Mario Zuccarello

The ABCs of Measuring Intracerebral Hemorrhage Volumes

BACKGROUND AND PURPOSE Hemorrhage volume is a powerful predictor of 30-day mortality after spontaneous intracerebral hemorrhage (ICH). We compared a bedside method of measuring CT ICH volume with measurements made by computer-assisted planimetric image analysis. METHODS The formula ABC/2 was used, where A is the greatest hemorrhage diameter by CT, B is the diameter 90 degrees to A, and C is the approximate number of CT slices with hemorrhage multiplied by the slice thickness. RESULTS The ICH volumes for 118 patients were evaluated in a mean of 38 seconds and correlated with planimetric measurements (R2 = 9.6). Interrater and intrarater reliability were excellent, with an intraclass correlation of .99 for both. CONCLUSIONS We conclude that ICH volume can be accurately estimated in less than 1 minute with the simple formula ABC/2.

Guidelines for the Management of Spontaneous Intracerebral Hemorrhage A Statement for Healthcare Professionals From a Special Writing Group of the Stroke Council, American Heart Association

Intracerebral hemorrhage (ICH) is more than twice as common as subarachnoid hemorrhage (SAH) and is much more likely to result in death or major disability than cerebral infarction or SAH.1 Although >315 randomized clinical therapeutic trials for acute ischemic stroke and 78 trials for SAH were complete or ongoing (oral communication, Cochrane Collaboration, May 16, 1995) as of 1995, only the results of 4 small randomized surgical trials (353 total patients)2 3 4 5 and 4 small medical trials (513 total patients)6 7 8 9 of ICH had been published. In these small randomized studies, neither surgical nor medical treatment has been shown conclusively to benefit patients with ICH. Advancing age and hypertension are the most important risk factors for ICH.10 11 12 13 14 15 ICH occurs slightly more frequently among men than women and is significantly more common among young and middle-aged blacks than whites of similar ages.10 16 Reported incidence rates of ICH among Asian populations are also higher than those reported for whites in the United States and Europe. Pathophysiological change in small arteries and arterioles due to sustained hypertension is generally regarded as the most important cause of ICH.11 12 14 17 18 Cerebral amyloid angiopathy is increasingly recognized as a cause of lobar ICH in the elderly.19 20 21 22 23 Other causes of ICH include vascular malformations, ruptured aneurysms, coagulation disorders, use of anticoagulants and thrombolytic agents, hemorrhage into a cerebral infarct, bleeding into brain tumors, and drug abuse.10 Of the estimated 37 000 Americans who experienced an ICH in 1997, 35% to 52% were dead at 1 month; half of the deaths occurred within the first 2 days.1 17 24 Only 10% of patients were living independently at 1 month; 20% were independent …

Early Surgical Treatment for Supratentorial Intracerebral Hemorrhage A Randomized Feasibility Study

BACKGROUND AND PURPOSE The safety and the effectiveness of the surgical treatment of spontaneous intracerebral hemorrhage (ICH) remain controversial. To investigate the feasibility of urgent surgical evacuation of ICH, we conducted a small, randomized feasibility study of early surgical treatment versus current nonoperative management in patients with spontaneous supratentorial ICH. METHODS Patients with spontaneous supratentorial ICH who presented to 1 university and 2 community hospitals were randomized to surgical treatment or best medical treatment. Principal eligibility criteria were ICH volume >10 cm(3) on baseline CT scan with a focal neurological deficit, Glasgow Coma Scale score >4 at the time of enrollment, randomization and therapy within 24 hours of symptom onset, surgery within 3 hours of randomization, and no evidence for ruptured aneurysm or arteriovenous malformation. The primary end point was the 3-month Glasgow Outcome Scale (GOS). A good outcome was defined as a 3-month GOS score >3. RESULTS Twenty patients were randomized over 24 months, 9 to surgical intervention and 11 to medical treatment. The median time from onset of symptoms to presentation at the treating hospitals was 3 hours and 17 minutes, the time from randomization to surgery was 1 hour and 20 minutes, and the time from onset of symptoms to surgery was 8 hours and 35 minutes. The likelihood of a good outcome (primary outcome measure: GOS score >3) for the surgical treatment group (56%) did not differ significantly from the medical treatment group (36%). There was no significant difference in mortality at 3 months. Analysis of the secondary 3-month outcome measures showed a nonsignificant trend toward a better outcome in the surgical treatment group versus the medical treatment group for the median GOS, Barthel Index, and Rankin Scale and a significant difference in the National Institutes of Health Stroke Scale score (4 versus 14; P=0.04). CONCLUSIONS Very early surgical treatment for acute ICH is difficult to achieve but feasible at academic medical centers and community hospitals. The trend toward less 3-month morbidity with surgical intervention in patients with spontaneous supratentorial ICH warrants further investigation of very early clot removal in larger randomized clinical trials.

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.

Preliminary findings of the minimally-invasive surgery plus rtPA for intracerebral hemorrhage evacuation (MISTIE) clinical trial

INTRODUCTION Compared to ischemic stroke, intracerebral hemorrhage (ICH) is easily and rapidly identified, occurs in younger patients, and produces relatively small initial injury to cerebral tissues--all factors suggesting that interventional amelioration is possible. Investigations from the last decade established that extent of ICH-mediated brain injury relates directly to blood clot volume and duration of blood exposure to brain tissue. Using minimally-invasive surgery plus recombinant tissue plasminogen activator (rtPA), MISTIE investigators explored aggressive avenues to treat ICH. METHODS We investigated the difference between surgical intervention plus rtPA and standard medical management for ICH. Subjects in both groups were medically managed according to standard ICU protocols. Subjects randomized to surgery underwent stereotactic catheter placement and clot aspiration. Injections of rtPA were then given through hematoma catheter every 8 h, up to 9 doses, or until a clot-reduction endpoint. After each injection the system was flushed with sterile saline and closed for 60 min before opening to spontaneous drainage. RESULTS Average aspiration of clots for all patients randomized to surgery plus rtPA was 20% of mean initial clot size. After acute treatment phase (aspiration plus rtPA), clot was reduced an average of 46%. Recorded adverse events were within safety limits, including 30-day mortality, 8%; symptomatic re-bleeding, 8%; and bacterial ventriculitis, 0%. Patients randomized to medical management showed 4% clot resolution in a similar time window. Preliminary analysis indicates that clot resolution rates are greatly dependent on catheter placement. Location of ICH also affects efficacy of aggressive treatment of ICH. CONCLUSION There is tentative indication that minimally-invasive surgery plus rtPA shows greater clot resolution than traditional medical management.

C-tau biomarker of neuronal damage in severe brain injured patients: association with elevated intracranial pressure and clinical outcome

Following traumatic brain injury, the neuronally-localized intracellular protein MAP-tau is proteolytically cleaved (C-tau) and gains access to cerebrospinal fluid (CSF) and serum. The present study compared initial CSF C-tau levels, initial Glasgow Coma Scale (GCS) scores and elevated intracranial pressure (ICP) as predictors of clinical outcome. In this preliminary, prospective study of consecutive severe traumatic brain injured patients (TBI) clinical outcome was quantified with the Glasgow Outcome Scale (GOS) at discharge (n=28). Sensitivity and specificity of initial C-tau levels and initial GCS scores as predictors of clinical outcome is reported. To assess disease specificity C-tau levels were compared between TBI patients and neurologic (n=87) and non-neurologic control patients (n=67). Initial CSF C-tau levels were elevated 40,000 fold in TBI patients compared to either neurologic or non-neurologic control patients (P<0.001). Initial C-tau levels were correlated with clinical outcome (P=0.006) and were a significant predictor of dichotomized clinical outcome (P=0.011) demonstrating a sensitivity of prediction of 92% and a specificity of 94%. Initial C-tau levels were also a significant predictor of subsequent ICP with higher initial C-tau levels associated with elevated ICP (P=0.014). Initial GCS score were correlated with clinical outcome (P=0.026) and demonstrated a sensitivity of 50% and a specificity of 100% for predicting dichotomized clinical outcome. Statistical analysis indicated that initial C-tau levels and initial GCS scores were independent predictors of clinical outcome. The present preliminary study demonstrates that initial CSF C-tau levels are a significant predictor of ICP and clinical outcome with particular sensitivity for identifying severe TBI patients with good clinical outcome. Future studies employing a larger sample size and clinical outcome assessment at longer periods after hospitalization will be needed to determine the utility of initial C-tau levels as a clinical biomarker in TBI.

Intraoperative Magnetic Resonance Imaging to Determine the Extent of Resection of Pituitary Macroadenomas during Transsphenoidal Microsurgery

OBJECTIVEWell-established surgical goals for pituitary macroadenomas include gross total resection for noninvasive tumors and debulking with optic chiasm decompression for invasive tumors. In this report, we examine the safety, reliability, and outcome of intraoperative magnetic resonance imaging (iMRI) used to assess the extent of resection, and thus the achievement of preoperative surgical goals, during transsphenoidal microneurosurgery. METHODSOur magnetic resonance operating room contains a Hitachi AIRIS II 0.3-T, vertical-field open magnet (Hitachi Medical Systems America, Inc., Twinsburg, OH). A motorized scanner tabletop moves the patient between the imaging and operative positions. For transsphenoidal surgery, the patient is positioned directly on the scanner tabletop so that the surgical field is located between 1.2 and 1.6 m from the magnet isocenter. At this location, the magnetic field strength is low (<20 G), thus permitting the use of many conventional surgical instruments. Thirty consecutive patients with pituitary macroadenomas underwent tumor resection in our magnetic resonance operating room by use of a standard transsphenoidal approach. After initial resection, the patient was advanced into the scanner for imaging. If residual tumor was demonstrated and deemed surgically accessible, the patient underwent immediate re-exploration. RESULTSiMRI was performed successfully in all 30 patients. In one patient, iMRI was used to clarify the significance of hemorrhage from the sellar region and resulted in immediate conversion of the procedure to a craniotomy. In the remaining 29 patients, initial iMRI demonstrated that the endpoint for extent of resection had been achieved in only 10 patients (34%) after an initial resection attempt, whereas 19 patients (66%) still had unacceptable residual tumor. All 19 of these latter patients underwent re-exploration. Ultimately, re-exploration resulted in the achievement of the planned endpoint for extent of resection in all of the 29 completed transsphenoidal explorations. Operative time was extended in all cases by at least 20 minutes. CONCLUSIONiMRI can be used to safely, reliably, and objectively assess the extent of resection of pituitary macroadenomas during the transsphenoidal approach. The surgeon is frequently surprised by the extent of residual tumor after an initial resection attempt and finds the intraoperative images useful for guiding further resection.

Minimally Invasive Surgery Plus Recombinant Tissue-type Plasminogen Activator for Intracerebral Hemorrhage Evacuation Decreases Perihematomal Edema

Background and Purpose— Perihematomal edema (PHE) can worsen outcomes after intracerebral hemorrhage (ICH). Reports suggest that blood degradation products lead to PHE. We hypothesized that hematoma evacuation will reduce PHE volume and that treatment with recombinant tissue-type plasminogen activator (rt-PA) will not exacerbate it. Methods— Minimally invasive surgery and rt-PA in ICH evacuation (MISTIE) phase II tested safety and efficacy of hematoma evacuation after ICH. We conducted a semiautomated, computerized volumetric analysis on computed tomography to assess impact of hematoma removal on PHE and effects of rt-PA on PHE. Volumetric analyses were performed on baseline stability and end of treatment scans. Results— Seventy-nine surgical and 39 medical patients from minimally invasive surgery and rt-PA in ICH evacuation phase II (MISTIE II) were analyzed. Mean hematoma volume at end of treatment was 19.6±14.5 cm3 for the surgical cohort and 40.7±13.9 cm3 for the medical cohort (P<0.001). Edema volume at end of treatment was lower for the surgical cohort: 27.7±13.3 cm3 than medical cohort: 41.7±14.6 cm3 (P<0.001). Graded effect of clot removal on PHE was observed when patients with >65%, 20% to 65%, and <20% ICH removed were analyzed (P<0.001). Positive correlation between PHE reduction and percent of ICH removed was identified (&rgr;=0.658; P<0.001). In the surgical cohort, 69 patients underwent surgical aspiration and rt-PA, whereas 10 underwent surgical aspiration only. Both cohorts achieved similar clot reduction: surgical aspiration and rt-PA, 18.9±14.5 cm3; and surgical aspiration only, 24.5±14.0 cm3 (P=0.26). Edema at end of treatment in surgical aspiration and rt-PA was 28.1±13.8 cm3 and 24.4±8.6 cm3 in surgical aspiration only (P=0.41). Conclusions— Hematoma evacuation is associated with significant reduction in PHE. Furthermore, PHE does not seem to be exacerbated by rt-PA, making such neurotoxic effects unlikely when the drug is delivered to intracranial clot.

Recent trends in the treatment of cerebral aneurysms: analysis of a nationwide inpatient database

OBJECT The most appropriate treatment for cerebral aneurysms, both ruptured and unruptured, is currently under debate, and updated guidelines have yet to be defined. The authors attempted to identify trends in therapy for cerebral aneurysms in the US as well as outcomes. METHODS The authors retrospectively reviewed data from the Nationwide Inpatient Sample hospital discharge database (Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality) for the period 1993-2003. Multiple variables were categorized and subjected to statistical analysis for International Classification of Diseases, 9th Revision, Clinical Modification codes related to subarachnoid hemorrhage (SAH), unruptured aneurysm, and clipping and endovascular treatment of cerebral aneurysm. RESULTS During the study period, the numbers of discharges remained stable for SAH but doubled for unruptured aneurysms. Concomitantly, the number of aneurysms treated with clip placement remained stable, and the number treated by means of endovascular procedures doubled. By the studys end, the mortality rates had decreased 20% for SAH and 50% for unruptured aneurysms. Increasing age was associated with increased mortality rates, mean length of hospital stay (LOS), and mean charges (p < 0.01). Endovascular treatment was used more often in older patients (p < 0.01). Teaching status and larger hospital size were associated with higher charges and longer hospital stays (although the association was not statistically significant) and with better outcomes (p < 0.05) and lower mortality rates (p < 0.05), especially in patients who underwent aneurysm clipping (p < 0.01). Endovascular treatment was associated with significantly higher mortality rates in small hospitals (p < 0.001) and steadily increasing morbidity rates (45%). Morbidity rates, mean LOS, and mean charges were higher for aneurysm clipping (p < 0.01). CONCLUSIONS From 1993 to 2003, endovascular techniques for aneurysm occlusion have been increasingly used, while the use of surgical clipping procedures has remained stable. Toward the end of the study period, better overall outcomes were observed in the treatment of cerebral aneurysms, both ruptured and unruptured. Large academic centers were associated with better results, particularly for surgical clip placement.

Low-Dose Recombinant Tissue-Type Plasminogen Activator Enhances Clot Resolution in Brain Hemorrhage: The Intraventricular Hemorrhage Thrombolysis Trial

Background and Purpose— Patients with intracerebral hemorrhage and intraventricular hemorrhage have a reported mortality of 50% to 80%. We evaluated a clot lytic treatment strategy for these patients in terms of mortality, ventricular infection, and bleeding safety events, and for its effect on the rate of intraventricular clot lysis. Methods— Forty-eight patients were enrolled at 14 centers and randomized to treatment with 3 mg recombinant tissue-type plasminogen activator (rtPA) or placebo. Demographic characteristics, severity factors, safety outcomes (mortality, infection, bleeding), and clot resolution rates were compared in the 2 groups. Results— Severity factors, including admission Glasgow Coma Scale, intracerebral hemorrhage volume, intraventricular hemorrhage volume, and blood pressure were evenly distributed, as were adverse events, except for an increased frequency of respiratory system events in the placebo-treated group. Neither intracranial pressure nor cerebral perfusion pressure differed substantially between treatment groups on presentation, with external ventricular device closure, or during the active treatment phase. Frequency of death and ventriculitis was substantially lower than expected and bleeding events remained below the prespecified threshold for mortality (18% rtPA; 23% placebo), ventriculitis (8% rtPA; 9% placebo), symptomatic bleeding (23% rtPA; 5% placebo, which approached statistical significance; P=0.1). The median duration of dosing was 7.5 days for rtPA and 12 days for placebo. There was a significant beneficial effect of rtPA on rate of clot resolution. Conclusions— Low-dose rtPA for the treatment of intracerebral hemorrhage with intraventricular hemorrhage has an acceptable safety profile compared to placebo and historical controls. Data from a well-designed phase III clinical trial, such as CLEAR III, will be needed to fully evaluate this treatment. Clinical Trial Registration— Participant enrollment began before July 1, 2005.