Cardiovascular safety of dihydroergotamine mesylate delivered by precision olfactory delivery (INP104) for the acute treatment of migraine.

OBJECTIVE: To report the cardiovascular (CV) safety of dihydroergotamine mesylate (DHE) administered by precision olfactory delivery (INP104) from two clinical trials. BACKGROUND: Although the absolute risk is low, migraine is associated with an increased risk of CV events. DHE is a highly effective acute treatment for migraine, but due to its theoretical risk of promoting arterial vasoconstriction, DHE is contraindicated in patients with CV disease or an unfavorable risk factor profile. The INP104 is a novel drug-device combination product approved for acute treatment of migraine that delivers DHE to the upper nasal space using precision olfactory delivery (POD®). METHODS: The STOP 101 was a Phase 1 open-label study that assessed the safety, tolerability, and bioavailability of INP104 1.45 mg, intravenous DHE 1.0 mg, and MIGRANAL (nasal DHE) 2.0 mg in healthy participants. The STOP 301 was a pivotal Phase 3, open-label study that assessed the safety, tolerability, and exploratory efficacy of INP104 1.45 mg over 24 and 52 weeks in patients with migraine. In both studies, active or a history of CV disease, as well as significant CV risk factors, were exclusion criteria. RESULTS: In STOP 101, 36 participants received one or more doses of investigational product. Treatment with intravenous DHE, but not INP104 or nasal DHE, resulted in clinically relevant changes from baseline in systolic blood pressure (BP; 11.4 mmHg, 95% confidence interval [CI] 7.9-15.0) and diastolic BP (13.3 mmHg, 95% CI 9.4-17.1) at 5 min post-dose, persisting up to 30 min post-dose for systolic BP (6.3 mmHg; 95% CI 3.0-9.5) and diastolic BP (7.9 mmHg, 95% CI 3.9-11.9). None of the treatments produced any clinically meaningful electrocardiogram (ECG) changes. In STOP 301, 354 patients received one or more doses of INP104. Over 24 weeks, five patients (1.4%) experienced a non-serious, vascular treatment-emergent adverse event (TEAE). Minimal changes were observed for BP and ECG parameters over 24 or 52 weeks. Off-protocol concomitant use of triptans and other ergot derivatives did not result in any TEAEs. CONCLUSION: In two separate studies, INP104 demonstrated a favorable CV safety profile when used in a study population without CV-related contraindications.

Advances in Management of the Stroke Etiology One-Percenters.

PURPOSE OF REVIEW: Uncommon causes of stroke merit specific attention; when clinicians have less common etiologies of stoke in mind, the diagnosis may come more easily. This is key, as optimal management will in many cases differs significantly from "standard" care. RECENT FINDINGS: Randomized controlled trials (RCT) on the best medical therapy in the treatment of cervical artery dissection (CeAD) have demonstrated low rates of ischemia with both antiplatelet and vitamin K antagonism. RCT evidence supports the use of anticoagulation with vitamin K antagonism in "high-risk" patients with antiphospholipid antibody syndrome (APLAS), and there is new evidence supporting the utilization of direct oral anticoagulation in malignancy-associated thrombosis. Migraine with aura has been more conclusively linked not only with increased risk of ischemic and hemorrhagic stroke, but also with cardiovascular mortality. Recent literature has surprisingly not provided support the utilization of L-arginine in the treatment of patients with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS); however, there is evidence at this time that support use of enzyme replacement in patients with Fabry disease. Additional triggers for reversible cerebral vasoconstriction syndrome (RCVS) have been identified, such as capsaicin. Imaging of cerebral blood vessel walls utilizing contrast-enhanced MRA is an emerging modality that may ultimately prove to be very useful in the evaluation of patients with uncommon causes of stroke. A plethora of associations between cerebrovascular disease and COVID-19 have been described. Where pertinent, authors provide additional tips and guidance. Less commonly encountered conditions with updates in diagnosis, and management along with clinical tips are reviewed.

Leptomeningeal Carcinomatosis Mimicking Reversible Cerebral Vasoconstriction Syndrome.

Leptomeningeal carcinomatosis is the result of metastatic infiltration of the leptomeninges by malignant cells originating from an extra-meningeal primary tumor site. We describe a patient with active breast cancer who presented with thunderclap headaches (THs) and imaging showing multi-segment irregular arterial narrowing of intracranial vasculature. A 58-year-old Caucasian woman with active stage IV estrogen receptor-positive breast adenocarcinoma and migraine presented with THs. Computed tomography and brain magnetic resonance imaging (MRI) without contrast were unremarkable. Over a period of one week, she had recurrent THs. Interval vessel imaging showed multi-segment irregular arterial narrowing. Treatment with verapamil was initiated for suspected reversible cerebral vasoconstriction syndrome (RCVS). She subsequently had two discrete episodes of confusion with aphasia and left upper extremity numbness. Repeat gadolinium-enhanced MRI showed nodular leptomeningeal enhancement. Lumbar puncture revealed malignant cells in the cerebrospinal fluid consistent with leptomeningeal carcinomatosis. She subsequently underwent whole brain radiation treatment and intrathecal chemotherapy and had no further episodes of TH. Our case emphasizes the importance of considering leptomeningeal carcinomatosis in the differential diagnosis of THs and reversible cerebral vasculopathy, especially in patients with known underlying active cancer. The illustration also proves the importance of a complete work-up in patients with known malignancy in the setting of suspected RCVS.

Acute telestroke evaluations during the COVID-19 pandemic.

We sought to analyze the effect of COVID-19 on telestroke requests and to characterize patients remotely evaluated for acute ischemic stroke (AIS) during this time. This study is a retrospective database review of all telestroke requests at one academic vascular neurology center telestroke network with seven remote sites in the USA between March 15 and April 30, 2020. Data were compared with historical cohort spanning same time frame in 2019 using parametric or nonparametric methods as appropriate. Among telestroke requests, characteristics of age, gender, race/ethnicity, National Institutes of Health Stroke Scale (NIHSS), primary diagnosis of AIS or transient ischemic attack (TIA), and number of patients receiving intravenous alteplase (IV-rtPA) and endovascular therapy (ET) were recorded. There was a 53% decrease in telestroke evaluation requests in 2020 from 2019 (p < 0.00001). Mean NIHSS in 2020 was 9.1 (SD ± 8.4) and mean NIHSS in 2019 was 7.2 (SD ± 7.3) (p = 0.122). Among patients with primary diagnosis of suspected AIS or TIA, mean age was 60.5 years in 2020 (SD ± 17.5) and mean age of 67.0 years in 2019 (SD ± 16.0) (p = 0.038). A significant lower number of telestroke evaluations were performed with a higher mean NIHSS overall and a lower mean age among AIS/TIA-suspected patients. Higher NIHSS and severity in all telestroke evaluations reflect neurological manifestations of AIS and mimics, possibly influenced by COVID-19. The younger age of those with suspected AIS or TIA reflects thrombotic complications in atypical stroke populations.

Acute Large Vessel Ischemic Stroke in Patients With COVID-19-Related Multisystem Inflammatory Syndrome.

BACKGROUND: Acute ischemic stroke (AIS) is rare in children, and diagnosis is often delayed. Neurological involvement may occur in multisystem inflammatory syndrome in children (MIS-C), but very few cases of AIS in patients with MIS-C have been reported. PATIENT DESCRIPTIONS: We two patients with AIS presenting with large vessel occlusive disease in previously healthy adolescents recently exposed to SARS-CoV-2 infection. RESULTS: Both patients were subsequently diagnosed with and treated for MIS-C. Here, we discuss the course of their treatments and clinical responses. CONCLUSION: Early recognition and diagnosis of AIS with large vessel occlusion in children with MIS-C is critical to make available all treatment options to improve clinical outcomes.

Timing of Anticoagulation after Stroke in Patients with Non-Valvular Atrial Fibrillation Assessment of Provider Practices.

BACKGROUND: Optimal timing of oral anticoagulation (TOAC) in acute ischemic stroke (AIS) in patients with atrial fibrillation (AF) is unknown. The risk of recurrent ischemic events when treatment is delayed is often weighed against that of hemorrhagic transformation (HT) when anticoagulation is started in the subacute phase, especially in moderate to large infarctions. Despite substantial evidence for the benefit of oral anticoagulation (OAC) in reducing stroke recurrence, current nationally recognized practice guidelines do not provide clear recommendations on the TOAC after AF-related AIS. MATERIALS AND METHODS: We surveyed neurologists on therapeutic approaches to timing of anticoagulation after stroke in patients with AF (without moderate or severe mitral stenosis or a mechanical heart valve) using an online questionnaire. Several ischemic and hemorrhagic stroke scenarios with various stroke sizes, locations, and high-risk thrombotic complications were presented, and survey respondents were asked to provide post-stroke timeframe for TOAC. Practice background, specialty and years of experience of respondents were recorded. RESULTS: Majority of participants favored early initiation of OAC in small infarcts. In moderate to larger infarct burden, or when ischemia was complicated by HT, there was an overall trend to delay any initiation of OAC, irrespective of specialty or years of experience. The overt presence of an additional cardiac embolic source such as cardiac thrombus led decisions for early anticoagulation. CONCLUSION: Although general practice trends were captured, optimal TOAC following AIS in AF remains unknown. Further research is warranted to determine optimal timing and anticoagulant selection.

Neurologic complications of nonbacterial thrombotic endocarditis.

Endocarditis is an inflammatory or infective condition affecting the cardiac valves or endocardium, often associated with serious neurological sequelae. Nonbacterial thrombotic endocarditis (NBTE)-referred to as degenerative, Libman-Sachs, marantic, verrucous, or terminal endocarditis-is a serious but rare cause of valvular heart disease characterized by deposition of sterile vegetations of fibrin and platelet aggregates on the cardiac valves, eventually resulting in life-threatening embolization of these thrombi to the brain, limbs, or visceral organs. NBTE may complicate a heterogeneous group of chronic conditions, predominantly connective tissue and autoimmune disorders, malignancies, and diseases associated with hypercoagulability states. NBTE usually affects the native rather than prosthetic valves, and unlike infective endocarditis (IE), sparing the involved valve function without its destruction. Compared to those seen in IE, vegetations in NBTE are small and friable, thus may easily be dislodged leading to systemic thromboembolism with devastating morbidities and mortality. There are no diagnostic criteria for NBTE, and antemortem diagnosis is challenging. The condition should be suspected in patients with thromboembolic events and vegetations on the cardiac valves on echocardiographic or cardiac imaging studies, in the absence of underlying infection, especially in disorders predisposing to coagulopathy. Early recognition and prompt treatment of the primary underlying disorder is essential. Anticoagulation with heparin or heparinoid products is recommended to prevent recurrent embolism. Surgical intervention is not indicated except in selected patients with life-threatening recurrent embolism.

Acute Ischemic Stroke and COVID-19: Experience From a Comprehensive Stroke Center in Midwest US.

Background: COVID-19 has been associated with increased risk of venous and arterial thromboembolism including ischemic stroke. We report on patients with acute ischemic stroke and concomitant COVID-19 in a diverse patient population. Methods: This is a retrospective analysis of patients hospitalized with acute ischemic stroke (AIS) and COVID-19 to our comprehensive stroke center in Chicago, IL, between March 1, 2020, and April 30, 2020. We reviewed stroke characteristics, etiologies, and composite outcomes. We then compared our cohort with historic patients with AIS without COVID-19 admitted in the same time frame in 2019 and 2020. Results: Out of 13 patients with AIS and COVID-19, Latinos and African-Americans compromised the majority of our cohort (76.8%), with age ranging from 31-80 years. Most strokes were cortical (84.6%) and more than 50% of patients had no identifiable source, and were categorized as embolic stroke of unknown source (ESUS). A trend toward less alteplase administration was noted in the COVID-19 stroke patients compared to the non-COVID group from 2020 and 2019 (7.1 vs. 20.7% p 0.435 and 7.1 vs. 27.2% p 0.178). Endovascular thrombectomy was performed in 3 (23%) patients. Systemic thrombotic complications occurred in 3 (23%) COVID-19 AIS patients. Median National Institutes of Health Stroke Scale and modified Rankin Scale at discharge were 11 (IQR 4-23) and 4 (IQR 3-4), respectively. In the logistic regression model corrected for age and sex, COVID-19 was associated with discharge to mRS > 2 (p 0.046, OR 3.82, CI 1.02-14.3). Eight patients (63.8%) were discharged home or to acute rehabilitation, and two deceased from COVID-19 complications. Conclusion: AIS in the setting of COVID-19 is associated with worse outcomes, especially among African-American and Latino populations. Large vessel disease with ESUS was common suggesting an increased risk of coagulopathy and endothelial dysfunction as a potential etiology.

Eptifibatide use following emergent carotid stenting in acute anterior circulation ischemic stroke with tandem occlusion.

BACKGROUND: Early revascularization of the extracranial internal carotid artery in acute anterior circulation ischemic stroke (ACIS) is feasible and may improve clinical outcome. When a stent is deployed, antithrombotic agents should be administered peri-procedurally to ensure stent patency. Our institution implemented a protocol for the use of eptifibatide as a means of maintaining stent patency in the treatment of ACIS associated with cervical internal carotid artery occlusion. METHODS: Our internal database was queried for patients who received emergent endovascular therapy (ET) for ACIS with stent placement and eptifibatide administration between July 2016 and 2019. RESULTS: Twenty nine patients met the study criteria. The etiology was large artery atherosclerosis in 26 cases. Two patients had a dissection (7%), and one had a carotid occlusion related to a recent carotid endarterectomy. Mean NIHSS was 14. Sixteen patients received IVrtPA. Extracranial-intracranial tandem occlusion (TO) was present in 21 of cases. All patients received an eptifibatide bolus followed by an infusion for approximately 24 hours post stent deployment. Head CT was obtained prior to initiation of oral dual antiplatelet therapy with aspirin and clopidogrel. Successful recanalization was achieved in all patients with no evidence of downstream embolization. Symptomatic intracerebral hemorrhage occurred in one patient. Stent occlusion occurred in two patients, only one of which was symptomatic. Favorable clinical outcome with mRS ≤ 2 at 3 months was achieved in seventeen patients. CONCLUSIONS: The use of eptifibatide post procedure was associated with low risk of symptomatic intracranial hemorrhage, including in patients treated with rtPA.

Neurological manifestations and COVID-19: Experiences from a tertiary care center at the Frontline.

OBJECTIVE: To report neurological manifestations seen in patients hospitalized with Coronavirus disease 2019 (COVID-19) from a large academic medical center in Chicago, Illinois. METHODS: We retrospectively reviewed data records of 50 patients with COVID-19 who were evaluated by the neurology services from March 1, 2020 - April 30, 2020. Patients were categorized into 2 groups based on timing of developing neurological manifestations: the "Neuro first" group had neurological manifestations upon initial assessment, and the "COVID first" group developed neurological symptoms greater than 24 h after hospitalization. The demographics, comorbidities, disease severity and neurological symptoms and diagnoses of both groups were analyzed. Statistical analysis was performed to compare the two groups. RESULTS: A total of 50 patients (48% African American and 24% Latino) were included in the analysis. Most common neurological manifestations observed were encephalopathy (n = 30), cerebrovascular disease (n = 20), cognitive impairment (n = 13), seizures (n = 13), hypoxic brain injury (n = 7), dysgeusia (n = 5), and extraocular movement abnormalities (n = 5). The "COVID-19 first" group had more evidence of physiologic disturbances on arrival with a more severe/critical disease course (83.3% vs 53.8%, p 0.025). CONCLUSION: Neurologic manifestations of COVID-19 are highly variable and can occur prior to the diagnosis of or as a complication of the viral infection. Despite similar baseline comorbidities and demographics, the COVID-19 patients who developed neurologic symptoms later in hospitalization had more severe disease courses. Differently from previous studies, we noted a high percentage of African American and Latino individuals in both groups.

Acute Stroke Care in the Coronavirus Disease 2019 Pandemic.

Coronavirus disease 2019 (COVID-19) is a pandemic respiratory disease with serious public health risk and has taken the world off-guard with its rapid spread. As the COVID-19 pandemic intensifies, overwhelming the healthcare system and the medical community, current practice for the management of acute ischemic stroke (AIS) will require modification, and guidelines should be relaxed while maintaining high standard quality of care. The aim of these suggestions is to avoid contributing to the rapid spread of COVID-19 as well as to conserve what are likely to be very limited resources (including personnel, intensive care/hospital beds as well as physicians) while maintaining high quality care for patients with AIS. We present our recommendations for the management of acute stroke during the COVID-19 pandemics.

Cerebral Vasculopathy and Spinal Arachnoiditis: Two Rare Complications of Ventriculitis Post Subarachnoid Hemorrhage.

This report describes a case of subarachnoid hemorrhage complicated by ventriculitis and subsequent delayed cerebral vasospasm, severe chronic spinal arachnoiditis, and Froin syndrome. A 60-year-old woman presented with diffuse aneurysmal subarachnoid hemorrhage and underwent successful coil embolization of ruptured left anterior cerebral artery aneurysm. Her course was complicated by bacterial ventriculitis and acute hydrocephalus necessitating ventriculoperitoneal shunt placement. She returned ten weeks later with recurrent headaches; CT angiography showed diffuse cerebral vasospasm. Spine magnetic resonance imaging ordered due to concern for mass or other obstruction of the cerebrospinal fluid obstruction based on lumbar puncture results showed leptomeningeal enhancement with loculated cerebrospinal fluid collections along the spinal canal concerning for spinal arachnoiditis and septal adhesions. Lumbar puncture was consistent with Froin syndrome. She was treated with calcium-channel blockers. Follow up imaging showed resolution of vasospasm, but progression of the arachnoiditis. No surgical intervention was pursued as the patient had no symptoms concerning myelopathy. Aneurysmal subarachnoid hemorrhage and ventriculitis may lead to delayed reversible vasculopathy as well as arachnoiditis, with "dry tap" and Froin-like syndrome picture. Workup should be initiated in patients who develop persistent headaches or myelopathic changes to investigate these possibilities.

Intravascular Lymphomatosis Presenting with Spinal Cord Infarction and Recurrent Ischemic Strokes.

Intravascular lymphomatosis (IVL) is a rare subtype of large B-cell lymphoma that follows an aggressive course with rapidly progressive neurological involvement and potentially fatal outcome.1 We report on a 64-year-old man with progressive myelopathy at T6-T7 and recurrent cerebral infarctions. This case is illustrative of the clinical course that is seen in IVL. It aims to present a timeline of imaging findings that demonstrate the progression of disease and characteristic pathology findings. We emphasize the importance of IVL on the differential diagnosis of spinal cord infarction.

Spinal Cord Infarction due to Fibrocartilaginous Embolism: A Report of 3 Cases.

Fibrocartilaginous embolism (FCE) is an uncommon cause of spinal cord infarction often misdiagnosed as transverse myelitis. The mechanism of ischemia is suspected to be due to retrograde embolization of nucleus pulposus material originating from Schmorl's nodes to the spinal vessels following acute disk herniation. We describe the clinical and imaging findings of FCE in 3 healthy young women with history of trivial spinal cord trauma, and recommend that FCE should be considered in the differential diagnosis of acute myelopathy.

Cerebral Infarctions Following Palliative Transarterial Chemoembolization with Embozene of a Vertebral Body Metastatic Tumor.

Preoperative transarterial chemoembolization has been widely used as an adjunct therapy for hypervascular metastatic spinal tumors. Several therapeutic iodized oil-based agents have been used in combination with anticancer drugs for injection into a feeding artery. Novel spherical agents with narrow-range particles and lower tendency to clump are preferred for the embolization of vascular malformations and hypervascular tumors. We describe the first case of cerebral embolization resulting in posterior circulation infarctions following transarterial embolization of a vascular vertebral body metastatic tumor with Embozene microspheres.

Fusiform Left Carotid-Ophthalmic Artery Aneurysm Presenting with Central Retinal Artery Occlusion.

Central retinal artery occlusion (CRAO) is a devastating ocular emergency characterized by acute painless visual loss in the ipsilateral eye. We describe the case of acute non-arteritic CRAO associated fusiform internal carotid-ophthalmic artery aneurysm with intraluminal thrombus. Despite the rarity of this condition, we suggest that carotid-ophthalmic artery aneurysm should be included in the differential diagnosis of CRAO.

Intravenous thrombolysis for ischemic stroke in recurrent oligodendroglioma: a case report.

Data on efficacy and safety of intravenous (IV) thrombolysis with recombinant tissue plasminogen activator (rtPA) in patients with acute ischemic stroke (AIS) and intracranial neoplasm are lacking. To date, only a handful of case reports have been published in the literature addressing the administration of IV rtPA to patients with AIS and coexisting brain neoplasms. We present the case of successful IV thrombolysis with rtPA for AIS in a patient with oligodendroglioma on bevacizumab without hemorrhagic complications. We summarize the published cases of thrombolysis in AIS in patients with intracranial neoplasms.

Atypical Chronic Headache and Recurrent Facial Ecchymosis: A Case Report.

We present the case of a 57-year-old woman with chronic paroxysmal headache and recurrent facial ecchymosis. The headaches are chronic, unilateral, sharp, electric shock-like, of short duration, without nausea nor vomiting, ptosis, miosis, conjunctival injection nor tearing. The facial ecchymoses have been mainly located in the periorbital and epicanthal areas. General, neurological and ophthalmological examinations were unremarkable. Work-up was unremarkable, including negative skin biopsy. The headache was difficult to include in any particular category given the atypical features, but the characteristics were suggestive of a variant of trigeminal autonomic cephalalgia with lack of responsiveness to indomethacin. We discuss the possible pathogenetic mechanism of the occurrence of facial ecchymosis in primary headache disorders.