Recovery from disorders of consciousness: mechanisms, prognosis and emerging therapies.

Substantial progress has been made over the past two decades in detecting, predicting and promoting recovery of consciousness in patients with disorders of consciousness (DoC) caused by severe brain injuries. Advanced neuroimaging and electrophysiological techniques have revealed new insights into the biological mechanisms underlying recovery of consciousness and have enabled the identification of preserved brain networks in patients who seem unresponsive, thus raising hope for more accurate diagnosis and prognosis. Emerging evidence suggests that covert consciousness, or cognitive motor dissociation (CMD), is present in up to 15-20% of patients with DoC and that detection of CMD in the intensive care unit can predict functional recovery at 1 year post injury. Although fundamental questions remain about which patients with DoC have the potential for recovery, novel pharmacological and electrophysiological therapies have shown the potential to reactivate injured neural networks and promote re-emergence of consciousness. In this Review, we focus on mechanisms of recovery from DoC in the acute and subacute-to-chronic stages, and we discuss recent progress in detecting and predicting recovery of consciousness. We also describe the developments in pharmacological and electrophysiological therapies that are creating new opportunities to improve the lives of patients with DoC.

Brexanolone as adjunctive therapy in super-refractory status epilepticus.

OBJECTIVE: Super-refractory status epilepticus (SRSE) is a life-threatening form of status epilepticus that continues or recurs despite 24 hours or more of anesthetic treatment. We conducted a multicenter, phase 1/2 study in SRSE patients to evaluate the safety and tolerability of brexanolone (USAN; formerly SAGE-547 Injection), a proprietary, aqueous formulation of the neuroactive steroid, allopregnanolone. Secondary objectives included pharmacokinetic assessment and open-label evaluation of brexanolone response during and after anesthetic third-line agent (TLA) weaning. METHODS: Patients receiving TLAs for SRSE control were eligible for open-label, 1-hour brexanolone loading infusions, followed by maintenance infusion. After 48 hours of brexanolone infusion, TLAs were weaned during brexanolone maintenance. After 4 days, the brexanolone dose was tapered. Safety and functional status were assessed over 3 weeks of follow-up. RESULTS: Twenty-five patients received open-label study drug. No serious adverse events (SAEs) were attributable to study drug, as determined by the Safety Review Committee. Sixteen patients (64%) experienced ≥1 SAE. Six patient deaths occurred, all deemed related to underlying medical conditions. Twenty-two patients underwent ≥1 TLA wean attempt. Seventeen (77%) met the response endpoint of weaning successfully off TLAs before tapering brexanolone. Sixteen (73%) were successfully weaned off TLAs within 5 days of initiating brexanolone infusion without anesthetic agent reinstatement in the following 24 hours. INTERPRETATION: In an open-label cohort of limited size, brexanolone demonstrated tolerability among SRSE patients of heterogeneous etiologies and was associated with a high rate of successful TLA weaning. The results suggest the possible development of brexanolone as an adjunctive therapy for SRSE requiring pharmacological coma for seizure control. Ann Neurol 2017;82:342-352.

Sleep in the neurological intensive care unit: feasibility of quantifying sleep after melatonin supplementation with environmental light and noise reduction.

PURPOSE: Sleep deprivation may be particularly detrimental to intensive care unit (ICU) patients. Polysomnography has demonstrated abnormal sleep in medical and surgical ICU populations. Both environmental factors and circadian disruption have been implicated. We hypothesized that patients in a neurologic ICU would demonstrate similar sleep disturbances and that a combination of sleep-promoting interventions would increase sleep time. METHODS: Twelve patients were enrolled in this pilot-randomized, controlled, study in a neurologic ICU. For adult patients undergoing continuous EEG for clinical purposes, noise-cancelling headphones and eye masks were worn, and an oral dose of melatonin was administered for 3 days, or until EEG was stopped. Sleep was scored according to standard criteria; EEG was characterized and analyzed quantitatively. RESULTS: Sixty-five percent of the patients' recordings were unscorable based on accepted standardized criteria; therefore, sleep measures could not be compared. For those with sleep that could be scored, total sleep time was normal, although sleep was fragmented and time spent in slow-wave or rapid eye movement sleep was notably decreased. Patients with unscorable recordings had worse injury severity measures, absent or significantly slower posterior dominant rhythm, and less coherence of posterior faster frequencies. Clinical outcomes were similar between intervention and control groups. CONCLUSIONS: Although sleep-promoting interventions were feasible, sleep quantification based on currently accepted criteria limited the ability to score sleep. Similar to other ICUs, sleep in the neurologic ICU is abnormal; patients with unscorable sleep-like states have greater injury severity. This study was limited by strict enrollment criteria. A reliable method to quantify sleep and sleep-like states in the ICU is needed.

Free Fatty acids and delayed cerebral ischemia after subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: The purpose of this study was to understand factors related to increases in serum free fatty acid (FFA) levels and association with delayed cerebral ischemia (DCI) after subarachnoid hemorrhage. METHODS: We performed serial measurement of systemic oxygen consumption by indirect calorimetry and FFA levels by liquid chromatography/mass spectrometry in the first 14 days after ictus in 50 consecutive patients with subarachnoid hemorrhage. Multivariable generalized estimating equation models identified associations with FFA levels in the first 14 days after SAH and Cox proportional hazards model used to identified associations with time to DCI. RESULTS: There were 187 measurements in 50 patients with subarachnoid hemorrhage (mean age, 56±14 years old; 66% women) with a median Hunt-Hess score of 3. Adjusting for Hunt-Hess grade and daily caloric intake, n-6 and n-3 FFA levels were both associated with oxygen consumption and the modified Fisher score. Fourteen (28%) patients developed DCI on median postbleed Day 7. The modified Fisher score (P=0.01), mean n-6:n-3 FFA ratio (P=0.02), and mean oxygen consumption level (P=0.04) were higher in patients who developed DCI. In a Cox proportional hazards model, the mean n-6:n-3 FFA ratio (P<0.001), younger age (P=0.05), and modified Fisher scale (P=0.004) were associated with time to DCI. CONCLUSIONS: Injury severity and oxygen consumption hypermetabolism are associated with higher n-FFA levels and an increased n-6:n-3 FFA ratio is associated with DCI. This may indicate a role for interventions that modulate both oxygen consumption and FFA levels to reduce the occurrence of DCI.

High-dose intra-arterial verapamil for the treatment of cerebral vasospasm after subarachnoid hemorrhage: prolonged effects on hemodynamic parameters and brain metabolism.

BACKGROUND: Studies attempting to establish the safety and efficacy of standard and high-dose intra-arterial infusions of calcium channel blockers for treatment of cerebral vasospasm have focused on hemodynamic changes during the angiographic procedure. OBJECTIVE: To evaluate longer-term drug effects over the hours following infusion and the effects on brain tissue oxygen tension or cerebral metabolism. METHODS: We studied 11 patients with poor-grade aneurysmal subarachnoid hemorrhages who underwent multimodality brain monitoring and angiography with infusion of high-dose intra-arterial verapamil (≥15 mg total dose). Hourly intracerebral microdialysis measurements and continuously recorded mean arterial pressure (MAP), intracranial pressure (ICP), cerebral perfusion pressure (CPP), and Pbto2 were analyzed for 6 hours before and 12 hours following treatment. RESULTS: A median dose of 23 mg (range, 15-55 mg) of intra-arterial verapamil was given. Compared with baseline values, reductions in CPP and MAP were maximal at 3 hours postangiography (from 105 ± 13 mm Hg to 95 ± 15 mm Hg and from 116 ± 12 mm Hg to 106 ± 16 mm Hg, P < .01) and persisted for up to 6 hours (P < .04); increases in vasopressor therapy were required in 8 procedures (53%). ICP significantly increased during the first 3 hours post angiography (P < .03). Brain glucose increased by 33% by hour 9 (P < .001). There were no significant changes in Pbto2 or the lactate/pyruvate ratio. CONCLUSION: High-dose intra-arterial verapamil causes increases in ICP and reductions in CPP, followed by an increase in brain glucose levels, without altering brain oxygen tension or oxidative metabolism. Patients undergoing high-dose intra-arterial verapamil therapy warrant close hemodynamic and ICP monitoring for at least 12 hours following treatment.

Focal motor seizures induced by alerting stimuli in critically ill patients.

PURPOSE: We have previously demonstrated that it is common for alerting stimuli to induce electrographic seizures and other periodic or rhythmic patterns in the critically ill; however, only 1 of the first 33 patients we reported with this phenomenon had a detectable clinical correlate. METHODS: Review of charts and video EEG findings in critically ill patients in a neurological ICU at a tertiary care medical center in Manhattan. RESULTS: We identified nine patients who had focal motor seizures repeatedly induced by alerting stimuli. All patients were comatose, and 8/9 had nonconvulsive status epilepticus at some point during their acute illness. Imaging abnormalities involved bilateral thalami in three patients, upper brainstem in one, and the perirolandic region in five. DISCUSSION: We hypothesize that in encephalopathic patients, alerting stimuli activate the arousal circuitry, and, when combined with hyperexcitable cortex, result in epileptiform activity or seizures. This activity can be focal or generalized, and is usually nonconvulsive, as is true of seizures in general in the critically ill. However, when the cortex is hyperexcitable in a specific region only, focal EEG findings arise. If the electrographic seizure activity is adequately synchronized and involves motor pathways, this can present as focal motor seizures, as seen in these nine patients. Alerting can induce seizures in encephalopathic/comatose patients. The observation of clear focal clinical seizures removes the last remaining doubt that these stimulus-induced patterns are indeed seizures by any definition, not simply abnormal arousal patterns.