Role of Genetics and Surgical Interventions for the Management of Cerebral Cavernous Malformations (CMM).

Cerebral cavernous malformations (CCMs) are comprised of tissue matter within the brain possessing anomalous vascular architecture. In totality, the dilated appearance of the cavernomatakes on a mulberry-like shape contributed by the shape and relation to vascular and capillary elements. Analyzing its pathophysiology along with its molecular and genetic pathways plays a vital role in whether or not a patient receives GKRS, medical management, or Surgery, the most invasive of procedures. To avoid neurological trauma, microsurgical resection of cavernomas canbe guided by the novel clinical application of a 3D Slicer with Sina/MosoCam. When cavernomas present in deep lesions with poor accessibility, gamma knife stereotactic radiosurgery (GKSR) is recommended. For asymptomatic and non-multilobal lesions, medical and symptom management is deemed standard, such as antiepileptic therapy. The two-hit hypothesis serves to explain the mutations in three key genes that are most pertinent to the progression of cavernomas: CCM1/KRIT1, CCM2/Malcavernin, and CCM3/PDCD10. Various exon deletions and frameshift mutations can cause dysfunction in vascular structure through loss and gain of function mutations. MEKK3 and KLF2/4 are involved in a protein kinase signaling cycle that promotes abnormal angiogenesis and cavernoma formation. In terms of potential treatments, RhoKinase inhibitors have shown to decrease endothelial to mesenchymal transition and CCM lesion development in mice models. All in all, understanding the research behind the molecular genetics in CCMs can foster personalized medicine and potentially create new neurosurgical and medicative treatments.

Imaging markers of the recurrent bleeding risk in patients with cerebral amyloid angiopathy / 国际脑血管病杂志

Cerebral amyloid angiopathy (CAA) is a cerebral small vascular disease caused by pathological deposition of β-amyloid protein in cortical and pial arteries and capillaries. It is the main cause of non-traumatic cerebral lobular hemorrhage and has a high risk of recurrent hemorrhage. Studies have shown that specific imaging markers, such as cerebral microbleeds, cortical superficial siderosis, convexal subarachnoid hemorrhage, centrum semiovale-perivascular spaces and the overall burden of cerebral small vascular disease, may be more effective in predicting the risk of bleeding recurrence in patients with CAA. This article reviews the imaging markers used to predict the risk of recurrent bleeding in patients with CAA, in order to provide a new direction for the establishment of a risk assessment system for recurrent bleeding.

Familial Early-Onset Alzheimer's Caused by Novel Genetic Variant and APP Duplication: A Cross-Sectional Study.

BACKGROUND: The clinical characteristics of symptomatic and asymptomatic carriers of early- onset autosomal dominant Alzheimer's (EOADAD) due to a yet-undescribed chromosomal rearrangement may add to the available body of knowledge about Alzheimer's disease and may enlighten novel and modifier genes. We report the clinical and genetic characteristics of asymptomatic and symptomatic individuals carrying a novel APP duplication rearrangement. METHODS: Individuals belonging to a seven-generation pedigree with familial cognitive decline or intracerebral hemorrhages were recruited. Participants underwent medical, neurological, and neuropsychological evaluations. The genetic analysis included chromosomal microarray, Karyotype, fluorescence in situ hybridization, and whole genome sequencing. RESULTS: Of 68 individuals, six females presented with dementia, and four males presented with intracerebral hemorrhage. Of these, nine were found to carry Chromosome 21 copy number gain (chr21:27,224,097-27,871,284, GRCh37/hg19) including the APP locus (APP-dup). In seven, Chromosome 5 copy number gain (Chr5: 24,786,234-29,446,070, GRCh37/hg19) (Chr5-CNG) cosegregated with the APP-dup. Both duplications co-localized to chromosome 18q21.1 and segregated in 25 pre-symptomatic carriers. Compared to non-carriers, asymptomatic carriers manifested cognitive decline in their mid-thirties. A third of the affected individuals carried a diagnosis of a dis-immune condition. CONCLUSION: APP extra dosage, even in isolation and when located outside chromosome 21, is pathogenic. The clinical presentation of APP duplication varies and may be gender specific, i.e., ICH in males and cognitive-behavioral deterioration in females. The association with immune disorders is presently unclear but may prove relevant. The implication of Chr5-CNG co-segregation and the surrounding chromosome 18 genetic sequence needs further clarification.

Anticoagulation after intracerebral hemorrhage in patients with atrial fibrillation: between Scylla and Charybdis.

BACKGROUND: Oral anticoagulants (OAC) are indicated in patients with atrial fibrillation (AF) and high risk of ischemic stroke. However, the introduction of anticoagulation in patients with AF and previous intracerebral hemorrhage (ICH) is controversial. We aimed to better understand the efficacy and safety of OAC in this context and to assess the factors that may influence this decision. METHODS: In a single-center retrospective observational study, patients with AF and ICH who survived hospitalization at a level A Stroke Unit between 2009 and 2018 were included. Patients were followed for two years after discharge. Data were collected regarding the introduction or not of OAC and the occurrence of major thrombotic/hemorrhagic events and death. RESULTS: Ninety-five patients (75.2 ± 9.9 years) were included and 40 patients (42.1%) started OAC. Patients were more likely to initiate anticoagulation if they had: mechanical prosthetic valves, previous AF (p = 0.005) and previous OAC therapy (p < 0001); and less if they had previous hemorrhagic stroke (p < 0.005). During follow-up, 10.5% had at least one major hemorrhagic event (60% anticoagulated), 20% had at least one major thrombotic event (all non-anticoagulated) and 20% died. The only factor associated with the risk of bleeding was ICH score (OR:2.49 per 1-point increase; 95%CI:1.14-5.46). Patients who initiated anticoagulation had lower mortality than non-anticoagulated (OR:0.296; 95%CI:0.090-0-975). Previous ICH and higher CHA2DS2-VASc were associated with higher mortality. CONCLUSION: In this retrospective series, anticoagulation reduced thrombotic events and overall mortality in patients admitted for ICH and AF, without a significant increase in bleeding risk.

A novel homozygous variant in JAM3 gene causing hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts (HDBSCC) with neonatal onset.

BACKGROUND: JAM3 gene, located on human chromosome 11q25, encodes a member of the junctional adhesion molecule (JAM) family. Mutations of this gene are associated with hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts (HDBSCC). CASE REPORT: Herein, we present a newborn male with a prenatal suspicion of bilateral cataracts but without fetal ultrasound findings of cortical malformations. He was postnatally diagnosed with a clinical picture of HDBSCC and Early-onset Developmental and Epileptic Encephalopathy (DEE), associated to a homozygous variant of JAM3 gene. CONCLUSION: Identification of this variant in affected individuals has implications for perinatal and postnatal management and genetic counseling. To the best of our knowledge, this is the first case reported of a child with a JAM3 variant in Italy, from a different ethnic background than the other reported children until now (Saudi Arabian, Turkish, Afghani, and Moroccan origin). JAM3 screening could be requested in prenatal diagnosis of fetal congenital cataracts and included in Next-Generation DNA Sequencing panels.

[Multiple cerebral hemorrhages due to varicella-zoster virus vasculopathy presenting as cranial nerve palsy].

A 72-year-old man was admitted to our hospital because of right facial muscle weakness and diplopia. He had been treated for aplastic anemia with cyclosporin for 2 years. Thirteen days before admission, a diagnosis of herpes zoster was made and treated with amenamevir. On admission, neurological examination revealed mild cognitive disturbance, mydriasis, weakness of the inferior rectus muscle of the left eye, and right peripheral facial nerve palsy. Cerebrospinal fluid (CSF) analysis showed elevated leukocytes and increased protein levels. Antibody index to varicella-zoster virus (VZV) was elevated in CSF to 25.6, although VZV DNA was negative by PCR. Head CT revealed multiple intracerebral hemorrhages in the left dorsal pons, left ventral midbrain, left thalamus, and left front-parietal lobe. MR angiography detected cerebral artery stenosis. In addition to intravenous acyclovir, the patient was treated with steroid pulse therapy and steroid tapering therapy. One month after admission, his symptoms improved. We diagnosed him with VZV vasculopathy. We believe that multiple intracerebral hemorrhages due to VZV vasculopathy caused facial and oculomotor nerve palsy. Our findings suggest that cerebral hemorrhage induced by VZV vasculopathy must be considered when differentiating cranial nerve palsy after herpes zoster.

[Toxoplasmosis-associated central nervous system vasculitis accompanied by multiple cerebral hemorrhages developing subsequent to cord blood transplantation].

A 57-year-old man with high-risk myelodysplastic syndrome underwent umbilical cord blood transplantation. He began receiving steroids on day 14 for acute graft-versus-host disease, and experienced dizziness on day 75 during gradual dose reduction. Multiple hemorrhages were observed in the cerebrum, cerebellum, and brainstem. His bleeding increased, and he underwent a brain biopsy on day 91. Subsequently, he was diagnosed with central nervous system vasculitis (CNSV) on the basis of the observed aggregation of mature CD3+ lymphocytes around small vessels and vascular wall invasion by lymphocytes and macrophages. After receiving high-dose steroid therapy, cerebral hemorrhage stopped; however, dysphasia occurred on day 113 and the patient died of cerebral edema on day 128. Toxoplasma DNA and tachyzoites were detected in the brain biopsy specimen during additional examinations; therefore, we suspected that the toxoplasmosis was related to the onset of CNSV. CNSV is a rare, rapidly progressing disease that may present as a fatal post-transplantation central nervous system complication. Investigating the causes of CNSV, including CNSV associated with toxoplasmosis, is critically important for improving the prognosis of patients with CNSV.

High-mobility group box-1 protein predicts hemorrhagic transformation after intravenous thrombolysis in patients with acute ischemic stroke / 国际脑血管病杂志

Objective@#To investigate the predictive value of serum high-mobility group box-1 protein (HMGB1) for hemorrhage transformation (HT) after intravenous thrombolysis in patients with acute ischemic stroke.@*Methods@#From February 2017 to September 2019, patients with acute ischemic stroke underwent intravenous thrombolysis in Lixin County People's Hospital, Bozhou, Anhui Province were enrolled prospectively. In the morning of the day after admission, fasting blood was collected to detect the level of serum HMGB1. Twenty-four hours after intravenous thrombolysis, CT reexamination was performed to determine whether HT occurred. The demographic and baseline clinical data were compared between the HT group and the non-HT group. Multivariate logistic regression analysis was used to determine the independent risk factors for HT after thrombolysis. Receiver operating characteristic (ROC) curve was used to analyze the predictive value of serum HMGB1 level to HT.@*Results@#A total of 182 patients were enrolled in the study, including 22 in the HT group and 160 in the non-HT group. The age, fasting blood glucose, serum HMGB1 level, and the proportion of history of atrial fibrillation and regular antiplatelet medication before onset in the HT group was significantly higher than those in the non-HT group, and the differences were statistically significant (all P<0.05). Multivariate logistic regression analysis showed that the increased serum HGMB1 level (odds ratio [OR] 2.145, 95% confidence interval[CI] 1.467-3.138; P=0.002), taking antiplatelet drugs regularly before onset (OR 5.496, 95% CI 1.700-17.768; P=0.004) and increased baseline fasting blood glucose level (OR 1.333, 95% CI 1.024-1.736; P=0.033) were the independent risk factors for HT after intravenous thrombolysis. ROC curve analysis showed that the area under the curve of serum HMGB1 level predicting HT after intravenous thrombolysis was 0.788 (95% CI 0.721-0.845; P<0.001). The sensitivity and specificity were 72.73% and 82.50%, respectively, when the best cutoff value was 7.97 μg/L.@*Conclusion@#The increased baseline HMGB1 level may predict the risk of HT after intravenous thrombolysis in patients with acute ischemic stroke.

Acute Spontaneous Subdural Hematoma in Posterior Fossa: Great Outcome.

BACKGROUND: Acute subdural hematomas are frequently seen in brain trauma-injured patients. However, spontaneous subdural hematomas are uncommon, especially those localized in the posterior fossa, where fewer than 10 case reports have been described in the medical literature. CASE DESCRIPTION: We describe a patient who suddenly had a headache and progressed rapidly to coma and signs of brainstem compression. She was diagnosed with posterior fossa subdural hematoma after image examinations that were endorsed by surgical findings. A posterior fossa craniectomy was performed and was associated with blood drainage. CONCLUSIONS: The patient had a great outcome, with no neurologic deficits at hospital discharge and the 1-year follow-up.

Clinical analysis of minimally invasive surgery in the treatment of hypertensive lobar cerebral hemorrhage / 天津医药

Objective To explore the clinical value and effect of neuronavigation-assisted neuroendoscopy for hypertensive lobar cerebral hemorrhage. Methods Clinical data of 35 cases treated with the neuroendoscopy (neuroendoscopy group) and 32 cases treated with the neuronavigation-assisted microscope (microscope group) were retrospectively analyzed. Data of the operative time, intraoperative blood loss and the clearance rate of hematoma, the postoperative complications (stress gastric ulcer, pulmonary infection, urinary tract infection and intracranial infection), the hospital stay, postoperative ability of daily life (ADL) in 6 months and fatality rates were observed and compared. Results The operative time and intraoperative blood loss were less in the neuroendoscopy group than those in the microscopy group, and the clearance rate of hematoma was higher in neuroendoscopy group than that in the microscopy group (P＜0.01). There was no significant difference in postoperative complications between the two groups (P＞0.05). The hospital stay was less in the neuroendoscopy group than that of the microscope group (P＜0.01). On the basis of ADL grading method, the prognosis of the endoscopy group was better than that of the craniotomy group (P＜0.05). There was no significant difference in the fatality rate between the neuroendoscopy group and the microscopy group (P＞0.05). Conclusion The neuronavigation-assisted neuroendoscopy is a safe and effective surgical method for hypertensive lobar cerebral hemorrhage, and which can improve the prognosis of patients with hypertensive intracerebral hemorrhage.

Recurrent Bleeding in Hemorrhagic Moyamoya Disease : Prognostic Implications of the Perfusion Status.

OBJECTIVE: Hemorrhagic moyamoya disease (hMMD) is associated with a poor clinical course. Furthermore, poorer clinical outcomes occur in cases of recurrent bleeding. However, the effect of hemodynamic insufficiency on rebleeding risk has not been investigated yet. This study evaluated the prognostic implications of the perfusion status during the clinical course of adult hMMD. METHODS: This retrospective study enrolled 52 adult hMMD patients between April 1995 and October 2010 from a single institute. Demographic data, clinical and radiologic characteristics, including hemodynamic status using single photon emission computed tomography (SPECT), and follow up data were obtained via a retrospective review of medical charts and imaging. Statistical analyses were performed to explore potential prognostic factors. RESULTS: Hemodynamic abnormality was identified in 44 (84.6%) patients. Subsequent revascularization surgery was performed in 22 (42.3%) patients. During a 58-month (median, range 3-160) follow-up assessment period, 17 showed subsequent stroke (hemorrhagic n=12, ischemic n=5, Actuarial stroke rate 5.8±1.4%/year). Recurrent hemorrhage was associated with decreased basal perfusion (HR 19.872; 95% CI=1.196-294.117) and omission of revascularization (10.218; 95%; CI=1.532-68.136). CONCLUSION: Decreased basal perfusion seems to be associated with recurrent bleeding. Revascularization might prevent recurrent stroke in hMMD by rectifying the perfusion abnormality. A larger-sized, controlled study is required to address this issue.

Recurrent Bleeding in Hemorrhagic Moyamoya Disease : Prognostic Implications of the Perfusion Status

OBJECTIVE: Hemorrhagic moyamoya disease (hMMD) is associated with a poor clinical course. Furthermore, poorer clinical outcomes occur in cases of recurrent bleeding. However, the effect of hemodynamic insufficiency on rebleeding risk has not been investigated yet. This study evaluated the prognostic implications of the perfusion status during the clinical course of adult hMMD. METHODS: This retrospective study enrolled 52 adult hMMD patients between April 1995 and October 2010 from a single institute. Demographic data, clinical and radiologic characteristics, including hemodynamic status using single photon emission computed tomography (SPECT), and follow up data were obtained via a retrospective review of medical charts and imaging. Statistical analyses were performed to explore potential prognostic factors. RESULTS: Hemodynamic abnormality was identified in 44 (84.6%) patients. Subsequent revascularization surgery was performed in 22 (42.3%) patients. During a 58-month (median, range 3-160) follow-up assessment period, 17 showed subsequent stroke (hemorrhagic n=12, ischemic n=5, Actuarial stroke rate 5.8+/-1.4%/year). Recurrent hemorrhage was associated with decreased basal perfusion (HR 19.872; 95% CI=1.196-294.117) and omission of revascularization (10.218; 95%; CI=1.532-68.136). CONCLUSION: Decreased basal perfusion seems to be associated with recurrent bleeding. Revascularization might prevent recurrent stroke in hMMD by rectifying the perfusion abnormality. A larger-sized, controlled study is required to address this issue.

Multiple Recurrent Cerebral Hemorrhages Related to Cerebral Amyloid Angiopathy with Arterial Hypertension

Cerebral amyloid angiopathy(CAA) is characterized by the deposition of amyloid beta-protein in the walls of small to medium-sized arteries of the leptomeninges and cerebral cortex. While often asymptomatic, CAA can develop into intracerebral hemorrhage facilitated by arterial hypertension. We report the case of a 52-year-old man with CAA and arterial hypertension who developed recurrent cerebral hemorrhages on three different occasions and in multiple non-overlapping loci over a period of nine years. Based on our findings, we recommend brain biopsies for all patients undergoing evacuation of multiple recurrence or atypical pattern intracerebral hemorrhages.

Remark on some clinical characteristics, CT scanner images and evaluate the value of SIRIRAJ grade in diagnosis for cerebral hemorrhages and cerebral infarction at the General Nghe An Hospital

A study on 114 patients at the Mental Department and Emergency Department in the General Nghe An Hospital from Aug 2002 to Aug 2004 showed that: cerebral stroke is common disorder in neurology. Cerebral hemorrhages patients have some symptoms such as: conscious disorders (90.5%); headache (95.2%); encephalic infarction with hemiplegia 72.2%. Cerebral hemorrhages with sudden onset (76.2%), serious conscious disorder (71.4%), headache (66.7%), and vomiting (57.1%), orbicularis disorder (80.9%), meningitis syndrome (57.1%). Although encephalic infarction onset is more serious, its symptoms are much lower than cerebral hemorrhages. The average blood pressure in patients with cerebral hemorrhages is higher than that in patients with encephalic infarction. 87.7% patients have one lesion nest identified by computed tomography (CT) scanner, in which infarction-hemorrhagic lesion was 7%. The method has high value in differential diagnosis between cerebral hemorrhages and cerebral infarction with the sensitivity of diagnosis of cerebral hemorrhages was 88.8% and encephalic infarction was 90.9%, the overall accuracy was 93.7%. Because the SIRIRAJ grade is simple, easy to count and mainly based on questioning patients, so it should be applied widely for doctors at community centers without CT scanner.