Audrey Quinn

A Review of Delayed Ischemic Neurologic Deficit Following Aneurysmal Subarachnoid Hemorrhage: Historical Overview, Current Treatment, and Pathophysiology

Delayed ischemic neurologic deficit (DIND) is a serious and poorly understood complication of aneurysmal subarachnoid hemorrhage. Although advances in treatment have improved prognosis for these patients, long-term clinical outcomes remain disappointing. Historically, angiographic vasospasm was thought to result in a DIND, although an increasing body of evidence suggests that this is an oversimplification, because interventions that have effectively targeted angiographic vasospasm have not improved outcome. Consequently, the relationship between angiographic vasospasm and neurologic outcome may be associative rather than causative. Although our understanding of the underlying molecular processes and pathophysiology is improving, responsible mediators or pathways have yet to be identified. The aim of this review is to summarize the key historical events that have helped shape our understanding of the pathophysiology of this phenomenon (microcirculation, autoregulation, microthrombosis, inflammation, apoptosis, spreading depolarization, oxidative stress) and to present the evidence underlying current treatment strategies (hemodynamic therapy, oral nimodipine, endovascular therapy, statins, cerebrospinal fluid drainage, thrombolysis, magnesium) and the translational and clinical research investigating DIND.

Lumbar Drainage of Cerebrospinal Fluid After Aneurysmal Subarachnoid Hemorrhage: A Prospective, Randomized, Controlled Trial (LUMAS)

Background and Purpose— A single-center prospective randomized controlled trial has been conducted to determine if lumbar drainage of cerebrospinal fluid after aneurysmal subarachnoid hemorrhage reduces the prevalence of delayed ischemic neurological deficit and improves clinical outcome. Methods— Patients with World Federation of Neurological Surgeons Grade 1 to 3 aneurysmal subarachnoid hemorrhage and modified Fisher Grades 2, 3, 4, and 3+4 were randomized to either the study group of standard therapy plus insertion of a lumbar drain or the control group of standard therapy alone. The primary outcome measure was the prevalence of delayed ischemic neurological deficit. Results— Two hundred ten patients with aneurysmal subarachnoid hemorrhage (166 female, 44 male; median age, 54 years; interquartile range, 45–62 years) were recruited into the control (n=105) and study (n=105) groups of the trial. World Federation of Neurological Surgeons grade was: 1 (n=139), 2 (n=60), and 3 (n=11); Fisher grade was: 2 (n=87), 3 (n=85), and 4 (n=38). The prevalence of delayed ischemic neurological deficit was 35.2% and 21.0% in the control and study groups, respectively (P=0.021). The prevalence of a modified Rankin Scale score of 4, 5, or 6 at Day 10 and 6 months, respectively, was 62.5% and 18.6% in the control group and 44.8% and 19.8% in the study group (P=0.009 and 0.83, respectively). Conclusions— Lumbar drainage of cerebrospinal fluid after aneurysmal subarachnoid hemorrhage has been shown to reduce the prevalence of delayed ischemic neurological deficit and improve early clinical outcome but failed to improve outcome at 6 months after aneurysmal subarachnoid hemorrhage. Clinical Trial Registration— URL: www.clinicaltrials.gov. Unique identifier: NCT00842049.

Subarachnoid Hemorrhage International Trialists Data Repository (SAHIT)

The outcome of patients with aneurysmal subarachnoid hemorrhage (SAH) has improved slowly over the past 25 years. This improvement may be due to early aneurysm repair by endovascular or open means, use of nimodipine, and better critical care management. Despite this improvement, mortality remains at about 40%, and many survivors have permanent neurologic, cognitive, and neuropsychologic deficits. Randomized clinical trials have tested pharmacologic therapies, but few have been successful. There are numerous explanations for the failure of these trials, including ineffective interventions, inadequate sample size, treatment side effects, and insensitive or inappropriate outcome measures. Outcome often is evaluated on a good-bad dichotomous scale that was developed for traumatic brain injury 40 years ago. To address these issues, we established the Subarachnoid Hemorrhage International Trialists (SAHIT) data repository. The primary aim of the SAHIT data repository is to provide a unique resource for prognostic analysis and for studies aimed at optimizing the design and analysis of phase III trials in aneurysmal SAH. With this aim in mind, we convened a multinational investigator meeting to explore merging individual patient data from multiple clinical trials and observational databases of patients with SAH and to create an agreement under which such a group of investigators could submit data and collaborate. We welcome collaboration with other investigators.

The VASOGRADE: A Simple Grading Scale for Prediction of Delayed Cerebral Ischemia After Subarachnoid Hemorrhage

Background and Purpose— Patients are classically at risk of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage. We validated a grading scale—the VASOGRADE—for prediction of DCI. Methods— We used data of 3 phase II randomized clinical trials and a single hospital series to assess the relationship between the VASOGRADE and DCI. The VASOGRADE derived from previously published risk charts and consists of 3 categories: VASOGRADE-Green (modified Fisher scale 1 or 2 and World Federation of Neurosurgical Societies scale [WFNS] 1 or 2); VASOGRADE-Yellow (modified Fisher 3 or 4 and WFNS 1–3); and VASOGRADE-Red (WFNS 4 or 5, irrespective of modified Fisher grade). The relation between the VASOGRADE and DCI was assessed by logistic regression models. The predictive accuracy of the VASOGRADE was assessed by receiver operating characteristics curve and calibration plots. Results— In a cohort of 746 patients, the VASOGRADE significantly predicted DCI (P<0.001). The VASOGRADE-Yellow had a tendency for increased risk for DCI (odds ratio [OR], 1.31; 95% CI, 0.77–2.23) when compared with VASOGRADE-Green; those with VASOGRADE-Red had a 3-fold higher risk of DCI (OR, 3.19; 95% CI, 2.07–4.50). Studies were not a significant confounding factor between the VASOGRADE and DCI. The VASOGRADE had an adequate discrimination for prediction of DCI (area under the receiver operating characteristics curve=0.63) and good calibration. Conclusions— The VASOGRADE results validated previously published risk charts in a large and diverse sample of subarachnoid hemorrhage patients, which allows DCI risk stratification on presentation after subarachnoid hemorrhage. It could help to select patients at high risk of DCI, as well as standardize treatment protocols and research studies.

Prognostic value of premorbid hypertension and neurological status in aneurysmal subarachnoid hemorrhage: pooled analyses of individual patient data in the SAHIT repository.

OBJECT The literature has conflicting reports about the prognostic value of premorbid hypertension and neurological status in aneurysmal subarachnoid hemorrhage (SAH). The aim of this study was to investigate the prognostic value of premorbid hypertension and neurological status in the SAH International Trialists repository. METHODS Patient-level meta-analyses were conducted to investigate univariate associations between premorbid hypertension (6 studies; n = 7249), admission neurological status measured on the World Federation of Neurosurgical Societies (WFNS) scale (10 studies; n = 10,869), and 3-month Glasgow Outcome Scale (GOS) score. Multivariable analyses were performed to sequentially adjust for the effects of age, CT clot burden, aneurysm location, aneurysm size, and modality of aneurysm repair. Prognostic associations were estimated across the ordered categories of the GOS using proportional odds models. Nagelkerkes R(2) statistic was used to quantify the added prognostic value of hypertension and neurological status beyond those of the adjustment factors. RESULTS Premorbid hypertension was independently associated with poor outcome, with an unadjusted pooled odds ratio (OR) of 1.73 (95% confidence interval [CI] 1.50-2.00) and an adjusted OR of 1.38 (95% CI 1.25-1.53). Patients with a premorbid history of hypertension had higher rates of cardiovascular and renal comorbidities, poorer neurological status (p ≤ 0.001), and higher odds of neurological complications including cerebral infarctions, hydrocephalus, rebleeding, and delayed ischemic neurological deficits. Worsening neurological status was strongly independently associated with poor outcome, including WFNS Grades II (OR 1.85, 95% CI 1.68-2.03), III (OR 3.85, 95% CI 3.32-4.47), IV (OR 5.58, 95% CI 4.91-6.35), and V (OR 14.18, 95% CI 12.20-16.49). Neurological status had substantial added predictive value greater than the combined value of other prognostic factors (R(2) increase > 10%), while the added predictive value of hypertension was marginal (R(2) increase < 0.5%). CONCLUSIONS This study confirmed the strong prognostic effect of neurological status as measured on the WFNS scale and the independent but weak prognostic effect of premorbid hypertension. The effect of premorbid hypertension could involve multifactorial mechanisms, including an increase in the severity of initial bleeding, the rate of comorbid events, and neurological complications.

Self-perceived health status following aneurysmal subarachnoid haemorrhage: a cohort study.

Objective The objective of the study was to assess the long-term self-reported health status and quality of life (QoL) of patients following an aneurysmal subarachnoid haemorrhage (ASAH) using a self-completed questionnaire booklet. Design A two-cohort study. Setting A regional tertiary neurosurgical centre. Participants 2 cohorts of patients with ASAH treated between 1998 and 2008 and followed up at approximately 1 year. Interventions Routine care. Primary and secondary outcomes A range of standardised scales included: AKC Short Sentences Test, the Barthel Index, the Self-Report Dysexecutive Questionnaire, the Everyday Memory Questionnaire, Stroke Symptom Checklist, Wimbledon Self-Report Scale, Modified Rankin Score (MRS) and a new Stroke-QoL. The data from summated scales were fit to the Rasch measurement model to validate the summed score. Results 214 patients (48%) returned the questionnaires; the majority (76%) had a World Federation of Neurosurgeons grade of 1 or 2. The most frequent aneurysm type was that of the anterior communicating artery (28%) with approximately 90% of aneurysms of the anterior circulation. Of those previously in full or part-time employment, 48.9% were unemployed at follow-up. All summated scales satisfied the Rasch measurement model requirements, such that their summed scores were a sufficient statistic. Given this, one-third of patients were noted to have a significant mood disorder and 25% had significant dysexecutive function. Patients with an MRS of 3, 4 or 5 had significantly worse scores on most outcome measures, but a significant minority of those with a score of zero had failed to return to work and displayed significant mood disorder. Conclusions A range of self-reported cognitive and physical deficits have been highlighted in a cohort of patients with ASAH. While the MRS has been shown to provide a reasonable indication of outcome, in routine clinical follow-up it requires supplementation by instruments assessing dysexecutive function, memory and mood.

A comparison of the outcome of aneurysmal subarachnoid haemorrhage before and after the introduction of an endovascular service

There has been a rapid change from predominantly surgical to endovascular treatment of ruptured intracranial aneurysms giving the opportunity to assess change in patient outcome during this transition. We identified and followed 139 patients with subarachnoid haemorrhage (SAH) treated in the year prior to (group 1) and following (group 2) the introduction of an endovascular service in a retrospective, cross-sectional study. A total of 78.7% of patients in group 1 underwent surgical treatment, 10.7% underwent endovascular treatment and 10.7% received no treatment, whereas patients in group 2 received 29.7%, 65.7% and 4.7%, respectively. MRS scores were obtained in 91% of patients in group 1 and in 89% of patients in group 2. A total of 30.7% and 24.0% of patients had a poor outcome in groups 1 and 2 respectively (p=0.34). The overall change in the management of ruptured cerebral aneurysms in the post-International Subarachnoid Aneurysm Trial (ISAT) era has not significantly changed cross-sectional outcome, although absolute differences appear to reflect difference in outcome noted in the ISAT.

New Modalities to Assess Efficacy of Triple-H Therapy: Early Experience

The traditional axiom that vasospasm induced reduction of blood flow leads to poor tissue oxygenation and ischaemic cellular injury culminating in delayed neurological deficits has been challenged and the efficacy of triple H therapy in reversal of the above is debated. In this study we assess cerebral physiology before and during onset of DIND and with application of triple H therapy with real time neuro-monitoring tools. Patients with Fisher grade 3/4/3 + 4/rebleed were consented. Probes for measuring rCBF, pTiO2, and Microdialysis parameters - glucose, glycerol, lactate, and pyruvate were inserted at time of coiling/clipping. Subsequent monitoring was done in HDU/ITU setting. Return of parameters to baseline was regarded as effective triple H therapy. Study is ongoing and the current paper presents our experience with first five patients. The results suggest safety and feasibility of multimodal monitoring in clinical setting to establish an understanding of relationship between clinical symptoms, brain perfusion, oxygenation, and metabolism in real time to test and guide therapy in future.

The SAFARI Score to Assess the Risk of Convulsive Seizure During Admission for Aneurysmal Subarachnoid Hemorrhage

BACKGROUND Seizure is a significant complication in patients under acute admission for aneurysmal SAH and could result in poor outcomes. Treatment strategies to optimize management will benefit from methods to better identify at‐risk patients. OBJECTIVE To develop and validate a risk score for convulsive seizure during acute admission for SAH. METHODS A risk score was developed in 1500 patients from a single tertiary hospital and externally validated in 852 patients. Candidate predictors were identified by systematic review of the literature and were included in a backward stepwise logistic regression model with in‐hospital seizure as a dependent variable. The risk score was assessed for discrimination using the area under the receiver operator characteristics curve (AUC) and for calibration using a goodness‐of‐fit test. RESULTS The SAFARI score, based on 4 items (age ≥ 60 yr, seizure occurrence before hospitalization, ruptured aneurysm in the anterior circulation, and hydrocephalus requiring cerebrospinal fluid diversion) had AUC = 0.77, 95% confidence interval (CI): 0.73‐0.82 in the development cohort. The validation cohort had AUC = 0.65, 95% CI 0.56‐0.73. A calibrated increase in the risk of seizure was noted with increasing SAFARI score points. CONCLUSION The SAFARI score is a simple tool that adequately stratified SAH patients according to their risk for seizure using a few readily derived predictor items. It may contribute to a more individualized management of seizure following SAH.

Identifying patient report outcomes relevant to aneurysmal subarachnoid hemorrhage follow-up.

Patients recovered from subarachnoid hemorrhage can be assessed for neuropsychological dysfunction using postal questionnaires. We assessed 214 patients using various tests of memory, mood and strategic thinking. Patients in good outcome categories (modified Rankin Scale [mRS] 0-1) nevertheless exhibited mood disorder (28%), memory deficit and executive dysfunction (20%). Return to work (49%) was most influenced by previous employment status, Rankin scale and mood.