Decreased DNA Methylation of RGMA is Associated with Intracranial Hypertension After Severe Traumatic Brain Injury: An Exploratory Epigenome-Wide Association Study.

BACKGROUND: Cerebral edema and intracranial hypertension are major contributors to unfavorable prognosis in traumatic brain injury (TBI). Local epigenetic changes, particularly in DNA methylation, may influence gene expression and thus host response/secondary injury after TBI. It remains unknown whether DNA methylation in the central nervous system is associated with cerebral edema severity or intracranial hypertension post TBI. We sought to identify epigenome-wide DNA methylation patterns associated with these forms of secondary injury after TBI. METHODS: We obtained genome-wide DNA methylation profiles of DNA extracted from ventricular cerebrospinal fluid samples at three different postinjury time points from a prospective cohort of patients with severe TBI (n = 89 patients, 254 samples). Cerebral edema and intracranial pressure (ICP) measures were clustered to generate composite end points of cerebral edema and ICP severity. We performed an unbiased epigenome-wide association study (EWAS) to test associations between DNA methylation at 419,895 cytosine-phosphate-guanine (CpG) sites and cerebral edema/ICP severity categories. Given inflated p values, we conducted permutation tests for top CpG sites to filter out potential false discoveries. RESULTS: Our data-driven hierarchical clustering across six cerebral edema and ICP measures identified two groups differing significantly in ICP based on the EWAS-identified CpG site cg22111818 in RGMA (Repulsive guidance molecule A, permutation p = 4.20 × 10-8). At 3-4 days post TBI, patients with severe intracranial hypertension had significantly lower levels of methylation at cg22111818. CONCLUSIONS: We report a novel potential relationship between intracranial hypertension after TBI and an acute, nonsustained reduction in DNA methylation at cg22111818 in the RGMA gene. To our knowledge, this is the largest EWAS in severe TBI. Our findings are further strengthened by previous findings that RGMA modulates axonal repair in other central nervous system disorders, but a role in intracranial hypertension or TBI has not been previously identified. Additional work is warranted to validate and extend these findings, including assessment of its possible role in risk stratification, identification of novel druggable targets, and ultimately our ability to personalize therapy in TBI.

Genetic Variants Associated With Intraparenchymal Hemorrhage Progression After Traumatic Brain Injury.

Importance: Intracerebral hemorrhage progression is associated with unfavorable outcome after traumatic brain injury (TBI). No effective treatments are currently available. This secondary injury process reflects an extreme form of vasogenic edema and blood-brain barrier breakdown. The sulfonylurea receptor 1-transient receptor potential melastatin 4 (SUR1-TRPM4) cation channel is a key underlying mechanism. A phase 2 trial of SUR1-TRPM4 inhibition in contusional TBI is ongoing, and a phase 3 trial is being designed. Targeted identification of patients at increased risk for hemorrhage progression may inform prognostication, trial design (including patient selection), and ultimately treatment response. Objective: To determine whether ABCC8 (SUR1) and TRPM4 genetic variability are associated with intraparenchymal hemorrhage (IPH) progression after severe TBI, based on the putative involvement of the SUR1-TRPM4 channel in this pathophysiology. Design, Setting, and Participants: In this genetic association study, DNA was extracted from 416 patients with severe TBI prospectively enrolled from a level I trauma academic medical center from May 9, 2002, to August 8, 2014. Forty ABCC8 and TRPM4 single-nucleotide variants (SNVs) were genotyped (multiplex, unbiased). Data were analyzed from January 7, 2020, to May 3, 2021. Main Outcomes and Measures: Primary analyses addressed IPH progression at 6, 24, and 120 hours in patients without acute craniectomy (n = 321). Multivariable regressions and receiver operating characteristic curves assessed SNV and haplotype associations with progression. Spatial modeling and functional predictions were determined using standard software. Results: Of the 321 patients included in the analysis (mean [SD] age, 37.0 [16.3] years; 247 [76.9%] male), IPH progression occurred in 102. Four ABCC8 SNVs were associated with markedly increased odds of progression (rs2237982 [odds ratio (OR), 2.60-3.80; 95% CI, 1.14-5.90 to 1.80-8.02; P = .02 to P < .001], rs2283261 [OR, 3.37-4.77; 95% CI, 1.07-10.77 to 1.89-12.07; P = .04 to P = .001], rs3819521 [OR, 2.96-3.92; 95% CI, 1.13-7.75 to 1.42-10.87; P = .03 to P = .009], and rs8192695 [OR, 3.06-4.95; 95% CI, 1.02-9.12 to 1.67-14.68]; P = .03-.004). These are brain-specific expression quantitative trait loci (eQTL) associated with increased ABCC8 messenger RNA levels. Regulatory annotations revealed promoter and enhancer marks and strong and/or active brain-tissue transcription, directionally consistent with increased progression. Three SNVs (rs2283261, rs2237982, and rs3819521) in this cohort have been associated with intracranial hypertension. Four TRPM4 SNVs were associated with decreased IPH progression (rs3760666 [OR, 0.40-0.49; 95% CI, 0.19-0.86 to 0.27-0.89; P = .02 to P = .009], rs1477363 [OR, 0.40-0.43; 95% CI, 0.18-0.88 to 0.23-0.81; P = .02 to P = .006], rs10410857 [OR, 0.36-0.41; 95% CI, 0.20-0.67 to 0.20-0.85; P = .02 to P = .001], and rs909010 [OR, 0.27-0.40; 95% CI, 0.12-0.62 to 0.16-0.58; P = .002 to P < .001]). Significant SNVs in both genes cluster downstream, flanking exons encoding the receptor site and SUR1-TRPM4 binding interface. Adding genetic variation to clinical models improved receiver operating characteristic curve performance from 0.6959 to 0.8030 (P = .003). Conclusions and Relevance: In this genetic association study, 8 ABCC8 and TRPM4 SNVs were associated with IPH progression. Spatial clustering, brain-specific eQTL, and regulatory annotations suggest biological plausibility. These findings may have important implications for neurocritical care risk stratification, patient selection, and precision medicine, including an upcoming phase 3 trial design for SUR1-TRPM4 inhibition in severe TBI.

B-Cell Lymphoma 2 (Bcl-2) Gene Is Associated with Intracranial Hypertension after Severe Traumatic Brain Injury.

Severe traumatic brain injury (TBI) activates the apoptotic cascade in neurons and glia as part of secondary cellular injury. B-cell lymphoma 2 (Bcl-2) gene encodes a pro-survival protein to suppress programmed cell death, and variation in this gene has potential to affect intracranial pressure (ICP). Participants were recruited from a single clinical center using a prospective observational study design. Inclusion criteria were: age 16-80 years; Glasgow Coma Scale (GCS) score 4-8; and at least 24 h of ICP monitoring treated between 2000-2014. Outcomes were mean ICP, spikes >20 and >25 mm Hg, edema, and surgical intervention. Odds ratios (OR), mean increases/decreases (B), and 95% confidence intervals (CIs) were reported. In 264 patients, average age was 39.2 years old and 78% of patients were male. Mean ICPs were 11.4 ± 0.4 mm Hg for patients with homozygous wild-type (AA), 12.8 ± 0.6 mm Hg for heterozygous (AG), and 14.3 ± 1.2 mm Hg for homozygous variant (GG; p = 0.023). Rs17759659 GG genotype was associated with more ICP spikes >20 mm Hg (p = 0.017) and >25 mm Hg (p = 0.048). Multi-variate analysis showed that GG relative to AA genotype had higher ICP (B = 2.7 mm Hg, 95% CI [0.5,4.9], p = 0.015), edema (OR = 2.5 [1.0, 6.0], p = 0.049) and need for decompression (OR = 3.7 [1.5-9.3], p = 0.004). In this prospective severe TBI cohort, Bcl-2 rs17759659 was associated with increased risk of intracranial hypertension, cerebral edema, and need for surgical intervention. The variant allele may impact programmed cell death of injured neurons, resulting in elevated ICP and post-traumatic secondary insults. Further risk stratification and targeted genotype-based therapies could improve outcomes after severe TBI.

Secondary Intracranial Hypertension in Pediatric Patients With Cryopyrin-Associated Periodic Syndrome.

BACKGROUND: Cryopyrin-associated periodic syndrome is characterized by periodic fever, rash, and joint pain. Papilledema rarely occurs. We present our series of patients with cryopyrin-associated periodic syndrome who clinically met the diagnostic criteria for Muckle-Wells syndrome and our experience with secondary intracranial hypertension. METHODS: Retrospective review of all patients with cryopyrin-associated periodic syndrome at Nationwide Children's Hospital from October 2015 to September 2017. RESULTS: Eighteen children met inclusion criteria: 15 females and three males, aged 1.5 to 16.2 years. Fifteen had periodic fever genetic testing; three had a known genetic defect identified, eight had a defect identified not currently known to be associated with cryopyrin-associated periodic syndrome, and four had no defect identified. Six patients (30%) developed headaches and were diagnosed with secondary intracranial hypertension. Lumbar puncture opening pressures ranged from 28 to 45 cm H2O. Only one patient had papilledema. Initial treatment was medical in all cases, by increasing interleukin-1 inhibitor dose and/or acetazolamide. One patient required a ventriculoperitoneal shunt for headache management. No visual acuity loss was detected. All six patients with secondary intracranial hypertension had a known genetic mutation or genetic variant of unknown significance; five involved the NLRP3 gene. CONCLUSIONS: In our series of 18 patients with cryopyrin-associated periodic syndrome, secondary intracranial hypertension occurred at a higher than expected rate. We suspect that genetic defects involving the NLRP3 gene may be a risk factor. Papilledema was present in only one patient. Physicians treating cryopyrin-associated periodic syndrome should be aware of this vision-threatening association and potential therapeutic approach.

A progressive and complex clinical course in two family members with ERF-related craniosynostosis: a case report.

BACKGROUND: ERF-related craniosynostosis are a rare, complex, premature trisutural fusion associated with a broad spectrum of clinical features and heterogeneous aetiology. Here we describe two cases with the same pathogenic variant and a detailed description of their clinical course. CASE PRESENTATION: Two subjects; a boy with a BLSS requiring repeated skull expansions and his mother who had been operated once for sagittal synostosis. Both developed intracranial hypertension at some point during the course, which was for both verified by formal invasive intracranial pressure monitoring. Exome sequencing revealed a pathogenic truncating frame shift variant in the ERF gene. CONCLUSIONS: Here we describe a boy and his mother with different craniosynostosis patterns, but both with verified intracranial hypertension and heterozygosity for a truncating variant of ERF c.1201_1202delAA (p.Lys401Glufs*10). Our work provides supplementary evidence in support of previous phenotypic descriptions of ERF-related craniosynostosis, particularly late presentation, an evolving synostotic pattern and variable expressivity even among affected family members.

Comparison of paired cerebrospinal fluid and serum cell-free mitochondrial and nuclear DNA with copy number and fragment length.

BACKGROUND: Most studies on cell-free DNA (cfDNA) were only for single body fluids; however, the differences in cfDNA distribution between two body fluids are rarely reported. Hence, in this work, we compared the differences in cfDNA distribution between cerebrospinal fluid (CSF) and serum of patients with brain-related diseases. METHODS: The fragment length of cfDNA was determined by using Agilent 2100 Bioanalyzer. The copy numbers of cell-free mitochondrial DNA (cf-mtDNA) and cell-free nuclear DNA (cf-nDNA) were determined by using real-time quantitative PCR (qPCR) and droplet digital PCR (ddPCR) with three pairs of mitochondrial ND1 and nuclear GAPDH primers, respectively. RESULTS: There were short (~60 bp), medium (~167 bp), and long (>250 bp) cfDNA fragment length distributions totally obtained from CSF and serum using Agilent 2100 Bioanalyzer. The results of both qPCR and ddPCR confirmed the existence of these three cfDNA fragment ranges in CSF and serum. According to qPCR, the copy numbers of long cf-mtDNA, medium, and long cf-nDNA in CSF were significantly higher than in paired serum. In CSF, only long cf-mtDNA's copy numbers were higher than long cf-nDNA. But in serum, the copy numbers of medium and long cf-mtDNA were higher than the corresponding cf-nDNA. CONCLUSION: The cf-nDNA and cf-mtDNA with different fragment lengths differentially distributed in the CSF and serum of patients with brain disorders, which might serve as a biomarker of human brain diseases.

Language Development, Hearing Loss, and Intracranial Hypertension in Children With TWIST1-Confirmed Saethre-Chotzen Syndrome.

Saethre-Chotzen syndrome (SCS) is an autosomal dominant condition defined by mutations affecting the TWIST1 gene on chromosome 7p21.1. Previous research has identified an elevated prevalence of intracranial hypertension and hearing impairment associated with this syndrome. This study aimed to investigate the influence of hearing history and presence of intracranial hypertension on language development in children with SCS.A retrospective study note analysis was performed for all patients with a confirmed TWIST1 gene abnormality who attended the Oxford Craniofacial Unit and underwent a language assessment over a 22-year period. Intracranial pressure monitoring, hearing status, and language outcomes were examined in detail.Thirty patients with genetically confirmed SCS and language assessment data were identified. Twenty-eight patients underwent surgical intervention; 10 presented with intracranial hypertension (5 prior to, and 5 after primary surgical intervention). Language data coinciding with the presentation of intracranial hypertension were available for 8 children. About 44% of children with intracranial hypertension presented with concurrent receptive and expressive language delay (n = 4/8). For both children (n = 2) with longitudinal language data available, the onset of intracranial hypertension reflected a concurrent decline in language skills. Audiometric data were available for 25 children, 80% (n = 20/25) had a history of hearing loss. About 50% of these had confirmed conductive hearing loss with middle ear effusion and the other 50% had presumed conductive hearing loss with middle ear effusion. About 100% of the children with available hearing data in our study had evidence of middle ear effusion in at least 1 ear. Results also indicated that 43% (n = 13/30) of the children presented with receptive and/or expressive language delay during childhood.Given the importance of hearing for language development and the preliminary findings of a potential decline in language skills in children during periods of intracranial hypertension, regular follow-up of hearing, language, and intracranial hypertension are indicated in children with SCS.

Familial Intracranial Hypertension in 2 Brothers With PTEN Mutation: Expansion of the Phenotypic Spectrum.

PTEN (Phosphatase and Tensin Homolog on chromosome TEN) encodes a vastly expressed tumor suppressor protein that antagonizes the PI3 K signaling pathway and alters the MTOR pathway. Mutations in PTEN have been described in association with a number of syndromes including PTEN hamartoma-tumor syndrome, macrocephaly/autism, and juvenile polyposis of infancy. Although there is a wide variability in the clinical and radiologic presentations of PTEN-related phenotypes, the most consistent features include macrocephaly and increased tumorigenesis. Intracranial hypertension may be idiopathic or secondary to multiple etiologies. We describe 2 siblings harboring a PTEN mutation who presented with macrocephaly and intracranial hypertension. Repeat brain MRIs were normal in both. Acetazolamide treatment normalized intracranial pressure, but several trials of medication tapering led to recurrence of intracranial hypertension symptoms. The clinical presentation of our patients expands the PTEN-related phenotypes. We discuss the possible pathophysiology in view of PTEN function.

Papilledema from gain-of-function mutations in the STAT3 gene.

BACKGROUND: Signal Transducer and Activator of Transcription 3 (STAT3) gain-of-function germline mutations are associated with diverse clinical manifestations, including autoimmune cytopenia, lymphadenopathy, immunodeficiency, endocrinopathy, and enteropathy. We describe a new feature: raised intracranial pressure with papilledema. MATERIALS AND METHODS: Report of two cases. RESULTS: The first patient had a de novo heterozygous c.2144C>T (p.Pro715Leu) mutation in the STAT3 gene. At age 1 she had papilledema with marked sheathing of the proximal vessels on the optic discs. Follow-up 8 years later showed chronic papilledema, cystoid macular edema, and vision loss. The second patient had a de novo heterozygous c.2147C>T (p.Thr716Met) mutation. At age 12 he developed papilledema, which recurred despite treatment. In both patients, repeated sampling of the cerebrospinal fluid demonstrated a lymphocytic pleocytosis. CONCLUSIONS: Papilledema can occur as a manifestation of STAT3 gain-of-function mutation, sometimes accompanied by prominent vascular sheathing and cystoid macular edema. The mechanism may be chronic meningeal infiltration by white blood cells, impairing cerebrospinal fluid absorption.

Genetic Survey of Adult-Onset Idiopathic Intracranial Hypertension.

BACKGROUND: Idiopathic intracranial hypertension (IIH) is a condition characterized by increased intracranial pressure of unknown cause. IIH has been shown to be associated with female sex as well as obesity. This genome-wide association study was performed to determine whether genetic variants are associated with this condition. METHODS: We analyzed the chromosomal DNA of 95 patients with IIH enrolled in the Idiopathic Intracranial Hypertension Treatment Trial and 95 controls matched on sex, body mass index, and self-reported ethnicity. The samples were genotyped using Illumina Infinium HumanCoreExome v1-0 array and analyzed using a generalized linear mixed model that accounted for population stratification using multidimensional scaling. RESULTS: A total of 301,908 single nucleotide polymorphisms (SNPs) were evaluated. The strongest associations observed were for rs2234671 on chromosome 2 (P = 4.93 × 10), rs79642714 on chromosome 6 (P = 2.12 × 10), and rs200288366 on chromosome 12 (P = 6.23 × 10). In addition, 3 candidate regions marked by multiple associated SNPs were identified on chromosome 5, 13, and 14. CONCLUSIONS: This is the first study to investigate the genetics of IIH in a rigorously characterized cohort. The study was limited by its modest size and thus would have only been able to demonstrate highly significant association on a genome-wide scale for relatively common alleles exerting large effects. However, several variants and loci were identified that might be strong candidates for follow-up studies in other well-phenotyped cohorts.

Downstream TRPM4 Polymorphisms Are Associated with Intracranial Hypertension and Statistically Interact with ABCC8 Polymorphisms in a Prospective Cohort of Severe Traumatic Brain Injury.

Sulfonylurea-receptor-1(SUR1) and its associated transient-receptor-potential cation channel subfamily-M (TRPM4) channel are key contributors to cerebral edema and intracranial hypertension in traumatic brain injury (TBI) and other neurological disorders. Channel inhibition by glyburide is clinically promising. ABCC8 (encoding SUR1) single-nucleotide polymorphisms (SNPs) are reported as predictors of raised intracranial pressure (ICP). This project evaluated whether TRPM4 SNPs predicted ICP and TBI outcome. DNA was extracted from 435 consecutively enrolled severe TBI patients. Without a priori selection, all 11 TRPM4 SNPs available on the multiplex platform (Illumina:Human-Core-Exome v1.0) were genotyped spanning the 25 exon gene. A total of 385 patients were analyzed after quality control. Outcomes included ICP and 6 month Glasgow Outcome Scale (GOS) score. Proxy SNPs, spatial modeling, and functional predictions were determined using established software programs. rs8104571 (intron-20) and rs150391806 (exon-24) were predictors of ICP. rs8104571 heterozygotes predicted higher average ICP (ß = 10.3 mm Hg, p = 0.00000029), peak ICP (ß = 19.6 mm Hg, p = 0.0007), and proportion ICP >25 mm Hg (ß = 0.16 p = 0.004). rs150391806 heterozygotes had higher mean (ß = 7.2 mm Hg, p = 0.042) and peak (ß = 28.9 mm Hg, p = 0.0015) ICPs. rs8104571, rs150391806, and 34 associated proxy SNPs in linkage-disequilibrium clustered downstream. This region encodes TRPM4's channel pore and a region postulated to juxtapose SUR1 sequences encoded by an ABCC8 DNA segment containing previously identified relevant SNPs. There was an interaction effect on ICP between rs8104571 and a cluster of predictive ABCC8 SNPs (rs2237982, rs2283261, rs11024286). Although not significant in univariable or a basic multivariable model, in an expanded model additionally accounting for injury pattern, computed tomographic (CT) appearance, and intracranial hypertension, heterozygous rs8104571 was associated with favorable 6 month GOS (odds ratio [OR] = 16.7, p = 0.007951). This trend persisted in a survivor-only subcohort (OR = 20.67, p = 0.0168). In this cohort, two TRPM4 SNPs predicted increased ICP with large effect sizes. Both clustered downstream, spanning a region encoding the channel pore and interacting with SUR1. If validated, this may guide risk stratification and eventually inform treatment-responder classification for SUR1-TRPM4 inhibition in TBI. Larger studies are warranted.

Downregulation of microRNA-149 in retinal ganglion cells suppresses apoptosis through activation of the PI3K/Akt signaling pathway in mice with glaucoma.

Glaucoma represents a major cause of blindness, generally associated with elevated intraocular pressure (EIOP). The aim of the present study was to investigate whether microRNA-149 (miR-149) affects retinal ganglion cells (RGCs) and the underlying mechanism based on a mouse model of chronic glaucoma with EIOP. The successfully modeled mice were administered with mimics or inhibitors of miR-149. Next, the number of RGCs, ultrastructural changes of RGCs, and purity of RGCs in the retinal tissues were detected. Moreover, the RGCs were collected and subsequently treated with 60 mmHg pressure and transfected with a series of plasmids aiding in the regulation of the expression of miR-149 and betacellulin (BTC). The levels of miR-149, BTC, phosphatidylinositol 3-kinase (PI3K), and Akt were subsequently determined. Finally, RGC viability and apoptosis were detected accordingly. Dual luciferase reporter gene assay provided validation, highlighting BTC was indeed a target gene of miR-149. The downregulation of miR-149 is accompanied by an increased number of RGCs and decreased ultrastructural RGC alterations. Additionally, downregulated miR-149 was noted to increase the levels of BTC, PI3K, and Akt in both the retinal tissues and RGCs, whereas the silencing of miR-149 was observed to promote the viability of RGC and inhibit RGC apoptosis. Taken together, the results of the current study provided validation suggesting that the downregulation of miR-149 confers protection to RGCs by means of activating the PI3K/Akt signaling pathway via upregulation of BTC in mice with glaucoma. Evidence presented indicated the promise of miR-149 inhibition as a potential therapeutic strategy for glaucoma treatment.

Postoperative resveratrol administration improves prognosis of rat orthotopic glioblastomas.

BACKGROUND: Although our previous study revealed lumbar punctured resveratrol could remarkably prolong the survival of rats bearing orthotopic glioblastomas, it also suggested the administration did not completely suppress rapid tumour growth. These evidences led us to consider that the prognosis of tumour-bearing rats may be further improved if this treatment is used in combination with neurosurgery. Therefore, we investigated the effectiveness of the combined treatment on rat orthotopic glioblastomas. METHODS: Rat RG2 glioblastoma cells were inoculated into the brains of 36 rats. The rats were subjected to partial tumour removal after they showed symptoms of intracranial hypertension. There were 28 rats that survived the surgery, and these animals were randomly and equally divided into the control group without postoperative treatment and the LP group treated with 100 µl of 300 µM resveratrol via the LP route. Resveratrol was administered 24 h after tumour resection in 3-day intervals, and the animals received 7 treatments. The intracranial tumour sizes, average life span, cell apoptosis and STAT3 signalling were evaluated by multiple experimental approaches in the tumour tissues harvested from both groups. RESULTS: The results showed that 5 of the 14 (35.7%) rats in the LP group remained alive over 60 days without any sign of recurrence. The remaining nine animals had a longer mean postoperative survival time (11.0 ± 2.9 days) than that of the (7.3 + 1.3 days; p < 0.05) control group. The resveratrol-treated tumour tissues showed less Ki67 labelling, widely distributed apoptotic regions, upregulated PIAS3 expression and reduced p-STAT3 nuclear translocation. CONCLUSIONS: This study demonstrates that postoperative resveratrol administration efficiently improves the prognosis of rat advanced orthotopic glioblastoma via inhibition of growth, induction of apoptosis and inactivation of STAT3 signalling. Therefore, this therapeutic approach could be of potential practical value in the management of glioblastomas.

Intracranial Pressure Trajectories: A Novel Approach to Informing Severe Traumatic Brain Injury Phenotypes.

OBJECTIVES: Intracranial pressure in traumatic brain injury is dynamic and influenced by factors like injury patterns, treatments, and genetics. Existing studies use time invariant summary intracranial pressure measures thus potentially losing critical information about temporal trends. We identified longitudinal intracranial pressure trajectories in severe traumatic brain injury and evaluated whether they predicted outcome. We further interrogated the model to explore whether ABCC8 polymorphisms (a known cerebraledema regulator) differed across trajectory groups. DESIGN: Prospective observational cohort. SETTING: Single-center academic medical center. PATIENTS: Four-hundred four severe traumatic brain injury patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We used group-based trajectory modeling to identify hourly intracranial pressure trajectories in days 0-5 post traumatic brain injury incorporating risk factor adjustment (age, sex, Glasgow Coma Scale 6score, craniectomy, primary hemorrhage pattern). We compared 6-month outcomes (Glasgow Outcome Scale, Disability Rating Scale, mortality) and ABCC8 tag-single-nucleotide polymorphisms associated with cerebral edema (rs2237982, rs7105832) across groups. Regression models determined whether trajectory groups predicted outcome. A six trajectory group model best fit the data, identifying cohorts differing in initial intracranial pressure, evolution, and number/proportion of spikes greater than 20 mm Hg. There were pattern differences in age, hemorrhage type, and craniectomy rates. ABCC8 polymorphisms differed across groups. GOS (p = 0.006), Disability Rating Scale (p = 0.001), mortality (p < 0.0001), and rs2237982 (p = 0.035) differed across groups. Unfavorable outcomes were surprisingly predicted by both low intracranial pressure trajectories and sustained intracranial hypertension. Intracranial pressure variability differed across groups (p < 0.001) and may reflect preserved/impaired intracranial elastance/compliance. CONCLUSIONS: We employed a novel approach investigating longitudinal/dynamic intracranial pressure patterns in traumatic brain injury. In a risk adjusted model, six groups were identified and predicted outcomes. If validated, trajectory modeling may be a first step toward developing a new, granular approach for intracranial pressure phenotyping in conjunction with other phenotyping tools like biomarkers and neuroimaging. This may be particularly relevant in light of changing traumatic brain injury demographics toward the elderly.

Intracranial hypertension in siblings with infantile hypercalcemia.

BACKGROUND: Idiopathic intracranial hypertension is a clinical condition with elevated intracranial pressure of uncertain etiology. Although various underlying causes are suspected and familial occurrence has also been reported, however, it still remains an unexplained phenomenon. CASE REPORT: We report the case of dizygotic siblings with a known CYP24A1 mutation resulting in chronic hypercalcemia and impairment of kidney function. At the same point in time both of them developed intracranial hypertension resistant to conservative therapy necessitating therefore ventriculoperitoneal shunt implantation. In both children magnetic resonance imaging showed slightly hypoplastic sinus transversus as the potential underlying cause. CONCLUSION: The simultaneous clinical presentation could be due to a genetic factor or might be a component of the underlying disease or the consequence of its treatment. Further cases and clinical experience are needed to clarify this issue.

Impact of the AGTR1 A1166C polymorphism on subcortical hyperintensities and cognition in healthy older adults.

Vascular aging consists of complex and multifaceted processes that may be influenced by genetic polymorphisms of the renin-angiotensin system. A polymorphism in the angiotensin II type 1 receptor gene (AGTR1/rs5186) has been associated with an increased risk for arterial stiffness, hypertension, and ischemic stroke. Despite these identified relationships, the impact of AGTR1 A1166C on white matter integrity and cognition is less clear in a healthy aging population. The present study utilized indices of neuroimaging and neuropsychological assessment to examine the impact of the A1166C polymorphism on subcortical hyperintensities (SH) and cognition in 49 healthy adults between ages 51-85. Using a dominant statistical model (CC + CA (risk) vs. AA), results revealed significantly larger SH volume for individuals with the C1166 variant (p < 0.05, partial eta(2) = 0.117) compared with those with the AA genotype. Post hoc analyses indicated that increased SH volume in C allele carriers could not be explained by vascular factors such as pulse pressure or body mass index. In addition, cognitive performance did not differ significantly between groups and was not significantly associated with SH in this cohort. Results suggest that presence of the C1166 variant may serve as a biomarker of risk for suboptimal brain integrity in otherwise healthy older adults prior to changes in cognition.

GAPO syndrome with pansutural craniosynostosis leading to intracranial hypertension.

GAPO syndrome stands for growth retardation (G), alopecia (A), pseudoanodontia (P) and optic atrophy (O). To date, only about 35 cases of this extremely rare syndrome have been reported. Craniosynostosis/craniostenosis is a condition with an abnormal head shape due to premature fusion of the calvarial sutures and can be either non-syndromic or syndromic. Overall, craniosynostosis has an incidence of about 1 in 2500 live-births. We present a patient with GAPO syndrome in association with craniosynostosis along with intracranial hypertension, which was the cause of her headache. To the best of our knowledge, this is the first such association in the literature.

Compound heterozygosity of the protein S-gene as a cause of severe cerebral sinovenous thrombosis in a 7-year-old child.

The genotype-phenotype relationship of compound heterozygous protein S-deficiency in a 7-year-old girl with reduced protein S-levels and a severe cerebral sinovenous thrombosis is illustrated. In this patient we identified a novel deletion in the protein S-gene causing a compound heterozygous state and subsequently a symptomatic protein S-deficiency. In case of thrombosis analysis of protein S is recommended. Low levels of protein S should be further investigated by molecular diagnostics.

Craniosynostosis: A rare complication of pycnodysostosis.

Uncommon features of rare genetic disorders are often poorly known, as the likelihood of having them reported is low. We describe a 7-year-old boy with clinical and radiological diagnosis of pycnodysostosis, and c.436G>C (p.G146R) mutation in CSTK). He developed intracranial hypertension that required surgical decompression. Despite patent fontanels, the cause of the intracranial hypertension was identified to be a combination of coronal and metopic craniosynostoses. Intracranial hypertension and craniosynostosis have only been reported once in pycnodysostosis, which is on the contrary characterized by delayed closure of the sutures and persistence of open fontanels. Our observation confirms that intracranial hypertension represents a rare but life-threatening complication of pycnodysostosis. We strongly suggest including systematic examination of fundus oculi and monitoring of OFC in the systematic clinical follow-up of these patients.