Alberto Pasqualin

Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage (CONSCIOUS-1) Randomized, Double-Blind, Placebo-Controlled Phase 2 Dose-Finding Trial

Background and Purpose— This randomized, double-blind, placebo-controlled, dose-finding study assessed efficacy and safety of 1, 5, and 15 mg/h intravenous clazosentan, an endothelin receptor antagonist, in preventing vasospasm after aneurysmal subarachnoid hemorrhage. Methods— Patients (n=413) were randomized to placebo or clazosentan beginning within 56 hours and continued up to 14 days after initiation of treatment. The primary end point was moderate or severe angiographic vasospasm based on centrally read, blinded evaluation of digital subtraction angiography at baseline and 7 to 11 days postsubarachnoid hemorrhage. A morbidity/mortality end point, including all-cause mortality, new cerebral infarct from any cause, delayed ischemic neurological deficit due to vasospasm, or use of rescue therapy, was evaluated by local assessment. Clinical outcome was assessed by the extended Glasgow Outcome Scale at 12 weeks. Results— Moderate or severe vasospasm was reduced in a dose-dependent fashion from 66% in the placebo group to 23% in the 15 mg/h clazosentan group (risk reduction, 65%; 95% CI, 47% to 78%; P<0.0001). No significant effects were seen on secondary end points. Post hoc analysis using a centrally assessed morbidity/mortality end point that included death and rescue therapy but only cerebral infarcts and delayed ischemic neurological deficit due to vasospasm on central review showed a trend toward improvement with clazosentan (37%, 28%, and 29% in the 1, 5, and 15 mg/h groups versus 39% in the placebo group, nonsignificant). Clazosentan was associated with increased rates of pulmonary complications, hypotension, and anemia. Conclusions— Clazosentan significantly decreased moderate and severe vasospasm in a dose-dependent manner and showed a trend for reduction in vasospasm-related morbidity/mortality in patients with aneurysmal subarachnoid hemorrhage when centrally assessed. Overall, the adverse effects were manageable and not considered serious.

Intracranial hematomas following aneurysmal rupture: experience with 309 cases.

Three hundred and nine consecutive cases of intracranial hematomas due to aneurysmal rupture--representing 34% of the total number of patients with aneurysms observed in a 12-year period--were evaluated; of these, 211 were submitted to computed tomography scan. Hematomas were present on admission in 71% of patients and occurred at rebleeding in 29%. Ruptured middle cerebral artery aneurysms caused an intracranial hematoma more frequently than aneurysms in other locations. Ventricular hematomas were frequently observed--especially at rebleeding--in cases with anterior communicating artery aneurysms. Basal ganglia hematomas were detected in eight cases with internal carotid bifurcation aneurysms and in three with middle cerebral artery aneurysms. Subdural hematomas were observed in 32 cases, mainly due to ruptured middle-cerebral-artery and internal-carotid-artery aneurysms. As for clinical evolution, a rapid deterioration was observed in 39% of cases and a chronic course in 46%; a subacute deterioration was far less frequent. Delayed deterioration from vasospasm was observed in 8% of cases, and appeared to be related to the amount of subarachnoid bleeding associated with the hematoma. One hundred and forty-two patients were submitted to surgical treatment (evacuation of hematoma together with exclusion of aneurysm); deep coma, poor medical condition, stabilized neurological disability, or combinations of these factors accounted for the high number of patients not operated upon. Regardless of treatment, 24% of patients showed good results and 58% died. Presence of a large hematoma, ventricular hemorrhage, and shift of the ventricles represented significant risk factors, associated with a poor prognosis. A comparison between two groups of patients admitted within 3 days of hemorrhage--47 operated on early, and 149 with delayed treatment--showed that better results were achieved by early operations, especially for cases in Hunts grades IV and V.

Angiographic Vasospasm Is Strongly Correlated With Cerebral Infarction After Subarachnoid Hemorrhage

Background and Purpose— The long-standing concept that delayed cerebral infarction after aneurysmal subarachnoid hemorrhage results exclusively from large artery vasospasm recently has been challenged. We used data from the CONSCIOUS-1 trial to determine the relationship between angiographic vasospasm and cerebral infarction after subarachnoid hemorrhage. Methods— We performed a post hoc exploratory analysis of the CONSCIOUS-1 data. All patients underwent catheter angiography before treatment and 9±2 days after subarachnoid hemorrhage. CT was performed before and after aneurysm treatment, and 6 weeks after subarachnoid hemorrhage. Angiograms and CT scans were assessed by centralized blinded review. Angiographic vasospasm was classified as none/mild (0%–33% decrease in arterial diameter), moderate (34%–66%), or severe (≥67%). Infarctions were categorized as secondary to angiographic vasospasm, other, or unknown causes. Logistic regression was conducted to determine factors associated with infarction. Results— Complete data were available for 381 of 413 patients (92%). Angiographic vasospasm was none/mild in 209 (55%) patients, moderate in 118 (31%), and severe in 54 (14%). Infarcts developed in 6 (3%) of 209 with no/mild, 12 (10%) of 118 patients with moderate, and 25 (46%) of 54 patients with severe vasospasm. Multivariate analysis found a strong association between angiographic vasospasm and cerebral infarction (OR, 9.3; 95% CI, 3.7–23.4). The significant association persisted after adjusting for admission neurological grade and aneurysm size. Method of aneurysm treatment was not associated with a significant difference in frequency of infarction. Conclusions— A strong association exists between angiographic vasospasm and cerebral infarction. Efforts directed at further reducing angiographic vasospasm are warranted.

Surgical versus medical treatment of spontaneous posterior fossa haematomas: a cooperative study on 205 cases.

22 Italian centres have joined together in a cooperative study aiming to define the ideal management of spontaneous posterior fossa haematomas. 205 cases have been evaluated: 155 cerebellar haematomas and 50 brainstem haematomas. Out of these, 190 cases, all studied by CT scan, are the subject of the present study. Cerebellar haematomas have been divided, according to a tomographic classification, into 3 groups: group 1 (4th ventricle not shifted), group 2 (4th ventricle shifted or obliterated) and group 3 (intraventricular blood). Each group has been subdivided into: A (no hydrocephalus), and B (hydrocephalus). Regardless of therapeutical modalities, mortality rate was 38% for cerebellar haematomas; level of consciousness a few hours after haemorrhage and size of the lesion appeared to be significant prognostic factors. As a whole, medical treatment gave better results than surgical treatment. Considering each tomographical group in detail, surgery should be limited to patients in group 2B and 3B, especially when exhibiting neurological deterioration. For brainstem haematomas, overall mortality was 57%. The possibility of survival was linked to the presence or absence of initial loss of consciousness and to the size of the lesion; while hydrocephalus did not influence the final outcome, ventricular blood was a risk factor. Surgical evacuation showed some value in chronic cases. However, medical treatment appears to be the best policy for brainstem haematomas of limited size; for larger lesions, the outcome appears to be uniformly fatal, regardless of the treatment employed.

Intracranial aneurysms and subarachnoid hemorrhage in children and adolescents

Thirty-eight cases of symptomatic cerebral aneurysms or spontaneous subarachnoid hemorrhage in children and adolescents were observed from 1965 to 1984; 33 cases were treated from 1970 to date. This group represents 2.6% of the total number of patients with subarachnoid hemorrhage treated at our institute in the same period. The cause of subarachnoid hemorrhage was unknown in 7 cases; an intracranial aneurysm had ruptured in 29 cases, and was unruptured but symptomatic in 2 remaining cases. Three aneurysms were mycotic. The most frequent aneurysmal locations were the internal carotid bifurcation and the anterior communicating artery; peripheral branches of the middle cerebral artery were also a relatively common location. Four patients were 3 years of age or younger: each presented peculiar clinical features, and 3 of the 4 had middle cerebral artery aneurysms. The remaining 34 patients were all above 9 years of age. Two groups were identified: (a) in 14 patients between 10 and 15 years of age, the aneurysm was most commonly at the internal carotid bifurcation (37%), and an intracerebral hematoma was observed in 50% of these cases; (b) in 20 patients between 16 and 20 years of age, the most common aneurysmal location was the anterior communicating artery (35%), and intracerebral hematomas were rare (10% of cases). Among patients with aneurysms, 19 underwent surgical exclusion by clip, with 10% morbidity and 5% mortality; 5 patients in moribund conditions were not operated on; 5 patients were conservatively treated; in 2 patients the aneurysm had disappeared at a second angiography. Ischemic deterioration from vasospasm was observed only in 3 patients, all above 17 years of age, and with a consistent or thick subarachnoid blood deposition on early CT scan. Hydrocephalus was also rarely observed (13% of cases), requiring a shunt in only 3 patients. Overall management results were significantly better than in adult patients, with 73% good results and 21% deaths. The better prognosis in the group under 20 years of age is probably accounted for (a) by the frequently observed reversibility of neural injury in young patients and (b) the very low incidence of ischemic disturbances in this age group.

The unruptured intracranial aneurysm treatment score A multidisciplinary consensus

Objective: We endeavored to develop an unruptured intracranial aneurysm (UIA) treatment score (UIATS) model that includes and quantifies key factors involved in clinical decision-making in the management of UIAs and to assess agreement for this model among specialists in UIA management and research. Methods: An international multidisciplinary (neurosurgery, neuroradiology, neurology, clinical epidemiology) group of 69 specialists was convened to develop and validate the UIATS model using a Delphi consensus. For internal (39 panel members involved in identification of relevant features) and external validation (30 independent external reviewers), 30 selected UIA cases were used to analyze agreement with UIATS management recommendations based on a 5-point Likert scale (5 indicating strong agreement). Interrater agreement (IRA) was assessed with standardized coefficients of dispersion (vr*) (vr* = 0 indicating excellent agreement and vr* = 1 indicating poor agreement). Results: The UIATS accounts for 29 key factors in UIA management. Agreement with UIATS (mean Likert scores) was 4.2 (95% confidence interval [CI] 4.1–4.3) per reviewer for both reviewer cohorts; agreement per case was 4.3 (95% CI 4.1–4.4) for panel members and 4.5 (95% CI 4.3–4.6) for external reviewers (p = 0.017). Mean Likert scores were 4.2 (95% CI 4.1–4.3) for interventional reviewers (n = 56) and 4.1 (95% CI 3.9–4.4) for noninterventional reviewers (n = 12) (p = 0.290). Overall IRA (vr*) for both cohorts was 0.026 (95% CI 0.019–0.033). Conclusions: This novel UIA decision guidance study captures an excellent consensus among highly informed individuals on UIA management, irrespective of their underlying specialty. Clinicians can use the UIATS as a comprehensive mechanism for indicating how a large group of specialists might manage an individual patient with a UIA.

Multidisciplinary consensus on assessment of unruptured intracranial aneurysms: proposal of an international research group.

Background and Purpose— To address the increasing need to counsel patients about treatment indications for unruptured intracranial aneurysms (UIA), we endeavored to develop a consensus on assessment of UIAs among a group of specialists from diverse fields involved in research and treatment of UIAs. Methods— After composition of the research group, a Delphi consensus was initiated to identify and rate all features, which may be relevant to assess UIAs and their treatment by using ranking scales and analysis of inter-rater agreement (IRA) for each factor. IRA was categorized as very high, high, moderate, or low. Results— Ultimately, 39 specialists from 4 specialties agreed (high or very high IRAs) on the following key factors for or against UIA treatment decisions: (1) patient age, life expectancy, and comorbid diseases; (2) previous subarachnoid hemorrhage from a different aneurysm, family history for UIA or subarachnoid hemorrhage, nicotine use; (3) UIA size, location, and lobulation; (4) UIA growth or de novo formation on serial imaging; (5) clinical symptoms (cranial nerve deficit, mass effect, and thromboembolic events from UIAs); and (6) risk factors for UIA treatment (patient age and life expectancy, UIA size, and estimated risk of treatment). However, IRAs for features rated with low relevance were also generally low, which underlined the existing controversy about the natural history of UIAs. Conclusions— Our results highlight that neurovascular specialists currently consider many features as important when evaluating UIAs but also highlight that the appreciation of natural history of UIAs remains uncertain, even within a group of highly informed individuals.

Endovascular Treatment or Neurosurgical Clipping of Ruptured Intracranial Aneurysms. Effect on Angiographic Vasospasm, Delayed Ischemic Neurological Deficit, Cerebral Infarction, and Clinical Outcome

Background and Purpose— The effects of aneurysm treatment modality (clipping or coiling) on the incidence of cerebral vasospasm and infarction after subarachnoid hemorrhage have not been clearly defined. We hypothesized that there may be a difference in angiographic and clinical vasospasm, cerebral infarction, and clinical outcome between patients undergoing clipping compared to coiling. Methods— A retrospective, exploratory analysis of 413 patients randomized into the CONSCIOUS-1 trial was conducted. Patients underwent baseline and follow-up catheter angiography and computed tomography, as well as clinical assessments. Radiology end points were adjudicated by central blinded review, and angiographic vasospasm was quantified by measurements of arterial diameters on catheter angiography. The effect of method of aneurysm treatment (clipping [n=199] or coiling [n=214]) on angiographic vasospasm, delayed ischemic neurological deficit, cerebral infarction, and clinical outcome was analyzed using univariate and multivariate logistic regression. Propensity matching was used to adjust for differences in baseline risk factors between clipped and coiled patients. Results— In all patients and the propensity-matched subset, aneurysm coiling was associated with a significantly reduced risk of angiographic vasospasm and delayed ischemic neurological deficit compared to clipping. Cerebral infarction and clinical outcome were not associated with clipping or coiling. Conclusions— In this exploratory analysis, aneurysm coiling was associated with less angiographic vasospasm and delayed ischemic neurological deficit than surgical clipping, whereas no effect on cerebral infarction or clinical outcome was observed. Whether this is attributable to differences in baseline risk factors between clipped and coiled patients or a true difference cannot be proven here.

Results of Treatment with Ventriculoatrial and Ventriculoperitoneal Shunt in Infantile Nontumoral Hydrocephalus

The authors present the results of surgical treatment in 165 children with nontumoral hydrocephalus, treated during a period of 11 years. The minimum period of follow-up was 1 year. The results in the group of children treated with a ventriculoatrial (VA) shunt were compared to those obtained in the group with a ventriculoperitoneal (VP) shunt. 45% of patients with VA shunts had one or more revisions, against 51% of patients with VP shunts. However, the incidence of revisions after 6 months from primary insertion was lower in the VP-shunted children. Most revisions were due to shunt malfunction: obstruction of the ventricular or abdominal catheter was the commonest finding. Among complications, the most serious was constituted by shunt infection (11% of cases). Most infections occurred at less than 2 months from surgery and were caused mainly by Staphylococci. 31% of infected patients died. Other frequent complications were due to shunt tubing lost in abdomen or in the ventricles and subdural hematoma. The overall mortality rate in the whole group was 18%, while the shunt-related mortality rate was 10.9%. Complications were more frequent in the VP-shunted patients, but were less than in VA-shunted patients and accounted for a lower mortality rate. Complications and mortality rate were prevalent in the patients presenting congenital communicating hydrocephalus or myelomeningocele. It is concluded that VP shunt is preferable to VA shunt in the treatment of infantile hydrocephalus.

Infraoptic course of the anterior cerebral artery associated with an anterior communicating artery aneurysm: anatomic case report and embryological considerations

OBJECTIVE AND IMPORTANCE: An infraoptic course of the proximal anterior cerebral artery is a rare anomaly that has been reported in 32 cases to date, often in association with cerebral aneurysms. This anomaly represents a maldevelopment in the embryogenesis of the anterior circle of Willis, resulting from the persistence of the primitive prechiasmal arterial anastomosis or an error in the development of the definitive ophthalmic artery (OphA). The case of a patient with a ruptured middle cerebral artery aneurysm and an anterior communicating artery aneurysm associated with this anomaly is described, and the anatomic features are outlined. CLINICAL PRESENTATION: A 30-year-old male patient with a right temporal hematoma and subarachnoid hemorrhage was admitted to our department 4 days after the hemorrhaging episode, with normal neurological examination results. Angiography revealed a right middle cerebral artery aneurysm and an anterior communicating artery aneurysm with an anomalous precommunicating tract. INTERVENTION: The patient was surgically treated 14 days after the hemorrhaging episode, through a right frontopterional craniotomy; both aneurysms were excluded by clipping. The anomalous infraoptic proximal tract of the anterior cerebral artery was well documented, with its origin adjacent to the OphA. The patient remained neurologically intact after surgery and was discharged 8 days later. CONCLUSION: The anomalous infraoptic course of the proximal anterior cerebral artery was associated with a low bifurcation of the ipsilateral internal carotid artery and the absence of the contralateral precommunicating tract in this patient. The strict anatomic relationship with the origin of the OphA suggests an error in the development of the definitive OphA, with persistence of an anastomotic loop between the primitive dorsal and ventral OphAs. It is concluded that, for aneurysm surgery, careful angiographic evaluation and an understanding of the neurovascular relationships in the circle of Willis are essential for a successful postoperative course, especially when very rare vascular anomalies are treated.