Michael K. Morgan

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.

Combined Endovascular Stent Implantation and Endosaccular Coil Placement for the Treatment of a Wide-necked Vertebral Artery Aneurysm: Technical Case Report

OBJECTIVE AND IMPORTANCE We describe a case in humans of the combined application of endovascular stent placement and Guglielmi detachable coil packing in the management of a wide-necked intracranial aneurysm. CLINICAL PRESENTATION A 56-year-old woman suffered a subarachnoid hemorrhage secondary to a large wide-necked left vertebral artery aneurysm. Because of the size of the neck of the aneurysm and the extent of its calcification evident on computed tomographic scans, it was deemed unsuitable for surgical intervention or for conventional endovascular coiling. Instead, a combined surgical and endovascular therapy was instituted. INTERVENTION The left vertebral artery was surgically exposed and cannulated to allow for the placement of an endovascular stent across the neck of the aneurysm to act as a buttress against which Guglielmi detachable coils could be packed. The patient suffered no ill effects as a result of this procedure and made a slow but steady recovery. CONCLUSION This report describes a case of a wide-necked intracranial artery aneurysm treated using a combination of endovascular stent implantation across an aneurysm neck and endosaccular coil placement to obliterate the aneurysm. The technique described provides another treatment to better manage the difficult entity of wide-necked intracranial aneurysms that may be unsuitable for clipping.

Computation of Hemodynamics in the Circle of Willis

Background and Purpose— Wall shear stress (WSS) and pressure are important factors in the development of cerebral aneurysms. We aimed to develop a computational fluid dynamics simulator for flow in the complete circle of Willis to study the impact of variations in vessel radii and bifurcation angles on WSS and pressure on vessel walls. Methods— Blood flow was modeled with Navier-Stokes equations as an incompressible newtonian fluid within rigid vessel walls. A model of the circle of Willis geometry was approximated as a network of tubes around cubic curves. Pulsatile inlet flow rates and constant outlet pressure were used as boundary conditions. Results— The simulations confirmed that differences in vessel radii and asymmetric branch angles influence WSS magnitude and spatial distribution. High WSS occurred at locations where aneurysms are frequent and in anatomic variants known to be associated with an increased risk for aneurysm development. Conclusions— Computational fluid dynamics analysis can be applied to the complete circle of Willis and should be used to study the pathophysiology of this complex vascular structure, including risk factors for aneurysm development. Further development of the method should include simulations with flexible vessel walls.

How safe is arteriovenous malformation surgery? A prospective, observational study of surgery as first-line treatment for brain arteriovenous malformations

OBJECTIVESExisting studies reporting the risk of surgery for brain arteriovenous malformations (AVMs) are often biased by the exclusion of patients not offered surgery. In this study, we examine the risk of surgery, including cases excluded from surgery because of the high surgical risk. METHODSData were collected on 640 consecutively enrolled AVMs in a database that included all patients not considered for surgery. RESULTSPatients with Spetzler-Martin grade 1 to 2 AVMs (n = 296) were treated with a surgical risk of 0.7% (95% confidence interval [CI], 0%-3%); patients with Spetzler-Martin grade 3 to 4 AVMs in noneloquent cortex (n = 65) were treated with a surgical risk of 17% (95% CI, 10%-28%). Patients with Spetzler-Martin grade 3 to 5 AVMs in eloquent cortex (n = 168) were treated with a surgical risk of 21% (95% CI, 15%-28%). However, because 14% of patients in this series with similar AVMs were refused surgery because of perceived surgical risk, these results are not generalizable to the population of patients with similar AVMs. CONCLUSIONThe results of this series suggest that it is reasonable to offer surgery as a preferred treatment option for Spetzler-Martin grade 1 to 2 AVMs. This study also reinforces the predictive value of the Spetzler-Martin grading system, with some caveats.

Surgical risks associated with the management of Grade I and II brain arteriovenous malformations.

OBJECTIVE Grade I and II arteriovenous malformations (AVMs) have been considered safe to resect. However, unoperated low-grade AVMs have not been considered in previously reported series. The aim of this study was to examine all cases, both operated and unoperated, to identify any characteristics of low-grade AVMs that comprise a subgroup that might pose a relatively higher risk. METHODS A prospectively enrolled AVM database included 237 patients in Spetzler-Martin Grade I or II. These patients were analyzed on the basis of demographic characteristics, angiographic and magnetic resonance imaging features, clinical presentation, method of treatment, and outcome. RESULTS Surgery was performed in 220 patients in Spetzler-Martin Grade I or II. Seventeen patients did not undergo treatment because of poor neurological condition (six patients), patient refusal (nine patients), and perceived surgical difficulty (AVM size approaching 3 cm adjacent to Brocas area) (two patients). The overall surgical morbidity rate was 0.9%, and the mortality rate was 0.5%. Adverse outcomes occurred in 1 (0.6%) of 180 patients with AVMs located away from eloquent cortex and in 2 (5%) of 40 patients with AVMs adjacent to eloquent cortex. None of 28 surgical patients with deep venous drainage had an adverse outcome. All 219 patients who survived surgery underwent postoperative angiography that confirmed cure. No postoperative hemorrhage has occurred in 1143 patient-years of follow-up (mean follow-up, 5.3 yr). CONCLUSION When considering adverse outcome in the surgical series of Grade I and II AVMs alone, no statistical difference between non-eloquently located AVMs (0.6%) and eloquently located AVMs (5% adverse outcome) can be detected. However, consideration of all Grade I and II AVMs, both surgical and nonsurgical, may prove that a difference in outcome exists between these two groups masked by case selection. Generalization of the chances of adverse outcomes to all Grade I and II AVMs (both operated and unoperated) suggests that the risk of performing surgery on noneloquent brain in our series was 0.6% and that in eloquent brain could have been as high as 9.5%, had all such patients undergone surgery.

Microsurgery for small arteriovenous malformations of the brain: results in 110 consecutive patients.

OBJECTIVETo examine the results of surgery in 110 consecutive patients with arteriovenous malformations (AVMs) smaller than 3 cm in diameter. These results are compared with the published results of other microsurgical series as well as with results for patients treated with focused irradiation. METHODSFrom January 1989 to November 1998, 121 patients with AVMs smaller than 3 cm were treated at our institution. One hundred ten patients underwent microsurgical removal of their AVMs. The presentation, preoperative neurological status, and postoperative outcome were recorded. Follow-up was complete for all surgical cases. RESULTSOf the 110 patients, 109 (99%) had angiographically confirmed obliteration of their AVMs. Two patients (1.8%) required reoperation for residual AVM. Two (4.3%) of 46 patients with AVMs in eloquent brain areas experienced worsening of their neurological status after surgery. One (1.6%) of 64 patients was worse neurologically after removal of an AVM in a noneloquent area. CONCLUSIONMicrosurgical removal is a safe and effective treatment for the majority of AVMs smaller than 3 cm in diameter. Although the treatment is accompanied by a risk of acute onset of neurological deficits, this tends to be transient in the majority of cases. Furthermore, microsurgical excision of small AVMs offers patients immediate protection from the natural history of their vascular lesions.

Magnesium: a useful adjunct in the prevention of cerebral vasospasm following aneurysmal subarachnoid haemorrhage.

UNLABELLED Despite recent advances in the management of aneurysmal subarachnoid haemorrhage delayed ischaemic deficits from cerebral vasospasm remains a major cause of morbidity and mortality. As magnesium is a potent cerebral vasodilator we have introduced routine supplementation in patients presented with subarachnoid haemorrhage to determine whether there has been a reduction in the incidence of cerebral vasospasm. METHOD All patients presented with aneurysmal subarachnoid haemorrhage from February 1997 were included except those who presented after day 5 following bleed. Identical management protocol was used except intravenous magnesium supplementation which was introduced to all patients from May 1999. Incidence of cerebral vasospasm on angiograms among the two groups was analysed. RESULTS Seven out of 10 patients who did not receive magnesium supplement developed vasospasm requiring intra-arterial papaverine compared with 2 of 13 patients among the treated group (P<0.008). CONCLUSIONS From our pilot study it appears that magnesium supplement has a beneficial role in the prevention of cerebral vasospasm following aneurysmal subarachnoid haemorrhage. Further studies would seem justified.

Chronic cerebral hypoperfusion and impaired neuronal function in rats.

Background and Purpose Studies in acute cerebral ischemia have shown that reductions in cerebral blood flow of up to 50% do not lead to infarction or alterations in neuronal electric activity. Little is known about the effects of chronic reductions in cerebral blood flow. The purpose of this study was to evaluate neuronal electrophysiological function in brain that had been subjected to a chronic reduction of cerebral blood flow of less than 50%. Based on existing knowledge of thresholds of cerebral ischemia, neuronal electrophysiological function should be unaffected by hypoperfusion of this magnitude. Methods An arteriovenous fistula model in the rat was used to induce chronic cerebral hypoperfusion with reductions of cerebral blood flow of 25% to 50% as measured previously by 14C-labeled autoradiography. Using in vitro electrophysiological brain slice techniques, long-term potentiation in hippocampal CA1 neurons was examined extracellularly after 6 months of chronic noninfarctional cerebral hypoperfusion. Brains were also examined histologically at this time for evidence of cerebral infarction. Results There was no evidence of cerebral infarction. Longterm potentiation was produced in 9 of 12 control animals and only 2 of 8 hypoperfused animals. This difference was significant (P<.05) and demonstrated that long-term potentiation was impaired in animals with chronic hypoperfusion. Conclusions Noninfarctional reductions in cerebral blood flow of up to 50% do impair neuronal function in chronic cerebral ischemia, a result quite distinct from that seen in acute ischemia. The threshold for neuronal dysfunction in chronic cerebral hypoperfusion is lower than that found in acute cerebral ischemia, suggesting that duration as well as severity of ischemic insult determines cellular viability. Chronic hypoperfusion may lead to a noninfarctional state with impaired neuronal function, a category of chronic cerebral ischemia not previously identified.

Chronic cerebral hypoperfusion: pathological and behavioral consequences.

OBJECTIVE Although the effects of acute ischemic insults to the brain are well known, the effects related to chronic ischemia are poorly delineated. The pathological and behavioral changes induced by a chronic noninfarctional reduction in cerebral blood flow of 25 to 50% maintained for 6 months were assessed. METHODS In each of 18 male Sprague-Dawley rats, an arteriovenous fistula was created in the neck via an anastomosis between the right external jugular vein and the right common carotid artery to induce cerebral hypoperfusion. Nineteen age-matched animals comprised a control group. Six months after surgery, the animals were examined using light and electron microscopic techniques, as well as via a battery of behavioral tests (motor, open field, and T-maze). RESULTS Examination of the hippocampus by using light microscopy revealed disorganization of the CA1 sector with an increased number of astrocytes. Transmission electron microscopy of the CA1 region demonstrated neurons with increased lipofuscin pigment and central nucleoli and astrocytes with more numerous cytosolic mitochondria. Motor performance testing revealed no gross motor deficits, although open-field assessment demonstrated increased exploratory behavior in rats with fistulas. Finally, T-maze testing results suggested that errors in working memory were more common in rats undergoing chronic cerebral hypoperfusion (P < 0.05). CONCLUSIONS These findings suggest that chronic reductions in cerebral blood flow of a magnitude previously thought to be harmless to neurons (i.e., reduced by 25-50%) do alter neuronal structure and affect whole animal behavior. Such a scenario may be responsible for a symptomatology secondary to arteriovenous steal and severe carotid stenoses. The mechanisms are still unknown.

Reversible cardiogenic shock complicating subarachnoid haemorrhage.

When rupture of a cerebral aneurysm results in cardiovascular collapse the prognosis may seem hopeless and active management may be withheld. We report five cases of aneurysmal subarachnoid haemorrhage associated with severe myocardial dysfunction and cardiogenic shock. Intensive treatment, including intravenous inotropes and intra-aortic balloon counterpulsation, resulted in good neurological and cardiovascular recovery. Patients with subarachnoid haemorrhage who develop profound cardiogenic shock should have aggressive intensive care as good recovery is likely Case 1—A 41 year old woman was admitted following a collapse preceded by a headache. Her initial Glasgow coma scale score was 6 and she had a fixed dilated right pupil. On intubation of the trachea, frank pulmonary oedema issued from the tracheal tube, and the chest radiograph confirmed pulmonary oedema. A cranial computed tomogram showed subarachnoid haemorrhage and a right subdural haematoma (fig 1). She immediately underwent evacuation of the subdural haematoma. After fluid resuscitation she required infusions of noradrenaline (1 μg/kg/minute), adrenaline (0.6 μg/kg/minute), and dobutamine (14 μg/kg/minute) to maintain adequate blood pressure. A pulmonary artery catheter was inserted and confirmed cardiogenic shock (table 1). The following day cerebral angiography showed an aneurysm of the pericallosal branch of the right anterior cerebral artery. An echocardiogram showed global impairment of left ventricular function. Estimated left ventricular ejection fraction was 25-30%; this deteriorated to 20% the following day. Mechanical ventilation and inotropic support were continued, and five days later the ejection fraction had improved to 40%. The aneurysm was clipped the following day, and she was discharged from intensive care seven days later. She remained in hospital for a further nine days and was then discharged to rehabilitation. At follow up, three months after discharge from our hospital, she was neurologically normal with no evidence of cardiac failure. Fig 1 Initial cranial computed tomogram in case 1, showing right subdural …