Isaac Josh Abecassis

Natural history of brain arteriovenous malformations: a systematic review

OBJECT The authors aimed to systematically review the literature to clarify the natural history of brain arteriovenous malformations (BAVMs). METHODS The authors searched PubMed for one or more of the following terms: natural history, brain arteriovenous malformations, cerebral arteriovenous malformations, and risk of rupture. They included studies that reported annual rates of hemorrhage and that included either 100 patients or 5 years of treatment-free follow-up. RESULTS The incidence of BAVMs is 1.12-1.42 cases per 100,000 person-years; 38%-68% of new cases are first-ever hemorrhage. The overall annual rates of hemorrhage for patients with untreated BAVMs range from 2.10% to 4.12%. Consistently implicated in subsequent hemorrhage are initial hemorrhagic presentation, exclusively deep venous drainage, and deep and infrantentorial brain location. The risk for rupture seems to be increased by large nidus size and concurrent arterial aneurysms, although these factors have not been studied as thoroughly. Venous stenosis has not been implicated in increased risk for rupture. CONCLUSIONS For patients with BAVMs, although the overall risk for hemorrhage seems to be 2.10%-4.12% per year, calculating an accurate risk profile for decision making involves clinical attention and accounting for specific features of the malformation.

Survival after surgery and stereotactic radiosurgery for patients with multiple intracranial metastases: results of a single-center retrospective study

OBJECTIVES Patients with systemic cancer and a single brain metastasis who undergo treatment with resection plus radiotherapy live longer and have a better quality of life than those treated with radiotherapy alone. Historically, whole-brain radiotherapy (WBRT) has been the mainstay of radiation therapy; however, it is associated with significant delayed neurocognitive sequelae. In this study, the authors looked at survival in patients with single and multiple intracranial metastases who had undergone surgery and adjuvant stereotactic radiosurgery (SRS) to the tumor bed and synchronous lesions. METHODS The authors retrospectively reviewed the records from an 8-year period at a single institution for consecutive patients with brain metastases treated via complete resection of dominant lesions and adjuvant radiosurgery. The cohort was analyzed for time to local progression, synchronous lesion progression, new intracranial lesion development, systemic progression, and overall survival. The Kaplan-Meier method (stratified by age, sex, tumor histology, and number of intracranial lesions prior to surgery) was used to calculate both progression-free and overall survival. A Cox proportional-hazards regression model was also fitted with the number of intracranial lesions as the predictor and survival as the outcome controlling for disease severity, age, sex, and primary histology. RESULTS The median overall follow-up among the 150-person cohort eligible for analysis was 17 months. Patients had an average age of 46.2 years (range 16-82 years), and 62.7% were female. The mean (± standard deviation) number of intracranial lesions per patient was 2.5 ± 2.3. The mean time between surgery and stereotactic radiosurgery (SRS) was 3.2 ± 4.1 weeks. Primary cancers included lung cancer (43.3%), breast cancer (21.3%), melanoma (10.0%), renal cell carcinoma (6.7%), and colon cancer (6.7%). The average number of isocenters per treated lesion was 7.6 ± 6.6, and the average treatment dose was 17.8 ± 2.8 Gy. One-year survival for patients in this cohort was 52%, and the 1-year local control rate was 77%. The median (±standard error) overall survival was 13.2 ± 1.9 months. There was no difference in survival between patients with a single lesion and those with multiple lesions (p = 0.319) after controlling for age, sex, and histology of primary tumor. Patients with primary breast histology had the greatest overall median survival (22.9 ± 6.2 months); patients with colorectal cancer had the shortest overall median survival (5.3 ± 1.8 months). The most common cause of death in this series was systemic progression (79%). CONCLUSIONS These results confirm that 1-year survival for patients with multiple intracranial metastases treated with resection followed by SRS to both the tumor bed and synchronous lesions is similar to established outcomes for patients with a single intracranial metastasis.

Dolichoectatic aneurysms of the vertebrobasilar system: clinical and radiographic factors that predict poor outcomes

OBJECTIVE Fusiform dolichoectatic vertebrobasilar aneurysms are rare, challenging lesions. The natural history of these lesions and medium- and long-term patient outcomes are poorly understood. The authors sought to evaluate patient prognosis after diagnosis of fusiform dolichoectatic vertebrobasilar aneurysms and to identify clinical and radiographic predictors of neurological deterioration. METHODS The authors reviewed multiple, prospectively maintained, single-provider databases at 3 large-volume cerebrovascular centers to obtain data on patients with unruptured, fusiform, basilar artery dolichoectatic aneurysms diagnosed between January 1, 2000, and January 1, 2015. RESULTS A total of 50 patients (33 men, 17 women) were identified; mean clinical follow-up was 50.1 months and mean radiographic follow-up was 32.4 months. At last follow-up, 42% (n = 21) of aneurysms had progressed and 44% (n = 22) of patients had deterioration of their modified Rankin Scale scores. When patients were dichotomized into 2 groups- those who worsened and those who did not-univariate analysis showed 5 variables to be statistically significantly different: sex (p = 0.007), radiographic brainstem compression (p = 0.03), clinical posterior fossa compression (p < 0.001), aneurysmal growth on subsequent imaging (p = 0.001), and surgical therapy (p = 0.006). A binary logistic regression was then created to evaluate these variables. The only variable found to be a statistically significant predictor of clinical worsening was clinical symptoms of posterior fossa compression at presentation (p = 0.01). CONCLUSIONS Fusiform dolichoectatic vertebrobasilar aneurysms carry a poor prognosis, with approximately one-half of the patients deteriorating or experiencing progression of their aneurysm within 5 years. Despite being high risk, intervention-when carefully timed (before neurological decline)-may be beneficial in select patients.

Timing of cranioplasty: a 10.75-year single-center analysis of 754 patients

OBJECTIVE Despite their technical simplicity, cranioplasty procedures carry high reported morbidity rates. The authors here present the largest study to date on complications after cranioplasty, focusing specifically on the relationship between complications and timing of the operation. METHODS The authors retrospectively reviewed all cranioplasty cases performed at Harborview Medical Center over the past 10.75 years. In addition to relevant clinical and demographic characteristics, patient morbidity and mortality data were abstracted from the electronic medical record. Cox proportional-hazards models were used to analyze variables potentially associated with the risk of infection, hydrocephalus, seizure, hematoma, and bone flap resorption. RESULTS Over the course of 10.75 years, 754 cranioplasties were performed at a single institution. Sixty percent of the patients who underwent these cranioplasties were male, and the median follow-up overall was 233 days. The 30-day mortality rate was 0.26% (2 cases, both due to postoperative epidural hematoma). Overall, 24.6% percent of the patients experienced at least 1 complication including infection necessitating explantation of the flap (6.6%), postoperative hydrocephalus requiring a shunt (9.0%), resorption of the flap requiring synthetic cranioplasty (6.3%), seizure (4.1%), postoperative hematoma requiring evacuation (2.3%), and other (1.6%). The rate of infection was significantly higher if the cranioplasty had been performed < 14 days after the initial craniectomy (p = 0.007, Holm-Bonferroni-adjusted p = 0.028). Hydrocephalus was significantly correlated with time to cranioplasty (OR 0.92 per 10-day increase, p < 0.001) and was most common in patients whose cranioplasty had been performed < 90 days after initial craniectomy. New-onset seizure, however, only occurred in patients who had undergone their cranioplasty > 90 days after initial craniectomy. Bone flap resorption was the least likely complication for patients whose cranioplasty had been performed between 15 and 30 days after initial craniectomy. Resorption was also correlated with patient age, with a hazard ratio of 0.67 per increase of 10 years of age (p = 0.001). CONCLUSIONS Cranioplasty performed between 15 and 30 days after initial craniectomy may minimize infection, seizure, and bone flap resorption, whereas waiting > 90 days may minimize hydrocephalus but may increase the risk of seizure.

The dual microcatheter technique for transvenous embolization of dural arteriovenous fistulae

Background Dural arteriovenous fistulae (dAVFs) comprise 10–15% of all intracranial arteriovenous malformations. The goal of surgical or endovascular intervention is complete obliteration of the fistulous connection(s). In cases where dAVF venous drainage is separate from normal cortical drainage, transvenous embolization can provide fast and effective fistula obliteration. Objective To describe a new method of efficient transvenous embolization (the ‘dual microcatheter technique’) for the treatment of dAVFs. Methods Three patients with dAVFs were treated using the dual microcatheter technique for transvenous embolization. Two microcatheters were placed in the distal aspect of the dAVF venous pouch, after which coil embolization reduced fistula flow, and liquid embolic agent injection with reflux into arterial feeders completed the obliteration of the fistula. Results Lesion grade ranged from Borden–Shucart grades 2 through 3. In all cases, dAVF venous drainage was isolated from the normal cerebral venous drainage. Dual microcatheter transvenous embolization was successful in all patients, with non-target embolization and no new postoperative deficits. At the last follow-up, all three patients were symptom-free without evidence of radiographic recurrence. Conclusions The dual microcatheter technique of transvenous dAVF embolization is safe and feasible in cases where dAVF venous outflow is isolated from normal cerebral venous drainage.

Clival Ectopic Pituitary Adenoma Mimicking a Chordoma: Case Report and Review of the Literature

Background. Purely ectopic pituitary adenomas are exceedingly rare. Here we report on a patient that presented with an incidental clival mass thought to be a chordoma. Endonasal resection, tumor pathology, and endocrinology workup revealed a prolactinoma. Case Presentation. A 41-year-old male presented with an incidental clival lesion presumed to be a chordoma. On MRI it involved the entire clivus, extended laterally to the petroclival junction, and invaded the cavernous sinuses bilaterally, encasing both internal carotid arteries, without direct extension into the sella. Intraoperatively, it was clear that the tumor originated from the clivus and that the sellar dura was completely intact. Frozen-section pathology was consistent with a pituitary adenoma. Immunostaining was positive for synaptophysin and prolactin with a low Ki-67 index, suggestive of a prolactinoma. Additional immunohistochemical stains seen in chordomas (EMA, S100, and Brachyury) and other metastatic tumors were negative. A postoperative endocrine workup revealed an elevated serum prolactin of 881.3 ng/mL (normal < 20). Conclusions. In conclusion, it is crucial to maintain an extensive differential diagnosis when evaluating a patient with a clival lesion. Ectopic clival pituitary adenomas, although rare, may warrant an endocrinological workup preoperatively as the majority may respond to medical treatment.

A Single-Institution Experience with Pineal Region Tumors: 50 Tumors Over 1 Decade

BACKGROUND Pineal region tumors are rare intracranial tumors that are more common in children than adults. Surgical management of tumors in this region using a tailored approach is a strategy that enhances extent of resection and neurological outcome. OBJECTIVE To review our institutional experience with pineal region tumors in children and adults over the past 10 years. METHODS Our institutional pathology database and patient records were retrospectively reviewed for details regarding clinical and radiological presentation, surgical management, extent of resection, morbidity, and neurological outcome. Statistical analysis was performed to assess for variables related to functional outcomes. RESULTS Fifty patients were identified as having undergone surgical management of a pineal region tumor with at least 1 year of follow-up. Forty-one percent presented with a Karnofsky Performance Scale (KPS) score of 70 or less, all of whom had concomitant hydrocephalus that required urgent treatment. The following variables were statistically significant to KPS score on admission: age, tumor volume, preoperative hydrocephalus, length of hospitalization (total and intensive care unit), and elevations in serum tumor markers. The median postoperative (2 months) KPS score was 90. The following variables were statistically significant with respect to change in KPS score postoperatively: tumor maximum diameter, KPS score on admission, and intensive care unit length of stay. The specific surgical strategy did not correlate to extent of tumor resection, morbidity, immediate neurological outcome, and progression-free survival. CONCLUSION Extent of resection, neurological outcome, and progression-free survival in the patients in our series were not related to the specific surgical approach employed and its perioperative complications.

Immunotherapy for Secondary Glioblastoma Multiforme: Toward an Isocitrate Dehydrogenase Vaccine

Glioblastoma multiforme (GBM) is the most common and lethal primary brain tumor. Without treatment, median survival is only 3 months after diagnosis. Even with “gold standard” therapy consisting of maximal surgical resection, fractionated radiotherapy, and temozolomide chemotherapy, median survival is only 14.6 months (4, 10, 12). Diverse tumor biology and intrinsic tumor capabilities to overcome current treatment tactics remain the major obstacle to achieving longer survival periods. New targeted therapies are being investigated with the hope that a more individualized treatment regimen translates into better outcomes. Immunotherapy has long been touted as a potential approach to cancer, stemming from the late 1800s when Coley (2) observed tumor reduction in patients with sarcoma after acute infection with Streptococcus pyogenes. The theory behind tumor vaccines is that the body’s immune system can be stimulated by a tumor-specific peptide sequence/antigen to activate or amplify a humoral and cytotoxic immune response targeted at the specific cancer cells a patient happens to harbor (Figure 1). Despite multiple attempts at developing personalized vaccines with promising results in animal studies (1), peptide and dendritic cell vaccinations have largely failed in human clinical trials. The reasons for these failures vary but include suboptimal antigen selection, inadequate immunogenic responses, and GBM-associated immune evasion (7). However, a new glimmer of hope at overcoming these obstacles can be found in a recent article in Nature by Schumacher et al. (11) from the Department of Neurooncology at the University Hospital Heidelberg and National Center for Tumor Disease in Heidelberg, Germany. They report the exciting results in their quest to develop a tumor vaccine using a peptide target that is intimately affiliated with glioma biology: isocitrate dehydrogenase (IDH1). IDH1 is 1 of 3 isozymes translated from 5 primary genes to form a homodimer involved in cellular metabolism. The protein is present in both the cytoplasm and the peroxisome. The most common and clinically relevant IDH1 gene mutation is a heterozygous missense mutation at codon 132 resulting in replacement of an arginine (R) with a histidine (H), connoted R132H. It is rarely found in primary GBMs and gliosarcomas but is found in diffuse World Health Organization grades II and III gliomas (and secondary GBMs)>70% of the time (3). On a molecular/epigenetic level, IDH1 mutation appears to be tumorigenic, displaying a hypermethylated CpG island methylator phenotype (CIMP) (9) that represses critical tumor suppressor translation (5, 14). Despite this finding, patients with the IDH1 mutation demonstrate a clear overall survival benefit with an increased sensitivity to both chemotherapy (8) and radiation (6). One explanation for this paradoxical finding is that IDH1 mutation

Moyamoya Disease in a Patient with VACTERL Association

BACKGROUND VACTERL association is characterized by a group of congenital malformations that tend to occur together. Rarely, concurrent cerebrovascular abnormalities have been reported. In this article, we present the first reported case of moyamoya disease in a patient with VACTERL association. CASE DESCRIPTION The patient presented in the neonatal period with esophageal atresia with distal tracheoesophageal fistula as well as an imperforate anus. He also had a ventricular septal defect and persistent foramen ovale. At age 11 years, he developed seizures and was diagnosed with moyamoya disease, for which he underwent bilateral pial synagiosis. CONCLUSIONS Our report adds moyamoya disease to the spectrum of rare diseases that may occur in the context of VACTERL association. Further studies may reveal whether a common pathophysiology exists between the 2 conditions. Our patients congenital heart disease and the association between renovascular and cardiac disease with moyamoya may suggest a systemic vasculopathy. Moyamoya should be considered in children with VACTERL association who present with neurologic deficits or seizures.

Survival after surgery and stereotactic radiosurgery for patients with multiple intracranial metastases: results of a single-center retrospective study: Clinical article

OBJECTIVES Patients with systemic cancer and a single brain metastasis who undergo treatment with resection plus radiotherapy live longer and have a better quality of life than those treated with radiotherapy alone. Historically, whole-brain radiotherapy (WBRT) has been the mainstay of radiation therapy; however, it is associated with significant delayed neurocognitive sequelae. In this study, the authors looked at survival in patients with single and multiple intracranial metastases who had undergone surgery and adjuvant stereotactic radiosurgery (SRS) to the tumor bed and synchronous lesions. METHODS The authors retrospectively reviewed the records from an 8-year period at a single institution for consecutive patients with brain metastases treated via complete resection of dominant lesions and adjuvant radiosurgery. The cohort was analyzed for time to local progression, synchronous lesion progression, new intracranial lesion development, systemic progression, and overall survival. The Kaplan-Meier method (stratified by age, sex, tumor histology, and number of intracranial lesions prior to surgery) was used to calculate both progression-free and overall survival. A Cox proportional-hazards regression model was also fitted with the number of intracranial lesions as the predictor and survival as the outcome controlling for disease severity, age, sex, and primary histology. RESULTS The median overall follow-up among the 150-person cohort eligible for analysis was 17 months. Patients had an average age of 46.2 years (range 16-82 years), and 62.7% were female. The mean (± standard deviation) number of intracranial lesions per patient was 2.5 ± 2.3. The mean time between surgery and stereotactic radiosurgery (SRS) was 3.2 ± 4.1 weeks. Primary cancers included lung cancer (43.3%), breast cancer (21.3%), melanoma (10.0%), renal cell carcinoma (6.7%), and colon cancer (6.7%). The average number of isocenters per treated lesion was 7.6 ± 6.6, and the average treatment dose was 17.8 ± 2.8 Gy. One-year survival for patients in this cohort was 52%, and the 1-year local control rate was 77%. The median (±standard error) overall survival was 13.2 ± 1.9 months. There was no difference in survival between patients with a single lesion and those with multiple lesions (p = 0.319) after controlling for age, sex, and histology of primary tumor. Patients with primary breast histology had the greatest overall median survival (22.9 ± 6.2 months); patients with colorectal cancer had the shortest overall median survival (5.3 ± 1.8 months). The most common cause of death in this series was systemic progression (79%). CONCLUSIONS These results confirm that 1-year survival for patients with multiple intracranial metastases treated with resection followed by SRS to both the tumor bed and synchronous lesions is similar to established outcomes for patients with a single intracranial metastasis.