Steven L. Giannotta

A Founder Mutation as a Cause of Cerebral Cavernous Malformation in Hispanic Americans

BACKGROUND Cerebral cavernous malformation is a vascular disease of the brain causing headaches, seizures, and cerebral hemorrhage. Familial and sporadic cases are recognized, and a gene causing familial disease has been mapped to chromosome 7. Hispanic Americans have a higher prevalence of cavernous malformation than do other ethnic groups, raising the possibility that affected persons in this population have inherited the same mutation from a common ancestor. METHODS We compared the segregation of genetic markers and clinical cases of cavernous malformation in Hispanic-American kindreds with familial disease; we also compared the alleles for markers linked to cavernous malformation in patients with familial and sporadic cases. RESULTS All kindreds with familial disease showed linkage of cavernous malformation to a short segment of chromosome 7 (odds supporting linkage, 4X10(10).1). Forty-seven affected members of 14 kindreds shared identical alleles for up to 15 markers linked to the cavernous-malformation gene, demonstrating that they had inherited the same mutation from a common ancestor. Ten patients with sporadic cases also shared these same alleles, indicating that they too had inherited the same mutation. Thirty-three asymptomatic carriers of the disease gene were identified, demonstrating the variability and age dependence of the development of symptoms and explaining the appearance of apparently sporadic cases. CONCLUSIONS Virtually all cases of familial and sporadic cavernous malformation among Hispanic Americans of Mexican descent are due to the inheritance of the same mutation from a common ancestor.

Transcallosal, interfornicial approaches for lesions affecting the third ventricle: surgical considerations and consequences

A group of 11 patients with a variety of lesions affecting the 3rd ventricle have been treated using a direct transcallosal interfornicial approach to the region. In 3 patients, no attendant hydrocephalus was present. In an effort to minimize potential cortical injury related to the approach, we studied the venous anatomy in the region of the coronal suture. Based on this study, appropriate flap placement and interhemispheric entry points were defined. Although no lasting, clinically apparent morbidity was observed in any of the 11 cases, we performed more sophisticated studies of the interhemispheric transfer of somesthetic and perceptual motor tasks, as well as psychometric testing related to parameters of intelligence and memory, 3 to 8 months postoperatively in 6 cases. The results and clinical material indicate that this surgical technique is a safe, feasible alternative in the management of a wide spectrum of pathological lesions within this region. A transcallosal, interfornicial approach offers excellent visualization of the entire 3rd ventricle without the dependence on hydrocephalus or an extensive extra-axial mass to enhance the exposure. With proper planning and technique, it may be accomplished with a minimum of physiological consequence.

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.

Temporary occlusion of the middle cerebral artery in intracranial aneurysm surgery: time limitation and advantage of brain protection

The risk of focal infarction secondary to the induced reversible arrest of local arterial flow during microsurgical dissection of middle cerebral artery (MCA) aneurysms was evaluated further to define the optimal approach to temporary arterial occlusion. To compare the effectiveness of brain-protection anesthetics, a group of patients treated with the intravenous agents, propofol, etomidate, and pentobarbital, administered individually or in combination, was compared to a group treated with the inhalational agent isoflurane. Forty-nine consecutive MCA aneurysm surgeries involving the temporary clipping of the parent vessel were retrospectively reviewed. Thirty-eight patients received intravenous brain-protection (IVBP) anesthesia. Groups of patients with and without infarctions, and receiving and not receiving IVBP, were compared based on the duration and nature of temporary arterial occlusion. Postoperative radiographic evidence of new infarction was used as the threshold for failure of occlusion tolerance. The overall infarction rate was 22.4% (11 of 49 patients), including 15.8% (six of 38 patients) in the IVBP group versus 45.5% (five of 11 patients) in the isoflurane (ISO) group. In the ISO group, the mean duration of temporary occlusion was 3.9 +/- 2.2 minutes for patients without infarction versus 12.2 +/- 4.3 minutes for patients with focal infarction (p < 0.01). In contrast, the mean duration was 13.6 +/- 10.6 minutes for patients without infarction and 18.5 +/- 9.9 minutes for patients with infarction in the IVBP group. All patients in the ISO group who underwent occlusion lasting 10 minutes or longer suffered an infarction versus five of 23 patients in the IVBP group. Patients with multiple aneurysms were found to be at increased risk of developing focal infarction, whereas those treated with intermittent temporary clip application were at a decreased risk. It is concluded that patients in whom focal iatrogenic ischemia is induced during MCA aneurysm clip ligation have a significant advantage compared with those receiving ISO when they are given pentobarbital as the primary neuroprotective agent or when they receive propofol or etomidate titrated to achieve electroencephalographic burst suppression, particularly if more than 10 minutes of occlusion time is required. It is also concluded that 10 minutes is a general guideline for safe, temporary occlusion of the MCA. The use of intermittent temporary arterial occlusion and patients with multiple aneurysms need further evaluation before specific recommendations can be made.

Gamma knife radiosurgery for pituitary adenoma: early results.

OBJECTIVEIn recent years, gamma knife radiosurgery (GKRS) has emerged as an important treatment modality in the management of pituitary adenomas. Treatment results after performing GKRS and the complications of this procedure are reviewed. METHODSBetween 1994 and 2002, a total of 78 patients with pituitary adenomas underwent a total of 84 GKRS procedures in our medical center. This patient group comprised 46 men (59%) and 32 women (41%). All patients were treated for recurrent or residual disease after surgery or radiotherapy, with 83% presenting with extensive tumor involvement. The cavernous sinus was involved in 75 patients (96%), and 22 patients (28%) had hormone-secreting adenomas. This latter subset of patients included 12 prolactinomas (15%), 6 growth-hormone secreting tumors (8%), and 4 adrenocorticotropic hormone-secreting tumors (5%). The median tumor volume was 2.3 cm3, and the median radiation dose was 15 Gy defined to the 50% isodose line. The mean and median follow-up periods were 41 and 36 months, respectively. RESULTSGKRS was tolerated well in these patients; acute toxicity was uncommon and of no clinical significance. Late toxicity was noted in three patients (4%) and consisted of VIth cranial nerve palsy. In two patients, there was spontaneous resolution of this palsy, and in one patient, it persisted for the entire 3-year duration of follow-up. Of the 15 patients who presented with cranial nerve dysfunction, 8 (53%) experienced complete recovery and 3 (20%) showed major improvement within 12 months of therapy. Tumor volume reduction was slow, with 30% of patients showing decreased tumor volume more than 3 years after undergoing GKRS. None of the 56 patients with nonfunctioning tumors showed progression in the treated volume, and 4 (18%) of the 22 hormone-secreting tumors relapsed (P = 0.008). Of the four patients with adrenocorticotropic hormone-secreting adenomas, therapy failed in two of them. All six patients with growth hormone-producing tumors responded well to therapy. Of the 12 patients with prolactinomas 10 (83%) had normalization of hormone level and 2 patients experienced increasing prolactin level. Two patients with prolactinomas had three normal pregnancies after undergoing GKRS. CONCLUSIONGKRS is a safe and effective therapy in selected patients with pituitary adenomas. None of the patients in our study experienced injury to the optic apparatus. A radiation dose higher than 15 Gy is probably needed to improve control of hormone-secreting adenomas. Longer follow-up is required for a more complete assessment of late toxicity and treatment efficacy.

Metastatic melanoma to the brain: prognostic factors after gamma knife radiosurgery.

PURPOSE To identify important prognostic factors predictive of survival and tumor control in patients with metastatic melanoma to the brain who underwent gamma knife radiosurgery. METHODS AND MATERIALS A total of 122 consecutive patients with 332 intracranial melanoma metastases underwent gamma knife radiosurgery over a 5-year period. Of these, 39 (32%) also received whole-brain irradiation (WBI). The median tumor volume was 0.8 cm(3) (range: 0.02-30.20 cm(3)), and the median prescribed dose was 20 Gy (range: 14-24 Gy). Median follow-up was 6.8 months. Univariate and multivariate analyses of survival and freedom from progression were performed using the following parameters: status of systemic disease, intracranial tumor volume, number of lesions, tumor location, Karnofsky performance status, gender, age, and WBI. RESULTS Overall median survival was 7.0 months from time of radiosurgery and 9.1 months from the onset of brain metastasis. In multivariate analysis, improved survival was noted in patients with total intracranial tumor volume <3 cm(3) (p = 0.003) and inactive systemic disease (p = 0.0065), whereas other parameters studied were of lesser importance (tumor location, p = 0.056, and Karnofsky performance status, p = 0.086), or of no significance (number of lesions, WBI, age, and gender). Freedom from subsequent brain metastasis depended on intracranial tumor volume (p = 0.0018) and status of systemic disease (p = 0.034). CONCLUSIONS Stereotactic radiosurgery is an effective treatment modality for patients with intracranial metastatic melanoma. Tumor volume and status of systemic disease are good independent predictors of survival and freedom from tumor progression.

Gamma knife radiosurgery for trigeminal neuralgia.

OBJECTIVE: The purpose of this study was to assess outcomes in patients treated with gamma knife radiosurgery for trigeminal neuralgia. METHODS: From 1997 to 2003, a total of 49 patients with trigeminal neuralgia underwent gamma knife radiosurgery. The trigeminal root entry zone immediately adjacent to the pons was targeted by use of a 4-mm collimator to deliver 40 Gy to the 50% isodose line (maximum dose, 80 Gy). Special care was taken to limit radiation dose to the adjacent pons to 12 Gy. Of the 49 study patients, all had undergone previous medical therapy, 8 (16%) had undergone microvascular decompression, 8 (16%) had undergone percutaneous rhizotomy, 2 (4%) had undergone linear accelerator-based radiosurgery, and 5 (10%) presented with multiple sclerosis. The median duration of symptoms was 6 years. There were 29 female patients (59%) and 20 male patients (41%). Facial pain outcomes were assessed by use of the Barrow Neurological Institute pain score. Other outcomes assessed included recurrence of symptoms and treatment toxicity. The median follow-up period was 49 months. RESULTS: At last evaluation, a total of 27 patients (61%) with idiopathic trigeminal neuralgia reported pain relief (scores of IIIb or less). This included 14 patients (32%) who reported complete pain relief when not receiving medications. Significant recurrence of pain after an initial interval of relief was reported by 10 patients (23%). Mean time to pain recurrence was 9.6 months (range, 2–36 mo). Mild to moderate facial numbness was experienced by 13 patients (29%), whereas 8 (18%) reported mild dysesthesias. CONCLUSION: Gamma knife radiosurgery established durable pain relief in 61% of patients with medically refractory idiopathic trigeminal neuralgia. A longer follow-up period is necessary to fully assess the incidence of late complications and recurrences.

Management of intraoperative rupture of aneurysm without hypotension.

A retrospective analysis was performed on all aneurysms operated on by one of us (SLG) from July 1980 to October 1988 to determine the factors that govern outcome from the intraoperative rupture of aneurysms. A total of 276 consecutive surgical procedures for 317 intracranial aneurysms produced 41 perioperative or intraoperative ruptures for analysis. Five cases were pre-exposure ruptures, 3 of which occurred during anesthetic induction. Four of these patients died, and 1 made a good recovery. Of the remaining 36 cases, outcome was analyzed in terms of the adjuncts used to deal with the intraoperative rupture. There was no statistically significant difference in outcome between those cases in which tamponade was used to control hemorrhage versus temporary clipping; however, those cases in which hypotension was used did less well than those in which it was not used. From October 1986 to October 1988, 108 operations for 132 aneurysms were performed without the use of induced hypotension. There were 16 intraoperative ruptures (14.8%). All 16 of these patients made a good recovery. In the group before 1986, of which there were 20 intraoperative ruptures (of 168 operations, 11.9%), 11 of those 20 patients suffered a permanent deficit or died. We conclude that hypotension may not be a necessary adjunct to the management of intraoperative rupture of aneurysms.

High dose glucocorticoids in the management of severe head injury.

Eighty-eight patients with a Glasgow coma score of 8 or less 6 hours after nonpenetrating head trauma were given either high dose methylprednisolone sodium succinate (30 mg/kg q6h X2, then 250 mg q6h X6, then tapering over 8 days), low dose methylprednisolone (1.5 mg/kg q6h X2, then 25 mg q6h X6, then tapering over 8 days), or placebo. Standard care including the removal of traumatic hematomas, assisted ventilation, and intracranial pressure monitoring and control was carried out. Follow-up assessments were performed on all surviving patients at 6 months and were graded according to the Glascow outcome scale. No statistically significant difference in outcome was seen between the low dose group and the placebo group. The high dose group experienced a mortality of 39% as compared to a 52% mortality in the low dose and placebo groups (P less than 0.05). Mortality differences were most marked in patients less than 40 years old, with the high dose group experiencing a mortality of 6% as compared to a 43% mortality for the low dose and placebo groups (P less than 0.05). For patients under 50 years old, the incidence of recovery of speech was 62% compared to 36% in the low dose and placebo groups (P less than 0.5). The increased survival in those treated with high dose corticoids, however, was associated with an increase in the poorer outcome categories.

Predictors and Outcomes of Intraprocedural Rupture in Patients Treated for Ruptured Intracranial Aneurysms. The CARAT Study

Background and Purpose— Intraprocedural rupture (IPR) is a well known complication of intracranial aneurysm treatment. Risks and predictors of IPR and its impact on outcome have not been clearly established. Methods— Potential predictors of IPR were evaluated in patients treated in the Cerebral Aneurysm Rerupture After Treatment (CARAT) study using multivariate logistic regression with stepwise elimination stratified by treatment modality. Periprocedural death or disability was defined as death or a change of ≥2 points on the Modified Rankin Scale at discharge compared to before treatment. Results— IPR occurred in 14.6% of 1010 patients (299 coiled, 711 clipped): 19% with clipping and 5% with coiling (P<0.001). Among those clipped, 31% with IPR had periprocedural death or disability compared to 18% without IPR (P=0.001); among those coiled, 63% with IPR had periprocedural death or disability compared to 15% without IPR (P<0.001). Overall, coronary artery disease and initial lower Hunt and Hess Grade were independent predictors of IPR. For those undergoing coiling, independent predictors of IPR were Asian race, black race, COPD, and lower initial Hunt and Hess Grade. Among those undergoing clipping, hyperlipidemia and lower initial Hunt and Hess Grade were both independent predictors of IPR. Conclusions— IPR was common in patients undergoing treatment of ruptured aneurysms, particularly with surgical clipping. The frequency of IPR with new disability was similar in the surgical and endovascular treatment groups. Coronary artery disease, hyperlipidemia, race, COPD, and lower Hunt and Hess Grade were associated with greater risk of IPR, which may reflect differences in vessel fragility but requires further confirmation.