Progressive arteriopathy with vasospasm in focal cerebral arteriopathy in childhood: a case report.

BACKGROUND: Focal cerebral arteriopathy (FCA) is a clinically important disease that often causes progressive arteriopathy. We report a case of FCA with progressive arteriopathy due to arterial shrinkage of the outer diameter found on T2-weighted three-dimensional sampling perfection with application optimized contrasts using different flip angle evolutions (3D-SPACE) imaging. CASE PRESENTATION: The patient was a 9-year-old girl who developed right hemiparesis. Acute infarction was detected in the basal ganglia. Vascular images revealed stenosis from the distal internal carotid artery (ICA) to the middle cerebral artery (MCA). Intravenous heparin was administered for 8 days, and the symptoms improved. However, 29 days after onset, right hemiparesis transiently developed again and magnetic resonance angiography (MRA) showed progressive stenosis from the ICA to MCA, while 3D-SPACE showed similar shrinkage of the outer diameter. Aspirin was started, and there was no subsequent recurrence. After 12 months, MRA and 3D-SPACE showed improvement of stenosis and arterial shrinkage. CONCLUSIONS: Given the time course, the change in the outer diameter was thought to be vasospasm. Thus, vasospasm may be one of the causes of progressive arteriopathy in FCA.

Suppressive effects of a transient receptor potential melastatin 8 (TRPM8) agonist on hyperthermia-induced febrile seizures in infant mice.

Background: Febrile seizures (FSs) are the most frequent type of seizures in infancy and childhood. Epileptiform discharges (EDs) on electroencephalogram at the time of first FS recurrence can increase the risk of epilepsy development. Therefore, inhibition of EDs is important. Recently, WS-3, a transient receptor potential melastatin 8 (TRPM8) agonist, reportedly suppressed penicillin G-induced cortical-focal EDs. However, the effects of TRPM8 agonists on FSs remain unknown. In this study, we aimed to clarify the effects of the TRPM8 agonist, and the absence of TRPM8 channels, on hyperthermia-induced FS by analyzing the fast ripple band. Methods: Hyperthermia (43°C for 30 min) induced by a heating pad caused FSs in postnatal day 7 wild-type (WT) and TRPM8 knockout (TRPM8KO) mice. FSs were defined as EDs occurring during behavioral seizures involving hindlimb clonus and loss of the righting reflex. Mice were injected with 1% dimethyl sulfoxide or 1 mM WS-3 20 min before the onset of hyperthermia, and electroencephalograms; movies; and rectal, brain and heating pad temperatures were recorded. Results: In wild-type mice, WS-3 reduced the fast ripple amplitude in the first FS without changing rectal and brain temperature thresholds. In contrast, the anti-FS effect induced by the TRPM8 agonist was not observed in TRPM8KO mice and, compared with wild-type mice, TRPM8 deficiency lowered the rectal and brain temperature thresholds for FSs, exacerbated the fast ripple amplitude, and prolonged the duration of the initial FS induced by hyperthermia. Conclusion: Our findings suggest that TRPM8 agonists can be used to treat hyperthermia-induced FSs.

Cross-tissue correlations of genome-wide DNA methylation in Japanese live human brain and blood, saliva, and buccal epithelial tissues.

Neuroepigenetics considers genetic sequences and the interplay with environmental influences to elucidate vulnerability risk for various neurological and psychiatric disorders. However, evaluating DNA methylation of brain tissue is challenging owing to the issue of tissue specificity. Consequently, peripheral surrogate tissues were used, resulting in limited progress compared with other epigenetic studies, such as cancer research. Therefore, we developed databases to establish correlations between the brain and peripheral tissues in the same individuals. Four tissues, resected brain tissue, blood, saliva, and buccal mucosa (buccal), were collected from 19 patients (aged 13-73 years) who underwent neurosurgery. Moreover, their genome-wide DNA methylation was assessed using the Infinium HumanMethylationEPIC BeadChip arrays to determine the cross-tissue correlation of each combination. These correlation analyses were conducted with all methylation sites and with variable CpGs, and with when these were adjusted for cellular proportions. For the averaged data for each CpG across individuals, the saliva-brain correlation (r = 0.90) was higher than that for blood-brain (r = 0.87) and buccal-brain (r = 0.88) comparisons. Among individual CpGs, blood had the highest proportion of CpGs correlated to the brain at nominally significant levels (19.0%), followed by saliva (14.4%) and buccal (9.8%). These results were similar to the previous IMAGE-CpG results; however, cross-database correlations of the correlation coefficients revealed a relatively low (brain vs. blood: r = 0.27, saliva: r = 0.18, and buccal: r = 0.24). To the best of our knowledge, this is the fifth study in the literature initiating the development of databases for correlations between the brain and peripheral tissues in the same individuals. We present the first database developed from an Asian population, specifically Japanese samples (AMAZE-CpG), which would contribute to interpreting individual epigenetic study results from various Asian populations.

Outcome prediction of pediatric moyamoya disease using midterm cerebral blood flow measured between staged anastomoses.

PURPOSE: Cognitive outcomes of pediatric moyamoya disease are variable and difficult to predict on the basis of initial neurological signs and examinations. To determine the best early time point for outcome prediction, we retrospectively analyzed the correlation between cognitive outcomes and the cerebrovascular reserve capacity (CRC) measured before, between, and after staged bilateral anastomoses. METHODS: Twenty-two patients aged 4-15 years were included in this study. CRC was measured before the first hemispheric surgery (preoperative CRC), 1 year after the first surgery (midterm CRC), and 1 year after the surgery on the other side (final CRC). The cognitive outcome was the Pediatric Cerebral Performance Category Scale (PCPCS) grade more than 2 years after the final surgery. RESULTS: The 17 patients with favorable outcomes (PCPCS grades 1 or 2) showed a preoperative CRC of 4.9% ± 11.2%, which was not better than that of the five patients with unfavorable outcomes (grade 3; 0.3% ± 8.5%, p = 0.5). The 17 patients with favorable outcomes showed a midterm CRC of 23.8% ± 15.3%, which was significantly better than that of the five patients with unfavorable outcomes (-2.5% ± 12.1%, p = 0.004). The difference was much more significant for the final CRC, which was 24.8% ± 13.1% in the patients with favorable outcomes and -11.3% ± 6.7% in those with unfavorable outcomes (p = 0.00004). CONCLUSION: Cognitive outcomes were first clearly discriminated by the CRC after the first-side unilateral anastomosis, which is the optimal early timing for the prediction of individual prognosis.

Endoscopically observed outer membrane of chronic subdural hematoma after endovascular embolization of middle meningeal artery.

Background: Embolization of the middle meningeal artery (MMA) has been established for chronic subdural hematoma (CSDH). Neuroendoscopic observation of the outer membrane of the hematoma was carried out after embolization. The treatment mechanism of embolization is discussed, focusing on the vasculature and inflammation of the membrane. Methods: Four patients with recurrent CSDH were included in this study. The MMA was embolized using Embosphere® particles in three patients. The outer membrane was observed with normal and narrow band images (NBIs). Results: The net-like vessels were not obstructed in the whole area of the outer membrane, but in a patchy fashion of embolized areas surrounded by nonembolized areas. In two patients, the nonembolized areas showed a hemorrhagic inflammatory red color. Histopathological examination confirmed hypertrophic dura with leukocyte infiltration. Dilated dural arteries and proliferated sinusoid arteries were located in the deep and superficial border cell layers. These arteries were visualized as green and brown on NBI, respectively. In the embolized area, the red membrane turned pink, indicating ischemia and subsiding inflammatory hyperemia. In the third patient, the outer membrane was white in both the nonembolized and embolized areas in endoscopic view, and the net-like vessels were sparse in both endoscopy and histology, indicating a scar inflammatory phase. The membrane transition was not observed in the patient that did not undergo embolization. Conclusion: Endoscopic observation revealed that embolization of the MMA blocked both the dural and sinusoidal arteries. Ischemic transformation causing the suppression of inflammation of the outer membrane is a suggested mechanism of MMA embolization.

Epileptic seizure-related changes in electrocorticogram, cortical temperature, and cerebral hemodynamics obtained via an implantable multimodal multichannel probe during preoperative monitoring: illustrative case.

BACKGROUND: Electrocorticography (EcoG) plays an essential role in the preoperative evaluation of epilepsy, despite its high invasiveness. Brain temperature and cerebral hemodynamics also reflect brain activity. This study examined whether a multimodal multichannel probe that simultaneously records EcoG, cortical temperature, and cerebral hemodynamics can contribute to improving the assessment of epileptic seizures. After preoperative monitoring was performed in a patient with epilepsy, three generalized seizures and two focal seizures were observed. OBSERVATIONS: A short-term power increase in the alternating current spectrogram, high-amplitude slow waves in direct current potential, an increase in cortical temperature, an increase in oxyhemoglobin (HbO2) concentration and total hemoglobin (HbT) concentration, and a decrease in deoxyhemoglobin (HHb) concentration, followed by a decrease in HbO2 and HbT concentrations and an increase in HHb concentration, were observed in generalized seizures. However, no changes in these pathophysiological signals were observed in focal seizures. LESSONS: Seizure-related changes regarding generalized seizures were consistent with the results of previous studies. The results of generalized and focal seizures indicate that epileptic brain activity propagated from the epileptic focus in the right frontal lobe to the measurement area near the motor cortex in generalized seizures but not in focal seizures.

Intracranial pressure spikes trigger spreading depolarizations.

Spreading depolarizations are highly prevalent and spatiotemporally punctuated events worsening the outcome of brain injury. Trigger factors are poorly understood but may be linked to sudden worsening in supply-demand mismatch in compromised tissue. Sustained or transient elevations in intracranial pressure are also prevalent in the injured brain. Here, using a mouse model of large hemispheric ischaemic stroke, we show that mild and brief intracranial pressure elevations (20 or 30 mmHg for just 3 min) potently trigger spreading depolarizations in ischaemic penumbra (4-fold increase in spreading depolarization occurrence). We also show that 30 mmHg intracranial pressure spikes as brief as 30 s are equally effective. In contrast, sustained intracranial pressure elevations to the same level for 30 min do not significantly increase the spreading depolarization rate, suggesting that an abrupt disturbance in the steady state equilibrium is required to trigger a spreading depolarization. Laser speckle flowmetry consistently showed a reduction in tissue perfusion, and two-photon pO2 microscopy revealed a drop in venous pO2 during the intracranial pressure spikes suggesting increased oxygen extraction fraction, and therefore, worsening supply-demand mismatch. These haemodynamic changes during intracranial pressure spikes were associated with highly reproducible increases in extracellular potassium levels in penumbra. Consistent with the experimental data, a higher rate of intracranial pressure spikes was associated with spreading depolarization clusters in a retrospective series of patients with aneurysmal subarachnoid haemorrhage with strong temporal correspondence. Altogether, our data show that intracranial pressure spikes, even when mild and brief, are capable of triggering spreading depolarizations. Aggressive prevention of intracranial pressure spikes may help reduce spreading depolarization occurrence and improve outcomes after brain injury.

Suppressive Effects of Transient Receptor Potential Melastatin 8 Agonist on Epileptiform Discharges and Epileptic Seizures.

Epilepsy is a relatively common condition, but more than 30% of patients have refractory epilepsy that is inadequately controlled by or is resistant to multiple drug treatments. Thus, new antiepileptic drugs based on newly identified mechanisms are required. A previous report revealed the suppressive effects of transient receptor potential melastatin 8 (TRPM8) activation on penicillin G-induced epileptiform discharges (EDs). However, it is unclear whether TRPM8 agonists suppress epileptic seizures or affect EDs or epileptic seizures in TRPM8 knockout (TRPM8KO) mice. We investigated the effects of TRPM8 agonist and lack of TRPM8 channels on EDs and epileptic seizures. Mice were injected with TRPM8 agonist 90 min after or 30 min before epilepsy-inducer injection, and electrocorticograms (ECoGs) were recorded under anesthesia, while behavior was monitored when awake. TRPM8 agonist suppressed EDs and epileptic seizures in wildtype (WT) mice, but not in TRPM8KO mice. In addition, TRPM8KO mice had a shorter firing latency of EDs, and EDs and epileptic seizures were deteriorated by the epilepsy inducer compared with those in WT mice, with the EDs being more easily propagated to the contralateral side. These findings suggest that TRPM8 activation in epileptic regions has anti-epileptic effects.

Association Between Spreading Depolarization and Delayed Cerebral Ischemia After Subarachnoid Hemorrhage: Post Hoc Analysis of a Randomized Trial of the Effect of Cilostazol on Delayed Cerebral Ischemia.

BACKGROUND: Delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (SAH) remains an important problem with a complex pathophysiology. We used data from a single-center randomized trial to assess the effect of a phosphodiesterase inhibitor, cilostazol, in patients with aneurysmal SAH to explore the relationships of DCI with vasospasm, spreading depolarization (SD) and microcirculatory disturbance. METHODS: A post hoc analysis of a single-center, prospective, randomized trial of the effect of cilostazol on DCI and SD after aneurysmal SAH was performed. From all randomized cohorts, patients who underwent both SD monitoring and digital subtraction angiography (DSA) on day 9 ± 2 from onset were included. Cerebral circulation time (CCT), which was divided into proximal CCT and peripheral CCT (as a measure of microcirculatory disturbance), was obtained from DSA. Logistic regression was conducted to determine factors associated with DCI. RESULTS: Complete data were available for 28 of 50 patients. Of the 28 patients, 8 (28.5%) had DCI during the study period. Multivariate analysis indicated a strong association between the number of SDs on the day DSA was performed (i.e., a delayed time point after SAH onset) and DCI (odds ratio 2.064, 95% confidence interval 1.045-4.075, P = 0.037, area under the curve 0.836), whereas the degree of angiographic vasospasm and peripheral CCT were not significant factors for DCI. CONCLUSIONS: There is a strong association between SD and DCI. Our results suggest that SD is an important therapeutic target and a potentially useful biomarker for DCI.

Necessity for craniospinal irradiation of germinoma with positive cytology without spinal lesion on MR imaging-A controversy.

BACKGROUND: Cerebrospinal fluid (CSF) cytology and spinal MR imaging are routinely performed for staging before treatment of intracranial germinoma. However, the interpretation of the results of CSF cytology poses 2 unresolved clinical questions: (1) Does positive CSF cytology correlate with the presence of spinal lesion before treatment? and (2) Is craniospinal irradiation (CSI) necessary for patients with positive CSF cytology in the absence of spinal lesion? METHODS: Multicenter retrospective analyses were performed based on a questionnaire on clinical features, spinal MR imaging finding, results of CSF cytology, treatments, and outcomes which was sent to 86 neurosurgical and 35 pediatrics departments in Japan. Pretreatment frequencies of spinal lesion on MR imaging were compared between the patients with positive and negative cytology. Progression-free survival (PFS) rates were compared between patients with positive CSF cytology without spinal lesion on MR imaging treated with CSI and with whole brain or whole ventricular irradiation (non-CSI). RESULTS: A total of 92 germinoma patients from 45 institutes were evaluated by both CSF cytology and spinal MR images, but 26 patients were excluded because of tumor markers, the timing of CSF sampling or incomplete estimation of spinal lesion. Of the remaining 66 germinoma patients, spinal lesions were equally identified in patients with negative CSF cytology and positive cytology (4.9% and 8.0%, respectively). Eleven patients treated with non-CSI had excellent PFS comparable to 11 patients treated with CSI. CONCLUSION: CSI is unnecessary for germinoma patients with positive CSF cytology without spinal lesions on MR imaging.

A focal brain-cooling device as an alternative to electrical stimulation for language mapping during awake craniotomy: patient series.

BACKGROUND: Functional mapping in awake craniotomy has the potential risk of electrical stimulation-related seizure. The authors have developed a novel mapping technique using a brain-cooling device. The cooling probe is cylindrical in shape with a thermoelectric cooling plate (10 × 10 mm) at the bottom. A proportional integration and differentiation-controlled system adjusts the temperature accurately (Japan patent no. P5688666). The authors used it in two patients with glioblastoma. Broca's area was identified by electrical stimulation, and then the cooling probe set at 5°C was attempted on it. OBSERVATIONS: Electrocorticogram was suppressed, and the temperature dropped to 8°C in 50 sec. A positive aphasic reaction was reproduced on Broca's area at a latency of 7 sec. A negative reaction appeared on the adjacent cortices despite the temperature decrease. The sensitivity and specificity were 60% and 100%, respectively. No seizures or other adverse events related to the cooling were recognized, and no histological damage to the cooled cortex was observed. LESSONS: The cooling probe suppressed topographical brain function selectively and reversibly. Awake functional mapping based on thermal neuromodulation technology could substitute or compensate for the conventional electrical mapping.

Suppressive Effects of Cooling Compounds Icilin on Penicillin G-Induced Epileptiform Discharges in Anesthetized Rats.

More than 30% of patients with epilepsy are refractory and have inadequate seizure control. Focal cortical cooling (FCC) suppresses epileptiform discharges (EDs) in patients with refractory focal cortical epilepsy. However, little is known about the mechanism by which FCC inhibits seizures at 15°C, and FCC treatment is highly invasive. Therefore, new antiepileptic drugs are needed that produce the same effects as FCC but with different mechanisms of action. To address this need, we focused on transient receptor potential melastatin 8 (TRPM8), an ion channel that detects cold, which is activated at 15°C. We examined whether TRPM8 activation suppresses penicillin G (PG)-induced EDs in anesthetized rats. Icilin, a TRPM8 and TRP Ankyrin 1 agonist, was administered after PG injection, and a focal electrocorticogram (ECoG) and cortical temperature were recorded for 4 h. We measured spike amplitude, duration, firing rate, and power density in each band to evaluate the effects of icilin. PG-induced EDs and increased delta, theta, alpha, and beta power spectra were observed in the ECoG. Icilin suppressed EDs while maintaining cortical temperature. In particular, 3.0-mM icilin significantly suppressed PG-induced spike amplitude, duration, and firing rate and improved the increased power density of each band in the EDs to the level of basal activity in the ECoG. These suppressive effects of 3.0-mM icilin on EDs were antagonized by administering N-(3-aminopropyl)-2-[(3-methylphenyl) methoxy]-N-(2-thienylmethyl)-benzamide hydrochloride (AMTB), a selective TRPM8 inhibitor. Our results suggest that TRPM8 activation in epileptic brain regions may be a new therapeutic approach for patients with epilepsy.

Risk of Deterioration of Geriatric Traumatic Brain Injury in Patients Treated with Antithrombotic Drugs.

OBJECTIVE: Developed countries have rapidly aging populations and the use of antithrombotic drugs is increasing. We investigated the effects of antithrombotic drugs and reversal of these drugs in patients with geriatric traumatic brain injury (TBI). METHODS: Age, sex, mechanism of injury, Glasgow Coma Scale on admission, head computed tomography findings, antithrombotic therapy, acute exacerbation, and outcomes at discharge were examined in 711 patients with geriatric TBI, complicated with traumatic intracranial hemorrhage using data from the Japan Neurotrauma Data Bank Project 2015 (JNTDB P2015). These items were compared between patients who did and did not receive antithrombotic therapy. We also conducted a questionnaire survey of reversal of antithrombotic therapy at hospitals participating in the JNTDB P2015. Acute exacerbation was compared in hospitals that did and did not regularly use reversal of this therapy. RESULTS: The major cause of injury was a fall. In head computed tomography, acute subdural hematoma was found in 65.7% of the subjects. Antithrombotic therapy was performed in 30.4% of subjects, and these subjects were significantly older than those who did not receive this therapy; many had a fall as the mechanism of injury, and the level of consciousness was significantly exacerbated with this therapy. In hospitals that performed regular reversal, late exacerbation of the level of consciousness was suppressed. CONCLUSIONS: Patients with geriatric TBI who are given antithrombotic drugs have a risk for late exacerbation, even if initially diagnosed with mild TBI. Therefore, there is a possibility that reversal of antithrombotic drugs is important to suppress the risk of deterioration of patients with TBI.

Limitations of Local Brain Cooling on Generalized Motor Seizures from Unknown Foci in Awake Rats.

Local brain cooling of an epileptic focus at 15°C reduces the number of spikes on an electrocorticogram (ECoG), terminates seizures, and maintains neurological functions. In this study, we attempted to suppress generalized motor seizures (GMSs) by cooling a unilateral sensorimotor area. GMSs were induced in rats by intraperitoneal injection of bicuculline methiodide, an antagonist of gamma-aminobutyric acid. While monitoring the ECoG and behavior, the right sensorimotor cortex was cooled for 10 min using an implanted device. The number of spikes recorded from the cooled cortex significantly decreased to 71.2% and 62.5% compared with the control group at temperatures of 15 and 5°C (both P <0.01), respectively. The number of spikes recorded from the contralateral mirror cortex reduced to 61.7% and 62.7% (both P <0.05), respectively. The ECoG power also declined to 85% and 50% in the cooled cortex, and to 94% and 49% in the mirror cortex by the cooling at 15 and 5°C, respectively. The spikes regained in the middle of the cooling period at 15°C and in the late period at 5°C. Seizure-free durations during the 10-min periods of cooling at 15 and 5°C lasted for 4.1 ± 2.2 and 5.9 ± 1.1 min, respectively. Although temperature-dependent seizure alleviation was observed, the effect of local cortical cooling on GMSs was limited compared with the effect of local cooling of the epileptic focus on GSMs.

Implantable Multi-Modality Probe for Subdural Simultaneous Measurement of Electrophysiology, Hemodynamics, and Temperature Distribution.

OBJECTIVE: The purpose of this paper is to demonstrate how the integration of the multi-channel measurement capabilities of near-infrared spectroscopy (NIRS), electrocorticography (ECoG), and negative temperature coefficient thermistor sensors into a single device compact enough for subdural implantation can provide beneficial information on various aspects of brain cortical activity and prove a powerful medical modality for pre-, intra-, and post-operative diagnoses in neurosurgery. METHODS: The development of a flexible multi-modal multi-channel probe for the simultaneous measurement of the NIRS, ECoG, and surficial temperature obtained from the cerebral cortex was carried out. Photoelectric bare chips for NIRS channels, miniature temperature-coefficient thermistors for measuring localized temperature variation, and 3-mm-diameter platinum plates for ECoG recording were assembled on a polyimide-based flexible printed circuit to create six channels for each modality. A conformal coating of Parylene-C was applied on all the channels except the ECoG to make the probe surface biocompatible. RESULTS: As a first-in-human study, the simultaneous measurement capability of the multi-modality probe, with sufficient signal-to-noise ratio and accuracy, to observe pathological neural activities in subjects during surgery and post-operative monitoring, with no complications two weeks since the implantation, was confirmed. CONCLUSION: The feasibility of using a single device to assess the dynamic pathological activity from three different aspects was determined for human patients. SIGNIFICANCE: The simultaneous and accurate multi-channel recording of electrical, hemodynamic, and thermographic cortical activities in a single device small enough for subdural implantation is likely to have major implications in neurosurgery and neuroscience.

A Palm-Sized Cryoprobe System With a Built-In Thermocouple and Its Application in an Animal Model of Epilepsy.

OBJECTIVE: The purpose of this study is to propose a palm-sized cryoprobe system with a built-in thermocouple (TC) for highly accurate and sensitive temperature measurements, and to verify the effectiveness of the system. METHODS: Conventional cryoprobe systems based on the boiling effect of a refrigerant have triple coaxial tubes. In the proposed system, the outer and middle coaxial tubes are made of two different metals that are welded only at the probe tip, thereby forming a TC. The thermoelectric properties of the built-in TC and measurement accuracy were investigated in agar in a constant-temperature chamber. The system was also applied in a penicillin G-induced rat brain epilepsy model. RESULTS: We verified that the built-in TC has appropriate thermoelectric properties and that the system more accurately and sensitively measured transient temperature changes at the probe tip wall compared to conventional systems, showing the cooling performance of the system. In the rat model, epileptiform activities disappeared on freezing, and reliable cell necrosis was achieved at an end temperature of -45.2 ± 1.6 °C. CONCLUSIONS: The proposed system is suitable for reliable cryosurgery. SIGNIFICANCE: The system is probably to be valuable for clarifying the relationship between freezing temperature and cell necrosis in vivo.

Epileptic Seizure Suppression by Focal Brain Cooling With Recirculating Coolant Cooling System: Modeling and Simulation.

A focal brain cooling system for treatment of refractory epilepsy that is implantable and wearable may permit patients with this condition to lead normal daily lives. We have developed such a system for cooling of the epileptic focus by delivery of cold saline to a cooling device that is implanted cranially. The outflow is pumped for circulation and cooled by a Peltier device. Here, we describe the design of the system and evaluate its feasibility by simulation. Mathematical models were constructed based on equations of fluid dynamics and data from a cat model. Computational fluid dynamics simulations gave the following results: 1) a cooling device with a complex channel structure gives a more uniform temperature in the brain; 2) a cooling period of <10 min is required to reach an average temperature of 25.0°Cat 2 mm below the brain surface, which is the target temperature for seizure suppression. This time is short enough for cooling of the brain before seizure onset after seizure prediction by an intracranial electroencephalogram-based algorithm; and 3) battery charging would be required once every several days for most patients. These results suggest that the focal brain cooling system may be clinically applicable.

Reduction of spike generation frequency by cooling in brain slices from rats and from patients with epilepsy.

This study aimed to understand the mechanism by which brain cooling terminates epileptic discharge. Cortical slices were prepared from rat brains (n = 19) and samples from patients with intractable epilepsy that had undergone temporal lobectomy (n = 7). We performed whole cell current clamp recordings at approximately physiological brain temperature (35℃) and at cooler temperatures (25℃ and 15℃). The firing threshold in human neurons was lower at 25℃ (-32.6 mV) than at 35℃ (-27.0 mV). The resting potential and spike frequency were similar at 25℃ and 35℃. Cooling from 25℃ to 15℃ did not change the firing threshold, but the resting potential increased from -65.5 to -54.0 mV and the waveform broadened from 1.85 to 6.55 ms, due to delayed repolarization. These changes enhanced the initial spike appearance and reduced spike frequency; moreover, spike frequency was insensitive to increased levels of current injections. Similar results were obtained in rat brain studies. We concluded that the reduction in spike frequency at 15℃, due to delayed repolarization, might be a key mechanism by which brain cooling terminates epileptic discharge. On the other hand, spike frequency was not influenced by the reduced firing threshold or the elevated resting potential caused by cooling.

Cilostazol decreases duration of spreading depolarization and spreading ischemia after aneurysmal subarachnoid hemorrhage.

OBJECTIVE: Traditionally, angiographic vasospasm (aVS) has been thought to cause delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH). However, successful treatment of aVS alone does not result in improved neurological outcome. Therefore, there may be other potential causes of poor neurological outcome, including spreading depolarization (SD). A recent study showed beneficial effects of cilostazol on DCI and neurological outcome. The present prospective clinical trial and experimental study focused on effects of cilostazol on SDs. METHODS: Fifty aSAH patients were treated with clip ligation and randomly assigned to a cilostazol (n = 23) or control group (n = 27). Effects of cilostazol on DCI, aVS, and SDs, measured with subdural electrodes, were examined. The effect of cilostazol on SD-induced perfusion deficits (spreading ischemia) was assessed in an aSAH-mimicking model. RESULTS: There was a trend for less DCI in the cilostazol group, but it did not reach our threshold for statistical significance (13.0% vs 40.0%, odds ratio = 0.266, 95% confidence interval [CI] = 0.059-1.192, p = 0.084). However, the total SD-induced depression duration per recording day (22.2 vs 30.2 minutes, ß = -251.905, 95% CI = -488.458 to -15.356, p = 0.043) and the occurrence of isoelectric SDs (0 vs 4 patients, ß = -0.916, 95% CI = -1.746 to -0.085, p = 0.037) were significantly lower in the cilostazol group. In rats, cilostazol significantly shortened SD-induced spreading ischemia compared to vehicle (Student t test, difference = 30.2, 95% CI = 5.3-55.1, p = 0.020). INTERPRETATION: Repair of the neurovascular response to SDs by cilostazol, as demonstrated in the aSAH-mimicking model, may be a promising therapy to control DCI. Ann Neurol 2018;84:873-885.

Thrombolysis with rt-PA under Rivaroxaban Anticoagulation in a Hypertensive Rat Model of Intraluminal Middle Cerebral Artery Occlusion.

BACKGROUND: The aim of this study was to assess the risk and the threshold of hemorrhagic transformation (HT) after treatment with recombinant tissue plasminogen activator (rtPA) under the novel oral anticoagulant, rivaroxaban. METHODS: Fifty-three spontaneous hypertensive rats were used in this study. We performed transient middle cerebral artery occlusion for 270 minutes. Placebo, 10 mg/kg or 20 mg/kg rivaroxaban were administered via a stomach tube 180 minutes after induction of ischemia, and rtPA (10 mg/kg) was administered just before reperfusion. Ninety minutes after rivaroxaban administration we measured the rivaroxaban plasma concentration and prothrombin time (PT). HT volume was assessed by hemoglobin spectrophotometry. Additionally, infarct volume, IgG leakage volume, and neurological outcome were assessed. RESULTS: Rivaroxaban plasma concentration and PT increased in a dose dependent manner but were lower than human peak levels after a once-daily dose of 20 mg rivaroxaban. HT volume increased after treatment with 20 mg/kg rivaroxaban compared with placebo treated controls or those treated with 10 mg/kg rivaroxaban (26.5 ± 5.4, 26.8 ± 8.7, and 41.4 ± 12.6 µL in placebo, 10 mg/kg, and 20 mg/kg treated groups, respectively; P < .05). CONCLUSIONS: Our results suggest that even at therapeutic plasma concentrations, rivaroxaban may increase the risk of HT after thrombolysis in some conditions, such as hypertension and/or a prolonged ischemic period.