Molecular Biomarkers Affecting Moyamoya Disease.

Although the pathogenetic pathway of moyamoya disease (MMD) remains unknown, studies have indicated that variations in the RING finger protein RNF 213 is the strongest susceptible gene of MMD. In addition to the polymorphism of this gene, many circulating angiogenetic factors such as growth factors, vascular progenitor cells, inflammatory and immune mediators, angiogenesis related cytokines, as well as circulating proteins promoting intimal hyperplasia, excessive collateral formation, smooth muscle migration and atypical migration may also play critical roles in producing this disease. Identification of these circulating molecules biomarkers may be used for the early detection of this disease. In this chapter, how the hypothesized pathophysiology of these factors affect MMD and the interactive modulation between them are summarized.

HDAC inhibitor protects chronic cerebral hypoperfusion and oxygen-glucose deprivation injuries via H3K14 and H4K5 acetylation-mediated BDNF expression.

Vascular dementia (VaD) is the second most common cause of dementia, but the treatment is still lacking. Although many studies have reported that histone deacetylase inhibitors (HDACis) confer protective effects against ischemic and hypoxic injuries, their role in VaD is still uncertain. Previous studies shown, one HDACi protected against cognitive decline in animals with chronic cerebral hypoperfusion (CCH). However, the underlying mechanisms remain elusive. In this study, we tested several 10,11-dihydro-5H-dibenzo[b,f]azepine hydroxamates, which act as HDACis in the CCH model (in vivo), and SH-SY5Y (neuroblastoma cells) with oxygen-glucose deprivation (OGD, in vitro). We identified a compound 13, which exhibited the best cell viability under OGD. The compound 13 could increase, in part, the protein levels of brain-derived neurotrophic factor (BDNF). It increased acetylation status on lysine 14 residue of histone 3 (H3K14) and lysine 5 of histone 4 (H4K5). We further clarified which promoters (I, II, III, IV or IX) could be affected by histone acetylation altered by compound 13. The results of chromatin immunoprecipitation and Q-PCR analysis indicate that an increase in H3K14 acetylation leads to an increase in the expression of BDNF promoter II, while an increase in H4K5 acetylation results in an increase in the activity of BDNF promoter II and III. Afterwards, these cause an increase in the expression of BDNF exon II, III and coding exon IX. In summary, the HDACi compound 13 may increase BDNF specific isoforms expression to rescue the ischemic and hypoxic injuries through changes of acetylation on histones.

Protective effects of 10,11-dihydro-5H-dibenzo[b,f]azepine hydroxamates on vascular cognitive impairment.

A series of 10,11-dihydro-5H-dibenzo [b,f]azepine hydroxamates (4-15) were synthesized, behaving as histone deacetylase inhibitors, and examined for their influence on vascular cognitive impairment (VCI), which correlated with dementia. The results revealed that (E)-3-(4-(((3-(3-chloro-10,11-dihydro-5H-dibenzo [b,f]azepin-5-yl)propyl)amino)methyl)phenyl)-N-hydroxy-acrylamide (13) increases cerebral blood flow (CBF), attenuates cognitive impairment, and improves hippocampal atrophy in in vivo study. It is also able to increase the level of histone acetylation (H3K14 or H4K5) in the cortex and hippocampus of chronic cerebral hypoperfusion (CCH) mice; as a result, it could be a potential HDAC inhibitor for the treatment of vascular cognitive impairment.

Multiplexed methylation profiles of tumor suppressor genes and clinical outcome in oligodendroglial tumors.

Aberrant methylation has been associated with transcriptional inactivation of tumor-related genes in a wide spectrum of human neoplasms. The influence of DNA methylation in oligodendroglial tumors is not fully understood. Genomic DNA was isolated from 61 oligodendroglial tumors for analysis of methylation using methylation-specific multiplex ligation-dependent probe amplification assay (MS-MLPA). We correlated methylation status with clinicopathological findings and outcome. The genes found to be most frequently methylated in oligodendroglial tumors were RASSF1A (80.3%), CASP8 (70.5%), and CDKN2A (52.5%). Kaplan-Meier survival curve analysis demonstrated longer duration of progression-free survival in patients with 19q loss, aged less than 38 years, and with a proliferative index of less than 5%. Methylation of the ESR1 promoter is significantly associated with shorter duration of overall survival and progression-free survival, and that methylation of IGSF4 and RASSF1A is significantly associated with shorter duration of progression-free survival. However, none of the methylation status of ESR1, IGSF4, and RASSF1A was of prognostic value for survival in a multivariate Cox model. A number of novel and interesting epigenetic alterations were identified in this study. The findings highlight the importance of methylation profiles in oligodendroglial tumors and their possible involvement in tumorigenesis.

Genetic and epigenetic alterations in primary-progressive paired oligodendroglial tumors.

The aim of the present study was to identify genetic and epigenetic alterations involved in the progression of oligodendroglial tumors. We characterized 21 paired, World Health Organization (WHO) grade II and III oligodendroglial tumors from patients who received craniotomies for the partial or complete resection of primary and secondary oligodendroglial tumors. Tumor DNA was analyzed for alterations in selected genetic loci (1p36, 9p22, 10q23-24, 17p13, 19q13, 22q12), isocitrate dehydrogenase 1 (IDH1), isocitrate dehydrogenase 2 (IDH2) and the CpG island methylation status of critical tumor-related genes (MGMT, P16, DAPK, PTEN, RASSF1A, Rb1). Alterations of these markers were common early in the tumorigenesis. In the primary tumors we identified 12 patients (57.1%) with 1p36 deletions, 17 (81.0%) with 19q13 deletions, 9 (42.9%) with 1p36/19q13 codeletions, 11 (52.3%) with 9p22 deletions, and 12 (57.1%) with IDH1 mutation. Epigenetic analysis detected promoter methylation of the MGMT, P16, DAPK, PTEN, RASSF1A, and Rb1 genes in 38.1%, 19.0%, 38.1%, 33.3%, 66.7%, and 14.3% of primary tumors, respectively. After progression, additional losses of 1p, 9p, 10q, 17p, 19q and 22q were observed in 3 (14.3%), 1 (4.8%), 3 (14.3%), 2 (9.5%), 1 (4.8%) and 3 (14.3%) cases, respectively. Additional methylations of the MGMT, P16, DAPK, PTEN, RASSF1A, and RB1 promoters was observed in 4 (19.0%), 2 (9.5%), 0 (0%), 6 (28.6%), 2(9.5%) and 3 (14.3%) cases, respectively. The status of IDH1 mutation remained unchanged in all tumors after progression. The primary tumors of three patients with subsequent progression to high-grade astrocytomas, all had 9p deletion, intact 1p, intact 10q and unmethylated MGMT. Whether this may represent a molecular signature of patients at-risk for the development of aggressive astrocytomas needs further investigation.

Single-Incision laparoscopic surgery (SILS) for ventriculoperitoneal shunt placement.

BACKGROUND: Single-incision laparoscopic surgery (SILS) may facilitate safer shunt placement and lower distal obstruction rate than is seen in conventional surgery. OBJECTIVE: We reviewed our 2-year experience in SILS for ventriculoperitoneal shunt placement to evaluate its usefulness and safety.Materials and Methods In this retrospective study, we enrolled patients older than 18 years with dilated ventricle and syndromes of hydrocephalus. A total of 31 patients underwent 31 primary ventriculoperitoneal shunt placement surgery and two underwent revision surgery. All the procedures were performed by the SILS technique. RESULTS: The entire duration of ventriculoperitoneal shunt implantation ranged from 45 to 80 minutes, with mean operation time of 65 ± 15.3 minutes. No major laparoscopy-related complications were noted. Shunt infection, peritonitis, and distal catheter malfunction occurred in one case (3.2%), proximal malfunction in one case (3.2%), and subcutaneous emphysema occurred in two cases (6.4%). The emphysema resolved within 2 days. Cosmetic results were "very good to good" in 17 patients (54.8%) and "satisfactory" in 14 patients (45.2%). The abdominal scars in most cases were nearly invisible. CONCLUSION: SILS is a safe and effective technique for ventriculoperitoneal shunt placement and can be accomplished with no higher risk of shunt infection and distal malfunction. Without an additional port, SILS allows good visualization of the peritoneal cavity to avoid major intra-abdominal complications. Only one 6-mm incision at the umbilicus area is required and is almost invisible after wound healing.

Hyperacute cerebral aneurysm rerupture during CT angiography.

OBJECT: The object of this study was to identify the clinical features and outcomes of a subgroup of patients with aneurysmal subarachnoid hemorrhage (SAH) who had active contrast extravasation from a ruptured aneurysm during initial cerebral CT angiography (CTA). METHODS: The authors performed a retrospective study of spontaneous SAH cases involving patients treated at their institute. They identified 9 cases in which active contrast extravasation was evident on the initial CT angiogram. Another 12 similar cases were also identified in a literature review and data was gathered from these cases to evaluate the outcomes. RESULTS: Analysis of all 21 cases revealed that the overall outcomes in cases characterized by active aneurysmal bleeding during CTA were poor. Seventy-six percent of patients had unfavorable results. Patients who showed poor neurological status at presentation died no matter what kind of treatment they received. In contrast, patients who presented with good neurological status initially had a chance of favorable outcome. Among the patients with good initial neurological status, most demonstrated rapid deterioration of their condition during the CTA examination; only those who received immediate and effective decompressive surgery and aneurysm obliteration had good results. CONCLUSIONS: Active aneurysmal rebleeding during CTA is an uncommon but devastating event. Though the mortality of this distinct group of patients remains high, a clinical subgroup may benefit from immediate surgery. Patients with good initial neurological status who show rapid neurological deterioration may still have a favorable outcome if they undergo timely and successful decompressive surgery and proper aneurysm obliteration. Patients who present with poor neurological status do badly, and there is no effective treatment for such patients.

Early parenchymal contrast extravasation predicts subsequent hemorrhage progression, clinical deterioration, and need for surgery in patients with traumatic cerebral contusion.

BACKGROUND: This study aimed to identify early radiologic signs that are predictive of hemorrhage progression and clinical deterioration in patients with traumatic cerebral contusion. We hypothesized that contrast extravasation (CE) and blood-brain barrier disruption might be associated with hemorrhage progression, brain edema, and clinical deterioration in these patients. METHODS: Twenty-two patients with traumatic cerebral contusion (diagnosed on initial noncontrast head computed tomography [CT]) who initially did not require surgical intervention were enrolled in this study. Contrast-enhanced and perfusion CT scans were performed within 6 hours of injury, and follow-up noncontrast CT scans were performed at 24 hours and 72 hours. RESULTS: In each noncontrast CT scan, the volumes of the contusion hemorrhage and edema were calculated using computerized planimetric techniques. The initial Glasgow Coma Scale, hemorrhage progression, clinical deterioration, and the need for subsequent surgery were recorded. The early radiologic findings were compared with these parameters and functional outcome at 6 months to identify predictive radiologic signs. CE was present in 9 of 22 patients (41%) and was highly associated with hemorrhage progression (p < 0.05), clinical deterioration (p < 0.01), and need for subsequent surgery (p < 0.01). In addition, patients with CE had a greater volume of edema at 24 hours (p < 0.01) and 72 hours (p < 0.01) than those who did not have CE. However, CE was not found to be associated with poor outcome. CONCLUSIONS: Early parenchymal CE is associated with hemorrhage progression, cerebral edema, clinical deterioration, and need for subsequent surgery. These patients should be monitored closely, and early surgery may be needed if deterioration occurs. Further elucidation of the pathophysiology is needed to formulate effective treatment for these high-risk patients.

Contemporary surgical outcome for skull base meningiomas.

Although surgical excision of meningioma and its dural base is the most common primary management, skull base meningiomas are quite different, and contemporary management usually consists of multimodal treatment with the aim of achieving the best possible functional outcome and quality of life (QOL) for these patients. As surgery plays an important role in the treatment of skull base meningiomas, it is crucial for neurosurgeons to appreciate the surgical outcome and QOL after meningioma surgery. Outcome is usually measured for meningiomas in terms of morbidity, mortality, time to recurrence, and QOL. The extent of resection, tumor grade, proliferative markers, and tumor location are significant factors in predicting the surgical outcome. Therefore, we address each of these factors in detail in this review. Advances in recent decades in microsurgical techniques, neuroimaging modalities, neuroanesthesia, and perioperative intensive care have substantially improved the surgical outcome; therefore, most surgical outcomes discussed in this review are cited from contemporary literature (2000 to the present) in order to depict the surgical outcome of contemporary microsurgery.

Early endoscope-assisted hematoma evacuation in patients with supratentorial intracerebral hemorrhage: case selection, surgical technique, and long-term results.

OBJECT: Currently, the effectiveness of minimally invasive evacuation of intracerebral hemorrhage (ICH) utilizing the endoscopic method is uncertain and the technique is considered investigational. The authors analyzed their experience with this method in terms of case selection, surgical technique, and long-term results. METHODS: The authors performed a retrospective analysis of the clinical and radiographic data obtained in 68 patients treated with endoscope-assisted ICH evacuation. Rebleeding, morbidity, and mortality were recorded as primary end points. Hematoma evacuation rate was calculated by comparing the pre- and postoperative CT scans. Glasgow Coma Scale scores and scores on the extended Glasgow Outcome Scale (GOSE) were recorded at the 6-month postoperative follow-up. The technical aspect of this report explains details of the procedure, the instruments that are used, the methods for hemostasis, and the role of hemostatic agents in the management of intraoperative hemorrhage. The pertinent literature was reviewed and summarized. RESULTS: All surgeries were performed within 12 hours of ictus, and 84% of the surgeries were performed within 4 hours. The mortality rate was 5.9%, and surgery-related morbidity occurred in 3 cases (4.4%). The hematoma evacuation rate was 93% overall-96% in the putaminal group, 86% in the thalamic group, and 98% in the subcortical group. The rebleeding rate was 1.5%. The mean operative time was 85 minutes, and the average blood loss was 56 ml. The mean GOSE score was 4.9 at 6-month follow-up. The authors acknowledge the limitations of these preliminary results in a small number of patients. CONCLUSIONS: The data suggest that early endoscope-assisted ICH evacuation is safe and effective in the management of supratentorial ICH. The rebleeding, morbidity, and mortality rates are low compared with rates reported in the literature for the traditional craniotomy method. This study also showed that early and complete evacuation of ICH may lead to improved outcomes in selected patients. However, the safety and efficacy of endoscope-assisted ICH evacuation should be further investigated in a large, prospective, randomized trial.

Perfusion computed tomographic imaging and surgical selection with patients after poor-grade aneurysmal subarachnoid hemorrhage.

BACKGROUND: Patients with ruptured aneurysms who present in coma have already experienced significant brain injury, require intensive resuscitation, have aneurysms that are difficult to treat, and generally fare poorly despite aggressive intervention. OBJECTIVE: To determine whether surgical outcomes in comatose patients with ruptured aneurysms in a modern series might be better than previously reported because of changing surgical indications and multidisciplinary management, and to determine whether perfusion computed tomography (PCT) imaging might help select patients for surgery. METHODS: A consecutive series of 78 patients with poor-grade aneurysms treated surgically was reviewed. Management consisted of resuscitation, early surgery, intracranial pressure control, comprehensive intensive care, and endovascular therapy for vasospasm. Cerebral blood flow (CBF), volume (CBV), and mean transit time (MTT) were measured on admission PCT studies and correlated with outcomes. RESULTS: Among 58 grade IV patients (74%) and 20 grade V patients (26%), 44 patients (56%) had favorable outcomes (Glasgow Outcome Scale 5 and 4), and 34 patients (44%) had unfavorable outcomes. Favorable outcomes among grade IV patients were observed in 71%, whereas mortality among grade V patients was 60%. Sixteen patients (89%) with normal cerebral perfusion had favorable outcomes and all 13 patients with hemispheric or global hypoperfusion had unfavorable outcomes. CONCLUSIONS: PCT provides physiological data that are immediately applicable and can guide decisions to aggressively manage comatose patients with ruptured aneurysms. Grade IV patients with normal or focally abnormal perfusion are good candidates for treatment, whereas grade V patients with hemispheric or global hypoperfusion are poor candidates. Surgery effectively excludes aneurysms with complex anatomy and relieves increased intracranial pressure with hematoma evacuation, lobectomy, and/or hemicraniectomy. Modern neurosurgical, endovascular, and neurointensive critical care produces favorable outcomes in a substantial percentage of carefully selected patients.

Cushing's disease in children: report of three cases.

Cushing's disease is rare in children and adolescents. We report the clinical presentations of three children with Cushing's disease. All three exhibited the typical symptoms and signs of weight gain and growth retardation. Tw o also demonstrated personality changes, hypertension and hypokalemia, the last of these being rarely reported in patients with Cushing's disease. Lack of diurnal changes in serum cortisol levels was the most common biochemical finding. Serum cortisol levels were suppressed by low-dose dexamethasone in one patient, which is not typical for patients with Cushing's disease. Imaging studies are essential for localizing the tumor. Transsphenoidal surgery remains the treatment of choice, and pituitary irradiation should be considered for those patients whose tumors cannot be totally removed. Careful follow-up of these patients with awareness of the possibilities of relapse and the complications of hypopituitarism is indicated.

Use of the "mortise and tenon" principle in the augmentation of autologous cranioplasty using bone cement in a child.

We report the case of a 20-month-old boy with autologous bone graft resorption that resulted in a floating bone graft and progressive asymmetric deformity of the skull. The patient had undergone decompressive craniectomy for acute subdural hematoma at the age of 13 months after a fall, followed by cranioplasty 1 month later with an autologous bone graft, which was stored in a freezer immediately after surgery. We used the mortise and tenon principle to replace the screws and plates to join a polymethylmethacrylate prosthesis to the skull, augmenting the resorbed autologous bone graft. The cosmetic effect was maintained and craniocerebral protection was restored. It is thought that this technique could be used for bone defects of various sizes in patients of any age in cases where screws and plates are not suitable.

Differential CT features of acute lentiform subdural hematoma and epidural hematoma.

OBJECTIVES: Acute subdural hematoma (SDH) normally appears as a panhemispheric collection of blood with a crescent configuration. However, a number of SDH show lentiform appearances, mimicking acute epidural hematoma (EDH). In this study, we reported our experiences with this special disease entity. Radiological features that aided in the accurate localization of the hematoma were also addressed. PATIENTS AND METHODS: From among 51 acute SDH cases who were surgically treated between July 2007 and April 2008, five cases whose SDH had a localized convex appearance were enrolled. Surgical records and CT images were retrospectively reviewed. Important CT features that could differentiate lentiform SDH from EDH were especially analyzed. RESULTS: Subdural adhesions were major causes of localized SDH in four out of five patients, all of whom had previous neurosurgical interventions or radiotherapy. Though those hematomas appeared as biconvex on CT scans, four differential features could be identified in favor of SDH. These included a crescentic tail, an obtuse angle at the margin of the hematoma, a dural line above the hematoma and a direct connection to the underlying intracerebral hematomas. CONCLUSIONS: Biconvex localized SDH might be misinterpreted as acute EDH if the diagnosis is based on the shape of the hematoma alone. This study emphasized that a detailed evaluation of surgical histories and CT features are mandatory in differentiating lentiform SDH and EDH.

Sarcoma of the cervical spine after radiation treatment for thyroid cancer.

STUDY DESIGN: Case report. OBJECTIVE: We report a rare case of postradiation sarcoma of the cervical spine 30 years after treatment for thyroid cancer. SUMMARY OF BACKGROUND DATA: The reported case is a 66-year-old man with a history of thyroid cancer treated with surgery and radiotherapy at the age of 36 years. He was disease-free for 30 years, but then developed left upper limb weakness and numbness. Magnetic resonance imaging showed a homogeneously enhanced mass lesion with cystic parts involving the C4 vertebral body and occupying the left side of the spinal canal with extension to the paraspinal space through the neural foramen. METHODS: Using staged posterior and anterior approaches, gross total tumor excision, C4 corpectomy, and spinal fusion were achieved. RESULTS: The histologic diagnosis revealed sarcoma that was immunoreactive to vimentin and focally to S100 and O13 antibodies. Radiation-induced sarcoma should be suspected in patients who have received radiation treatment previously and present with new neurologic symptoms and signs in the irradiated area. The patient's muscle power returned to 5/5, except for the left upper extremity, which reached 2/5; he was free from recurring symptoms during the follow-up period. CONCLUSION: Because of advancements in diagnostic techniques and therapeutic methods, more patients survive primary cancer, and therefore an increase in the number of cases of postradiation sarcoma is expected. Postradiation sarcomas have extremely long latent periods, and one should therefore always keep in mind such a complication of previous radiation treatment.

O(6)-Methylguanine-DNA methyltransferase expression and prognostic value in brain metastases of lung cancers.

O(6)-Methylguanine-DNA methyltransferase (MGMT) is critical for repairing pro-mutagenic DNA bases and is correlated with response to alkylating agents in cancers. Since there is great interest in pursuing the potential role of temozolomide, a novel alkylating agent, in the treatment of brain metastases, this study aimed to evaluate MGMT expression as well as its prognostic value in this devastating disease. We studied the expression and methylation status of MGMT in 86 brain metastases of lung cancers. Twenty of them had matched primary lung tumor tissues available for direct comparison. MGMT expression was assessed by immunohistochemistry (IHC); the methylation status of MGMT promoter was analyzed by nested methylation-specific PCR (MSP) and validated by quantitative real-time PCR analysis. Positive nuclear MGMT expression was detected more frequently in brain metastases as compared with primary lung cancers (83% versus 50%, P=0.004). The discordance in MGMT expression persisted in the 20 paired primary and metastatic tumors (P=0.031). MGMT promoter hypermethylation was highly correlated with loss of MGMT expression. Both univariate and multivariate analyses showed that median overall survival was significantly longer in patients with positive MGMT expression in brain metastases (16.5 versus 3.5 months, P<0.001). In conclusion, MGMT expression was enhanced in brain metastases as compared with the primary lung cancers. MGMT expression in brain metastases was significantly correlated with better survival.

Brain stem cavernous malformations.

We retrospectively reviewed the clinical experience of 30 patients with brain stem cavernous malformations (BSCM) treated operatively and non-operatively at our hospital between 1983 and 2005 to elucidate the natural history of BSCM and the factors that affect surgical outcome. Inpatient charts, imaging studies, operative records, and follow-up results were evaluated. The average follow up was 48.5 months. Twenty-two patients (73.3%) received surgical extirpation and of these 86.4% improved or stabilized and 13.6% deteriorated with permanent or severe morbidity. There was no mortality. Size, preoperative status, and surgical timing were factors related to surgical outcome. In the non-operative group, 50% of the patients were the same or better, 25% deteriorated, and 25% died. With appropriate patient selection, resection of BSCM can be achieved with acceptable morbidity compared with the ominous natural history of these lesions.