Spreading Depolarizations Suppress Hematoma Growth in Hyperacute Intracerebral Hemorrhage in Mice.

BACKGROUND: Spreading depolarizations (SDs) occur in all types of brain injury and may be associated with detrimental effects in ischemic stroke and subarachnoid hemorrhage. While rapid hematoma growth during intracerebral hemorrhage triggers SDs, their role in intracerebral hemorrhage is unknown. METHODS: We used intrinsic optical signal and laser speckle imaging, combined with electrocorticography, to investigate the effects of SD on hematoma growth during the hyperacute phase (0-4 hours) after intracortical collagenase injection in mice. Hematoma expansion, SDs, and cerebral blood flow were simultaneously monitored under normotensive and hypertensive conditions. RESULTS: Spontaneous SDs erupted from the vicinity of the hematoma during rapid hematoma growth. We found that hematoma growth slowed down by >60% immediately after an SD. This effect was even stronger in hypertensive animals with faster hematoma growth. To establish causation, we exogenously induced SDs (every 30 minutes) at a remote site by topical potassium chloride application and found reduced hematoma growth rate and final hemorrhage volume (18.2±5.8 versus 10.7±4.1 mm3). Analysis of cerebral blood flow using laser speckle flowmetry revealed that suppression of hematoma growth by spontaneous or induced SDs coincided and correlated with the characteristic oligemia in the wake of SD, implicating the vasoconstrictive effect of SD as one potential mechanism of action. CONCLUSIONS: Our findings reveal that SDs limit hematoma growth during the early hours of intracerebral hemorrhage and decrease final hematoma volume.

Optogenetic Spreading Depolarizations Do Not Worsen Acute Ischemic Stroke Outcome.

BACKGROUND: Spreading depolarizations (SDs) are believed to contribute to injury progression and worsen outcomes in focal cerebral ischemia because exogenously induced SDs have been associated with enlarged infarct volumes. However, previous studies used highly invasive methods to trigger SDs that can directly cause tissue injury (eg, topical KCl) and confound the interpretation. Here, we tested whether SDs indeed enlarge infarcts when induced via a novel, noninjurious method using optogenetics. METHODS: Using transgenic mice expressing channelrhodopsin-2 in neurons (Thy1-ChR2-YFP), we induced 8 optogenetic SDs to trigger SDs noninvasively at a remote cortical location in a noninjurious manner during 1-hour distal microvascular clip or proximal an endovascular filament occlusion of the middle cerebral artery. Laser speckle imaging was used to monitor cerebral blood flow. Infarct volumes were then quantified at 24 or 48 hours. RESULTS: Infarct volumes in the optogenetic SD arm did not differ from the control arm in either distal or proximal middle cerebral artery occlusion, despite a 6-fold and 4-fold higher number of SDs, respectively. Identical optogenetic illumination in wild-type mice did not affect the infarct volume. Full-field laser speckle imaging showed that optogenetic stimulation did not affect the perfusion in the peri-infarct cortex. CONCLUSIONS: Altogether, these data show that SDs induced noninvasively using optogenetics do not worsen tissue outcomes. Our findings compel a careful reexamination of the notion that SDs are causally linked to infarct expansion.

Dexmedetomidine and Other Analgosedatives Alter Pupil Characteristics in Critically Ill Patients.

In critically ill patients with neurologic disease, pupil examination abnormalities can signify evolving intracranial pathology. Analgesic and sedative medications (analgosedatives) target pupillary pathways, but it remains unknown how analgosedatives alter pupil findings in the clinical care setting. We assessed dexmedetomidine and other analgosedative associations with pupil reactivity and size in a heterogeneous cohort of critically ill patients with acute intracranial pathology. DESIGN: Retrospective cohort study. SETTING: Two neurologic ICUs between 2016 and 2018. PATIENTS: Critically ill adult patients with pupil measurements within 60 minutes of analgosedative administration. Patients with a history of intrinsic retinal pathology, extracranial injury, inaccessible brain imaging, or no Glasgow Coma Scale (GCS) data were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We used mixed-effects linear regression accounting for intrapatient correlations and adjusting for sex, age, GCS score, radiographic mass effect, medication confounders, and ambient light. We tested the association between an initiation or increased IV infusion of dexmedetomidine and pupil reactivity (Neurologic Pupil Index [NPi]) and resting pupil size (mm) obtained using NeurOptics NPi-200 (NeurOptics, Irvine, CA) pupillometer. Of our 221 patients with 9,897 pupil observations (median age, 60 [interquartile range, 50-68]; 59% male), 37 patients (166 pupil observations) were exposed to dexmedetomidine. Dexmedetomidine was associated with higher average NPi (ß = 0.18 per 1 unit increase in rank-normalized NPi ± 0.04; p < 0.001) and smaller pupil size (ß = -0.25 ± 0.05; p < 0.001). Exploratory analyses revealed that acetaminophen was associated with higher average NPi (ß = 0.04 ± 0.02; p = 0.02) and that most IV infusion analgosedatives including propofol, fentanyl, and midazolam were associated with smaller pupil size. CONCLUSIONS: Dexmedetomidine is associated with higher pupil reactivity (high NPi) and smaller pupil size in a cohort of critically ill patients with neurologic injury. Familiarity with expected pupil changes following analgosedative administration is important for accurate interpretation of pupil examination findings, facilitating optimal management of patients with acute intracranial pathology.

Rho-Kinase Inhibition Improves the Outcome of Focal Subcortical White Matter Lesions.

BACKGROUND: Subcortical white matter lesions are exceedingly common in cerebral small vessel disease and lead to significant cumulative disability without an available treatment. Here, we tested a rho-kinase inhibitor on functional recovery after focal white matter injury. METHODS: A focal corpus callosum lesion was induced by stereotactic injection of N5-(1-iminoethyl)-L-ornithine in mice. Fasudil (10 mg/kg) or vehicle was administered daily for 2 weeks, starting one day after lesion induction. Resting-state functional connectivity and grid walk performance were studied longitudinally, and lesion volumes were determined at one month. RESULTS: Resting-state interhemispheric functional connectivity significantly recovered between days 1 and 14 in the fasudil group (P<0.001), despite worse initial connectivity loss than vehicle before treatment onset. Grid walk test revealed an increased number of foot faults in the vehicle group compared with baseline, which persisted for at least 4 weeks. In contrast, the fasudil arm did not show an increase in foot faults and had smaller lesions at 4 weeks. Immunohistochemical examination of reactive astrocytosis, synaptic density, and mature oligodendrocytes did not reveal a significant difference between treatment arms. CONCLUSIONS: These data show that delayed fasudil posttreatment improves functional outcomes after a focal subcortical white matter lesion in mice. Future work will aim to elucidate the mechanisms.

Cortical Spreading Depolarization, Blood Flow, and Cognitive Outcomes in a Closed Head Injury Mouse Model of Traumatic Brain Injury.

BACKGROUND: Cortical spreading depolarizations (CSDs) are associated with worse outcomes in many forms of acute brain injury, including traumatic brain injury (TBI). Animal models could be helpful in developing new therapies or biomarkers to improve outcomes in survivors of TBI. Recently, investigators have observed CSDs in murine models of mild closed head injury (CHI). We designed the currently study to determine additional experimental conditions under which CSDs can be observed, from mild to relatively more severe TBI. METHODS: Adult male C57Bl/6J mice (8-14 weeks old) were anesthetized with isoflurane and subjected to CHI with an 81-g weight drop from 152 or 183 cm. CSDs were detected with minimally invasive visible light optical intrinsic signal imaging. Cerebral blood flow index (CBFi) was measured in the 152-cm drop height cohort using diffuse correlation spectroscopy at baseline before and 4 min after CHI. Cognitive outcomes were assessed at 152- and 183-cm drop heights for the Morris water maze hidden platform, probe, and visible platform tests. RESULTS: CSDs occurred in 43% (n = 12 of 28) of 152-cm and 58% (n = 15 of 26) of 183-cm drop height CHI mice (p = 0.28). A lower baseline preinjury CBFi was associated with development of CSDs in CHI mice (1.50 ± 0.07 × 10-7 CHI without CSD [CSD-] vs. 1.17 ± 0.04 × 10-7 CHI with CSD [CSD+], p = 0.0001). Furthermore, in CHI mice that developed CSDs, the ratio of post-CHI to pre-CHI CBFi was lower in the hemisphere ipsilateral to a CSD compared with non-CSD hemispheres (0.19 ± 0.07 less in the CSD hemisphere, p = 0.028). At a 152-cm drop height, there were no detectable differences between sham injured (n = 10), CHI CSD+ (n = 12), and CHI CSD- (n = 16) mice on Morris water maze testing at 4 weeks. At a 183-cm drop height, CHI CSD+ mice had worse performance on the hidden platform test at 1-2 weeks versus sham mice (n = 15 CHI CSD+, n = 9 sham, p = 0.045), but there was no appreciable differences compared with CHI CSD- mice (n = 11 CHI CSD-). CONCLUSIONS: The data suggest that a lower baseline cerebral blood flow prior to injury may contribute to the occurrence of a CSD. Furthermore, a CSD at the time of injury can be associated with worse cognitive outcome under the appropriate experimental conditions in a mouse CHI model of TBI.

CADASIL mutations sensitize the brain to ischemia via spreading depolarizations and abnormal extracellular potassium homeostasis.

Cerebral autosomal dominant arteriopathy, subcortical infarcts, and leukoencephalopathy (CADASIL) is the most common monogenic form of small vessel disease characterized by migraine with aura, leukoaraiosis, strokes, and dementia. CADASIL mutations cause cerebrovascular dysfunction in both animal models and humans. Here, we showed that 2 different human CADASIL mutations (Notch3 R90C or R169C) worsen ischemic stroke outcomes in transgenic mice; this was explained by the higher blood flow threshold to maintain tissue viability compared with that in wild type (WT) mice. Both mutants developed larger infarcts and worse neurological deficits compared with WT mice, regardless of age or sex after filament middle cerebral artery occlusion. However, full-field laser speckle flowmetry during distal middle cerebral artery occlusion showed comparable perfusion deficits in mutants and their respective WT controls. Circle of Willis anatomy and pial collateralization also did not differ among the genotypes. In contrast, mutants had a higher cerebral blood flow threshold, below which infarction ensued, suggesting increased sensitivity of brain tissue to ischemia. Electrophysiological recordings revealed a 1.5- to 2-fold higher frequency of peri-infarct spreading depolarizations in CADASIL mutants. Higher extracellular K+ elevations during spreading depolarizations in the mutants implicated a defect in extracellular K+ clearance. Altogether, these data reveal a mechanism of enhanced vulnerability to ischemic injury linked to abnormal extracellular ion homeostasis and susceptibility to ischemic depolarizations in CADASIL.

Cortical Spreading Depolarizations in a Mouse Model of Subarachnoid Hemorrhage.

BACKGROUND: Cortical spreading depolarizations (CSDs) are associated with worse outcomes in patients with aneurysmal subarachnoid hemorrhage (SAH). Animal models are required to assess whether CSDs can worsen outcomes or are an epiphenomenon; however, little is known about the presence of CSDs in existing animal models. Therefore, we designed a study to determine whether CSDs occur in a mouse model of SAH. METHODS: A total of 36 mice were included in the study. We used the anterior prechiasmatic injection model of SAH under isoflurane anesthesia. A needle was inserted through the mouse olfactory bulb with the point terminating at the base of the skull, and arterial blood or saline (100 µl) was injected over 10 s. Changes in cerebral blood volume over the entire dorsal cortical surface were assessed with optical intrinsic signal imaging for 5 min following needle insertion. RESULTS: CSDs occurred in 100% of mice in the hemisphere ipsilateral to olfactory bulb needle insertion (CSD1). Saline-injected mice had 100% survival (n = 10). Blood-injected mice had 88% survival (n = 23 of 26). A second, delayed, CSD ipsilateral to CSD1 occurred in 31% of blood-injected mice. An increase in the time interval between CSD1 and blood injection was associated with the occurrence of a second CSD in blood-injected mice (mean intervals 26.4 vs. 72.7 s, p < 0.0001, n = 18 and 8). We observed one blood-injected animal with a second CSD in the contralateral hemisphere and observed terminal CSDs in mice that died following SAH injection. CONCLUSIONS: The prechiasmatic injection model of SAH includes CSDs that occur at the time of needle insertion. The occurrence of subsequent CSDs depends on the timing between CSD1 and blood injection. The mouse prechiasmatic injection model could be considered an SAH plus CSD model of the disease. Further work is needed to determine the effect of multiple CSDs on outcomes following SAH.

Cortical Spreading Depolarizations and Clinically Measured Scalp EEG Activity After Aneurysmal Subarachnoid Hemorrhage and Traumatic Brain Injury.

BACKGROUND: Spreading depolarizations (SDs) are associated with worse outcome following subarachnoid hemorrhage (SAH) and traumatic brain injury (TBI), but gold standard detection requires electrocorticography with a subdural strip electrode. Electroencephalography (EEG) ictal-interictal continuum abnormalities are associated with poor outcomes after TBI and with both delayed cerebral ischemia (DCI) and poor outcomes after SAH. We examined rates of SD detection in patients with SAH and TBI with intraparenchymal and subdural strip electrodes and assessed which continuous EEG (cEEG) measures were associated with intracranially quantified SDs. METHODS: In this single-center cohort, we included patients with SAH and TBI undergoing ≥ 24 h of interpretable intracranial monitoring via eight-contact intraparenchymal or six-contact subdural strip platinum electrodes or both. SDs were rated according to established consensus criteria and compared with cEEG findings rated according to the American Clinical Neurophysiology Society critical care EEG monitoring consensus criteria: lateralized rhythmic delta activity, generalized rhythmic delta activity, lateralized periodic discharges, generalized periodic discharges, any ictal-interictal continuum, or a composite scalp EEG tool for seizure risk estimation: the 2HELPS2B score. Among patients with SAH, cEEG was assessed for validated DCI biomarkers: new or worsening epileptiform abnormalities and new background deterioration. RESULTS: Over 6 years, SDs were recorded in 5 (18%) of 28 patients recorded with intraparenchymal electrodes and 4 (40%) of 10 patients recorded with subdural strip electrodes. There was no significant association between occurrence of SDs and day 1 cEEG findings (American Clinical Neurophysiology Society main terms lateralized periodic discharges, generalized periodic discharges, lateralized rhythmic delta activity, or seizures, individually or in combination). After SAH, established cEEG DCI predictors were not associated with SDs. CONCLUSIONS: Intraparenchymal recordings yielded low rates of SD, and documented SDs were not associated with ictal-interictal continuum abnormalities or other cEEG DCI predictors. Identifying scalp EEG correlates of SD may require training computational EEG analytics and use of gold standard subdural strip electrocorticography recordings.

Association of External Ventricular Drain Wean Strategy with Shunt Placement and Length of Stay in Subarachnoid Hemorrhage: A Prospective Multicenter Study.

BACKGROUND: Survivors of aneurysmal subarachnoid hemorrhage (SAH) face a protracted intensive care unit (ICU) course and are at risk for developing refractory hydrocephalus with the need for a permanent ventriculoperitoneal shunt (VPS). Management of the external ventricular drain (EVD) used to provide temporary cerebrospinal fluid diversion may influence the need for a VPS, ICU length of stay (LOS), and drain complications, but the optimal EVD management approach is unknown. Therefore, we sought to determine the effect of EVD discontinuation strategy on VPS rate. METHODS: This was a prospective multicenter observational study at six neurocritical care units in the United States. The target population included adults with suspected aneurysmal SAH who required an EVD. Patients were preassigned to rapid or gradual EVD weans based on their treating center. The primary outcome was the rate of VPS placement. Secondary outcomes were EVD duration, ICU LOS, hospital LOS, and drain complications. RESULTS: A rapid EVD wean protocol was associated with a lower rate of VPS placement, including a delayed posthospitalization shunt, in an adjusted Cox proportional analysis (hazard ratio 0.52 [p = 0.041]) and adjusted logistic regression model (odds ratio 0.43 [95% confidence interval 0.18-1.03], p = 0.057). A rapid wean was also associated with 2.1 fewer EVD days (p = 0.007) and saved an estimated 2.5 ICU days (p = 0.049), as compared with a gradual wean protocol. There were fewer nonfunctioning EVDs in the rapid group (odds ratio 0.32 [95% confidence interval 0.11-0.92]). Furthermore, we found that the time to first wean and the number of weaning attempts were important independent covariates that affected the likelihood of receiving a VPS and the duration of ICU admission. CONCLUSIONS: A rapid EVD wean was associated with decreased rates of VPS placement, decreased ICU LOS, and decreased drain complications in survivors of aneurysmal SAH. These findings suggest that a randomized multicentered controlled study comparing rapid vs. gradual EVD weaning protocols is justified.

Focal Subcortical White Matter Lesions Disrupt Resting State Cortical Interhemispheric Functional Connectivity in Mice.

The corpus callosum is the largest white matter tract and critical for interhemispheric connectivity. Unfortunately, neurocognitive deficits after experimental white matter lesions are subtle and variable, limiting their translational utility. We examined resting state functional connectivity (RSFC) as a surrogate after a focal lesion in the lateral corpus callosum induced by stereotaxic injection of L-NIO in mice. RSFC was performed via optical intrinsic signal imaging through intact skull before and on days 1 and 14 after injection, using interhemispheric homotopic and seed-based temporal correlation maps. We measured the lesion volumes at 1 month in the same cohort. L-NIO induced focal lesions in the corpus callosum. Interhemispheric homotopic connectivity decreased by up to 50% 24 h after L-NIO, partially sparing the visual cortex. All seeds showed loss of connectivity to the contralateral hemisphere. Moreover, ipsilesional motor and visual cortices lost connectivity within the same hemisphere. Sham-operated mice did not show any lesion or connectivity changes. RSFC imaging reliably detects acute disruption of long interhemispheric and intrahemispheric connectivity after a corpus callosum lesion in mice. This noninvasive method can be a functional surrogate to complement neurocognitive testing in both therapeutic and recovery studies after white matter injury.

Blunt and Penetrating Severe Traumatic Brain Injury.

Severe traumatic brain injury is a common problem. Current practices focus on the importance of early resuscitation, transfer to high-volume centers, and provider expertise across multiple specialties. In the emergency department, patients should receive urgent intracranial imaging and consideration for tranexamic acid. Close observation in the intensive care unit environment helps identify problems, such as seizure, intracranial pressure crisis, and injury progression. In addition to traditional neurologic examination, patients benefit from use of intracranial monitors. Monitors gather physiologic data on intracranial and cerebral perfusion pressures to help guide therapy. Brain tissue oxygenation monitoring and cerebromicrodialysis show promise in studies.

Aneurysmal Subarachnoid Hemorrhage.

Aneurysmal subarachnoid hemorrhage is a neurologic emergency that requires immediate patient stabilization and prompt diagnosis and treatment. Early measures should focus on principles of advanced cardiovascular life support. The aneurysm should be evaluated and treated in a comprehensive stroke center by a multidisciplinary team capable of endovascular and, operative approaches. Once the aneurysm is secured, the patient is best managed by a dedicated neurocritical care service to prevent and manage complications, including a syndrome of delayed neurologic decline. The goal of such specialized care is to prevent secondary injury, reduce length of stay, and improve outcomes for survivors of the disease.

Spreading depression as an innate antiseizure mechanism.

Spreading depression (SD) is an intense and prolonged depolarization in the central nervous systems from insect to man. It is implicated in neurological disorders such as migraine and brain injury. Here, using an in vivo mouse model of focal neocortical seizures, we show that SD may be a fundamental defense against seizures. Seizures induced by topical 4-aminopyridine, penicillin or bicuculline, or systemic kainic acid, culminated in SDs at a variable rate. Greater seizure power and area of recruitment predicted SD. Once triggered, SD immediately suppressed the seizure. Optogenetic or KCl-induced SDs had similar antiseizure effect sustained for more than 30 min. Conversely, pharmacologically inhibiting SD occurrence during a focal seizure facilitated seizure generalization. Altogether, our data indicate that seizures trigger SD, which then terminates the seizure and prevents its generalization.

Hydrophilic polymer embolization following flow diversion of cerebral aneurysms.

Foreign body embolization is a rare and potentially under-recognized complication of neuroendovascular procedures. This complication should be considered in the differential diagnosis for clinical or radiological deterioration following neurovascular interventions. We report a case of foreign body hydrophilic coating embolization that occurred following an attempted flow diversion of an intracranial aneurysm with dramatic flare-up after repeat exposure. We also provide a literature review of all reported cases of hydrophilic polymer embolization following flow diversion procedures.

Treatment of Subarachnoid Hemorrhage-associated Delayed Cerebral Ischemia With Milrinone: A Review and Proposal.

Delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage continues to be associated with high levels of morbidity and mortality. This complication had long been thought to occur secondary to severe cerebral vasospasm, but expert opinion now favors a multifactorial etiology, opening the possibility of new therapies. To date, no definitive treatment option for DCI has been recommended as standard of care, highlighting a need for further research into potential therapies. Milrinone has been identified as a promising therapeutic agent for DCI, possessing a mechanism of action for the reversal of cerebral vasospasm as well as potentially anti-inflammatory effects to treat the underlying etiology of DCI. Intra-arterial and intravenous administration of milrinone has been evaluated for the treatment of DCI in single-center case series and cohorts and appears safe and associated with improved clinical outcomes. Recent results have also brought attention to the potential outcome benefits of early, more aggressive dosing and titration of milrinone. Limitations exist within the available data, however, and questions remain about the generalizability of results across a broader spectrum of patients suffering from DCI. The development of a standardized protocol for milrinone use in DCI, specifically addressing areas requiring further clarification, is needed. Data generated from a standardized protocol may provide the impetus for a multicenter, randomized control trial. We review the current literature on milrinone for the treatment of DCI and propose a preliminary standardized protocol for further evaluation of both safety and efficacy of milrinone.

Subarachnoid hemorrhage leads to early and persistent functional connectivity and behavioral changes in mice.

Aneurysmal subarachnoid hemorrhage (SAH) leads to significant long-term cognitive deficits, which can be associated with alterations in resting state functional connectivity (RSFC). However, modalities such as fMRI-which is commonly used to assess RSFC in humans-have practical limitations in small animals. Therefore, we used non-invasive optical intrinsic signal imaging to determine the effect of SAH on RSFC in mice up to three months after prechiasmatic blood injection. We assessed Morris water maze (MWM), open field test (OFT), Y-maze, and rotarod performance from approximately two weeks to three months after SAH. Compared to sham, we found that SAH reduced motor, retrosplenial, and visual seed-based connectivity indices. These deficits persisted in retrosplenial and visual cortex seeds at three months. Seed-to-seed analysis confirmed early attenuation of correlation coefficients in SAH mice, which persisted in predominantly posterior network connections at later time points. Seed-independent global and interhemispheric indices of connectivity revealed decreased correlations following SAH for at least one month. SAH led to MWM hidden platform and OFT deficits at two weeks, and Y-maze deficits for at least three months, without altering rotarod performance. In conclusion, experimental SAH leads to early and persistent alterations both in hemodynamically derived measures of RSFC and in cognitive performance.

Rapid hematoma growth triggers spreading depolarizations in experimental intracortical hemorrhage.

Recurrent waves of spreading depolarization (SD) occur in brain injury and are thought to affect outcomes. What triggers SD in intracerebral hemorrhage is poorly understood. We employed intrinsic optical signaling, laser speckle flowmetry, and electrocorticography to elucidate the mechanisms triggering SD in a collagenase model of intracortical hemorrhage in mice. Hematoma growth, SD occurrence, and cortical blood flow changes were tracked. During early hemorrhage (0-4 h), 17 out of 38 mice developed SDs, which always originated from the hematoma. No SD was detected at late time points (8-52 h). Neither hematoma size, nor peri-hematoma perfusion were associated with SD occurrence. Further, arguing against ischemia as a trigger factor, normobaric hyperoxia did not inhibit SD occurrence. Instead, SDs always occurred during periods of rapid hematoma growth, which was two-fold faster immediately preceding an SD compared with the peak growth rates in animals that did not develop any SDs. Induced hypertension accelerated hematoma growth and resulted in a four-fold increase in SD occurrence compared with normotensive animals. Altogether, our data suggest that spontaneous SDs in this intracortical hemorrhage model are triggered by the mechanical distortion of tissue by rapidly growing hematomas.

Optogenetic Spreading Depression Elicits Trigeminal Pain and Anxiety Behavior.

OBJECTIVE: Cortical spreading depression (SD) is an intense depolarization underlying migraine aura. Despite the weight of evidence linking SD to the pain phase of migraine, controversy remains over a causal role of SD in cephalgia because of the invasive nature of previous SD induction methods. To overcome this problem, we used a novel minimally invasive optogenetic SD induction method and examined the effect of SD on behavior. METHODS: Optogenetic SD was induced as a single event or repeatedly every other day for 2 weeks. End points, including periorbital and hindpaw mechanical allodynia, mouse grimace, anxiety, and working memory, were examined in male and female mice. RESULTS: A single SD produced bilateral periorbital mechanical allodynia that developed within 1 hour and resolved within 2 days. Sumatriptan prevented periorbital allodynia when administered immediately after SD. Repeated SDs also produced bilateral periorbital allodynia that lasted 4 days and resolved within 2 weeks after the last SD. In contrast, the hindpaw withdrawal thresholds did not change after repeated SDs suggesting that SD-induced allodynia was limited to the trigeminal region. Moreover, repeated SDs increased mouse grimace scores 2 days after the last SD, whereas a single SD did not. Repeated SDs also increased thigmotaxis scores as a measure of anxiety. In contrast, neither single nor repeated SDs affected visuospatial working memory. We did not detect sexual dimorphism in any end point. INTERPRETATION: Altogether, these data show a clinically congruent causal relationship among SD, trigeminal pain, and anxiety behavior, possibly reflecting SD modulation of hypothalamic, thalamic, and limbic mechanisms. ANN NEUROL 2021;89:99-110.

Posterior Reversible Encephalopathy Syndrome in Patients with Coronavirus Disease 2019: Two Cases and A Review of The Literature.

INTRODUCTION: Encephalopathy is a common complication of coronavirus disease 2019. Although the encephalopathy is idiopathic in many cases, there are several published reports of patients with posterior reversible encephalopathy syndrome in the setting of coronavirus disease 2019. OBJECTIVE: To describe the diverse presentations, risk factors, and outcomes of posterior reversible encephalopathy syndrome in patients with coronavirus disease 2019. METHODS: We assessed patients with coronavirus disease 2019 and a diagnosis of posterior reversible encephalopathy syndrome at our institution from April 1 to June 24, 2020. We performed a literature search to capture all known published cases of posterior reversible encephalopathy syndrome in patients with coronavirus disease 2019. RESULTS: There were 2 cases of posterior reversible encephalopathy syndrome in the setting of coronavirus 2019 at our institution during a 3-month period. One patient was treated with anakinra, an interleukin-1 inhibitor that may disrupt endothelial function. The second patient had an underlying human immunodeficiency virus infection. We found 13 total cases in our literature search, which reported modest blood pressure fluctuations and a range of risk factors for posterior reversible encephalopathy syndrome. One patient was treated with tocilizumab, an interleukin-6 inhibitor that may have effects on endothelial function. All patients had an improvement in their neurological symptoms. Interval imaging, when available, showed radiographic improvement of brain lesions. CONCLUSIONS: Risk factors for posterior reversible encephalopathy syndrome in patients with coronavirus disease 2019 may include underlying infection or immunomodulatory agents with endothelial effects in conjunction with modest blood pressure fluctuations. We found that the neurological prognosis for posterior reversible encephalopathy syndrome in the setting of coronavirus disease 2019 infection is favorable. Recognition of posterior reversible encephalopathy syndrome in this patient population is critical for prognostication and initiation of treatment, which may include cessation of potential offending agents and tight blood pressure control.