generally safe treatment (Level A). There are insufficient data to support or refute the use of phenol, alcohol, or botulinum toxin type B (Level U). For generalized spasticity that warrants treatment, diazepam should be considered for short-term treatment, with caution regarding toxicity (Level B), and tizanidine may be considered (Level C). There are insufficient data to support or refute use of dantrolene, oral baclofen, or continuous intrathecal baclofen (Level U).

Hemorrhage From Cavernous Malformations of the Brain: Definition and Reporting Standards

Background and Purpose— Cavernous malformations of the brain (CMs) cause intracranial hemorrhage, but its reported frequency varies, partly attributable to study design. To improve the validity of future research, we aimed to develop a robust definition of CM hemorrhage. Methods— We systematically reviewed the published literature (Ovid Medline and Embase to June 1, 2007) for definitions of CM hemorrhage used in studies of the untreated clinical course of ≥20 participants with CM(s), to inform the development of a consensus statement on the clinical and imaging features of CM hemorrhage at a scientific workshop of the Angioma Alliance. Results— A systematic review of 1426 publications about CMs in humans, revealed 15 studies meeting our inclusion criteria. Although 14 (93%) studies provided a definition of CM hemorrhage, data were less complete on the confirmatory type(s) of imaging (87%), whether CM hemorrhage should be clinically symptomatic (73%), and whether hemorrhage had to extend outside the CM or not (47%). We define a CM hemorrhage as requiring acute or subacute onset symptoms (any of: headache, epileptic seizure, impaired consciousness, or new/worsened focal neurological deficit referable to the anatomic location of the CM) accompanied by radiological, pathological, surgical, or rarely only cerebrospinal fluid evidence of recent extra- or intralesional hemorrhage. The definition includes neither an increase in CM diameter without other evidence of recent hemorrhage, nor the existence of a hemosiderin halo. Conclusions— A consistent approach to clinical and brain imaging classification of CM hemorrhage will improve the external validity of future CM research.

Consensus statement on standard of care for congenital myopathies.

Recent progress in scientific research has facilitated accurate genetic and neuropathological diagnosis of congenital myopathies. However, given their relatively low incidence, congenital myopathies remain unfamiliar to the majority of care providers, and the levels of patient care are extremely variable. This consensus statement aims to provide care guidelines for congenital myopathies. The International Standard of Care Committee for Congenital Myopathies worked through frequent e-mail correspondences, periodic conference calls, 2 rounds of online surveys, and a 3-day workshop to achieve a consensus for diagnostic and clinical care recommendations. The committee includes 59 members from 10 medical disciplines. They are organized into 5 working groups: genetics/diagnosis, neurology, pulmonology, gastroenterology/nutrition/speech/oral care, and orthopedics/rehabilitation. In each care area the authors summarize the committee’s recommendations for symptom assessments and therapeutic interventions. It is the committee’s goal that through these recommendations, patients with congenital myopathies will receive optimal care and improve their disease outcome.

ATP1A3 mutations in infants: a new rapid-onset dystonia-Parkinsonism phenotype characterized by motor delay and ataxia.

We report new clinical features of delayed motor development, hypotonia, and ataxia in two young children with mutations (R756H and D923N) in the ATP1A3 gene. In adults, mutations in ATP1A3 cause rapid‐onset dystonia–Parkinsonism (RDP, DYT12) with abrupt onset of fixed dystonia. The parents and children were examined and videotaped, and samples were collected for mutation analysis. Case 1 presented with fluctuating spells of hypotonia, dysphagia, mutism, dystonia, and ataxia at 9 months. After three episodes of hypotonia, she developed ataxia, inability to speak or swallow, and eventual seizures. Case 2 presented with hypotonia at 14 months and pre‐existing motor delay. At age 4 years, he had episodic slurred speech, followed by ataxia, drooling, and dysarthria. He remains mute. Both children had ATP1A3 gene mutations. To our knowledge, these are the earliest presentations of RDP, both with fluctuating features. Both children were initially misdiagnosed. RDP should be considered in children with discoordinated gait, and speech and swallowing difficulties.

Hemorrhage from cavernous malformations of the brain: definition and reporting standards. Angioma Alliance Scientific Advisory Board.

Background and Purpose— Cavernous malformations of the brain (CMs) cause intracranial hemorrhage, but its reported frequency varies, partly attributable to study design. To improve the validity of future research, we aimed to develop a robust definition of CM hemorrhage. Methods— We systematically reviewed the published literature (Ovid Medline and Embase to June 1, 2007) for definitions of CM hemorrhage used in studies of the untreated clinical course of ≥20 participants with CM(s), to inform the development of a consensus statement on the clinical and imaging features of CM hemorrhage at a scientific workshop of the Angioma Alliance. Results— A systematic review of 1426 publications about CMs in humans, revealed 15 studies meeting our inclusion criteria. Although 14 (93%) studies provided a definition of CM hemorrhage, data were less complete on the confirmatory type(s) of imaging (87%), whether CM hemorrhage should be clinically symptomatic (73%), and whether hemorrhage had to extend outside the CM or not (47%). We define a CM hemorrhage as requiring acute or subacute onset symptoms (any of: headache, epileptic seizure, impaired consciousness, or new/worsened focal neurological deficit referable to the anatomic location of the CM) accompanied by radiological, pathological, surgical, or rarely only cerebrospinal fluid evidence of recent extra- or intralesional hemorrhage. The definition includes neither an increase in CM diameter without other evidence of recent hemorrhage, nor the existence of a hemosiderin halo. Conclusions— A consistent approach to clinical and brain imaging classification of CM hemorrhage will improve the external validity of future CM research.

Predictors of workplace satisfaction for U.S. medical school faculty in an era of change and challenge.

Purpose To examine the current state of satisfaction with the academic medicine workplace among U.S. medical school faculty and the workplace factors that have the greatest influence on global satisfaction. Method The authors used data from the 2009 administration of a medical school faculty job satisfaction survey and used descriptive statistics and &khgr;2 analyses to assess levels of overall satisfaction within faculty subgroups. Multiple regressions used the mean scores of the 18 survey dimensions and demographic variables to predict three global satisfaction measures. Results The survey was completed by 9,638 full-time faculty from 23 U.S. medical schools. Respondents were mostly satisfied on global satisfaction measures including satisfaction with their department (6,506/9,128; 71.3%) and medical school (5,796/9,124; 63.5%) and whether they would again choose to work at their medical school (5,968/8,506; 70.2%). The survey dimensions predicted global satisfaction well, with the final models explaining 51% to 67% of the variance in the dependent measures. Predictors across models include organization, governance, and transparency; focus of mission; recruitment and retention effectiveness; department relationships; workplace culture; and nature of work. Conclusions Despite the relatively unpredictable environmental challenges facing medical schools today, leaders have opportunities to influence and improve the workplace satisfaction of their faculty. Examples of opportunities include fostering a culture characterized by open communication and occasions for faculty input, and remaining vigilant regarding factors contributing to faculty burnout. Understanding what drives faculty satisfaction is crucial for medical schools as they continue to seek excellence in all missions and recruit and retain high-quality faculty.

Familial versus sporadic cavernous malformations: differences in developmental venous anomaly association and lesion phenotype.

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.

Endothelial TLR4 and the microbiome drive cerebral cavernous malformations

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.