Bivalirudin as a substitute for heparin in neurointervention for patients with heparin-induced thrombocytopenia.

OBJECTIVES: Heparin-induced thrombocytopenia is a known complication of heparin exposure with potentially life-threatening sequelae. Direct thrombin inhibitors can be substituted for heparin in patients with heparin-induced thrombocytopenia that require anticoagulation. However, the use of direct thrombin inhibitors as a substitute for heparin has not been widely reported in the neuroendovascular literature. MATERIALS AND METHODS: Here we report the first use of the direct thrombin inhibitor bivalirudin in a neuroendovascular procedure as a substitute for heparin in a patient with a ruptured pseudoaneurysm and heparin-induced thrombocytopenia, and review the literature on the use of bivalirudin and argatroban for such patients. RESULTS: Bivalirudin was safely and effectively used in the case reported, with no thrombotic or hemorrhagic complications. Our literature review revealed a paucity of studies on the use of heparin alternatives, including bivalirudin, in neuroendovascular procedures in patients with heparin-induced thrombocytopenia. CONCLUSIONS: Heparin-induced thrombocytopenia is an important iatrogenic disease process in patients undergoing neuroendovascular procedures, and developing protocols to diagnose and manage heparin-induced thrombocytopenia is important for healthcare systems. While further research needs to be done to establish the full range of anticoagulation options to substitute for heparin, our case indicates bivalirudin as a potential candidate.

Analysis of Mechanical Thrombectomy for Acute Ischemic Stroke on Nights and Weekends Versus Weekdays at Comprehensive Stroke Centers.

OBJECTIVE: The "weekend effect" has been shown to affect outcomes in acute ischemic stroke. We sought to compare metrics and outcomes of emergent stroke thrombectomy at three affiliated comprehensive stroke centers on weekdays versus nights/weekends for a three-year period beginning in 2015, when thrombectomy became common practice for large vessel occlusion acute ischemic stroke. METHODS: We performed a retrospective analysis of all stroke thrombectomy patients treated from 2015 to 2018 to compare standard thrombectomy metrics and outcomes in patients presenting during weekdays or nights/weekends. RESULTS: Two hundred-sixteen mechanical thrombectomy cases were evaluated, with 50.9% of patients presenting on weekdays and 49.1% presenting on nights/weekends. There were no statistical differences in baseline characteristics in demographics, stroke risk factors, or stroke severity, but patients presenting on nights/weekends had longer times from last known normal to presentation (130 versus 72.5 minutes, p=0.03). Door-to-groin times were delayed in patients presenting on nights/weekends compared to weekdays (median 104.5 versus 86 minutes, respectively; p=0.007) but groin-to-reperfusion times were similar (51.5 versus 48 minutes, respectively; p=0.4). Successful reperfusion was similar in both groups (90.6% nights/weekends versus 90% weekdays; p=1.0) as were the incidence of symptomatic intracerebral hemorrhage (10.4% nights/weekend versus 7.3% weekdays; p=0.48) and 90-day good functional outcomes based on the modified Rankin Scale did not differ between the two groups in a shift analysis (p=0.545). CONCLUSIONS: Despite delays in door-to-groin puncture times in acute ischemic stroke patients presenting on nights/weekends compared to weekdays, we did not identify significant differences in successful reperfusion or functional outcomes in this cohort. Further studies are warranted to continue to evaluate differences in stroke care on nights/weekends versus weekdays.

Robot-assisted resection of pre-sacral schwannoma.

Resection of a giant pre-sacral schwannoma originating from the right S2 nerve in a 22-year-old woman illustrates the potential for robotic surgery. The da Vinci Robot Surgical System facilitates visualization deep in the pelvis and allows for bimanual wristed instrument control to dissect the tumor from surrounding sensitive structures. Neurostimulation to identify critical nerves is possible and complete resection of the tumor can be achieved. There were no complications, she remained neurologically intact, the estimated blood loss was less than 75 ml, the total hospital stay was 3 days, and she returned to work within 2 weeks of her operation. In select patients, robot-assisted surgery may have advantages. The video can be found here: https://youtu.be/SYjUA-WcyGI .

Dynamics and allosteric potential of the AMPA receptor N-terminal domain.

Glutamate-gated ion channels (ionotropic glutamate receptors, iGluRs) sense the extracellular milieu via an extensive extracellular portion, comprised of two clamshell-shaped segments. The distal, N-terminal domain (NTD) has allosteric potential in NMDA-type iGluRs, which has not been ascribed to the analogous domain in AMPA receptors (AMPARs). In this study, we present new structural data uncovering dynamic properties of the GluA2 and GluA3 AMPAR NTDs. GluA3 features a zipped-open dimer interface with unconstrained lower clamshell lobes, reminiscent of metabotropic GluRs (mGluRs). The resulting labile interface supports interprotomer rotations, which can be transmitted to downstream receptor segments. Normal mode analysis reveals two dominant mechanisms of AMPAR NTD motion: intraprotomer clamshell motions and interprotomer counter-rotations, as well as accessible interconversion between AMPAR and mGluR conformations. In addition, we detect electron density for a potential ligand in the GluA2 interlobe cleft, which may trigger lobe motions. Together, these data support a dynamic role for the AMPAR NTDs, which widens the allosteric landscape of the receptor and could provide a novel target for ligand development.

Subunit-selective N-terminal domain associations organize the formation of AMPA receptor heteromers.

The assembly of AMPA-type glutamate receptors (AMPARs) into distinct ion channel tetramers ultimately governs the nature of information transfer at excitatory synapses. How cells regulate the formation of diverse homo- and heteromeric AMPARs is unknown. Using a sensitive biophysical approach, we show that the extracellular, membrane-distal AMPAR N-terminal domains (NTDs) orchestrate selective routes of heteromeric assembly via a surprisingly wide spectrum of subunit-specific association affinities. Heteromerization is dominant, occurs at the level of the dimer, and results in a preferential incorporation of the functionally critical GluA2 subunit. Using a combination of structure-guided mutagenesis and electrophysiology, we further map evolutionarily variable hotspots in the NTD dimer interface, which modulate heteromerization capacity. This 'flexibility' of the NTD not only explains why heteromers predominate but also how GluA2-lacking, Ca(2+)-permeable homomers could form, which are induced under specific physiological and pathological conditions. Our findings reveal that distinct NTD properties set the stage for the biogenesis of functionally diverse pools of homo- and heteromeric AMPAR tetramers.

Management of moyamoya disease: a review of current and future therapeutic strategies.

Moyamoya disease (MMD) is characterized by idiopathic, progressive stenosis of the circle of Willis and the terminal portion of the internal carotid arteries with the development of prominent small collateral vessels and a characteristic moyamoya or puff-of-smoke radiographic appearance. The incidence and prevalence of MMD varies by region, age, and sex, with higher rates in Asian and East Asian populations compared to North American or European populations. There is a bimodal distribution of patients diagnosed with MMD. Pediatric patients are more commonly diagnosed within the 1st decade of life, whereas adult patients present in the 5th or 6th decade of life. Overall, there is a nearly 2:1 female-to-male ratio. Ischemic symptoms are the most common presentation in pediatric and adult populations, but adult patients are nearly twice as likely to present with intracranial hemorrhage compared to their pediatric counterparts. Surgical revascularization is indicated in symptomatic cases, and antiplatelet therapy may be a useful adjunct to prevent recurrent symptoms. Direct and combined bypass procedures seem to be more effective in adults, whereas children respond well to indirect bypass. The identification of key genetic, molecular, and environmental factors including RNF213 and GUCY1A3 loss-of-function mutations, angiogenic growth factors, autoantibodies, CNS infections, and radiation exposure suggest multiple pathways for the development of moyamoya arteriopathy. Further research is needed to better understand the heterogeneity of pathogenetic mechanisms that lead to moyamoya and to identify novel therapeutic targets to prevent, stabilize, and treat MMD.

AMPA receptor assembly: atomic determinants and built-in modulators.

Glutamate-gated ion channels (iGluRs) predominantly operate as heterotetramers to mediate excitatory neurotransmission at glutamatergic synapses. The subunit composition of the receptors determines their targeting to synaptic sites and signalling properties and is therefore a fundamental parameter for neuronal computations. iGluRs assemble as obligatory or preferential heteromers; the mechanisms underlying this selective assembly are only starting to emerge. Here we review recent work in the field and provide an in-depth update on atomic determinants in the assembly domains, which have been facilitated by recent advances in iGluR structural biology. We also discuss the role of alternative RNA processing in the ligand-binding domain, which modulates a central subunit interface and has the capacity to modulate receptor formation in response to external cues. Finally, we review the emerging physiological significance of signalling via distinct iGluR heterotetramers and provide examples of how recruitment of functionally diverse receptors modulates excitatory neurotransmission under physiological and pathological conditions.

Holohemispheric Prostate Carcinoma Dural Metastasis Mimicking Subdural Hematoma: Case Report and Review of the Literature.

Prostate carcinomas are the most common malignancy to metastasize to the dura. These metastases can commonly mimic subdural hematomas and may similarly present with brain compression. The optimal management and outcomes after surgical management are not well characterized. We present a case of prostate carcinoma metastatic to the dura that was initially thought to be a large isodense subdural hematoma and was treated with surgical decompression. We also review the literature regarding prostate dural metastases mimicking subdural hematomas and discuss the relevant imaging findings, treatments, and outcomes. Dural metastasis should be considered when a patient with known metastatic prostate cancer presents with imaging evidence of a subdural mass.

Embolization of the internal maxillary artery via open retrograde superficial temporal artery approach.

Sentinel bleeds in head and neck cancer patients present as an ominous symptom often necessitating urgent endovascular embolization. However, this approach can be complicated in patients who have previously undergone head and neck cancer ablation and reconstruction, thus altering the standard arterial vascular supply. Herein we describe an innovative method of internal maxillary artery (IMA) access in a patient with a sentinel bleed who previously underwent proximal external carotid artery (ECA) rerouting for free flap reconstruction. The open retrograde superficial temporal artery approach for IMA embolization is minimally invasive and effective and should be considered for head and neck cancer patients at risk of hemorrhage from distal ECA branches without a proximal ECA embolization option.

Retrospective review of 290 small carotid cave aneurysms over 17 years.

OBJECTIVE: The carotid cave is a unique intradural region located along the medial aspect of the internal carotid artery. Small carotid cave aneurysms confined within this space are bound by the carotid sulcus of the sphenoid bone and are thought to have a low risk of rupture or growth. However, there is a lack of data on the natural history of this subset of aneurysms. METHODS: The authors present a retrospective case series of 290 small (≤ 4 mm) carotid cave aneurysms evaluated and managed at their institution between January 2000 and June 2017. RESULTS: No patient presented with a subarachnoid hemorrhage attributable to a carotid cave aneurysm, and there were no instances of aneurysm rupture or growth during 911.0 aneurysm-years of clinical follow-up or 726.3 aneurysm-years of imaging follow-up, respectively. CONCLUSIONS: This series demonstrates the benign nature of small carotid cave aneurysms.

Parasellar xanthogranulomas.

OBJECT: Xanthogranulomas are rare inflammatory masses most often found in the skin and eye. The incidence of intracranial xanthogranulomas is 1.6%-7%, with those found in the sellar and parasellar region being exceedingly rare and their etiology controversial. Sellar and parasellar xanthogranulomas are rarely reported in the western hemisphere, and their incidence in Western countries is unknown. METHODS: A prospectively acquired database of all endonasal endoscopic transsphenoidal surgeries performed at Weill Cornell Medical College was queried. Patients with histologically confirmed xanthogranulomas who were diagnosed and treated between 2003 and 2013 were included in the study. Patient history, demographic data, histological findings, and surgical approach were also evaluated. RESULTS: A total of 643 endonasal endoscopic procedures had been performed at the time of this study. Four patients (0.6%) were identified as having a histologically confirmed xanthogranuloma of the parasellar region, compared with an incidence of 6.7% for craniopharyngioma (CP) and 2% for Rathke cleft cyst (RCC). The most common symptom was visual loss, followed by headache. Preoperative diagnosis was CP in all cases. All patients underwent extended endonasal endoscopic transsphenoidal surgery with gross-total resection. Two patients developed panhypopituitarism after surgery. There were no CSF leaks. The mean follow-up was 61 months, at which time there were no recurrences. The key histological features differentiating xanthogranulomas from CPs were accumulation of foamy macrophages, multinucleated foreign body giant cells, cholesterol clefts, and hemosiderin deposits without stratified squamous epithelium. These histological features appear commonly as part of the spectrum of a secondary inflammatory response in an RCC. CONCLUSIONS: Parasellar xanthogranulomas most closely approximate CPs clinically but pathological evidence may suggest an RCC origin. Gross-total resection can be achieved through extended endonasal endoscopic transsphenoidal approaches, and is curative.

Pentraxins coordinate excitatory synapse maturation and circuit integration of parvalbumin interneurons.

Circuit computation requires precision in the timing, extent, and synchrony of principal cell (PC) firing that is largely enforced by parvalbumin-expressing, fast-spiking interneurons (PVFSIs). To reliably coordinate network activity, PVFSIs exhibit specialized synaptic and membrane properties that promote efficient afferent recruitment such as expression of high-conductance, rapidly gating, GluA4-containing AMPA receptors (AMPARs). We found that PVFSIs upregulate GluA4 during the second postnatal week coincident with increases in the AMPAR clustering proteins NPTX2 and NPTXR. Moreover, GluA4 is dramatically reduced in NPTX2(-/-)/NPTXR(-/-) mice with consequent reductions in PVFSI AMPAR function. Early postnatal NPTX2(-/-)/NPTXR(-/-) mice exhibit delayed circuit maturation with a prolonged critical period permissive for giant depolarizing potentials. Juvenile NPTX2(-/-)/NPTXR(-/-) mice display reduced feedforward inhibition yielding a circuit deficient in rhythmogenesis and prone to epileptiform discharges. Our findings demonstrate an essential role for NPTXs in controlling network dynamics highlighting potential therapeutic targets for disorders with inhibition/excitation imbalances such as schizophrenia.

Comparative dynamics of NMDA- and AMPA-glutamate receptor N-terminal domains.

Ionotropic glutamate receptors (iGluRs) harbor two extracellular domains: the membrane-proximal ligand-binding domain (LBD) and the distal N-terminal domain (NTD). These are involved in signal sensing: the LBD binds L-glutamate, which activates the receptor channel. Ligand binding to the NTD modulates channel function in the NMDA receptor subfamily of iGluRs, which has not been observed for the AMPAR subfamily to date. Structural data suggest that AMPAR NTDs are packed into tight dimers and have lost their signaling potential. Here, we assess NTD dynamics from both subfamilies, using a variety of computational tools. We describe the conformational motions that underly NMDAR NTD allosteric signaling. Unexpectedly, AMPAR NTDs are capable of undergoing similar dynamics; although dimerization imposes restrictions, the two subfamilies sample similar, interconvertible conformational subspaces. Finally, we solve the crystal structure of AMPAR GluA4 NTD, and combined with molecular dynamics simulations, we characterize regions pivotal for an as-yet-unexplored dynamic spectrum of AMPAR NTDs.

Intrinsic motions in the N-terminal domain of an ionotropic glutamate receptor detected by fluorescence correlation spectroscopy.

Ionotropic glutamate receptors (iGluRs) mediate excitatory neurotransmission in the central nervous system and play key roles in brain development and disease. iGluRs have two distinct extracellular domains, but the functional role of the distal N-terminal domain (NTD) is poorly understood. Crystal structures of the NTD from some non-N-methyl-d-aspartate (NMDA) iGluRs are consistent with a rigid body that facilitates receptor assembly but suggest an additional dynamic role that could modulate signaling. Here, we moved beyond spatial and temporal limitations of conventional protein single-molecule spectroscopy by employing correlation analysis of extrinsic oxazine fluorescence fluctuations. We observed nanosecond (ns)-to-microsecond (µs) motions of loop segments and helices within a region of an AMPA-type iGluR NTD, which has been identified previously to be structurally variable. Our data reveal that the AMPA receptor NTD undergoes rapid conformational fluctuations, suggesting an inherent allosteric capacity for this domain in addition to its established assembly function.

Structural basis of the cross-reactivity of genetically related human anti-HIV-1 mAbs: implications for design of V3-based immunogens.

Human monoclonal antibodies 447-52D and 537-10D, both coded by the VH3 gene and specific for the third variable region (V3) of the HIV-1 gp120, were found to share antigen-binding structural elements including an elongated CDR H3 forming main-chain interactions with the N terminus of the V3 crown. However, water-mediated hydrogen bonds and a unique cation-pi sandwich stacking allow 447-52D to be broadly reactive with V3 containing both the GPGR and GPGQ crown motifs, while the deeper binding pocket and a buried Glu in the binding site of 537-10D limit its reactivity to only V3 containing the GPGR motif. Our results suggest that the design of immunogens for anti-V3 antibodies should avoid the Arg at the V3 crown, as GPGR-containing epitopes appear to select for B cells making antibodies of narrower specificity than V3 that carry Gln at this position.

Electrooculogram based system for computer control using a multiple feature classification model.

This paper discusses the creation of a system for computer-aided communication through automated analysis and processing of electrooculogram signals. In situations of disease or trauma, there may be an inability to communicate with others through standard means such as speech or typing. Eye movement tends to be one of the last remaining active muscle capabilities for people with neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS) also known as Lou Gehrig's disease. Thus, there is a need for eye movement based systems to enable communication. To meet this need, the Telepathix system was designed to accept eye movement commands denoted by looking to the left, looking to the right, and looking straight ahead to navigate a virtual keyboard. Using a ternary virtual keyboard layout and a multiple feature classification model, a typing speed of 6 letters per minute was achieved.