Sulfonylurea Receptor 1 in Central Nervous System Injury: An Updated Review

Hinchazón celular; Edema; Traumatismo cerebralCellular swelling; Edema; Traumatic brain injuryInflor cel·lular; Edema; Traumatisme cerebralSulfonylurea receptor 1 (SUR1) is a member of the adenosine triphosphate (ATP)-binding cassette (ABC) protein superfamily, encoded by Abcc8, and is recognized as a key mediator of central nervous system (CNS) cellular swelling via the transient receptor potential melastatin 4 (TRPM4) channel. Discovered approximately 20 years ago, this channel is normally absent in the CNS but is transcriptionally upregulated after CNS injury. A comprehensive review on the pathophysiology and role of SUR1 in the CNS was published in 2012. Since then, the breadth and depth of understanding of the involvement of this channel in secondary injury has undergone exponential growth: SUR1-TRPM4 inhibition has been shown to decrease cerebral edema and hemorrhage progression in multiple preclinical models as well as in early clinical studies across a range of CNS diseases including ischemic stroke, traumatic brain injury, cardiac arrest, subarachnoid hemorrhage, spinal cord injury, intracerebral hemorrhage, multiple sclerosis, encephalitis, neuromalignancies, pain, liver failure, status epilepticus, retinopathies and HIV-associated neurocognitive disorder. Given these substantial developments, combined with the timeliness of ongoing clinical trials of SUR1 inhibition, now, another decade later, we review advances pertaining to SUR1-TRPM4 pathobiology in this spectrum of CNS disease—providing an overview of the journey from patch-clamp experiments to phase III trials.No funding directly supported the writing of this review. R.M.J. is supported by grants from the National Institute of Neurological Disorders and Stroke (NINDS) (K23NS101036; R01NS115815), and the Barrow Neurological Foundation. J.M.S. is supported by grants from the Department of Veterans Affairs (I01RX003060; 1I01BX004652), the Department of Defense (SC170199), the National Heart, Lung and Blood Institute (R01HL082517) and the NINDS (R01NS102589; R01NS105633)

Percutaneous Drainage of Chronic Destructive Lumbar Osteomyelitis Abscess Via the Use of Bilateral Transpedicular Trocar Access

Pyogenic spondylodiskitis is an infection of intervertebral disks and spinal vertebral bodies. Various minimally invasive approaches to the infected disk spaces/abscesses have been described for management of early stages of the infection. Patients with chronic occurrence present with extensive infection, neurologic deficits, and bone destruction. Such patients commonly have substantial medical comorbidities. Despite the increased risks of complications, they often are treated with open surgical approaches without minimally invasive options. We describe a bilateral transpedicular approach to vertebral body abscess in a chronically infected patient with intraoperative contiguous irrigation. We present 2 cases, a 58-year-old man and a 61-year-old man, both with a diagnosis of vertebral osteomyelitis. Images of lumbar spine showed epidural abscess and adjacent vertebral body destruction. Because of their poor clinical condition and chronicity of disease, these patients underwent percutaneous bilateral transpedicular approach. Patients in poor health and with chronic vertebral osteomyelitis may benefit from minimally invasive percutaneous transpedicular drainage and irrigation of the abscess, representing a minimally invasive and effective treatment alternative for these patients

Parasagittal and parafalcine meningiomas: integral strategy for optimizing safety and retrospective review of a single surgeon series

Background: Parafalcine and parasagittal meningiomas present unique challenges for resection. Although maximal safe resection is the primary goal of surgical management for these lesions, venous infarction and eloquent cortical structure damage occur in up to 14% of cases. Therefore, optimal preoperative planning and intraoperative technique is critical. Methods: We retrospectively reviewed a single surgeon's case series with resection of 58 parafalcine and parasagittal meningiomas. Operative strategy included not crossing the superior sagittal sinus (SSS) during craniotomy, not resecting the falx, use of motor evoked potentials (MEPs) to avoid damage to eloquent brain, and selective use of preoperative embolization. Results: Fifty-eight patients, 45 with parasagittal meningiomas and 13 with parafalcine meningiomas were evaluated. Median age 58.34 years and mean follow-up was 7.7 months. Gross total resection (GTR) was achieved in 51.7% of patients and near-gross total resection rate was 48.3%. Postoperative day one discharge rate was 62.1%. Complication rate was 8.6%, with new postoperative neurologic deficit rate of 5.2%. Tumor recurrence/growth documented on postoperative imaging rate was 3.4%. Conclusions: In our series of parasagittal and parafalcine meningioma resection, we report a 51.7% GTR rate associated with a low complication rate. Techniques to minimize perioperative morbidity include not crossing the SSS on craniotomy, avoiding falx resection, using MEPs, and selective preoperative embolization to optimize the chance of a maximal safe resection. We utilize a strategy of conservative initial tumor resection focused on maximizing the chances of a favorable neurologic outcome, followed as necessary by adjuvant therapies such as radiosurgery and salvage therapies such as laser interstitial thermal therapy, although longer follow-up comparable to that of series with more radical approaches is required to determine if long term outcomes are comparable

Emerging therapeutic targets for cerebral edema

INTRODUCTION: Cerebral edema is a key contributor to death and disability in several forms of brain injury. Current treatment options are limited, reactive, and associated with significant morbidity. Targeted therapies are emerging based on a growing understanding of the molecular underpinnings of cerebral edema. AREAS COVERED: We review the pathophysiology and relationships between different cerebral edema subtypes to provide a foundation for emerging therapies. Mechanisms for promising molecular targets are discussed, with an emphasis on those advancing in clinical trials, including ion and water channels (AQP4, SUR1-TRPM4) and other proteins/lipids involved in edema signaling pathways (AVP, COX2, VEGF, and S1P). Research on novel treatment modalities for cerebral edema [including recombinant proteins and gene therapies] is presented and finally, insights on reducing secondary injury and improving clinical outcome are offered. EXPERT OPINION: Targeted molecular strategies to minimize or prevent cerebral edema are promising. Inhibition of SUR1-TRPM4 (glyburide/glibenclamide) and VEGF (bevacizumab) are currently closest to translation based on advances in clinical trials. However, the latter, tested in glioblastoma multiforme, has not demonstrated survival benefit. Research on recombinant proteins and gene therapies for cerebral edema is in its infancy, but early results are encouraging. These newer modalities may facilitate our understanding of the pathobiology underlying cerebral edema

Sulfonylurea Receptor 1 in Central Nervous System Injury : An Updated Review

Sulfonylurea receptor 1 (SUR1) is a member of the adenosine triphosphate (ATP)-binding cassette (ABC) protein superfamily, encoded by Abcc8, and is recognized as a key mediator of central nervous system (CNS) cellular swelling via the transient receptor potential melastatin 4 (TRPM4) channel. Discovered approximately 20 years ago, this channel is normally absent in the CNS but is transcriptionally upregulated after CNS injury. A comprehensive review on the pathophysiology and role of SUR1 in the CNS was published in 2012. Since then, the breadth and depth of understanding of the involvement of this channel in secondary injury has undergone exponential growth: SUR1-TRPM4 inhibition has been shown to decrease cerebral edema and hemorrhage progression in multiple preclinical models as well as in early clinical studies across a range of CNS diseases including ischemic stroke, traumatic brain injury, cardiac arrest, subarachnoid hemorrhage, spinal cord injury, intracerebral hemorrhage, multiple sclerosis, encephalitis, neuromalignancies, pain, liver failure, status epilepticus, retinopathies and HIV-associated neurocognitive disorder. Given these substantial developments, combined with the timeliness of ongoing clinical trials of SUR1 inhibition, now, another decade later, we review advances pertaining to SUR1-TRPM4 pathobiology in this spectrum of CNS disease-providing an overview of the journey from patch-clamp experiments to phase III trials

Magnetic Resonance–Guided Laser Interstitial Thermal Therapy for Mesial Temporal Epilepsy: A Case Series Analysis of Outcomes and Complications at 2-Year Follow-Up

Laser interstitial thermal therapy (LITT) presents an important new minimally invasive tool in the management of drug-resistant mesial temporal epilepsy (MTE). However, because of its relative novelty, not much is known about long-term seizure freedom rates. The objective of this study was to evaluate the postsurgical seizure outcome following LITT after a minimum follow-up period of 2 years. Medical records of all patients who underwent LITT for MTE from 2013 to 2018 at our comprehensive epilepsy center under a single surgeon were retrospectively reviewed. Data related to demographics, presurgical evaluations, and seizure outcome were compared between seizure-free (SF) and non–seizure-free (NSF) patients. In all, 26 patients were identified with at least 2 years of follow-up. Mean age was 43.8 years ± 11.6 years, and 46.2% were female. After a mean follow-up time of 42.9 months (range, 24.3–58.8 months), 61.5% (16/26) were free of disabling seizures, and 26.9% (7/26) had only rare disabling seizures. Whereas seizure-freedom rates between patients with and without mesial temporal sclerosis (MTS) were not statistically different (68% vs. 43%, P = 0.23), NSF patients without MTS had a shorter median time to first seizure than did NSF patients with MTS (0.55 month vs. 10 months, log-rank test P = 0.007). Postoperative complications occurred in 2 patients (7.7%), consisting of 1 permanent and 1 transient homonymous hemianopia. LITT appears to be a safe and effective initial surgical option for treatment-resistant MTE. Among patients who have seizures after treatment, those without MTS appear to have seizures earlier than those with MTS

Sulfonylurea Receptor 1 in Central Nervous System Injury: An Updated Review

Sulfonylurea receptor 1 (SUR1) is a member of the adenosine triphosphate (ATP)-binding cassette (ABC) protein superfamily, encoded by Abcc8, and is recognized as a key mediator of central nervous system (CNS) cellular swelling via the transient receptor potential melastatin 4 (TRPM4) channel. Discovered approximately 20 years ago, this channel is normally absent in the CNS but is transcriptionally upregulated after CNS injury. A comprehensive review on the pathophysiology and role of SUR1 in the CNS was published in 2012. Since then, the breadth and depth of understanding of the involvement of this channel in secondary injury has undergone exponential growth: SUR1-TRPM4 inhibition has been shown to decrease cerebral edema and hemorrhage progression in multiple preclinical models as well as in early clinical studies across a range of CNS diseases including ischemic stroke, traumatic brain injury, cardiac arrest, subarachnoid hemorrhage, spinal cord injury, intracerebral hemorrhage, multiple sclerosis, encephalitis, neuromalignancies, pain, liver failure, status epilepticus, retinopathies and HIV-associated neurocognitive disorder. Given these substantial developments, combined with the timeliness of ongoing clinical trials of SUR1 inhibition, now, another decade later, we review advances pertaining to SUR1-TRPM4 pathobiology in this spectrum of CNS disease—providing an overview of the journey from patch-clamp experiments to phase III trials

Outcomes in patients with aneurysmal subarachnoid hemorrhage receiving sulfonylureas: a propensity-adjusted analysis

OBJECTIVE: Aneurysmal subarachnoid hemorrhage (aSAH) is associated with increased blood-brain barrier permeability, disrupted tight junctions, and increased cerebral edema. Sulfonylureas are associated with reduced tight-junction disturbance and edema and improved functional outcome in aSAH animal models, but human data are scant. We analyzed neurological outcomes in aSAH patients prescribed sulfonylureas for diabetes mellitus. METHODS: Patients treated for aSAH at a single institution (August 1, 2007-July 31, 2019) were retrospectively reviewed. Patients with diabetes were grouped by presence or absence of sulfonylurea therapy on hospital admission. The primary outcome was favorable neurological status at last follow-up (modified Rankin Scale score ≤2). Variables with an unadjusted p-value of \u3c0.20 were included in a propensity-adjusted multivariable logistic regression analysis to identify predictors of favorable outcomes. RESULTS: Of 1013 aSAH patients analyzed, 129 (13%) had diabetes at admission and 16 of these (12%) were taking sulfonylureas. Fewer diabetic than nondiabetic patients had favorable outcomes (40% [52/129] vs. 51% [453/884], p=0.03). Among diabetic patients, sulfonylurea use (OR 3.90, 95% CI 1.05-15.9, p=0.046), Charlson Comorbidity Index \u3c4 (OR 3.66, 95% CI 1.24-12.1, p=0.02), and absence of delayed cerebral infarction (OR 4.09, 95% CI 1.20-15.5, p=0.03) were associated with favorable outcomes in the multivariable analysis. CONCLUSIONS: Diabetes was strongly associated with unfavorable neurological outcomes. An unfavorable outcome in this cohort was mitigated by sulfonylureas, supporting some preclinical evidence of a possible neuroprotective roles for these medications in aSAH. These results warrant further study on dose, timing, and duration of administration in humans

36-month clinical outcomes of patients with venous thromboembolism: GARFIELD-VTE

Background: Venous thromboembolism (VTE), encompassing both deep vein thrombosis (DVT) and pulmonary embolism (PE), is a leading cause of morbidity and mortality worldwide.Methods: GARFIELD-VTE is a prospective, non-interventional observational study of real-world treatment practices. We aimed to capture the 36-month clinical outcomes of 10,679 patients with objectively confirmed VTE enrolled between May 2014 and January 2017 from 415 sites in 28 countries.Findings: A total of 6582 (61.6 %) patients had DVT alone, 4097 (38.4 %) had PE +/- DVT. At baseline, 98.1 % of patients received anticoagulation (AC) with or without other modalities of therapy. The proportion of patients on AC therapy decreased over time: 87.6 % at 3 months, 73.0 % at 6 months, 54.2 % at 12 months and 42.0 % at 36 months. At 12-months follow-up, the incidences (95 % confidence interval [CI]) of all-cause mortality, recurrent VTE and major bleeding were 6.5 (7.0-8.1), 5.4 (4.9-5.9) and 2.7 (2.4-3.0) per 100 person-years, respectively. At 36-months, these decreased to 4.4 (4.2-4.7), 3.5 (3.2-2.7) and 1.4 (1.3-1.6) per 100 person-years, respectively. Over 36-months, the rate of all-cause mortality and major bleeds were highest in patients treated with parenteral therapy (PAR) versus oral anti-coagulants (OAC) and no OAC, and the rate of recurrent VTE was highest in patients on no OAC versus those on PAR and OAC. The most frequent cause of death after 36-month follow-up was cancer (n = 565, 48.6 %), followed by cardiac (n = 94, 8.1 %), and VTE (n = 38, 3.2 %). Most recurrent VTE events were DVT alone (n = 564, 63.3 %), with the remainder PE, (n = 236, 27.3 %), or PE in combination with DVT (n = 63, 7.3 %).Interpretation: GARFIELD-VTE provides a global perspective of anticoagulation patterns and highlights the accumulation of events within the first 12 months after diagnosis. These findings may help identify treatment gaps for subsequent interventions to improve patient outcomes in this patient population