Time to Steroid Independence After Laser Interstitial Thermal Therapy vs Medical Management for Treatment of Biopsy-Proven Radiation Necrosis Secondary to Stereotactic Radiosurgery for Brain Metastasis.

BACKGROUND: Radiation necrosis (RN) after stereotactic radiosurgery (SRS) for brain metastases (BM) can result in significant morbidity, compounded by the effects of extended steroid therapy. Laser interstitial thermal therapy (LITT) is a minimally invasive procedure that can offer definitive treatment for RN while potentially obviating the need for prolonged steroid use. OBJECTIVE: To compare LITT vs medical management (MM) in the treatment of RN. METHODS: A multicenter, retrospective study was performed of SRS-treated patients with BM who developed biopsy-proven RN and were treated with LITT or MM. Clinical outcome data were compared by treatment modality. RESULTS: Seventy-two patients met criteria with a median follow-up of 10.0 months (4.2-25.1), and 57 patients (79%) underwent LITT. Four MM (27%) and 3 LITT patients (5%) demonstrated radiographic progression (P = .031) at a median of 5.3 and 4.0 months (P = .40). There was no significant difference in overall survival (LITT median of 15.2 vs 11.6 months, P = .60) or freedom from local progression (13.6 vs 7.06 months, P = .40). Patients stopped steroid therapy earlier in the LITT cohort at a median of 37 days compared with 245 days (P < .001). When controlled for follow-up duration, patients treated with LITT were 3 times more likely to be weaned off steroids before the study end point (P = .003). CONCLUSION: These data suggest that LITT for treatment of biopsy-proven RN after SRS for BM significantly decreases time to steroid independence. Prospective trials should be designed to further validate the utility of LITT for RN and its impact on steroid-induced morbidity.

The novel persistent sodium current inhibitor PRAX-562 has potent anticonvulsant activity with improved protective index relative to standard of care sodium channel blockers.

OBJECTIVE: This study investigates the effects of PRAX-562 on sodium current (INa ), intrinsic neuronal excitability, and protection from evoked seizures to determine whether a preferential persistent INa inhibitor would exhibit improved preclinical efficacy and tolerability compared to two standard voltage-gated sodium channel (NaV ) blockers. METHODS: Inhibition of INa  was characterized using patch clamp analysis. The effect on intrinsic excitability was measured using evoked action potentials recorded from hippocampal CA1 pyramidal neurons in mouse brain slices. Anticonvulsant activity was evaluated using the maximal electroshock seizure (MES) model, and tolerability was assessed by measuring spontaneous locomotor activity (sLMA). RESULTS: PRAX-562 potently and preferentially inhibited persistent INa induced by ATX-II or the SCN8A mutation N1768D (half-maximal inhibitory concentration [IC50 ] = 141 and 75 nmol·L-1 , respectively) relative to peak INa tonic/resting block (60× preference). PRAX-562 also exhibited potent use-dependent block (31× preference to tonic block). This profile is considerably different from standard NaV blockers, including carbamazepine (CBZ; persistent INa IC50 = 77 500 nmol·L-1 , preference ratios of 30× [tonic block], less use-dependent block observed at various frequencies). In contrast to CBZ, PRAX-562 reduced neuronal intrinsic excitability with only a minor reduction in action potential amplitude. PRAX-562 (10 mg/kg po) completely prevented evoked seizures without affecting sLMA (MES unbound brain half-maximal efficacious concentration = 4.3 nmol·L-1 , sLMA half-maximal tolerated concentration = 69.7 nmol·L-1 , protective index [PI] = 16×). In contrast, CBZ and lamotrigine (LTG) had PIs of approximately 5.5×, with significant overlap between doses that were anticonvulsant and that reduced locomotor activity. SIGNIFICANCE: PRAX-562 demonstrated robust preclinical anticonvulsant activity similar to CBZ but improved compared to LTG. PRAX-562 exhibited significantly improved preclinical tolerability compared with standard NaV blockers (CBZ and LTG), potentially due to the preference for persistent INa . Preferential targeting of persistent INa may represent a differentiated therapeutic option for diseases of hyperexcitability, where standard NaV blockers have demonstrated efficacy but poor tolerability.

Discovery of the First Orally Available, Selective KNa1.1 Inhibitor: In Vitro and In Vivo Activity of an Oxadiazole Series.

The gene KCNT1 encodes the sodium-activated potassium channel KNa1.1 (Slack, Slo2.2). Variants in the KCNT1 gene induce a gain-of-function (GoF) phenotype in ionic currents and cause a spectrum of intractable neurological disorders in infants and children, including epilepsy of infancy with migrating focal seizures (EIMFS) and autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Effective treatment options for KCNT1-related disease are absent, and novel therapies are urgently required. We describe the development of a novel class of oxadiazole KNa1.1 inhibitors, leading to the discovery of compound 31 that reduced seizures and interictal spikes in a mouse model of KCNT1 GoF.

Flow diversion of fusiform intracranial aneurysms.

Fusiform aneurysms are less common than saccular aneurysms, but have higher associated mortality and rebleeding rates. Recently, flow diversion has emerged as a possible treatment option. The purpose of this study was to determine the safety and efficacy of the Pipeline Embolization Device (PED) for the treatment of ruptured and unruptured fusiform aneurysms. This was a retrospective analysis of patients with fusiform intracranial aneurysms treated with a PED at a quaternary care center between January 2012 and September 2019. Occlusion rates, neurologic morbidity/mortality, and other clinical variables were analyzed. Twenty-nine patients with 30 fusiform aneurysms were treated with a PED. Sixteen aneurysms (53%) were located in the anterior circulation and 14 aneurysms (47%) were in the posterior circulation. The mean maximal diameter of the aneurysms was 10.1 ± 5.6 mm (range 2.3-25 mm). Angiographic and clinical follow-up were available for 28 aneurysms (93%). The median follow-up was 17.4 months (IQR 4.8 to 28 months) and occlusion rates were graded according to the O'Kelly-Marotta (OKM) scale. Of patients with DSA follow-up, 15 aneurysms (60%) were completely occluded (OKM D) and 19 aneurysms (76%) had a favorable occlusion result (OKM C1-3 and D). The overall complication rate was 26.7% with a neurological morbidity rate of 6.7% and neurological mortality rate of 3.4%. Flow diversion can be an effective treatment for both ruptured and unruptured fusiform aneurysms. Nevertheless, complete occlusion rates are lower than for saccular aneurysms. Therefore, flow diversion should be considered only if other more direct treatment options, such as clipping or stent/coiling are not applicable. Flow diversion should be used cautiously in patients presenting with rupture.

Management of unruptured incidentally found intracranial saccular aneurysms.

Unruptured intracranial saccular aneurysms occur in 3-5% of the general population. As the use of diagnostic medical imaging has steadily increased over the past few decades with the increased availability of computed tomography (CT) and magnetic resonance imaging (MRI), so has the detection of incidental aneurysms. The management of an unruptured intracranial saccular aneurysm is challenging for both patients and physicians, as the decision to intervene must weigh the risk of rupture and resultant subarachnoid hemorrhage against the risk inherent to the surgical or endovascular procedure. The purpose of this paper is to provide an overview of factors to be considered in the decision to offer treatment for unruptured intracranial aneurysms in adults. In addition, we review aneurysm and patient characteristics that favor surgical clipping over endovascular intervention and vice versa. Finally, the authors propose a novel, simple, and clinically relevant algorithm for observation versus intervention in unruptured intracranial aneurysms based on the PHASES scoring system.

Combined Targeting of the BRD4-NUT-p300 Axis in NUT Midline Carcinoma by Dual Selective Bromodomain Inhibitor, NEO2734.

NUT midline carcinoma (NMC) is a rare, aggressive subtype of squamous carcinoma that is driven by the BRD4-NUT fusion oncoprotein. BRD4, a BET protein, binds to chromatin through its two bromodomains, and NUT recruits the p300 histone acetyltransferse (HAT) to activate transcription of oncogenic target genes. BET-selective bromodomain inhibitors have demonstrated on-target activity in patients with NMC, but with limited efficacy. P300, like BRD4, contains a bromodomain. We show that combining selective p300/CBP and BET bromodomain inhibitors, GNE-781 and OTX015, respectively, induces cooperative depletion of MYC and synergistic inhibition of NMC growth. Treatment of NMC cells with the novel dual p300/CBP and BET bromodomain-selective inhibitor, NEO2734, potently inhibits growth and induces differentiation of NMC cells in vitro; findings that correspond with potentiated transcriptional effects from combined BET and p300 bromodomain inhibition. In three disseminated NMC xenograft models, NEO2734 provided greater growth inhibition, with tumor regression and significant survival benefit seen in two of three models, compared with a lead clinical BET inhibitor or "standard" chemotherapy. Our findings provide a strong rationale for clinical study of NEO2734 in patients with NMC. Moreover, the synergistic inhibition of NMC growth by CBP/p300 and BET bromodomain inhibition lays the groundwork for greater mechanistic understanding of the interplay between p300 and BRD4-NUT that drives this cancer.

Endovascular Treatment of Ruptured Enlarging Dissecting Anterior Spinal Artery Aneurysm.

BACKGROUND: Aneurysms of the anterior spinal artery are extremely rare. Unlike intracranial saccular aneurysms, they do not occur at branch points, are typically pseudoaneurysms, and rupture secondary to a dissection. They typically present with subarachnoid hemorrhage and demonstrate clinical and radiographic improvement over time without treatment. METHODS: We present here the first case to date of a ruptured anterior spinal artery aneurysm with clinical and radiographic progression treated with Onyx embolization. Our patient was unique in the presentation with acute onset of spinal cord injury American Spinal Injury Association B and an extensive thoracolumbar subdural hematoma. RESULTS: An emergent skip-level laminectomy and subdural decompression were performed with no improvement in examination. This was followed by progressive radiographic enlargement of the aneurysm, treated successfully with Onyx embolization. CONCLUSIONS: We analyze this case and review the literature on thoracic anterior spinal artery and artery of Adamkiewicz aneurysms.

Transitioning the Doctor of Nursing Practice Final Project Defense to Large Venue Poster Sessions.

BACKGROUND: Accelerated growth in Doctor of Nursing Practice (DNP) programs has mandated the need for innovative strategies for doctoral students to defend their final scholarly work while protecting the integrity and rigor of the experience. METHOD: A poster defense strategy was implemented and evaluated via a faculty focus group and a Likert-scale survey. Sessions highlighting eight projects each were scheduled at 75-minute intervals allowing for both informal poster viewing and formal audience questioning facilitated by a moderator. Evaluation of the event trended positive, with focus group members celebrating the energy around each session, noting the significant increase in audience size compared to past podium defenses. CONCLUSION: Evaluators who attended previous DNP project defenses all indicated that the large venue poster session approach was just as or more effective than previous methods. [J Nurs Educ. 2020;59(1):51-53.].

Lawn Mower Versus Left Ventricular Assist Device: A Case of Traumatic Coronary Injury.

A 77-year-old man with history of ischemic cardiomyopathy and left ventricular assist device (LVAD) presented with abdominal pain after a lawn mower accident. Examination and imaging revealed a displaced LVAD driveline and a pericardial hematoma secondary to traumatic coronary artery injury. The patient was treated with coronary artery coil embolization. (Level of Difficulty: Advanced.).

Inferolateral thalamic ischemia secondary to PCA P2 perforator occlusion mimics MCA stroke syndrome.

Paramedian thalamic strokes following occlusion of the posterior medial (paramedian) thalamic perforators have been previously described in great detail. However, the stroke syndrome associated with occlusion of posterior lateral (inferolateral) thalamic perforators is less commonly known. We present an illustrative case of an inferolateral thalamic perforator stroke mimicking a middle cerebral artery (MCA) syndrome and provide a review of the literature. A 62-year-old male presented with dysarthria, contralateral hemisensory loss, and contralateral weakness, concerning for possible MCA stroke. However, close examination revealed the hemiparesis to be ataxic in nature. Imaging revealed a left PCA P2 segment occlusion and lacunar infarction of the ventral lateral (VL) and ventral posterior (VP) thalamus, the main thalamic destination of cerebellar and sensory pathways. The case is unique because the P1 segment and posterior communicating artery (Pcom) remained patent, resulting in selective occlusion of only the posterior lateral (inferolateral) thalamic perforators at the P2 level. Acute loss of the posterior lateral (inferolateral) thalamic perforators at the proximal P2 segment results in a ventral lateral and ventral posterior thalamic stroke characterized by contralateral hemisensory loss, contralateral ataxic hemiparesis, and dysarthria. It is important to recognize the inferolateral thalamic stroke syndrome, as it may be mistaken clinically for an MCA occlusion. The benefit of mechanical thrombectomy for this type of stroke is not well established and should be considered carefully.

Musculoskeletal Injury in Paddle Sport Athletes.

INTRODUCTION: Kayak racing has been an Olympic sport since 1936. The sport is evolving with the introduction of ocean skis and stand-up-paddle boards (SUP). Musculoskeletal injury incidence surveys have been conducted for ultra-marathon events, but no data have been published for other racing formats. OBJECTIVE: To identify and compare the rates and types of injuries sustained by paddling athletes as a function of discipline and training parameters in Sprint, Marathon, Ultra-Marathon, and Ocean events. METHODS: Competitors from 6 kayak and/or ocean surf-ski races in Australia were surveyed. Before each race, competitors were asked to complete a questionnaire. The questionnaire investigated paddling-related injuries over the previous 5 years, athlete morphology, flexibility, equipment and its setup, training volume, and environment. RESULTS: Five hundred eighty-three competitors were surveyed. Disciplines included 173 racing-kayak (K1), 202 touring-kayak, 146 ocean-skis, 42 SUP, and 20 other. The top 5 paddling-related injuries were shoulder (31%), low back (23.5%), wrist (16.5%), neck (13.7%), and elbow (11.0%). The highest percentage of injury was found in K1 paddlers for shoulder (40.5%), SUP for low back (33.3%), and ocean-ski for wrist (22.6%). After controlling for on-water training hours, the relative risk (RR) of wrist injury was significantly increased in ocean-ski paddlers (1.86) and in paddlers with decreased flexibility (1.53-1.83). Relative risk of shoulder and low-back injury was significantly increased in athletes with lower training volumes (1.82-2.07). Younger athletes had lower RR of wrist and shoulder injury (0.58-0.62).

Masson's tumor presenting as a left frontal intraparenchymal hemorrhage resulting in severe expressive aphasia during pregnancy: case report.

Intravascular papillary endothelial hyperplasia (IPEH), commonly known as Masson's tumor, is a benign lesion that manifests as an excessive proliferation of endothelial cells within a vessel wall. IPEH is extremely rare in the brain, with only 36 intracranial cases previously described in the literature. It is commonly mistaken for more malignant pathologies, such as angiosarcoma. Careful histopathological examination is required for diagnosis, as no clinical or radiographic features are characteristic of this lesion. In this first published case of intracranial IPEH presenting during pregnancy, the authors describe a 32-year-old female with a left frontal intraparenchymal hemorrhage resulting in complete expressive aphasia at 28 weeks 6 days' gestation. An MRI scan obtained at a local hospital demonstrated an area of enhancement within the hemorrhage. The patient underwent a left frontoparietal craniotomy for hematoma evacuation and gross-total resection (GTR) of an underlying hemorrhagic mass at 29 weeks' gestation. This case illustrates the importance of multidisciplinary patient care and the feasibility of intervention in the early third trimester with subsequent term delivery. While GTR of IPEH is typically curative, the decision to proceed with surgical treatment of any intracranial lesion in pregnancy must balance maternal stability, gestational age, and suspected pathology.

CSF volume provocation maneuvers during lumbar puncture as a possible predictive tool for diagnosing spontaneous intracranial hypotension.

OBJECTIVES: Spontaneous intracranial hypotension (SIH) is a pathologic state of low CSF volume caused by a CSF to venous fistula or CSF leak. It is diagnosed based on symptoms, imaging, and CSF pressure but is often a diagnostic challenge because no single test is highly sensitive. Physician-induced changes in CSF volume may result in changes in patient symptoms, as has been shown with idiopathic intracranial hypertension (IIH). The purpose of this study is to determine the sensitivity of CSF volume provocation maneuvers in the diagnosis of SIH. PATIENTS AND METHODS: We reviewed consecutive patients that underwent lumbar puncture from January 2015 to January 2017. Patients were included if they met ICHD3 criteria for SIH and CSF volume provocation maneuvers were performed. Cases were considered concordant if there was improvement of symptoms with addition of CSF. RESULTS: 1084 patients underwent 2250 CT-guided lumbar punctures from January 2015 to January 2017. 92 patients with SIH were identified and 62 of these patients underwent CSF volume provocation maneuvers. 58% (36/62) had concordant lumbar puncture encounters with symptom improvement upon addition of artificial CSF. CONCLUSION: CSF volume provocation maneuvers demonstrate 58% sensitivity for identifying patients with SIH, better than those reported for CSF opening pressure and myelography. A positive symptomatic response to CSF volume provocation maneuvers was independent of the other objective tests used for SIH and may aid in the often-challenging diagnostic workup of these patients. Future prospective case-controlled studies are needed.

Treatment of a Fusiform Anterior Cerebral Artery Aneurysm by Remodeling the Circle of Willis with Flow Diversion: A Novel Technical Note.

BACKGROUND: Fusiform aneurysms are challenging lesions to manage given their poorly understood natural history and lack of a distinct neck. Historically, they have been treated surgically but endovascular management has recently evolved as a viable alternative. In this case, we describe a novel flow diversion technique for treatment of a fusiform anterior cerebral artery (ACA) aneurysm by jailing the compromised parent vessel obtaining endovascular aneurysm trapping. METHODS: A 25-year-old man underwent brain magnetic resonance imaging and magnetic resonance angiography for workup of a headache, which revealed a fusiform right ACA A1 segment aneurysm. The patient subsequently underwent catheter digital subtraction angiography, which confirmed a 9 × 5.5 mm fusiform right ACA A1 segment aneurysm. The patient elected to undergo endovascular treatment. A Pipeline Embolization Device (Medtronic, Dublin, Ireland) was placed from the right anterior cerebral artery to the right middle cerebral artery, thereby jailing the right ACA A1 segment. RESULTS: At 6-month follow-up, the patient was asymptomatic and his headache had resolved. An angiogram was obtained, showing patency of the Pipeline Embolization Device and near complete occlusion of the right ACA A1 segment. The right ACA A2 segment remained patent via collateral flow through the anterior communicating artery. These findings were confirmed on magnetic resonance imaging. The patient remained asymptomatic for the duration of the follow-up. CONCLUSIONS: This case illustrates the efficacy of the Pipeline Embolization Device for treatment of a fusiform anterior circulation aneurysm via remodeling the circle of Willis.

Neuroactive Steroid N-Methyl-d-aspartate Receptor Positive Allosteric Modulators: Synthesis, SAR, and Pharmacological Activity.

Neuroactive steroids (NASs) play a pivotal role in maintaining homeostasis is the CNS. We have discovered that one NAS in particular, 24(S)-hydroxycholesterol (24(S)-HC), is a positive allosteric modulator (PAM) of NMDA receptors. Using 24(S)-HC as a chemical starting point, we have identified other NASs that have good in vitro potency and efficacy. Herein, we describe the structure activity relationship and pharmacokinetic optimization of this series that ultimately led to SGE-301 (42). We demonstrate that SGE-301 enhances long-term potentiation (LTP) in rat hippocampal slices and, in a dose-dependent manner, improves cognition in a rat social recognition study.

Predictors of Clinical Outcome After Treatment of Intracranial Aneurysms with the Pipeline Embolization Device.

BACKGROUND: Flow-diverting stents have revolutionized the endovascular treatment of intracranial aneurysms. The purpose of this study is to identify predictors of adverse outcomes associated with the pipeline embolization device (PED). METHODS: A retrospective analysis of all patients treated with PED at a single high-volume center from January 2014 to September 2018. Patient outcomes, neurologic morbidity/mortality, and other clinical variables were analyzed. RESULTS: We treated 204 aneurysms in 170 patients with PED. Mean length of follow-up was 11 months. Most (181) aneurysms (89%) were located in the anterior circulation, and 23 (11%) were found in the posterior circulation. Most aneurysms were saccular (82%), followed by fusiform (11%), blister (4%), and dissecting pseudoaneurysms (3%). Mean aneurysm size was 8.2 + 5.7 mm with 145 (71%) small aneurysms (≤10 mm), 53 (26%) large aneurysms (between 10 and 25 mm), and 6 (3%) giant aneurysms (≥25 mm). Ninety-two percent of aneurysms were unruptured, and 8% were ruptured. The overall major neurologic morbidity/mortality was 4.7% and 1.8%, respectively. The all-cause mortality was 2.9%. Predictors of neurologic morbidity/mortality included the baseline modified Rankin Scale (P = 0.001), aneurysm neck size (P = 0.003), aneurysm size (P = 0.006), anterior versus posterior location (P = 0.02), and rupture at presentation (0.006). The P2Y12 Reactivity Unit, parent vessel diameter, and patient age did not correlate with adverse events. CONCLUSIONS: The PED has a satisfactory safety profile in both on- and off-label indications. A poor clinical patient baseline, wider aneurysm neck or larger size, and rupture predict an increased risk of an unfavorable outcome.

Endovascular repair of an acute symptomatic carotid artery dissection through the false dissecting carotid lumen.

A 48-year-old woman presented with an acute ischemic stroke (National Institutes of Health Stroke Scale (NIHSS) 21) six hours after symptom onset. Workup revealed a left cervical internal carotid artery (ICA) occlusive dissection, which was emergently reconstructed with a flow-diverting stent. A routine Duplex scan one hour later suggested reocclusion of the ICA, confirmed by angiography. The true lumen of the ICA could not be accessed and therefore the "false lumen" of the ICA dissection was entered proximally. The true lumen and ultimately the flow-diverting stent were accessed via the false lumen. In analogy to the subintimal arterial flossing with antegrade-retrograde intervention technique described for peripheral vascular disease, several stents were placed in telescoping fashion from the true common carotid lumen through the "false dissecting" lumen of the proximal ICA into the distal true lumen. The stent construct remained patent, and the patient recovered clinically to an NIHSS of 1.

Treatment of direct carotid-cavernous fistulas with flow diversion - does it work?

Direct carotid-cavernous fistulas (CCFs) are high flow lesions that can be challenging to treat. A number of recent reports suggest that flow diversion may be a viable treatment option. We present a case of a post-traumatic CCF successfully treated with flow diversion and provide a review of the literature. Our results suggest that flow diversion is a potentially effective treatment option for CCFs and is most successful when used as an adjunctive therapy.

Thromboembolic Events with Enterprise Versus Pipeline: Porcine In Vivo Experiment.

BACKGROUND: Thromboembolic complications are serious adverse events associated with stenting of intracranial aneurysms. For the development of novel devices, currently no practical model exists to evaluate distal embolic events. The purpose of the current study was 2-fold: 1) assess the feasibility of a porcine carotid bifurcation model for in vivo testing of stent thrombogenicity and 2) compare the thrombogenicity of the Enterprise vascular reconstruction device versus the Pipeline embolization device (PED). METHODS: Six Yorkshire pigs underwent implantation of size-matched devices across the carotid bifurcation. Each animal received 1 Enterprise and 1 PED contralaterally. Baseline and 2-week follow-up angiography were performed. Images were analyzed including detailed measurements of the rete mirabile, a small-vessel conglomerate supplied by branches of the common carotid artery. RESULTS: In the absence of thromboembolic events at 2 weeks (n = 8), the perfused rete area measured 134.4 ± 6.9 mm2. In the presence of thromboembolic events (n = 4), the perfused rete was reduced to an area covering 37.1 ± 8.6 mm2 (P < 0.01). There was no difference in thrombogenicity between Enterprise and PED with a thromboembolic event rate of 33.3% for both devices (P > 0.99). CONCLUSION: The swine carotid stent model allows in vivo analysis of device-related thrombogenicity and distal embolic event rates. Size reduction of the perfused rete mirabile indicates the presence of thromboembolic events. Both Enterprise and PED were associated with similar thrombogenicity in this experiment.