Clinical safety and feasibility of a novel implantable neuroimmune modulation device for the treatment of rheumatoid arthritis: initial results from the randomized, double-blind, sham-controlled RESET-RA study.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that causes persistent synovitis, bone damage, and progressive joint destruction. Neuroimmune modulation through electrical stimulation of the vagus nerve activates the inflammatory reflex and has been shown to inhibit the production and release of inflammatory cytokines and decrease clinical signs and symptoms in RA. The RESET-RA study was designed to determine the safety and efficacy of an active implantable device for treating RA. METHODS: The RESET-RA study is a randomized, double-blind, sham-controlled, multi-center, two-stage pivotal trial that enrolled patients with moderate-to-severe RA who were incomplete responders or intolerant to at least one biologic or targeted synthetic disease-modifying anti-rheumatic drug. A neuroimmune modulation device (SetPoint Medical, Valencia, CA) was implanted on the left cervical vagus nerve within the carotid sheath in all patients. Following post-surgical clearance, patients were randomly assigned (1:1) to active stimulation or non-active (control) stimulation for 1 min once per day. A predefined blinded interim analysis was performed in patients enrolled in the study's initial stage (Stage 1) that included demographics, enrollment rates, device implantation rates, and safety of the surgical procedure, device, and stimulation over 12 weeks of treatment. RESULTS: Sixty patients were implanted during Stage 1 of the study. All device implant procedures were completed without intraoperative complications, infections, or surgical revisions. No unanticipated adverse events were reported during the perioperative period and at the end of 12 weeks of follow-up. No study discontinuations were due to adverse events, and no serious adverse events were related to the device or stimulation. Two serious adverse events were related to the implantation procedure: vocal cord paresis and prolonged hoarseness. These were reported in two patients and are known complications of surgical implantation procedures with vagus nerve stimulation devices. The adverse event of vocal cord paresis resolved after vocal cord augmentation injections with filler and speech therapy. The prolonged hoarseness had improved with speech therapy, but mild hoarseness persists. CONCLUSIONS: The surgical procedures for implantation of the novel neuroimmune modulation device for the treatment of RA were safe, and the device and its use were well tolerated. TRIAL REGISTRATION: NCT04539964; August 31, 2020.

Adjuvant proton beam therapy in patients with grade 2 meningiomas.

Background: The World Health Organization (WHO) grade 2 meningiomas behave aggressively with a high proclivity toward recurrence despite maximal surgical resection. Our institution, a pioneer of proton therapy, uses exclusively proton beam radiation, and thus, we present a retrospective cohort analysis of patients with WHO grade 2 meningiomas treated with adjuvant proton beam therapy (PBT) at our institution between 2007 and 2019. The effects of adjuvant PBT were evaluated. Methods: Data collected include diagnosis, gender, histological subtype, WHO grade, the extent of surgical resection, adjuvant PBT radiation, details of the PBT radiation, recurrence, any additional PBT radiation, systemic medical therapy, and disease-specific survival. Results: Among the WHO grade 2 meningiomas (n = 50) recommended PBT, 80% and 78% of patients with gross-total resection (GTR) and subtotal resection (STR), respectively, followed through with PBT. The median radiation dose of PBT was 59.5 Gy and 59.92 Gy for patients with GTR and STR, respectively, with a median of 33 fractions delivered in 1.8 Gy doses for both groups. Combined 3-year progression-free survival (PFS) was 96%, and 5-year PFS was 92%. Combined overall survival was 95% at five years. Minimal radiation side effects were reported with no grade 3 or higher toxicities. Conclusion: Our results suggest that adjuvant PBT is well tolerated with minimal radiation toxicity. Alternative to photon radiation, PBT may be considered at least as safe and effective for adjuvant treatment of WHO grade 2 meningiomas when it is available.

Delayed revascularization in acute ischemic stroke patients.

Stroke shares a significant burden of global mortality and disability. A significant decline in the quality of life is attributed to the so-called post-stroke cognitive impairment including mild to severe cognitive alterations, dementia, and functional disability. Currently, only two clinical interventions including pharmacological and mechanical thrombolysis are advised for successful revascularization of the occluded vessel. However, their therapeutic effect is limited to the acute phase of stroke onset only. This often results in the exclusion of a significant number of patients who are unable to reach within the therapeutic window. Advances in neuroimaging technologies have allowed better assessment of salvageable penumbra and occluded vessel status. Improvement in diagnostic tools and the advent of intravascular interventional devices such as stent retrievers have expanded the potential revascularization window. Clinical studies have demonstrated positive outcomes of delayed revascularization beyond the recommended therapeutic window. This review will discuss the current understanding of ischemic stroke, the latest revascularization doctrine, and evidence from clinical studies regarding effective delayed revascularization in ischemic stroke.

Molecular hydrogen therapy for neurological diseases: a review of current evidence.

Reactive oxygen species and other free radicals cause oxidative stress which is the underlying pathogenesis of cellular injury in various neurological diseases. Molecular hydrogen therapy with its unique biological property of selectively scavenging pathological free radicals has demonstrated therapeutic potential in innumerable animal studies and some clinical trials. These studies have implicated several cellular pathways affected by hydrogen therapy in explaining its anti-inflammatory and antioxidative effects. This article reviews relevant animal and clinical studies that demonstrate neuroprotective effects of hydrogen therapy in stroke, neurodegenerative diseases, neurotrauma, and global brain injury.

Preoperative opiate use leads to increased postoperative opiate use and readmissions after anterior cervical discectomy and fusion.

Background: Determine effects of pre-operative opiate use on anterior cervical discectomy and fusion (ACDF) surgery outcomes. Methods: The study design was a single center retrospective cohort study. Patient records were reviewed from 2013 and 2018 for elective 1 to 2 level ACDF surgeries. Patients were classified as: opiate naive (ON: no history of opiate) use, acute opiate (AO: <6 months preoperatively) use, and chronic opiate (CO: 6-12 months preoperatively) use based on prescription history before surgery. Opiate use was quantified by milligram morphine equivalents (MME) at 6-12 months preop, 0-6 months preop, 0-6 months postop, and 6-12 months postop. Charts were reviewed for American Society of Anesthesiologists (ASA) physical status classification and smoking history. Results: Readmission rates were 9.8% for ON, 9.1% for AO, and 30% for CO (P value <0.05). Average opiate use measured in MME 6-12 months post-surgery was 5.76 for ON, 18.44 for AO, and 39.92 for CO (P value <0.05). Readmission rate between nonsmokers, former smokers, and active smokers was 4.4%, 0%, and 10.8% (P value <0.05) at 30-90 days post-surgery, and 1.1%, 14.5%, and 2.5% (P value <0.05) in the 91 days to 1-year post-surgery. Conclusions: There is statistically significant relationship between CO and higher readmission rates after ACDF. Preoperative opiate use is also associated with increased opiate use 6-12 months after surgery. Smoking history is also associated with increased readmission rates.

Meningioma Related Epilepsy- Pathophysiology, Pre/postoperative Seizures Predicators and Treatment.

Meningiomas are the most common primary brain tumors accounting for about 30% of all brain tumors. The vast majority of meningiomas are slow-growing and of benign histopathology rendering them curable by surgery alone. Symptomatic lesions depend on the location with signs of mass effect or neurological deficits. Seizures are the presenting symptoms in approximately 30% of cases, which negatively affect quality of life, limit independence, impair cognitive functioning, as well as increase the risk for psychiatric comorbidities including depression. Although surgical resection may offer seizure freedom in 60-90% of meningiomas, seizures persist after surgical resection in approximately 12-19% of patients. Anti-seizure medications (ASMs) are employed in management, however, are limited by adverse neurocognitive side-effects and inefficacy in some patients. The potential predictors of pre- and post-operative seizures in meningioma patients have been identified in the literature. Understanding various factors associated with seizure likelihood in meningioma patients can help guide more effective seizure control and allow for better determination of risk before and after surgery.

72-year-old man with right homonymous hemianopia and gait instability.

An elderly man presented with right homonymous hemianopia and gait instability. He was found to have a left occipital ring enhancing lesion that was resected. Neuropathologic examination demonstrated a Cladophialophora bantiana brain abscess (cerebral phaeohyphomycosis).

Striking MRI Changes of Focal Cortical Dysplasia Over Time: A Case Series and Literature Review.

PURPOSE OF REVIEW: Brain MRI findings of focal cortical dysplasia (FCD) can undergo dramatic changes over time, which may be related to long-term epilepsy or a combination of histopathologic changes that necessitate further investigation. RECENT FINDINGS: We describe 2 cases of FCD type IIb that initially displayed inconspicuous findings on MRI, however progressed to obvious signal changes on subsequent MRI 10-17 years later. Pathologic analysis indicates that the interval changes are likely attributed to reactive astrogliosis and diffuse parenchymal rarefaction. A few case reports and case series showing similar MRI changes have been described in the literature, the majority in pediatric patients. The adult cases we present add to the scientific evidence of these changes occurring in the adult population. SUMMARY: Our observations lead to several clinical suggestions, including closer interval follow-up imaging for nonlesional cases, the addition of postprocessing imaging methods, earlier surgical intervention, and meticulous surgical planning.

Molecular Hydrogen Application in Stroke: Bench to Bedside.

Stroke is a major cause of mortality and morbidity worldwide. Effective treatments are limited. Molecular hydrogen is emerging as a novel medical gas with therapeutic potential for various neurological diseases, including stroke. We reviewed the experimental and clinical findings of the effects of molecular hydrogen therapy in stroke patients and models. The underlying neuroprotective mechanisms against stroke pathology were also discussed.

Review of Atypical and Anaplastic Meningiomas: Classification, Molecular Biology, and Management.

Although the majority of meningiomas are slow-growing and benign, atypical and anaplastic meningiomas behave aggressively with a penchant for recurrence. Standard of care includes surgical resection followed by adjuvant radiation in anaplastic and partially resected atypical meningiomas; however, the role of adjuvant radiation for incompletely resected atypical meningiomas remains debated. Despite maximum treatment, atypical, and anaplastic meningiomas have a strong proclivity for recurrence. Accumulating mutations over time, recurrent tumors behave more aggressively and often become refractory or no longer amenable to further surgical resection or radiation. Chemotherapy and other medical therapies are available as salvage treatment once standard options are exhausted; however, efficacy of these agents remains limited. This review discusses the risk factors, classification, and molecular biology of meningiomas as well as the current management strategies, novel therapeutic approaches, and future directions for managing atypical and anaplastic meningiomas.

Optimizing Radiosurgery for Trigeminal Neuralgia: Impact of Radiation Dose and Anatomic Target on Patient Outcomes.

OBJECTIVE: Radiosurgery is an increasingly popular treatment for trigeminal neuralgia (TN); however, several treatment variables require further study. This meta-analysis was conducted to clarify ambiguity in the literature and optimize treatment parameters. METHODS: A random-effects proportions meta-analysis using subgroup analysis and meta-regression investigated the association of prescription dose and anatomic target on outcomes in patients with typical TN. The PRISMA guidelines were used. Radiation doses used ranged from 70 to 90 Gy and the anatomic targets were either the root entry zone or a more distal nerve location. Outcome measures were pain at last follow-up and the development of bothersome numbness. RESULTS: Increasing radiation prescription dose was associated with improved outcomes across all analyzed doses (P < 0.001). Patients treated at a distal trigeminal nerve target had better pain control compared with a root entry zone target (P < 0.001). Despite a higher median dose, a distal target was independently associated with improved pain control. There were similar rates of bothersome numbness across radiation doses and both treatment targets. CONCLUSIONS: Higher radiation dose was associated with superior pain control without increasing bothersome numbness. Independent of dose, the distal target was also associated with improved pain control. Bothersome numbness was not related to dose or target.

The Activation of Phosphatidylserine/CD36/TGF-ß1 Pathway prior to Surgical Brain Injury Attenuates Neuroinflammation in Rats.

Neuroinflammation plays an important pathological role in experimental surgical brain injury (SBI). Apoptotic associated with phosphatidylserine (PS) externalization promotes anti-inflammatory mediator TGF-ß1 release. In the present study, we investigated the anti-neuroinflammation effect of PS liposome or isoflurane pretreatment via PS/CD36/TGF-ß1 signaling in a rat model of SBI. A total of 120 male Sprague-Dawley rats (weighing 280-330 gms) were used. SBI was induced by partial right frontal lobe corticotomy. Intranasal PS liposome or isoflurane inhalation was administered prior to SBI induction. CD36 small interfering RNA (siRNA) was administered intracerebroventricularly. Recombinant Annexin V protein (rAnnexin V) was delivered intranasally. Post-SBI assessments included neurological tests, brain water content, Western blot, and immunohistochemistry. Endogenous CD36 protein levels but not TGF-ß1 was significantly increased within peri-resection brain tissues over 72 h after SBI. SBI rats were associated with increased brain water content surrounding corticotomy and neurological deficits. PS liposome pretreatment significantly reduced brain water content and improved some neurological deficits at 24 hours and 72 hours after SBI. PS liposome increased CD36 and TGF-ß1 protein levels, but decreased IL-1ß and TNFα protein levels in peri-resection brain tissues at 24 hours after SBI. CD36 siRNA or rAnnexin V partially countered the protective effect of PS liposome. Isoflurane pretreatment produced similar antineuroinflammation and neurological benefits in SBI rats partially by upregulating CD36/Lyn/TGF-ß1 signaling. Collectively, our findings suggest that the activation of PS/CD36/TGF-ß1 pathway by PS liposome or isoflurane prior to SBI could attenuate neuroinflammation and improve neurological outcomes in rats. PS liposome or isoflurane pretreatment may serve as an effective preventive strategy to minimize the brain injury caused by neurosurgical procedures in patients.

Surgery for Spine Disease and Intractable Pain.

Painful conditions, particularly due to head pain, spinal disease, and neuropathic pain, are highly prevalent in modern society, resulting in a significant impact on the individual due to the disability of the condition and the direct cost of associated treatments [...].

Stem Cell Therapy in Brain Ischemia: The Role of Mitochondrial Transfer.

Mitochondrial dysfunction is an important pathological process in the setting of ischemic brain injury. Stem cell-mediated mitochondrial transfer provides an efficient intercellular process to supply additional mitochondria in the ischemic brain tissues. In this review, we summarize the mitochondrial pathology associated with brain ischemia, mechanisms of stem cell-mediated mitochondrial transfer, and in vitro/in vivo experimental findings of mitochondrial transfer from stem cells to ischemic vascular endothelial cells/neurons as potential therapeutic strategy in the management of ischemic brain injury.

Subarachnoid Hemorrhage-Related Epilepsy.

Epilepsy is a significant worldwide public health problem that leads to reduced quality of life and negative psychosocial consequences and significantly increases mortality rates in those who are affected. The development of epilepsy from subarachnoid hemorrhage (SAH) has an important negative impact on long-term survival, functional status, and cognitive recovery in patients following aneurysmal rupture. Anticonvulsant medication (AED) administration to prevent the development of epilepsy following SAH is controversial, and studies to date have not shown effectiveness of AED use as prophylaxis. This paper reviews the pathophysiology of SAH in the development of epilepsy, the scope of the problem of epilepsy related to SAH, and the studies that have evaluated AED administration as prophylaxis for seizures and epilepsy.

The Role of Transcranial Doppler in Cerebral Vasospasm: A Literature Review.

Transcranial Doppler ultrasonography (TCD) is a noninvasive technique used to detect vasospasms following a subarachnoid hemorrhage. While the gold standard to evaluate vasospasms is angiography, this technique is invasive and poses additional risks as compared to TCD. TCD is performed by insonating circle of Willis arteries to measure cerebral flow velocity. TCD allows dynamic monitoring of CBF-V and vessel pulsatility, with a high temporal resolution. It is relatively inexpensive, repeatable, and portable; however, the performance of TCD is highly operator dependent and can be difficult, especially with inadequate acoustic windows. This review summarizes the use of transcranial Doppler ultrasonography (TCD) for the assessment of cerebral vasospasm.

SCING-Spinal Cord Injury Neuroprotection with Glyburide: a pilot, open-label, multicentre, prospective evaluation of oral glyburide in patients with acute traumatic spinal cord injury in the USA.

INTRODUCTION: Acute traumatic spinal cord injury (tSCI) is a devastating neurological disorder with no pharmacological neuroprotective strategy proven effective to date. Progressive haemorrhagic necrosis (PHN) represents an increasingly well-characterised mechanism of secondary injury after tSCI that negatively impacts neurological outcomes following acute tSCI. Preclinical studies evaluating the use of the Food and Drug Administration-approved sulfonylurea receptor 1-transient receptor potential melastatin 4 channel blocker glyburide in rodent models have shown reduced secondary microhaemorrhage formation and the absence of capillary fragmentation, the pathological hallmark of PHN. METHODS AND ANALYSIS: In this initial phase multicentre open-label pilot study, we propose to enrol 10 patients with acute cervical tSCI to primarily assess the feasibility, and safety of receiving oral glyburide within 8 hours of injury. Secondary objectives include pharmacokinetics and preliminary evaluations on neurological recovery as well as blood and MRI-based injury biomarkers. Analysis will be performed using the descriptive and non-parametric statistics. ETHICS AND DISSEMINATION: Glyburide has been shown as an effective neuroprotective agent in preclinical tSCI models and in the treatment of ischaemic stroke with the additional risk of a hypoglycaemic response. Given the ongoing secondary injury and the traumatic hyperglycaemic stress response seen in patients with tSCI, glyburide; thus, offers an appealing neuroprotective strategy to supplement standard of care treatment. The study protocol was approved by the Ohio State University Biomedical Institutional Review Board. The protocol was amended in February 2017 with changes related to study feasibility and patient recruitment. Specifically, the route of administration was changed to the oral form to allow for streamlined and rapid drug administration, and the injury-to-drug time window was extended to 8 hours in an effort to further enhance enrolment. Participants or legally authorised representatives are informed about the trial and its anticipated risks orally and in written form using an approved informed consent form prior to inclusion. The findings of this study will be disseminated to the participants and to academic peers through scientific conferences and peer-reviewed journal publications. TRIAL REGISTRATION NUMBERS: NCT02524379 and 2014H0335.

Inhalation of high-concentration hydrogen gas attenuates cognitive deficits in a rat model of asphyxia induced-cardiac arrest.

Cognitive deficits are a devastating neurological outcome seen in survivors of cardiac arrest. We previously reported water electrolysis derived 67% hydrogen gas inhalation has some beneficial effects on short-term outcomes in a rat model of global brain hypoxia-ischemia induced by asphyxia cardiac arrest. In the present study, we further investigated its protective effects in long-term spatial learning memory function using the same animal model. Water electrolysis derived 67% hydrogen gas was either administered 1 hour prior to cardiac arrest for 1 hour and at 1-hour post-resuscitation for 1 hour (pre- & post-treatment) or at 1-hour post-resuscitation for 2 hours (post-treatment). T-maze and Morris water maze were used for hippocampal memory function evaluation at 7 and 14 days post-resuscitation, respectively. Neuronal degeneration within hippocampal Cornu Ammonis 1 (CA1) regions was examined by Fluoro-Jade staining ex vivo. Hippocampal deficits were detected at 7 and 18 days post-resuscitation, with increased neuronal degeneration within hippocampal CA1 regions. Both hydrogen gas treatment regimens significantly improved spatial learning function and attenuated neuronal degeneration within hippocampal CA1 regions at 18 days post-resuscitation. Our findings suggest that water electrolysis derived 67% hydrogen gas may be an effective therapeutic approach for improving cognitive outcomes associated with global brain hypoxia-ischemia following cardiac arrest. The study was approved by the Animal Health and Safety Committees of Loma Linda University, USA (approval number: IACUC #8170006) on March 2, 2017.

Gamma Knife Radiosurgery for Trigeminal Neuralgia: A Comparison of Dose Protocols.

: Purpose: A variety of treatment plans including an array of prescription doses have been used in radiosurgery treatment of trigeminal neuralgia (TN). However, despite a considerable experience in the radiosurgical treatment of TN, an ideal prescription dose that balances facial dysesthesia risk with pain relief durability has not been determined. METHODS AND MATERIALS: This retrospective study of patients treated with radiosurgery for typical TN evaluates two treatment doses in relation to outcomes of pain freedom, bothersome facial numbness, and patient satisfaction with treatment. All patients were treated with radiosurgery for intractable and disabling TN. A treatment dose protocol change from 80 to 85 Gy provided an opportunity to compare two prescription doses. The variables evaluated were pain relief, treatment side-effect profile, and patient satisfaction. RESULTS: Typical TN was treated with 80 Gy in 26 patients, and 85 Gy in 37 patients. A new face sensory disturbance was reported after 80 Gy in 16% and after 85 Gy in 27% (p = 0.4). Thirteen failed an 80 Gy dose whereas seven failed an 85 Gy dose. Kaplan-Meier analysis found that at 29 months 50% failed an 80 Gy treatment compared with 79% who had durable pain relief after 85 Gy treatment (p = 0.04). CONCLUSION: The 85 Gy dose for TN provided a more durable pain relief compared to the 80 Gy one without a significantly elevated occurrence of facial sensory disturbance.

Targeting mast cell as a neuroprotective strategy.

Background: Mast cells (MCs) are perivascularly located immune cells of haematopoietic origin. Emerging evidences suggest that the activation of MCs play important roles in the pathogenesis of blood brain barrier disruption, neuroinflammation, and neurodegeneration. Objectives: In this review, we aimed to discuss the detrimental effects of MCs in response to various types of brain injury, as well as the therapeutic potential and neuroprotective effects of targeting the activation and degranulation of MCs, particularly in the management of the acute phase. Methods: An extensive online literature search was conducted through Pubmed/Central on March 2018. Then, we comprehensively summarized the effects of the activation of brain MCs in acute brain injury along with current pharmacological strategies targeting at the activation of MCs. Results: The review of the current literature indicated that the activation and degranulation of brain MCs significantly contribute to the acute pathological process following different types of brain injury including focal and global cerebral ischaemia, intracerebral haemorrhage, subarachnoid haemorrhage, and traumatic brain injury. Conclusions: Brain MCs significantly contribute to the acute pathological processes following brain injury. In that regard, targeting brain MCs may provide a novel strategy for neuroprotection.