Nimodipine is a dihydropyridine calcium channel antagonist that blocks the flux of extracellular calcium through L-type, voltage-gated calcium channels. While nimodipine is FDAapproved for the prevention and treatment of neurological deficits in patients with aneurysmal subarachnoid hemorrhage (aSAH), it affects myriad cell types throughout the body, and thus, likely has more complex mechanisms of action than simple inhibition of cerebral vasoconstriction. Newer understanding of the pathophysiology of delayed ischemic injury after a variety of acute neurologic injuries including aSAH, traumatic brain injury (TBI) and ischemic stroke, coupled with advances in the drug delivery method for nimodipine, have reignited interest in refining its potential therapeutic use. In this context, this review seeks to establish a firm understanding of current data on nimodipine’s role in the mechanisms of delayed injury in aSAH, TBI, and ischemic stroke, and assess the extensive clinical data evaluating its use in these conditions. In addition, we will review pivotal trials using locally administered, sustained release nimodipine and discuss why such an approach has evaded demonstration of efficacy, while seemingly having the potential to significantly improve clinical care.

OBJECTIVE: Retrospective clinical data and case studies support a therapeutic effect of ketamine in suppression of spreading depolarization (SD) following brain injury. Preclinical data strongly support efficacy in terms of frequency of SD as well as recovery from electrocorticography (ECoG) depression. The authors present the results of the first prospective controlled clinical trial testing the role of ketamine used for clinical sedation on occurrence of SD.METHODS: Ten patients with severe traumatic brain injury (TBI) or aneurysmal subarachnoid hemorrhage (SAH) were recruited for this pilot trial. A standard ECoG strip was placed at the time of craniotomy, and the patients were then placed on an alternating every-6-hour schedule of ketamine or other sedation agent. The order of treatment was randomized. The ketamine dose was adjusted to clinical effect or maintained at a subanesthetic basal dose (0.1 mg/kg/hr) if no sedation was required. SD was scored using standard criteria, blinded to ketamine dosing. Occurrence of SD was compared with the hourly dose of ketamine to determine the effect of ketamine on SD occurrence.RESULTS: Successful ECoG recordings were obtained in all 10 patients: 8 with SAH and 2 with TBI. There were a total of 1642 hours of observations with adequate ECoG: 833 hours off ketamine and 809 hours on ketamine. Analysis revealed a strong dose-dependent effect such that hours off ketamine or on doses of less than 1.15 mg/kg/hr were associated with an increased risk of SD compared with hours on doses of 1.15 mg/kg/hr or more (OR 13.838, 95% CI 1.99–1000). This odds ratio decreased with lower doses of 1.0 mg/kg/hr (OR 4.924, 95% CI 1.337–43.516), 0.85 mg/kg/hr (OR 3.323, 95% CI 1.139–16.074), and 0.70 mg/kg/hr (OR 2.725, 95% CI 1.068–9.898) to a threshold of no effect at 0.55 mg/kg/hr (OR 1.043, 95% CI 0.565–2.135). When all ketamine data were pooled (i.e., on ketamine at any dose vs off ketamine), a nonsignificant overall trend toward less SD during hours on ketamine (χ² = 3.86, p = 0.42) was observed.CONCLUSIONS: Ketamine effectively inhibits SD over a wide range of doses commonly used for sedation, even in nonintubated patients. These data also provide the first prospective evidence that the occurrence of SD can be influenced by clinical intervention and does not simply represent an unavoidable epiphenomenon after injury. These data provide the basis for future studies assessing clinical improvement with SD-directed therapy.Clinical trial registration no.: NCT02501941 (clinicaltrials.gov)

The authors report on a 57-year-old woman in whom progression to brain death occurred on day 9 after aneurysmal subarachnoid hemorrhage without evidence of significant brain edema or vasospasm. Neuromonitoring demonstrated that brain death was preceded by a series of cortical spreading depolarizations that occurred in association with progressive hypoxic episodes. The depolarizations induced final electrical silence in the cortex and ended with a terminal depolarization that persisted > 7 hours. To the authors’ knowledge, this is the first report of terminal spreading depolarization in the human brain prior to clinical brain death and major cardiopulmonary failure.

OBJECTIVE: Decompressive craniectomy is used for uncontrolled intracranial pressure in traumatic brain injury and malignant hemispheric stroke. Subcutaneous preservation of the autologous bone flap in the abdomen is a simple, portable technique but has largely been abandoned due to perceived concerns of resorption. The authors sought to characterize their experience with subcutaneous preservation of the bone flap and cranioplasty.METHODS: The authors performed a retrospective single-institution review of subcutaneous preservation of the autologous bone flap after decompressive craniectomy from 2005 to 2015. The primary outcome was clinically significant bone resorption, defined as requiring a complete mesh implant at the time of cranioplasty, or delayed revision. The outcome also combined cases with any minor bone resorption to determine predictors of this outcome. Logistic regression modeling was used to determine the risk factors for predicting resorption. A cost comparison analysis was also used via the 2-sided t-test to compare the cost of cranioplasty using an autologous bone flap with standard custom implant costs.RESULTS: A total of 193 patients with craniectomy were identified, 108 of whom received a cranioplasty. The mean time to cranioplasty was 104.31 days. Severe resorption occurred in 10 cases (9.26%): 4 were clinically significant (2 early and 2 late) and 6 demonstrated type II (severe) necrosis on CT, but did not require revision. Early resorption of any kind (mild or severe) occurred in 28 (25.93%) of 108 cases. Of the 108 patients, 26 (24.07%) required supplemental cranioplasty material. Late resorption of any kind (mild or severe) occurred in 6 (5.88%) of 102 cases. Of these, a clinically noticeable but nonoperative deformity was noted in 4 (3.92%) and minor (type I) necrosis on CT in 37 (37%) of 100. Bivariate analysis identified fragmentation of bone (OR 3.90, 95% CI 1.03–14.8), shunt-dependent hydrocephalus (OR 7.97, 95% CI 1.57–40.46), and presence of post-cranioplasty drain (OR 9.39, 95% CI 1.14–1000) to be significant risk factors for bone resorption. A binary logistic regression optimized using Fisher’s scoring determined the optimal multivariable combination of factors. Fragmentation of bone (OR 5.84, 95% CI 1.38–28.78), diabetes (OR 7.61, 95% CI 1.37–44.56), and shunt-dependent hydrocephalus (OR 9.35, 95% CI 1.64–56.21) were found to be most predictive of resorption, with a C value of 0.78. Infections occurred in the subcutaneous pocket in 5 (2.60%) of the 193 cases and after cranioplasty in 10 (9.26%) of the 108 who underwent cranioplasty. The average cost of cranioplasty with autologous bone was $2156.28 ± $1144.60 (n = 15), and of a custom implant was $35,118.60 ± $2067.51 (3 different sizes; p < 0.0001).CONCLUSIONS: Craniectomy with autologous bone cranioplasty using subcutaneous pocket storage is safe and compares favorably to cryopreservation in terms of resorption and favorably to a custom synthetic implant in terms of cost. While randomized data are required to definitively prove the superiority of one method, subcutaneous preservation has enough practical advantages with low risk to warrant routine use for most patients.

OBJECTIVE: Most patients with chronic subdural hematoma (cSDH) recover after surgical evacuation with a straightforward course. There is a subset of patients who develop transient and fluctuating deficits not explained by seizures, stroke, or mass effect after evacuation. The objective of this study was to investigate whether these postoperative neurological deficits may be related to temporary brain dysfunction caused by cortical spreading depolarizations (SDs). METHODS: The authors conducted a prospective observational study of 40 patients who underwent cSDH evacuation. At the time of surgery, a 1 × 6 subdural electrode strip was placed on the cortex parallel to the subdural drain. Clinical outcomes were assessed utilizing the Markwalder Grading Scale, need for clinical EEG for new deficit, and presence of new deficits. RESULTS: Definitive SD was detected in 6 (15%) of 40 patients. Baseline and cSDH characteristics did not differ between patients with and without SD. More patients experienced postoperative neurological deterioration if they had SD (50%) compared to those without SD (8.8%; p = 0.03). Only 2 patients in the entire cohort demonstrated early neurological deterioration, both of whom had SD. One of these cases demonstrated a time-locked new focal neurological deficit (aphasia) at the start of a series of multiple clusters of SD. CONCLUSIONS: This is the first observation of SD occurring after cSDH evacuation. SD occurred at a rate of 15% and was associated with neurological deterioration. This may represent a novel mechanism for otherwise unexplained fluctuating neurological deficit after cSDH evacuation. This could provide a new therapeutic target, and SD-targeted therapies should be evaluated in prospective clinical trials.

Background: Delayed cerebral ischemia remains one of the principal therapeutic targets after aneurysmal subarachnoid hemorrhage. While large vessel vasospasm may contribute to ischemia, increasing evidence suggests that physiological impairment through disrupted impaired cerebral autoregulation (CA) and spreading depolarizations (SDs) also contribute to delayed cerebral ischemia and poor neurological outcome. This study seeks to explore the intermeasure correlation of different measures of CA, as well as correlation with SD and neurological outcome. Methods: Simultaneous measurement of 7 continuous indices of CA was calculated in 19 subjects entered in a prospective study of SD in aneurysmal subarachnoid hemorrhage undergoing surgical aneurysm clipping. Intermeasure agreement was assessed, and the association of each index with modified Rankin Scale score at 90 days and occurrence of SD was assessed. Results: There were 4102 hours of total monitoring time across the 19 subjects. In time-resolved assessment, no CA measures demonstrated significant correlation; however, most demonstrate significant correlation averaged over 1 hour. Pressure reactivity (PRx), oxygen reactivity, and oxygen saturation reactivity were significantly correlated with modified Rankin Scale score at 90 days. PRx and oxygen reactivity also were correlated with the occurrence of SD events. Across multiple CA measure reactivity indices, a threshold between 0.3 and 0.5 was most associated with intervals containing SD. Conclusions: Different continuous CA indices do not correlate well with each other on a highly time-resolved basis, so should not be viewed as interchangeable. PRx and oxygen reactivity are the most reliable indices in identifying risk of worse outcome in patients with aneurysmal subarachnoid hemorrhage undergoing surgical treatment. SD occurrence is correlated with impaired CA across multiple CA measurement techniques and may represent the pathological mechanism of delayed cerebral ischemia in patients with impaired CA. Optimization of CA in patients with aneurysmal subarachnoid hemorrhage may lead to decreased incidence of SD and improved neurological outcomes. Future studies are needed to evaluate these hypotheses and approaches.