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Background and Purpose: The optimal endovascular stroke therapy (EVT) care delivery structure is unknown. Here, we present our experience in creating an integrated stroke system (ISS) to expand EVT availability throughout our region while maintaining hospital and physician quality standards. Methods: We identified all consecutive patients with large vessel occlusion acute ischemic stroke treated with EVT from January 2014 to February 2019 in our health care system. In October 2017, we implemented the ISS, in which 3 additional hospitals (4 total) became EVT-performing hospitals (EPHs) and physicians were rotated between all centers. The cohort was divided by time into pre-ISS and post-ISS, and the primary outcome was time from stroke onset to EPH arrival. Secondary outcomes included hospital and procedural quality metrics. We performed an external validation using data from the Southeast Texas Regional Advisory Council. Results: Among 513 patients with large vessel occlusion acute ischemic stroke treated with EVT, 58% were treated pre-ISS and 43% post-ISS. Over the study period, EVT procedural volume increased overall but remained relatively low at the 3 new EPHs (P P P Conclusions: In our system, increasing EVT availability decreased time from stroke onset to EPH arrival. The ISS provides a framework to maintain quality in lower volume hospitals.

Qiu et al. present a novel deep learning strategy to generate high-resolution visualizations of Alzheimer’s disease risk in humans that are highly interpretable and can accurately predict Alzheimer’s disease status. They then test the model by comparing its performance to that of neurologists and neuropathological data., Alzheimer’s disease is the primary cause of dementia worldwide, with an increasing morbidity burden that may outstrip diagnosis and management capacity as the population ages. Current methods integrate patient history, neuropsychological testing and MRI to identify likely cases, yet effective practices remain variably applied and lacking in sensitivity and specificity. Here we report an interpretable deep learning strategy that delineates unique Alzheimer’s disease signatures from multimodal inputs of MRI, age, gender, and Mini-Mental State Examination score. Our framework linked a fully convolutional network, which constructs high resolution maps of disease probability from local brain structure to a multilayer perceptron and generates precise, intuitive visualization of individual Alzheimer’s disease risk en route to accurate diagnosis. The model was trained using clinically diagnosed Alzheimer’s disease and cognitively normal subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset (n = 417) and validated on three independent cohorts: the Australian Imaging, Biomarker and Lifestyle Flagship Study of Ageing (AIBL) (n = 382), the Framingham Heart Study (n = 102), and the National Alzheimer’s Coordinating Center (NACC) (n = 582). Performance of the model that used the multimodal inputs was consistent across datasets, with mean area under curve values of 0.996, 0.974, 0.876 and 0.954 for the ADNI study, AIBL, Framingham Heart Study and NACC datasets, respectively. Moreover, our approach exceeded the diagnostic performance of a multi-institutional team of practicing neurologists (n = 11), and high-risk cerebral regions predicted by the model closely tracked post-mortem histopathological findings. This framework provides a clinically adaptable strategy for using routinely available imaging techniques such as MRI to generate nuanced neuroimaging signatures for Alzheimer’s disease diagnosis, as well as a generalizable approach for linking deep learning to pathophysiological processes in human disease.

Background: Ischemic stroke has no approved treatments to enhance recovery. ALD-401 is an enriched population of aldehyde dehydrogenase-bright stem cells, capable of reducing neurological deficits in animal models. The primary objective of this trial was to determine the safety of internal carotid artery, intra-arterially delivered autologous bone marrow–derived ALD-401 in patients with disabling middle cerebral artery stroke in comparison with sham harvest with sham infusion. Secondary objectives were to determine feasibility and efficacy. Methods: This was a prospective phase 2, industry-funded, randomized, sham-controlled, parallel-group, multicenter study with blinded assessments. One hundred subjects were planned, aged 30 to 83 years, with confirmed first-time middle cerebral artery ischemic stroke with modified Rankin scale ≥3. Study patients were randomly assigned 3:2 to bone marrow harvest at 11 to 17 days after stroke followed 2 days later by intracarotid infusion of ALD-401 versus sham harvest and then sham infusion in the same timeframe. The primary study outcome was safety based on the incidence of a 4-point National Institutes of Health Stroke Scale worsening and the proportion of serious adverse events. Efficacy was based on modified Rankin scale change at 90 days. Other secondary outcomes were the proportions of patients experiencing adverse events, disability by Barthel Index, quality of life using EQ-5D, rehabilitation utilization, disability at 1 year, and MRI evidence of complications. Results: There were no infusional or allergic reactions and no difference in treatment emergent adverse events. Four patients had small areas of asymptomatic restricted diffusion on MRI in the treatment group. There was no significant difference between the ALD-401 and placebo groups on the modified Rankin scale for the intent-to-treat population at day 90 (mean difference, 0.3; 95% CI, –0.3 to 0.8; P =0.330). There were no significant differences between the groups on any of the secondary efficacy measures. Conclusions: Intracarotid infusion of ALD-401 does not lead to clinical adverse events in patients with subacute ischemic stroke, although there was a higher incidence of small lesions on MRI in the treatment group. There was no difference in the primary efficacy end point between the groups. The study provides a framework for the design and conduct of future intra-arterial cell therapy trials in stroke. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01273337.

Objective We aim to report intra-arterial thrombectomy transfer metrics for ischemic stroke patients that were transferred to hub hospitals for possible intra-arterial thrombectomy in multiple geographic regions throughout the state of Texas and to identify potential barriers and delays in the intra-arterial thrombectomy transfer process. Method We prospectively collected data from 8 participating Texas comprehensive stroke/thrombectomy capable centers from 7 major regions in the State of Texas. We collected baseline clinical and imaging data related to the pre-transfer evaluation, transfer metrics, and post-transfer clinical and imaging data. Results A total of 103 acute ischemic stroke patients suspected/confirmed to have large vessel occlusions between December 2016 to May 2019 that were transferred to hubs as possible intra-arterial thrombectomy candidates were enrolled. A total of 56 (54%) patients were sent from the spoke to the hub via ground ambulance with 47 (46%) patients traveling via air ambulance. The median spoke arrival to hub arrival time was 174 min, median spoke arrival to departure from spoke was 131 min, and median travel time was 39 min. The spoke arrival time to transfer initiation was 68 min. CT-perfusion obtained at the spoke and earlier initiation of transfer were statistically associated with shorter transfer times. Conclusion Transfer of intra-arterial thrombectomy patients in Texas may take over 4 h from spoke arrival to hub arrival. This time may be shortened by earlier transfer initiation and acceptance.

Background and Purpose: Noncontrast head CT and CT perfusion (CTP) are both used to screen for endovascular stroke therapy (EST), but the impact of imaging strategy on likelihood of EST is undetermined. Here, we examine the influence of CTP utilization on likelihood of EST in patients with large vessel occlusion (LVO). Methods: We identified patients with acute ischemic stroke at 4 comprehensive stroke centers. All 4 hospitals had 24/7 CTP and EST capability and were covered by a single physician group (Neurology, NeuroIntervention, NeuroICU). All centers performed noncontrast head CT and CT angiography in the initial evaluation. One center also performed CTP routinely with high CTP utilization (CTP-H), and the others performed CTP optionally with lower utilization (CTP-L). Primary outcome was likelihood of EST. Multivariable logistic regression was used to determine whether facility type (CTP-H versus CTP-L) was associated with EST adjusting for age, prestroke mRS, National Institutes of Health Stroke Scale, Alberta Stroke Program Early CT Score, LVO location, time window, and intravenous tPA (tissue-type plasminogen activator). Results: Among 3107 patients with acute ischemic stroke, 715 had LVO, of which 403 (56%) presented to CTP-H and 312 (44%) presented to CTP-L. CTP utilization among LVO patients was greater at CTP-H centers (72% versus 18%, CTP-H versus CTP-L, P Conclusions: We identified an increased likelihood for undergoing EST in centers with lower CTP utilization, which was not associated with worse clinical outcomes or increased hemorrhage. These findings suggest under-treatment bias with routine CTP.

Alzheimer’s disease (AD) is the primary cause of dementia worldwide (1), with an increasing morbidity burden that may outstrip diagnosis and management capacity as the population ages. Current methods integrate patient history, neuropsychological testing and magnetic resonance imaging (MRI) to identify likely cases, yet effective practices remain variably-applied and lacking in sensitivity and specificity (2). Here we report an explainable deep learning strategy that delineates unique AD signatures from multimodal inputs of MRI, age, gender, and mini-mental state examination (MMSE) score. Our framework linked a fully convolutional network (FCN) to a multilayer perceptron (MLP) to construct high resolution maps of disease probability from local brain structure. This enabled precise, intuitive visualization of individual AD risk en route to accurate diagnosis. The model was trained using clinically-diagnosed AD and cognitively normal (NC) subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset (n=417) (3), and validated on three independent cohorts: the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL, n=382) (4), the Framingham Heart Study (FHS, n=102) (5), and the National Alzheimer’s Coordinating Center (NACC, n=582) (6). Model performance was consistent across datasets, with mean accuracy values of 0.966, 0.948, 0.815, and 0.916 for ADNI, AIBL, FHS and NACC, respectively. Moreover, our approach exceeded the diagnostic performance of a multi-institutional team of practicing neurologists (n=11), and high-risk cerebral regions predicted by the model closely tracked postmortem histopathological findings. This framework provides a clinically-adaptable strategy for using routinely available imaging techniques such as MRI to generate nuanced neuroimaging signatures for AD diagnosis, as well as a generalizable approach for linking deep learning to pathophysiological processes in human disease.

Cerebral vasospasm is a serious complication following aneurysmal subarachnoidhemorrhage (SAH); it causes delayed cerebral ischemia (DCI) or infarction. Arterial vasospasmis considered the most common cause of disability and mortality among survivors of aneurysmalSAH. Monitoring for vasospasm is extremely important starting from the first day following ahemorrhage. The mechanism of vasospasm is not completely understood, but most data andstudies link the incidence of vasospasm to inflammatory responses secondary to extravasationof blood into the subarachnoid space. It is essential for critical care teams and health careproviders caring for patients with aneurysmal SAH to understand the clinical presentation andmanagement of cerebral vasospasm. In our review, we focus on the guidelines for monitoringand basic management of vasospasm and DCI which include monitoring options, hemodynamicand endovascular therapy, triggers for intervention, and triggers for treatment de-escalation.

Objectives To identify whether intracranial atherosclerotic disease large vessel occlusion strokes differ compared to embolic large vessel occlusion strokes in angiographic response to mechanical thrombectomy and clinical course. Methods Retrospective analysis of acute ischemic stroke patients with large vessel occlusion, due to intracranial atherosclerotic disease or embolic etiology, who underwent mechanical thrombectomy in a primary stroke center from 11/2015 to 4/2018. We categorized patients into intracranial atherosclerotic disease or embolic large vessel occlusion based on the procedural findings. We compared pretreatment, procedural variables, and post-procedural outcomes. Results Ninety-five patients were included, 13 with intracranial atherosclerotic disease large vessel occlusion strokes and 82 with embolic large vessel occlusion strokes. Between the two groups, there was no statistically significant difference in angiographic success (100% for intracranial atherosclerotic disease and 89% for embolic large vessel occlusion strokes); first pass success (38% for intracranial atherosclerotic disease and 34% for embolic large vessel occlusion strokes); puncture-to-first-pass time; puncture-to-recanalization time (68 minutes for intracranial atherosclerotic disease and 62 minutes for embolic large vessel occlusion strokes); number of passes; or clinical outcomes. Intracranial angioplasty was performed in 6 (46%) of intracranial atherosclerotic disease large vessel occlusion patients, and in 5 (6%) of embolic large vessel occlusion patients (p Conclusions Similar angiographic success and procedural time metrics are achievable with intracranial atherosclerotic disease large vessel occlusion and embolic large vessel occlusion therapy. This occurred with more frequent intracranial angioplasty for intracranial atherosclerotic disease large vessel occlusion strokes.

Arteriovenous malformations (AVMs) in the pediatric population are relatively rare but reportedly carry a higher rate of rupture than in adults. This could be due to the fact that most pediatric AVMs are only detected after rupture. We aimed to review the current literature regarding the natural history and the clinical outcome after multimodality AVM treatment in the pediatric population, as optimal management for pediatric AVMs remains controversial. A multidisciplinary approach using multimodality therapy if needed has been proved to be beneficial in approaching these lesions in all age groups. Microsurgical resection remains the gold standard for the treatment of all accessible pediatric AVMs. Embolization and radiosurgery should be considered as an adjunctive therapy. Embolization provides a useful adjunct therapy to microsurgery by preventing significant blood loss and to radiosurgery by decreasing the volume of the AVM. Radiosurgery has been described to provide an alternative treatment approach in certain circumstances either as a primary or adjuvant therapy.

Cerebrovascular injuries after blunt or penetrating head and neck trauma often lead to significant disability from ischemic stroke, hemorrhagic stroke and uncontrolled extracranial hemorrhage. Trauma causes carotid or vertebral dissection, occlusion, pseudoaneurysm, arteriovenous fistula, vessel transection, traumatic epistaxis, venous sinus thrombosis and carotid cavernous fistula. The rapid development of neuroendovascular techniques over the past two decades has led to effective therapies for each of these injuries. Controlled lesion embolization may use coils, liquid embolics (onyx or n-butyl cyanoarcrylate), polyvinyl alcohol particles or detachable balloons; there is stent angioplasty with uncovered, overlapping and covered stents or mechanical thrombolysis using stent-retrievers or aspiration catheters and the use of balloon occlusion tests and supraselective angiography to delineate safety of vessel sacrifice and to diagnose occult lesions respectively. Furthermore, the proliferation of stroke centers has increased local availability of rapid neuroendovascular expertise at many major trauma centers. Neuroendovascular therapies are less invasive than surgery, can often preserve the injured parent vessels and aid in treating conditions where surgery may be limited. In the absence of randomized controlled trials we present a narrative review of current endovascular therapeutic applications for each of these injuries. This expands the therapies at trauma teams' disposal in the continued effort to control bleeding, reduce secondary injury and prevent disability after trauma. Further research is necessary to inform the role of endovascular techniques after trauma. In particular, comparative studies are necessary to quantify the risk and benefits in conditions where surgical options also exist.

Introduction/purpose Bradycardia and hypotension are recognized complications after carotid artery angioplasty and stenting (CAS). Typically this is short-lived but may persist up to 1 week in cases with post stent angioplasty. We report the occurrence of prolonged bradycardia greater than 1 week after CAS without post stent angioplasty. Results A 58 year old man with past medical history of hypertension, diabetes mellitus, gout and smoking presented with left-sided hemiplegia and dysphagia. MRI demonstrated infarction within the right basal ganglia and right frontoparietal white matter. CT Angiography demonstrated, 99% stenosis of right ICA with tandem occlusion of the right middle cerebral artery. Due to tandem occlusion with poor collaterals and age younger than 70 years CAS was elected. Pretreatment was with aspirin and ticagrelor as he was clopidogrel resistant. Conscious sedation with fentanyl 25 µg and anticoagulation with bivalirudin was used. Angiography confirmed ICA stenosis greater than 70% by NASCET criteria. A balance middleweight 0.014-inch wire was used to cross the stenosis and the spider filter embolic protection device, 5 mm, was deployed. Submaximal angioplasty was performed using a 4 mm viatrac balloon to 8 atms. At this point the patient began to experience significant bradycardia and was given atropine. The balloon was removed. A protege 8–6 mm × 40 mm tapered stent was then deployed. Post-stenting angioplasty was not performed. The filter was retrieved. Final control angiogram internal carotid artery revealed less than 10% stenosis by NASCET criteria. Directly following the procedure, the patient’s BP was 84/53 with a HR of 63. A norepinephrine infusion was started and the patient was transferred to ICU. Hypotension persisted 20 hours. However, the patient also became profoundly bradycardic (heart rate equal 20–30 beats per minute). For the following 9 days, the patient continued to experience persistent bradycardia with intermittent asymptomatic decreases in BP (mean arterial pressure 40–60 mmHg) during periods of lowest heart rate. The bradycardia represented sinus bradycardia with sinus pauses without any heart block or junctional rhythms. Discussion Angioplasty induce sinus hypersensitivity syndrome is a complication of carotid angioplasty and stenting. Previous studies suggested that bradycardia lasts for a mean of 26 hours and almost never longer than 48 hours. To our knowledge prior to our report, the longest period of persistent bradycardia after carotid stenting was 7 days. Unlike our case, this occurred in a patient who had post stenting angioplasty. Also of note, the patient in our report did not experience any bradycardia during the 2 days prior to carotid angioplasty and stenting while on ticagrelor. Conclusion Rarely, prolonged bradycardia may occur and persist for greater than 1 week after carotid angioplasty and stenting even in cases without post stent angioplasty. Disclosures D. Archer: None. J. Ferdous: None. Y. Alderazi: None.

Summary The practice of medicine relies on the patient–physician relationship, knowledge, and clinical judgment. Randomized controlled trials (RCTs) remain the least biased method for studying the effects of interventions in selected populations and are the only method to control adequately for unknown confounders. However, physicians face the limitations of RCTs on a daily basis as they treat relatively unselected populations and individual patients. We explore the benefits and limitations of RCTs for some neurologic disorders, and discuss the difficulties of predicting individualized outcomes and anticipating treatment responses in those heterogeneous conditions. Observational studies and advances in understanding neurologic diseases complement RCTs in decision-making. Considerable challenges remain for personalized medicine; for now, clinicians must rely on their ability to integrate evidence and clinical judgment.

Background Pivotal clinical trials suggest that intravenous (IV) recombinant tissue plasminogen activator (rt-PA) benefits stroke patients regardless of the underlying etiology. Paradoxical strokes, presumed to be caused by fibrin-rich clots originating in the venous circulation, may respond better to fibrinolysis than other ischemic stroke subtypes. In this study, we compared the response with IV rt-PA in paradoxical stroke patients and other stroke subtypes. Methods In total, 486 patients treated with IV rt-PA at a single institution were retrospectively reviewed. Adjudication of stroke mechanism was based on chart review. Five major stroke mechanisms—cardioembolic, artery-to-artery emboli, lacunar, cryptogenic, and paradoxical—were identified by final diagnosis from chart reviews. Mimics, undefined etiology, and defined etiology not falling into the major mechanisms were excluded. Analysis of variance and general linear model were used to assess the differences between groups. Results A total of 323 patients were analyzed. We found significant differences in clinical outcome between stroke mechanisms, including discharge National Institutes of Health Stroke Scale (NIHSS) ( P = .007), discharge Rankin ( P = .011), discharge disposition ( P = .000), and infarct volume ( P = .007). Post hoc analysis showed that cardioembolic patients had the worst outcomes (discharge NIHSS score 11.12 ± 12.26), whereas paradoxical strokes had the best outcomes (discharge NIHSS score 3.67 ± 4.90), but these did not approach statistical significance. However, regression analysis showed that 4 variables—congestive heart failure, admission NIHSS, age, and mean infarct volume—rather than stroke mechanism were the true predictors of poor outcome. Conclusions Paradoxical strokes had better outcomes after IV fibrinolysis than other ischemic stroke subtypes, but this difference is attributable to younger age and milder stroke severity on presentation.

Many patients with stroke-mimicking conditions receive treatment with intravenous fibrinolysis (IVF), a treatment associated with potentially serious complications. We sought to determine if any clinical or radiographic characteristics can help predict stroke mimics among IVF candidates.This retrospective study was carried out at a single institution. Patients treated with intravenous recombinant tissue plasminogen activator (rt-PA; n = 193) were divided into 3 categories: acute ischemic stroke (n = 142), aborted stroke (n = 21), and stroke mimics (n = 30). Analysis of variance and the chi-square test were used to assess differences, while logistic regression models were computed to predict groups.Mimics treated with rt-PA did not experience complications (intracranial bleeding, systemic hemorrhage, or angioedema), and had better neurologic and functional outcomes than stroke patients (P.05). Several variables helped differentiate strokes from mimics, including atherosclerosis on computed tomographic angiography (odds ratio [OR] 23.6; 95% confidence interval [CI] 8.4-66.2), atrial fibrillation (OR 11.4; 95% CI 1.5-86.3), age50 years (OR 7.2; 95% CI 2.8-18.5), and focal weakness (OR 4.15; 95% CI 1.75-9.8). Other variables decreased chances of stroke: migraine history (OR 0.05; 95% CI 0.01-0.4), epilepsy (OR 0.13; 95% CI 0.02-0.8), paresthesia (OR 0.1; 95% CI 0.04-0.3), and precordialgia (OR 0.045; 95% CI 0.002-0.9). A regression model using focal weakness, computed tomographic angiography findings, and precordialgia had a 90.2% predictive accuracy.IVF has low complication rates in stroke mimics. Certain clinical characteristics appear predictive of stroke mimics, particularly normal computed tomographic angiography. If confirmed, this may help prevent giving IVF to patients without stroke.

Background Temporomandibular joint (TMJ) ankylosis causes disability through impaired digestion, mastication, speech, and appearance. Surgical treatment increases range of motion with resultant functional improvement. However, substantial perioperative blood loss can occur (up to 3 L) if the internal maxillary artery (IMAX) is injured as it traverses the ankylotic mass. Achieving hemostasis is difficult because of limited proximal IMAX access and poor visualization. Our aim is to investigate the technical feasibility and preliminary safety of preoperative IMAX embolization in patients undergoing TMJ ankylosis surgery. Methods Case series using chart reviews of 2 patients who underwent preoperative embolization before TMJ ankylosis surgery. Results Both patients were women (28 and 51 years old) who had severely restricted mouth opening. Embolization was performed using general anesthesia with nasal intubation on the same day of TMJ surgery. Both patients underwent bilateral IMAX embolization using pushable coils (Vortex, Boston Scientific) of distal IMAX followed by n-butyl-cyanoacrylate (Trufill, Cordis) embolization from coil mass up to proximal IMAX. There were no complications from the embolization procedures. Both patients had normal neurologic examination results. TMJ surgery occurred with minimal operative blood loss (≤300 mL for each surgery). Maximum postoperative mouth opening was 35 mm and 34 mm, respectively. One patient had a postoperative TMJ wound infection that was managed with antibiotics. Conclusions Preoperative IMAX embolization before TMJ ankylosis surgery is technically feasible with encouraging preliminary safety. There were no complications from the embolization procedures and surgeries occurred with low volumes of blood loss.

Background: There is limited experience in the community with intravenous tissue plasminogen activator (rt-PA) administered 3 to 4.5 hours after acute ischemic stroke (AIS) onset. Many patients do not meet entry criteria of pivotal clinical trials because of severe stroke, age >80, severe hypertension (sHTN), or history of previous stroke and diabetes. Whether rt-PA benefits these patients is unclear. Thus, we investigated the outcomes of stroke patients treated with rt-PA with or without these adverse clinical characteristics. Methods: Chart review of patients with AIS treated with intravenous rt-PA at a single institution. Outcomes at discharge were compared between patients with severe stroke, age >80, sHTN, or previous stroke/diabetes and those without these characteristics. Good outcome was defined as modified Rankin score (mRS) of 0 to 1. Analysis of variance and t tests were used to compare the outcomes. Results: Of the 118 cases analyzed, 103 (87%) were treated ≤3 hours and 15 (13%) between 3 and 4.5 hours. Sixty-three (53%) patients had severe stroke, age >80, sHTN, or previous stroke/diabetes, whereas 55 (47%) did not. Compared to controls, patients with these adverse characteristics were less likely to have good outcomes (35% vs 56%, p = .02). No patients treated within the 3- to 4.5-hour window experienced symptomatic intracranial hemorrhage (sICH). Eight patients treated between 3 and 4.5 hours had severe stroke, age >80, sHTN, or previous stroke/diabetes. Of these, 6 had poor outcomes. Conclusions: In a highly selected group of patients treated with intravenous rt-PA, lack of adherence to current guidelines did not improve stroke outcomes. This was related to more severe strokes at baseline, not sICH. Prospective studies of this patient group are needed.

Perineuritis is an unusual cause of direct peripheral nerve injury. We describe the clinicopathologic features of a 56-year-old man with mononeuritis multiplex due to Lyme disease; sural nerve biopsy demonstrated florid perineuritis. Treatment with intravenous ceftriaxone resulted in marked neurologic improvement. This study supports the notion that perineuritis forms part of the pathogenesis in acute Lyme neuroborreliosis.

Summary Alcohol is a substance that impacts the social, psychological, medical, economic and religious spheres of our existence. It is part of every society. Alcohol in moderation can be beneficial. Alcohol abuse mediates its effects both on the developing and the developed brain, directly or indirectly, and has acute and chronic complications. Damage to the developing brain can result from alcohol consumption in pregnancy. Misuse of alcohol in adults can affect both the central and the peripheral nervous system. Direct effects arise due to the toxic and intoxicating effects of alcohol. Nutritional deficiencies are thought to mediate most of the indirect effects of alcohol, as patients with alcohol dependence tend to eat less and derive most of their caloric intake from the alcoholic beverages they consume. Alcohol-related disease places a burden on our health-care systems. In this review, we examine the pathological effects of alcohol on the nervous system.

Background and Purpose: Platelet function testing in neurointerventional (NI) procedures is still controversial. We compared the clinical outcomes between antiplatelet responders and nonresponders based on the results of the VerifyNow (VN) testing method. Methods: This is a retrospective single-center analysis of all consecutive patients who underwent NI stenting procedures from January 2007 through July 2013 and had documented preprocedural aspirin (ASA) and clopidogrel VN assays. Patients were divided into two groups based on their responsiveness to antiplatelet. Baseline characteristics, good functional outcome measured by the modified Rankin Scale (mRS) at 90 days, combined procedural complication rate defined as postprocedural stroke, in-stent thrombosis, and intraoperative rupture were compared between the two groups. Results: Our cohort included 37 patients: 26 were in the responder group (RG) and 11 were in the nonresponder group (NRG). Baseline characteristics were similar between the two groups. Even though the combined complication rate was similar between the two groups [NRG: 2/11 (18%) vs. RG: 2/26 (7%); p = 0.33], there was a trend for a higher rate of good functional outcome (90-day mRS: 0-2) in the RG (22/22, 100%) as compared to the NRG (8/10, 80%) (p = 0.0907). Conclusion: Overall, utilizing the VN antiplatelet function testing did not significantly change the clinical outcome after the NI procedures. Larger randomized trials are warranted to provide a better understanding of the utility of the antiplatelet testing in NI stenting procedures.

TIA as a medical emergency requires early appropriate management to minimize the risk of adverse outcomes.1 Traditionally, we addressed this challenge by admitting all patients with TIA to the hospital, presuming that this would offer the best care available with the least possible delay. Over the past decade, increasing evidence has emerged that not all patients with TIA require hospital admission, and that some or even most patients can be safely managed in the outpatient setting.2

A 45-year-old man presented with a painful bulging right eye and blindness 6 weeks after a motorcycle accident and traumatic brain injury. He had a complete right oculomotor nerve palsy and only perception of light. MRI revealed ipsilateral pontomesencephalic edema (figure, A and B). Catheter angiography showed a direct right carotid-cavernous fistula (figure, C). Two months after coil embolization, the ptosis, proptosis and ophthalmoplegia resolved. MRI revealed resolution of pontomesencephalic edema (figure, D). The presumed mechanism was transmission of arterialized pressures of the cavernous sinus via a bridging vein to the anterior pontomesencephalic vein, generating venous hypertension and vasogenic edema.1,2

For the past two decades, intravenous tissue plasminogenactivator (IV tPA) has been the gold standardtreatment of acute ischemic stroke (AIS) for patientspresenting to the hospital in the first 4.5 hours aftersymptom onset. However, in patients with AIS due tointracranial large vessel occlusion (LVO), IV tPA hasvery poor recanalization rates. This group of patientshas significantly worse outcomes than those withoutLVO. Endovascular therapy has evolved significantlysince the first trial in 1998. With the publication of recenttrials using modern stent-retriever devices andselection of patients with LVO, endovascular therapyhas become the standard of care for patients with themost severe ischemic strokes. In this article we outlinethe two decade evolution of this therapy.

Flow diverters (pipeline embolization device, Silk flow diverter, and Surpass flow diverter) have been developed to treat intracranial aneurysms. These endovascular devices are placed within the parent artery rather than the aneurysm sac. They take advantage of altering hemodynamics at the aneurysm/parent vessel interface, resulting in gradual thrombosis of the aneurysm occurring over time. Subsequent inflammatory response, healing, and endothelial growth shrink the aneurysm and reconstruct the parent artery lumen while preserving perforators and side branches in most cases. Flow diverters have already allowed treatment of previously untreatable wide neck and giant aneurysms. There are risks with flow diverters including in-stent thrombosis, perianeurysmal edema, distant and delayed hemorrhages, and perforator occlusions. Comparative efficacy and safety against other therapies are being studied in ongoing trials. Antiplatelet therapy is mandatory with flow diverters, which has highlighted the need for better evidence for monitoring and tailoring antiplatelet therapy. In this paper we review the devices, their uses, associated complications, evidence base, and ongoing studies.

Two non-identical brothers were diagnosed with anaplastic oligoastrocytoma within 4 months of each other and a maternal grandmother was diagnosed with oligodendroglioma 21 years previously. Familial clustering of oligodendrogliomas is rare.

In this issue of Neurology ®, Wang et al.1 report the results of a subanalysis of the Clopidogrel in High-risk Patients with Acute Non-disabling Cerebrovascular Events (CHANCE) trial of dual antiplatelet agents administered within 24 hours of onset of high-risk TIA (defined as ABCD2 score ≥4) or minor stroke (defined as NIH Stroke Scale score ≤3). In this study, they explored the outcomes of functional disability, as measured by the modified Rankin Scale, and quality of life, as measured by the EuroQol-5 Dimension. The published CHANCE trial results demonstrated that the combination of clopidogrel and aspirin (for 21 days, followed by clopidogrel alone until 90 days) was superior to aspirin plus placebo for 90 days in preventing recurrent stroke after TIA or minor stroke.2 The current study demonstrates the superiority of dual antiplatelet therapy compared to aspirin in improving the 90-day functional outcome. The analysis suggests that this is mediated via a reduction in the occurrence of disabling stroke. The finding has importance to patients, clinicians, and policymakers, because disability from stroke has personal, economic, and societal implications.

Background Symptomatic intracranial hemorrhage (sICH) occurs uncommonly after ischemic stroke therapy with tissue plasminogen activator (tPA). Clotting factor administration may be a treatment option. Objective To determine if treatment with clotting factors (fresh frozen plasma [FFP] or cryoprecipitate) was associated with improved outcomes in sICH. Methods We conducted a retrospective cohort study within University of Texas at Houston Stroke registry involving consecutive patients from February 1, 2007, to June 30, 2011, with tPA-related sICH, including cases with subsequent intra-arterial therapy. Outcomes were Modified Rankin Scale (mRS) score at discharge, death, and hematoma expansion. Results Of 921 patients treated with tPA, 48 (5.2%) had sICH and 45 met criteria for the study. Nineteen patients received clotting factors (42.2%; 18 received FFP and 7 received cryoprecipitate), whereas 26 (57.8%) patients received conservative management without clotting factors. None of the patients treated with clotting factors and only 2 of those who did not receive clotting factors had a good outcome, mRS score of 2 or less. All the patients treated with clotting factors and most of those not treated were left bedridden or dead (mRS score 4-6), 19 (100%) versus 22 (85%). Mortality was 9 (47.4%) versus 9 (34.6%), respectively. There was no difference in hematoma expansion between the 2 groups. Conclusions We found no evidence that treatment for sICH with clotting factors has a favorable effect on clinical or radiological outcomes. However, the sample was small because of the low frequency of sICH. New treatments are urgently needed for this uncommon yet serious condition.

Background and Objectives: Argatroban is a direct thrombin inhibitor that safely augments the benefit of tPA in animal stroke models. The Argatroban tPA Stroke Study (ARTSS-1), was a recently completed NIH sponsored, Phase IIa, prospective, open-label, safety and activity study of Argatroban and tPA in patients with ischemic stroke ( NCT00268762 ). Symptomatic hemorrhage occurred in 4.6% and rates of complete recanalization were 30% and 63% at 2 and 24 hours, respectively. We hypothesized that stroke subtypes might respond differently to the treatment combination. Methods: A total of 65 patients with intracranial large vessel occlusive disease were given standard dose (0.9mg/kg) tPA and a 100 μg/kg bolus of argatroban followed by infusion of 1 μg/kg per minute for 48 hours adjusted to a PTT of 1.75 times baseline. Pre-tPA vessel imaging using TCD or CTA confirmed intracranial occlusions. A multivariate logistic regression was performed to test whether stroke subtype independently influenced recanalization after controlling for: NIHSS, antithrombotic use, diabetes, age and clot location (ICA, MCA, Vertebrobasilar). Results: Recanalization data was available for 47 patients at 2-hours. Baseline characteristics are displayed in the table. After adjusting for age, NIHSS, diabetes, clot location and previous antithrombotic use, there was no difference between any recanalization at 2-hours in the different stroke etiologies. Interestingly, M1 clots were more likely to recanalize compared with M2 (OR 6.2; 95% CI 1.3-25, p=0.019). Results were similar when only analyzing 2-hours complete recanalization. Conclusion: Although all large vessel stroke subtypes recanalize at similar rates when treated with combination Argatroban and rtPA, larger thrombi may benefit to a greater degree. A randomized, controlled clinical trial of this promising adjunctive therapy is warranted and ongoing (ARTSS-2 trial, NCT01464788 ).

Background and Objectives: Early neurological improvement (ENI) at 2-hours post thrombolysis has recently been proposed to most accurately predict recanalization when repeat vascular imaging is not available. However, these studies analyzed recanalization at a delayed time point (≥24 hours). The Argatroban tPA Stroke Study (ARTSS-1), is a recently completed NIH sponsored, Phase IIa, prospective, open-label, safety and activity study of Argatroban and rtPA in patients with ischemic stroke ( NCT00268762 ). We hypothesized 2-hour recanalization correlates with ENI (NIHSS improvement of 20% or greater from baseline). Methods: A total of 65 patients with intracranial large vessel occlusive disease were given standard dose (0.9mg/kg) tPA and a 100 μg/kg bolus of argatroban followed by infusion of 1 μg/kg per minute for 48 hours adjusted to a PTT of 1.75 times baseline. Pre-tPA vessel imaging using TCD or CTA confirmed intracranial occlusions. A multivariate logistic regression tested whether recanalization at 2 hours was associated with ENI after controlling for age, NIHSS, clot location (ICA, MCA or vertebrobasilar). We analyzed whether patients with ENI had statistically significant greater odds of an excellent mRS (0 or 1) at day 7. Results: Recanalization data was available for 47 patients at 2-hours. ENI occurred at 2-hours in 46% patients. Patients with any recanalization (complete or partial) at 2-hours were more likely to experience ENI (OR 3.4; 95% CI 0.71-16.6, p=0.124). This association strengthened when 2-hour complete recanalization was analyzed (OR 5.4; 95% CI 0.98-29.2, p=0.053). In an unadjusted analysis, patients with ENI at 2-hours were five times more likely to have excellent mRS outcomes at day 7 (OR 4.7; 95% CI 1.4-15.6, p=0.01). In the adjusted model, the association remained significant (OR 3.8; 95%CI 1.1-13.4, p=0.041). Conclusion: Two-hour recanalization is predictive of early neurological improvement and better early clinical outcomes in patients treated with combination Argatroban and tPA. A randomized, controlled clinical trial of this promising adjunctive therapy is warranted and ongoing (ARTSS-2 trial, NCT01464788 ).

Discoveries of the mechanisms that underlie the pathogenesis of multiple sclerosis have been acquired at an impressive rate over the last few decades and, as a consequence, a growing number of treatments are becoming available for this disease. This review first analyzes the experience from the early stages of the disease-modifying therapies, then, expanding on the concept of early treatment for improved outcomes, it focuses on natalizumab and its major complication, progressive multifocal leukoencephalopathy. We offer views on the risks associated with the use of natalizumab by underscoring the importance of the JC virus serology and by providing preliminary data on our experience with the extended interval dosing of natalizumab. This approach, which advocates individualized treatment plans, raises the question of the minimum effective natalizumab dose. Extended interval dosing suggests efficacy can be maintained while providing advantages of costs and convenience over regular monthly dosing. More data examining this strategy are necessary.

Objective & Background: Significant intracranial hemorrhage (sigICH), defined as either symptomatic intracerebral hemorrhage SICH or parenchymal hematoma type 2 (PH2), is a concerning complication of thrombolysis for acute ischemic stroke (AIS). While clotting factors have been incorporated into clinical protocols, the effectiveness of such treatment for sigICH has not been evaluated. We investigated the effects of clotting factors, fresh frozen plasma FFP and cryoprecipitate, in patients with sigICH post thrombolysis. Methods: We retrospectively evaluated all patients with sigICH after TPA for AIS in the prospective University of Texas at Houston Stroke registry; January 2007 - July 2011. We included all patients who received TPA for AIS and subsequently developed sigICH. Patients either received clotting factors (FFP or cryoprecipitate) or conservative management. The primary outcome measure was modified Rankin scale at discharge. The other outcome was death. We collected data on confounding variables: Stroke risk factors, infarct prognostic variables and intracerebral hematoma prognostic variables. Statistical analysis was by Fisher-exact, Chi-square and Mann-Whitney-U tests. Results: Out of 921 patients receiving TPA, sigICH occurred in 50. We excluded 3 because of enrollment in clinical trials. Out of 47 patients, 37 received IV TPA alone and 10 received IV TPA with subsequent intra-arterial therapy. Clotting factors were given in 22/47 (46.8%) patients; 18 received FFP & 9 received cryoprecipitate. The rest received no specific therapies for hemorrhage. There was no difference in stroke severity between groups before and after TPA. The incidence of hydrocephalus was higher in patients receiving clotting factors. There were no differences in outcomes at discharge in either group; the majority of patients in both groups had poor outcomes (mRS was >3). Mortality was high and not different between the two groups. Fibrinogen levels before and after clotting factors did not significantly differ from the patients who received only conservative management. Table 1. Conclusions: We found that clinical outcome of sigICH post TPA is poor. Furthermore, our data suggest that clotting factors do not improve the poor outcome associated with sigICH after t-PA. Our study is limited by small sample size, and the higher incidence of hydrocephalus in those receiving clotting factors may have influenced the outcomes. Nevertheless, our data suggest that new therapies are urgently needed for t-PA associated intracranial hemorrhage.

Stem cell transplantation is an investigational therapy for multiple sclerosis. The authors describe a case of catastrophic demyelinating encephalomyelitis following stem cell transplantation in a 17-year-old girl. Nine months after an initial diagnosis of multiple sclerosis, she underwent stem cell transplantation in Costa Rica. Subsequently, she deteriorated and was transported back to the United States with headache and vomiting progressing to quadriparesis, locked-in syndrome, and superimposed encephalopathy. Magnetic resonance imaging and brain biopsy were consistent with fulminant demyelinating encephalomyelitis with enhancing parenchyma and leptomeninges. Cerebrospinal fluid analysis revealed lymphocytic pleocytosis and high protein. The protracted illness required tracheostomy and gastrostomy. After methyleprednisone, intravenous immunoglobulin, and cyclophosphamide, she improved during 2.5 months to an ambulatory, functionally independent state. Subsequently, typical less severe multiple sclerosis relapses occurred. This case demonstrates that stem cell transplantation may provoke life-threatening encephalomyelitis in patients with multiple sclerosis. This highlights the need to restrict transplantation to trials with appropriate safety controls.

Antithrombotic medication is a cornerstone of acute ischemic stroke treatment and secondary prevention. The efficacy of thrombolysis with alteplase in acute stroke has been demonstrated in several clinical trials. This safe and costeffective therapy has transformed the practice of stroke care and has led to subsequent trials of other antithrombotic medications for treatment of ischemic stroke in the acute phase. These antithrombotics include thrombolytic, antiplatelet and anticoagulant agents. While, no other medication has yet demonstrated adequate efficacy, our current and evolving understanding of infarct expansion, ischemic penumbra, collateral circulation and the blood brain barrier is allowing testing of antithrombotic medications tailored to individual patient pathophysiology in clinical trials. This understanding accompanies developments in neuroimaging and organization of stroke care that allow for wide-spread recruitment in these trials. Alteplase remains the mainstay treatment of arterial acute ischemic stroke; however, anticoagulation is the standard therapy for cerebral venous sinus thrombosis. Antithrombotic use in acute stroke, arterial and venous, has demonstrated efficacy but leaves many questions unanswered. This patient population is a fertile ground for novel research, especially as it relates to; combination antithrombotic therapy, combination of pharmacological and mechanical thrombolysis, and the transition to secondary prevention. Here we review the current antithrombotics in the acute phase of ischemic stroke highlighting the evidence-base and areas of uncertainty.

Primary intracranial plasma cell granuloma (PCG) is a rare form of inflammatory pseudotumour often characterized by non-neoplastic proliferation of plasma cells. The following case indicates a potential role for steroid therapy after subtotal resection.

Introduction/purpose Developmental venous anomalies (DVAs) are variations of normal transmedullary veins that are necessary for the drainage of white and gray matter. DVAs are predominantly benign anatomic variations and are usually incidentally discovered. In exceedingly rare cases, DVAs can be symptomatic due to mechanical or flow-related pathophysiological mechanisms. Restriction of outflow can produce a variety of morphological and clinical presentations ranging from venous congestive edema to hemorrhage. We present a case of a 53-year-old female with an infratentorial thrombosed DVA that caused venous congestive edema. Materials and methods A retrospective review of the patient’s electronic medical record including inpatient notes and all radiological exams was performed. Results A 53 year-old female without past medical history presented to the emergency room with 3 days of headache, vertigo and ataxia. On physical examination, she demonstrated left upper extremity dysmetria and abnormal gait. MRI of the brain showed tortuous venous structures in the left cerebellar hemisphere and left side of the pons converging into a prominent structure with extensive susceptibility artifact. There was increased T2/FLAIR signal in the pons, left brachium pontis and dorsal medulla. These findings were consistent with a thrombosed developmental venous anomaly causing venous congestive edema. The patient was placed on steroids and diagnostic cerebral angiography confirmed the DVA. No other vascular malformation was identified. Demonstration of a thrombosed DVA in the absence of an associated cavernous malformation, arteriovenous malformation or dural fistula justified treatment with anticoagulation. Her symptoms improved on steroids and she was continued on anticoagulation. Conclusion Although the vast majority of DVAs are benign lesions, understanding the pathophysiological mechanisms behind symptomatic DVAs is important for treatment. We present a case of thrombosed DVA in the absence of additional vascular abnormality, thus justifying anticoagulation therapy. Differentiating a thrombosed DVA from a partially thrombosed arteriovenous malformation or dural fistula is vital as these other conditions may warrant surgery, radiosurgery or endovascular embolization. Disclosures K. Amuluru: None. Y. Alderazi: None. C. Gandhi: None.