Nervous System Malformations Research Articles

Abstract 126: The Influence of Physical Activity on Cavernous Malformation Hemorrhage

Background: Cavernous malformations (CM) are low flow vascular malformations of the central nervous system. Brainstem location and prior hemorrhage increase the risk for future hemorrhage. Little is known about the influence of physical activity on increasing the risk of hemorrhage. Methods: Consecutive patients with radiologically confirmed CM were recruited to participate in a prospective registry beginning in 2015. A structured interview, survey, and examination were performed at baseline. Patients were asked if anything unusual occurred in the days leading to initial clinical presentation. Medical records and magnetic resonance imaging (MRI) studies were reviewed. Patients were surveyed about their involvement in select physical activity after the diagnosis of CM was made. Follow up surveys were sent annually to patients to ascertain new clinical hemorrhages. Follow up was censored at last follow up, hemorrhage, surgery, or death. Univariate analysis was performed to assess whether involvement in select physical activities increased the risk of prospective hemorrhage. Results: Of 195 patients, 117 (60 %) were female and the average age at diagnosis was 41 years (31-56 years). One hundred and three (52.8%) patients returned the survey about physical activity after diagnosis (cerebral n=100; spine n=3). Twenty-three patients had a prospective hemorrhage over 539.4 patient years. Five of these patients were removed from the analysis because they had less than 6 weeks of physical activity exposure before censor. Of 98 remaining patients, there was no difference in prospective hemorrhage risk in those patients participating 3 or more times monthly in walking, running, lifting more than 20 pound weights, lifting less than 20 pound weights, or participating in non-contact sports. Very few patients reported participation in contact sports (n=5), scuba diving (n=2) or high altitude climbing (n=1) more than 3 times monthly. Conclusion: Aerobic activity and non-contact sports do not increase the risk of hemorrhage in patients with cerebral CM and patients should not be restricted. Less information is known about contact sports, high altitude climbing or scuba diving and those with spinal cord CM.

A Case of Complete Neu-Laxova Syndrome: Report and Literature Review

Neu-Laxova syndrome (NLS) is a rare autosomal recessive and early fatal disease. It is a complex entity that includes intrauterine growth retardation, abnormal facial structure, limb and skeletal abnormalities, and ichthyosis and severe malformations of the central nervous system. We report a rare case of recurrence of Neu-Laxova syndrome in a 32-year-old pauciparous woman, which occurred after a first cousin’s consanguineous marriage. Typical ultrasound findings included hydramnios, severe intrauterine growth restriction, craniofacial and central nervous system abnormalities such as ventriculomegaly. The newborn shows a terrible face with a usual craniofacial aspect, eyeball proptosis, puffy hands and feet, large bilateral cleft lip/palate, severe hall body ichthyosis. The overcome was fatal, the death occurred in less than one hour after birth. Consanguinity remains the most implicated cause which is high in developing countries. Prenatal serial ultrasound examinations with genetic counselling should be performed on high-risk pregnant women to terminate affected pregnancies.

The etiopathogenic and morphological spectrum of anencephaly: a comprehensive review of literature.

Anencephaly is a severe malformation of the central nervous system (CNS), being one of the most common types of neural tube defects. It is defined as total or partial absence of the calvarium, with absence of the brain. Anencephaly has an incidence of 1 to 5 in every 1000 births, and the mortality rate is 100% during intrauterine life or within hours or days after birth. The etiology of anencephaly remains unclear, but various maternal-related environmental and genetic risk factors have been reported, which include diabetes, obesity, exposure to different drugs or toxins, genetic polymorphisms and mutations, as well as positive family history for neural tube defects. One of the most important nutritional factors in the development of anencephaly is folate deficiency. Methylenetetrahydrofolate reductase (MTHFR) gene codes the enzyme involved in the intracellular metabolism of folic acid; the 677C-T polymorphism of this gene causes the thermolability of the enzyme and decreased enzymatic activity, which is also dependent of folate plasmatic level. Etiopathogenesis of anencephaly includes several mutations in various other genes, such as: platelet-derived growth factor receptor alpha (PDGFRA), cadherin epidermal growth factor (EGF) laminin G (LAG) seven-pass G-type receptor 1 (CELSR1), Vang-like 1 (VANGL1) and Vang-like 2 (VANGL2), the last two being involved in the process of neurulation. Screening tests include maternal serum alpha-fetoprotein level and ultrasound (US) examination. During the first trimester US screening, anencephaly is now detected in all cases, but in order to decrease the complication rate of pregnancy termination, the diagnosis should be established as soon as possible, during the pregnancy confirmation US. We conclude that given that anencephaly is a severe malformation of the CNS, morphological characterization could improve the screening by US that is mandatory in the first trimester in order to plan the best, safe and early management.

Identification of the KRIT1 Protein by LexA-Based Yeast Two-Hybrid System.

Cerebral cavernous malformation (CCM) is a vascular malformation of the central nervous system that is associated with leaky capillaries, and a predisposition to serious clinical conditions including intracerebral hemorrhage and seizures. Germline or sporadic mutations in the CCM1/KRIT1 gene are responsible for the majority of cases of CCM. In this article, we describe the original characterization of the CCM1/KRIT1 gene. This cloning was done through the use of a variant of the yeast two-hybrid screen known as the interaction trap, using the RAS-family GTPase KREV1/RAP1A as a bait. The partial clone of KRIT1 (Krev1 Interaction Trapped) initially identified was extended through 5'RACE and computational analysis to obtain a full-length cDNA, then used in a sequential screen to define the integrin-associated ICAP1 protein as a KRIT1 partner protein. We discuss how these interactions are relevant to the current understanding of KRIT1/CCM1 biology, and provide a protocol for library screening with the Interaction Trap.

Antioxidant and cytotoxic activities of curly dock (Rumex crispus L., Polygonaceae) fruit extract

Background/Aim. Congenital malformations still represent one of the most important causes of prenatal and infant death. The study aim was to analyze occurrence, outcomes and risk factors of different types of congenital anomalies. Methods. The study included all pregnant women directed to Clinic of Obstetrics and Gynecology, Clinical Center of Serbia, Belgrade due to prenatally diagnosed congenital fetal anomalies during past ten years (January 1, 2008?December 31, 2017). Upon admission to our Clinic a detailed general medical and obstetrical history were taken from every patient. All women underwent genetic testing. Ultrasonography and magnetic resonance were diagnostic methods for fetal malformations confirmation. Results. The study included 773 pregnant women aged from 18 to 46 years. Out of registered nine different groups of fetal anomalies/malformations, the most common were malformations of the central nervous system, while majority of fetuses had combined multiple anomalies. Genetic cause for congenital anomalies was present in 25.2% of pregnancies. Medical pregnancy abortion was performed in 71.8% of cases. Only 10.2% of pregnancies ended in term. The best outcome for children was obtained in case of gastrointestinal anomalies (52% live born). Contrary, only one child with neck and thorax malformations could be saved. According to logistic regression the most important predictor of having a child with combined multiple anomalies was mother?s age, while predictor of central nervous system anomalies was gestational diabetes. The significant predictor of genetic anomalies was mother?s age. Conclusion. In our sample neurological congenital anomalies were the most common, although abnormalities of all organ systems were registered. Majority of pregnancies had to be discontinued due to combined multiple anomalies caused by genetic disorders. Older mother?s age and diabetes can imply on the increased risk for fetal malformations.

Diagnostic Value of Magnetic Resonance Imaging in Fetal Lateral Ventriculomegaly and the Relationship Between the Degree of Isolated Lateral Ventriculomegaly and Neonatal Prognosis

Abstract Objective: To assess the value of magnetic resonance imaging (MRI) in fetal lateral ventriculomegaly diagnosed with ultrasound, and to study the relationship between the degree of isolated lateral ventriculomegaly and neonatal prognosis. Methods: The pregnancy information and outcomes of 97 cases of fetal ventriculomegaly were retrospectively reviewed in the Tianjin Central Hospital of Gynecology Obstetrics from January 2016 to December 2017. The maternal age was 18–42 years, and the fetal gestational age at diagnosis was 19+4 to 37+3 weeks. MRI and ultrasound were used to compared the diagnosis of fetal lateral ventriculomegaly and evaluated the development of the nervous system after birth. Results: Among 97 pregnancy cases, associated central nervous system malformations were observed in 36 cases on ultrasound or ultrasound + MRI. Central nervous system malformations were diagnosed with ultrasound in 15 cases (15/36, 41.7%) and with ultrasound + MRI in 25 cases (25/36, 69.4%). Pearson χ 2 test was used to compare the detection rates between the groups, and the difference was statistically significant (P < 0.05). We followed up 61 cases of isolated lateral ventriculomegaly for 1–3 years after birth. According to the width of the lateral ventricle of the fetus in middle pregnancy, the subjects were grouped as follows: mild 33 cases (lateral ventricle width 10.0–12.0 mm), moderate 23 cases (lateral ventricle width 12.1–15.0 mm), and severe 5 cases (lateral ventricle width >15.0 mm). The rate of normal growth and development in the mild group was 90.9% (30/33), that in the moderate group was 69.6% (16/23), and that in the severe group was 40.0% (2/5), and the difference between groups was statistically significant (P < 0.05). Conclusion: Ultrasound combined with MRI can detect more central nervous system malformations, and the degree of isolated lateral ventriculomegaly is closely related to fetal prognosis.

Assessment of the Knowledge of Risk Factors of Congenital Hydrocephalus among Mothers Attending Antenatal Clinics in a Rural Tertiary Hospital Irrua, Edo State.

Background One of the congenital central nervous system malformations with great impact on the mental and psychosocial development of children is congenital hydrocephalus and it happens to be one of the most common. A large vacuum exists between knowledge on maternal environmental risk factors associated with congenital hydrocephalus, most especially in our rural community which consists of a large segment of our society. Our study aimed to determine the knowledge and perception of mothers on factors existing in the maternal environment that potentially puts an increased risk of developing congenital hydrocephalus. Materials and Methods This was a cross-sectional study design spanning a period of 8 months (March 2018–October 2018), in which the knowledge and perception of the risk factors of congenital hydrocephalus among mothers attending antenatal clinic in Irrua specialist teaching hospital, a rural tertiary hospital in Irrua, Edo state, Nigeria, were assessed using a random sampling technique. Interviewer-administered questionnaires (reviewed and validated) were used. The data collected were entered and analyzed using SPSS version 21. Results The findings showed varying levels of knowledge of congenital hydrocephalus. Less than half (44.0%) of the respondents had poor knowledge, 34.5% had fair knowledge, and 21.6% had good knowledge. There was a statistically significant relationship between knowledge of congenital hydrocephalus and respondents’ knowledge of the risk factors of congenital hydrocephalus. Most (52.6%) had good perception of the risk factors of congenital hydrocephalus, while 23.3% had poor perception. Conclusion This study revealed a fairly good knowledge of congenital hydrocephalus and its risk factors among mothers, most especially those with a good level of education.

A Five Years Study of Occurrence and Associated Risk Factors for Birth Defects in a Tertiary Care Hospital in Central Nepal

Introduction: Congenital anomalies account for 7.0% of neonatal deaths in Nepal. The present study was carried out to determine the overall rate of congenital malformations, incidence and prevalence in live births, still birth and incidence affecting various organ systems, at Bharatpur Hospital, Nepal.
 Methods: All the intramural deliveries between Jan 2015 to Dec 2019 were included in the study. All the newborns were looked for congenital malformations after birth within seven days. Antenatal ultrasonography findings were noted. 2D echocardiography was also used for all congenital heart diseases, along with routine X-ray chest. A total of 131 babies with congenital problem were studied and the information was recorded in WHO NBBD Proforma. Data were recorded in MS Excel and SPSS 16 version was used for analysis. 
 Results: Out of the total 60160 deliveries, 131 (0.21% of total birth) were with congenital malformations, sex wise distribution was 65 (49.5%) females and 63 (48.7%) males and three (1.8%) were ambiguous. Oro-facial malformation (49, 37.4%) was the commonest form of malformation followed by the musculoskeletal system (31, 23.6 %), centre nervous system (31, 23.6%) and congenital malformations of genital organs (8, 6.0%). 
 Conclusions: The incidence of congenital malformation in this study was 0.21%. Females were more common than males and oro-facial malformation was the commonest type of malformation. Lack of antenatal visit, lack of folic acid during pre-conception period and low socioeconomic status were the commonest risk factors.

How does the ZIKA infection is higher among black women?

Introduction: ZIKA is a single-stranded RNA, from the Flaviviridae family. The infection of this virus became extremely visible during its epidemic in 2015 at South America, after the outbreak many speculations that includes newborns with central nervous system malformations and neurological disorders.
 Objective: determine the epidemiological profile of the Brazilian female population afflicted with Zika virus, by means of database research of 2017.
 Results: the higher incidence shows the social inequality of those affected by arboviruses: young, poor, black and brown women, the majority of population in the Northeast and North of Brazil.
 Conclusion: Brazilian epidemiology of Zika virus and Congenital Zika Virus is concentrated in the black and poor female population due to the historical and cultural Brazilian history of colonization, as it is concentrated in the same region where the Aedes mosquito has an easy procreation due to a wet and hot summer leading to propagation of arboviruses.

Aberrant Oligodendrogenesis in Down Syndrome: Shift in Gliogenesis?

Down syndrome (DS), or trisomy 21, is the most prevalent chromosomal anomaly accounting for cognitive impairment and intellectual disability (ID). Neuropathological changes of DS brains are characterized by a reduction in the number of neurons and oligodendrocytes, accompanied by hypomyelination and astrogliosis. Recent studies mainly focused on neuronal development in DS, but underestimated the role of glial cells as pathogenic players. Aberrant or impaired differentiation within the oligodendroglial lineage and altered white matter functionality are thought to contribute to central nervous system (CNS) malformations. Given that white matter, comprised of oligodendrocytes and their myelin sheaths, is vital for higher brain function, gathering knowledge about pathways and modulators challenging oligodendrogenesis and cell lineages within DS is essential. This review article discusses to what degree DS-related effects on oligodendroglial cells have been described and presents collected evidence regarding induced cell-fate switches, thereby resulting in an enhanced generation of astrocytes. Moreover, alterations in white matter formation observed in mouse and human post-mortem brains are described. Finally, the rationale for a better understanding of pathways and modulators responsible for the glial cell imbalance as a possible source for future therapeutic interventions is given based on current experience on pro-oligodendroglial treatment approaches developed for demyelinating diseases, such as multiple sclerosis.

Efficacy of Sox10 Promoter Methylation in the Diagnosis of Intestinal Neuronal Dysplasia From the Peripheral Blood

OBJECTIVES:Intestinal neuronal dysplasia (IND) is a common malformation of the enteric nervous system. Diagnosis requires a full-thickness colonic specimen and an experienced pathologist, emphasizing the need for noninvasive analytical methods. Recently, the methylation level of the Sox10 promoter has been found to be critical for enteric nervous system development. However, whether it can be used for diagnostic purposes in IND is unclear.METHODS:Blood and colon specimens were collected from 32 patients with IND, 60 patients with Hirschsprung disease (HD), and 60 controls. Sox10 promoter methylation in the blood and the Sox10 expression level in the colon were determined, and their correlation was analyzed. The diagnostic efficacy of blood Sox10 promoter methylation was analyzed by receiver operating characteristic curve.RESULTS:The blood level of Sox10 promoter methylation at the 32nd locus was 100% (90%–100%; 95% confidence interval [CI], 92.29%–96.37%) in control, 90% (80%–90%; 95% CI, 82.84%–87.83%) in HD, and 60% (50%–80%; 95% CI, 57.12%–69.76%) in IND specimens. Sox10 promoter methylation in the peripheral blood was negatively correlated with Sox10 expression in the colon, which was low in control, moderate in HD, and high in IND specimens (r = −0.89). The area under the curve of Sox10 promoter methylation in the diagnosis of IND was 0.94 (95% CI, 0.874–1.000, P = 0.000), with a cutoff value of 85% (sensitivity, 90.6%; specificity, 95.0%). By applying a cutoff value of 65%, promoter methylation was more indicative of IND than HD.DISCUSSION:The analysis of Sox10 promoter methylation in the peripheral blood can be used as a noninvasive method for IND diagnosis.

Serum metallome in pregnant women and the relationship with congenital malformations of the central nervous system: a case-control study

BackgroundCongenital malformations of the central nervous system (CNS) consist of a wide range of birth defects of multifactorial origin.MethodsConcentrations of 44 metals were determined by Inductively Coupled Plasma Mass Spectrometry in serum of 111 mothers in the second trimester of pregnancy who carried a malformed fetus and compared them with serum concentrations of the same metals in 90 mothers with a normally developed fetus at the same week of pregnancy.Data are reported as means ± standard deviations.ResultsWe found a direct relationship between congenital defects of the CNS and maternal serum concentration of aluminum: it was statistically higher in women carrying a fetus with this class of malformation, compared both to mothers carrying a fetus with another class of malformation (6.45 ± 15.15 μg/L Vs 1.44 ± 4.21 μg/L, p < 0.0006) and to Controls (i.e. mothers carrying a normally-developed fetus) (6.45 ± 15.15 μg/L Vs 0.11 ± 0.51 μg/L, p < 0.0006). Moreover, Aluminum abundances were below the limit of detection in the majority of control samples.ConclusionCAluminum may play a role in the onset of central nervous system malformations, although the exact Aluminum species and related specific type of malformation needs further elucidation.

Septo-optic dysplasia with cerebellar hemiagenesis - a rare congenital malformation.

Septo-optic dysplasia (De morsier’s syndrome) is a rare congenital malformation of the central nervous system and represents a clinical spectrum rather than a specific entity. It is defined by any combination of pituitary hypoplasia with or without consequent panhypopituitarism,optic nerve hypoplasia and midline neurological abnormalities such as absent septum pellucidum and corpus collasum agenesis or thinning. Septo-optic dysplasia with associated cerebellar hemiagenesis is a much rarer congenital anomaly and may represent one end of this spectrum.

Association of Neuregulin 1 rs7835688 G > C, rs16879552 T > C and rs2439302 G > C Polymorphisms with Susceptibility to Non-Syndromic Hirschsprung’s Disease

Background Hirschsprung’s disease (HSCR) is a heterogeneous congenital malformation of the enteric nervous system with a complex genetic etiology. We investigated if there was an association between Neuregulin-1 (NRG1) rs7835688 G > C, rs16879552 T > C and rs2439302 G > C polymorphisms and the risk of HSCR. Methods: We determined and compared the frequency of NRG1 polymorphisms rs7835688 G > C, rs16879552 T > C and rs2439302 G > C in 70 children with HSCR and 90 controls by TaqMan SNPs genotyping assays. Results: No significant differences in allele or genotype frequencies of NRG1 rs7835688 G > C, rs16879552 T > C and rs2439302 G > C polymorphisms were observed between HSCR cases and controls. Analyses showed that the NRG1 rs7835688 G > C, rs16879552 T > C and rs2439302 G > C polymorphisms were not significantly associated with an increased risk of non-syndromic HSCR. Conclusions: Our findings suggested that NRG1 rs7835688 G > C, rs16879552 T > C and rs2439302 G > C polymorphisms are not a risk factor in development of HSCR.

Análise espacial e espaço-temporal das anomalias congênitas do sistema nervoso no Estado da Paraíba entre os anos de 2010 a 2016

Introdução: No Brasil, a anomalia congênita do sistema nervoso tem sido a mais frequente dentre as anomalias. O conhecimento da sua distribuição geográfica, tanto no espaço quanto ao longo do tempo, pode auxiliar os gestores públicos no processo de tomada decisão sobre as áreas que devem ser priorizadas no monitoramento dessa doença. Objetivo: Detectar aglomerados espaciais e espaço-temporais das anomalias congênitas do sistema nervoso. Método: Estudo ecológico a partir de dados secundários do Sistema de Informações sobre Nascidos Vivos no período de 2010 a 2016 no estado da Paraíba. Foram estimadas as Razões de Incidências Espacial e aplicada a estatística Scan circular e Scan espaço-temporal para a detecção dos aglomerados das anomalias citadas anteriormente. Resultados: O padrão espacial foi diferente ao longo dos anos da ocorrência destas anomalias, uma vez que os aglomerados espaciais foram detectados em diferentes regiões do estado, exceto nos anos 2013 e 2015 que foi verificada uma maior concentração nas regiões do centro-oeste e noroeste do estado. Conslusão: Os achados indicaram as áreas que devem serpriorizadas para o monitoramento de anomalias congênitas do sistema nervoso no estado da Paraíba, tanto no tempo quanto no espaço.

Correlation between fetal cranial nervous system malformation and chromosome abnormality

Objective To investigate the correlation between fetal cranial nervous system malformation and chromosome abnormality. Methods The pregnant women with fetal cerebral nervous system dysplasia were collected from January 2013 to August 2018 at the Prenatal Diagnostic Center of the Sixth Affiliated Hospital of Guangzhou Medical University.The fetus was diagnosed by ultrasonography and karyotype analysis. Results A total of 18 cases of abnormal karyotypes were detected from 85 patient samples, and the abnormal rates were 21.18%.Single cranial nervous system malformation was found in 47 cases, abnormal karyotypes in 4 cases, multiple system malformation in 38 cases, and abnormal karyotypes in 14 cases, and the abnormal karyotype rate of multiple system malformation was higher than that of single cranial nervous malformation (36.84% vs.8.51%, χ2=10.101, P=0.001 5). And the 88.89%(16/18 cases)of abnormal karyotypes were founded in the early and middle pregnancy (≤28 weeks). The abnormal karyotype detection rates of cranial nervous system malformation associated with cardiovascular, skeletal and limb, facial neck abnormalities were 58.82% (10/17 cases), 50.00% (6/12 cases) and 50.00% (9/18 cases), respectively.In the fetal phenotypes, the abnormal karyotype detection rates of choroid plexus cysts were up to 64.29%, followed by arachnoid cysts (50.00%), craniocerebral abnormalities (45.45%) and holoprosencephaly (36.36%). Conclusions Chromosomal aneuploidy or structural abnormalities can lead to abnormal development of the fetal cranial nervous system, in which the rates of abnormal karyotypes on fetal cranial nervous with cardiovascular malformation and choroid plexus cysts are the highest. Key words: Fetal cranial nervous malformation; Chromosome karyotype; Trisomy 18; Early and middle pregnancy; Choroid plexus cysts

Role of the Checklist in Neurosurgery, a Realistic Perspective to “The Need for Surgical Safety Checklists in Neurosurgery Now and in the Future - a Systematic Review”

Gross total resection of arteriovenous malformations (AVMs) of the central nervous system confirmed by formal angiography is accepted as a cure for patients. In some cases, this may not be possible. Even though in these cases other treatment modalities such as endovascular embolization and radiotherapy can be used, long-term follow-up is lacking in the literature.Here we report a case of a 57-year-old woman with history of a right-sided parieto-occipital/periatrial AVM, initially treated with a combination of endovascular embolization and radiotherapy.The patient subsequently presented (12 years later) with a symptomatic, enlarging, contrast-enhancing mass at the same location that was angiographically occult but ultimately proven to be an AVM on a background of reactive changes on pathology.

Experiences from the first 10 years of a perinatal palliative care program: A retrospective chart review.

Perinatal palliative care is a relatively new component of paediatric palliative care which supports families who are expecting the birth of a child with a life-limiting condition. This study seeks to understand the characteristics of the infants and families referred for perinatal palliative care and the context for referrals in terms of diagnoses, referral characteristics, interventions, and outcomes. A retrospective chart review of infants with prenatally diagnosed life-limiting conditions that were referred for perinatal palliative care. Eighty-five referrals were made for perinatal palliative care during the 10-year period, of which, 84 chose to continue with the service. Average gestational age at diagnosis was 23 weeks, and the mean time between diagnosis and referral to palliative care was 7 weeks. Stillbirths were common, occurring in 29% cases. Of livebirths, 59% of the infants survived for 2 days, and 80% died within 30 days. The most commonly referred conditions were trisomy 13 or 18 (24%), severe central nervous system malformations (20%), and severe congenital cardiac disease (16%). Referrals were most often made by neonatologists (39%), and maternal-fetal medicine specialists (36%). Our study confirms previously observed characteristics of diagnosis, referrals, and outcomes, while providing the most detailed account of lifespans for particular diagnoses to date. Our findings validate the need for perinatal palliative care, as 99% of those referred continued with the service. Future research should adopt a prospective approach to identify critical factors affecting decision making of families and physicians in the wake of a life-limiting diagnosis.

De Novo Mutations in FOXJ1 Result in a Motile Ciliopathy with Hydrocephalus and Randomization of Left/Right Body Asymmetry

Hydrocephalus is one of the most prevalent form of developmental central nervous system (CNS) malformations. Cerebrospinal fluid (CSF) flow depends on both heartbeat and body movement. Furthermore, it has been shown that CSF flow within and across brain ventricles depends on cilia motility of the ependymal cells lining the brain ventricles, which play a crucial role to maintain patency of the narrow sites of CSF passage during brain formation in mice. Using whole-exome and whole-genome sequencing, we identified an autosomal-dominant cause of a distinct motile ciliopathy related to defective ciliogenesis of the ependymal cilia in six individuals. Heterozygous de novo mutations in FOXJ1, which encodes a well-known member of the forkhead transcription factors important for ciliogenesis of motile cilia, cause a motile ciliopathy that is characterized by hydrocephalus internus, chronic destructive airway disease, and randomization of left/right body asymmetry. Mutant respiratory epithelial cells are unable to generate a fluid flow and exhibit a reduced number of cilia per cell, as documented by high-speed video microscopy (HVMA), transmission electron microscopy (TEM), and immunofluorescence analysis (IF). TEM and IF demonstrate mislocalized basal bodies. In line with this finding, the focal adhesion protein PTK2 displays aberrant localization in the cytoplasm of the mutant respiratory epithelial cells.

Predictors of Initial Presentation with Hemorrhage in Patients with Cavernous Malformations

Cavernous malformations (CMs) are low-flow vascular malformations of the central nervous system which are incidental or present with hemorrhage, seizures, or focal neurologic deficit (FND). Little is known about the time course of symptoms and the predictors of initial hemorrhagic presentation. Beginning in 2015, consecutive patients with radiologically confirmed CMs were recruited and completed a structured interview and written survey at baseline. Medical records and magnetic resonance imaging studies were reviewed. Data collected included the following: comorbid conditions, select medication use, and location of CMs. Logistic-regression models determined predictors of initial presentation with hemorrhage. Of 202 patients, 58.4% were women (average age at diagnosis, 43.7 ± 16.5 years). Of the patients, 37.1%, 6.5%, and 14.8% presented with hemorrhage, FND, and seizures, respectively. CM was an incidental finding in 40.6%. Most patients presenting with hemorrhage (66.7%) deteriorated over 2-30 days after symptom onset. Brainstem location correlated with a higher likelihood of initial presentation with hemorrhage. Aspirin use and nonsteroidal anti-inflammatory drug use were more common in patients with CMs who did not present with hemorrhage. The effect of estrogen and aspirin was stronger in the sporadic compared with the familial form of CMs. In women, estrogen use increased the likelihood of presenting with hemorrhage. This prospective cohort study confirms brainstem location increases the likelihood of presenting with hemorrhage, but also supports a potential role of select medications on the initial clinical presentation of CMs. Further data from combined cohorts may aid in determining whether the influence of medications is different in familial versus sporadic form CMs.