H. Hunt Batjer

Lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm

Genetic risk factors for intracranial aneurysm (IA) are not yet fully understood. Genomewide association studies have been successful at identifying common variants; however, the role of rare variation in IA susceptibility has not been fully explored. In this study, we report the use of whole exome sequencing (WES) in seven densely-affected families (45 individuals) recruited as part of the Familial Intracranial Aneurysm study. WES variants were prioritized by functional prediction, frequency, predicted pathogenicity, and segregation within families. Using these criteria, 68 variants in 68 genes were prioritized across the seven families. Of the genes that were expressed in IA tissue, one gene (TMEM132B) was differentially expressed in aneurysmal samples (n=44) as compared to control samples (n=16) (false discovery rate adjusted p-value=0.023). We demonstrate that sequencing of densely affected families permits exploration of the role of rare variants in a relatively common disease such as IA, although there are important study design considerations for applying sequencing to complex disorders. In this study, we explore methods of WES variant prioritization, including the incorporation of unaffected individuals, multipoint linkage analysis, biological pathway information, and transcriptome profiling. Further studies are needed to validate and characterize the set of variants and genes identified in this study.

A Clinical Study of the Parameters and Effects of Temporary Arterial Occlusion in the Management of Intracranial Aneurysms

Temporary occlusion of intracranial arteries has emerged as a valuable technical adjunct in the management of intracranial aneurysms. The current study considered 121 patients (from a group of 234 consecutive aneurysm patients treated during a 2-yr period) who underwent elective temporary arterial occlusion. Twenty-one patients were excluded from further study because of an intraoperative rupture of an aneurysm, the elective sacrifice of afferent or efferent vessels, or the performance of an extracranial-intracranial arterial bypass graft; the remaining 100 patients underwent elective temporary occlusion under a standard neuroanesthetic regimen, including etomidate-induced burst suppression, normotension, normovolemia, and normothermia. In the postoperative period, radiographic evidence of ischemic brain injury in the distribution of the arteries occluded was selected as the end point for the failure of occlusion tolerance. The parameters evaluated with respect to this end point included the duration and nature of the temporary arterial occlusion, the number of the occlusive episodes, the specific vascular territory occluded, patient age, neurological status, presence of subarachnoid hemorrhage, vasospasm, and aneurysm size. Several parameters were found to be related to the postoperative development of ischemic injury. Patients more than 61 years of age and those in poor neurological condition (Hunt and Hess Grades III to IV) did not tolerate temporary occlusion as well as patients who were younger and in better condition. Patients occluded for less than 14 minutes routinely tolerated the iatrogenic ischemia; the 95% confidence level for the toleration of occlusion without the development of infarction occurred at 19 minutes. All patients occluded for more than 31 minutes had both clinical and radiographic evidence of cerebral infarction.(ABSTRACT TRUNCATED AT 250 WORDS)

Posteroinferior cerebellar artery aneurysms: Surgical results for 38 patients

OBJECTIVEnPosteroinferior cerebellar artery aneurysms have an incidence of approximately 0.49%. Reports in the literature are sparse concerning outcomes in this patient population. We report our results for 38 consecutive patients who were treated during the last 6.5 years.nnnMETHODSnAll patients (n = 38) with posteroinferior cerebellar artery aneurysms that were surgically treated at Zale-Lipshy University Hospital between January 1990 and May 1997 were retrospectively reviewed. Data were collected and analyzed relating to demographics, condition at presentation, lesion characteristics, associated medical problems, postsurgical complications, and outcome.nnnRESULTSnSixty-six percent of the patients (n = 25) experienced neurological sequelae, which included symptomatic vasospasm, hydrocephalus, dysarthria, paresis, diplopia, ataxia, and facial paralysis. Many, however, showed significant improvement during their hospitalization and during the course of the ensuing year. Seventy-four percent of the patients had a Glasgow Outcome Scale score of 1 or 2 at the time of discharge, 91% at 6 months after surgery, and 89% at 1 year after surgery.nnnCONCLUSIONnThis review summarizes the presentations and outcomes of 38 consecutive surgical cases during a 6.5-year period and concludes that posteroinferior cerebellar artery aneurysms are not benign entities. The study does, however, also demonstrate that patients have significant recuperative potential after the treatment of these lesions.

Evidence of redistribution of cerebral blood flow during treatment for an intracranial arteriovenous malformation.

The presence of an intracranial arteriovenous malformation has a dramatic impact on local circulatory dynamics. Treatment of some arteriovenous malformations can result in disastrous hyperemic states caused by redistribution of previously shunted blood. This report describes serial hemodynamic measurements of both cerebral blood flow and flow velocity in 3 patients during treatment for arteriovenous malformations. Measurements of cerebral blood flow were made by computed tomographic scan employing the stable xenon inhalation technique; flow velocity, including autoregulatory characteristics, was measured by transcranial Doppler ultrasonogram. Substantial hyperemia developed in one patient (Case 1) after resection and in another (Case 3) after embolization. Embolization resulted in restoration of normal regional cerebral blood flow in a patient who demonstrated hypoperfusion before treatment (Case 2). In Patient 1, postoperative hyperemia was associated with persistently elevated flow velocities, and may have been accompanied by hemispheric neurological deficits. Sequential hemodynamic measurements may predict patients at risk of perioperative complications, and may become useful clinical guidelines for the extent and timing of embolization and for the timing of surgery after intracranial hemorrhage or preoperative embolization procedures.

Natural history of brain arteriovenous malformations: a systematic review

OBJECTnThe authors aimed to systematically review the literature to clarify the natural history of brain arteriovenous malformations (BAVMs).nnnMETHODSnThe 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.nnnRESULTSnThe 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.nnnCONCLUSIONSnFor 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.

The Use of Acetazolamide-enhanced Regional Cerebral Blood Flow Measurement to Predict Risk to Arteriovenous Malformation Patients

Regional hemodynamic disturbances may complicate the treatment of certain cerebral arteriovenous malformations (AVM) and occasionally produce life-threatening situations. Acetazolamide-enhanced quantitative regional cerebral blood flow studies were performed preoperatively in 35 patients to determine if patterns of vasoreactivity could be identified that might be markers for postoperative morbidity. Ipsilateral and contralateral regions of hypoperfusion were identified on resting studies, and a steal index was calculated by dividing the regional cerebral blood flow in the steal region by the flow in a normal cerebellar region. Flow in these regions of interest was again quantitated after the administration of acetazolamide, a known cerebral vasodilator. A delta value was calculated by subtracting the resting index values from the acetazolamide indices. Abnormally enhanced vasoreactivity (vasodilation) to acetazolamide stimulation was noted in these threatened territories in AVM that had perforating vessel feeding and angiographic steal phenomena, that developed hyperemic disturbances, and that resulted in poor outcomes. These findings call into question traditional theories of AVM-related hemodynamic decompensation and suggest unique smooth muscle derangements in cerebral vasculature in some AVM patients.

Three-dimensional hemodynamics in intracranial aneurysms: Influence of size and morphology

To use four‐dimensional (4D)‐flow MRI for the comprehensive in vivo analysis of hemodynamics and its relationship to size and morphology of different intracranial aneurysms (IA). We hypothesize that different IA groups, defined by size and morphology, exhibit different velocity fields, wall shear stress, and vorticity.

Interdisciplinary evaluation of cerebral hemodynamics in the treatment of arteriovenous fistulae associated with giant varices

The techniques for the treatment of intracranial arteriovenous fistulae include angiographic balloon occlusion of the fistula as well as direct surgical attack. Regardless of the method, the occurrence of severe hyperemia caused by a lack of autoregulation after obliteration of the fistula remains a significant concern. We report the use of single photon emission computed tomography and transcranial Doppler studies to assess the occurrence of hyperemia during trial balloon occlusion of such fistulae in two patients. Single photon emission computed tomography and transcranial Doppler studies confirmed the lack of hyperemia during the test occlusion, allowing consideration of treatment plans involving acute fistula occlusion without the difficulty imposed by gradual occlusion and permitting a more accurate evaluation of risk. The purpose of this report is to illustrate how clinical evaluation of intracranial hemodynamics can contribute significantly to treatment decisions.

3D Hemodynamics in Intracranial Aneurysms: Influence of Size and Morphology

To use four‐dimensional (4D)‐flow MRI for the comprehensive in vivo analysis of hemodynamics and its relationship to size and morphology of different intracranial aneurysms (IA). We hypothesize that different IA groups, defined by size and morphology, exhibit different velocity fields, wall shear stress, and vorticity.

Advances and innovations in brain arteriovenous malformation surgery

Arteriovenous malformations (AVMs) of the brain are very complex and intriguing pathologies. Since their initial description by Luschka and Virchow in the middle of the 19th century, multiple advances and innovations have revolutionized their management and surgical treatment. Here, we review the historical landmarks in the surgical treatment of AVMs and then illustrate the most recent and futuristic technologies aiming to improve outcomes in AVM surgeries. In particular, we examine potential advances in patient selection, imaging, surgical technique, neuroanesthesia, and postoperative neuro-rehabilitation and quantitative assessments. Finally, we illustrate how concurrent advances in radiosurgery and endovascular techniques might present new opportunities to treat AVMs more safely from a surgical perspective.