A feasibility and safety study of afamelanotide in acute stroke patients - an open label, proof of concept, phase iia clinical trial.

BACKGROUND: Neuroprotective agents have the potential to improve the outcomes of revascularisation therapies in acute ischemic stroke patients (AIS) and in those unable to receive revascularisation. Afamelanotide, a synthetic α-melanocyte stimulating hormone analogue, is a potential novel neuroprotective agent. We set out to assess the feasibility and safety of afamelanotide for the first time in AIS patients. METHODS: AIS patients within 24 h of onset, with perfusion abnormality on imaging (Tmax) and otherwise ineligible for revascularisation therapies were enrolled. Afamelanotide 16 mg implants were administered subcutaneously on Day 0 (D0, day of recruitment), D1 and repeated on D7 and D8, if not well recovered. Treatment emergent adverse events (TEAEs) and neurological assessments were recorded regularly up to D42. Magnetic resonance imaging (MRI) with FLAIR sequences were also performed on D3 and D9. RESULTS: Six patients (5 women, median age 81, median NIHSS 6) were recruited. Two patients received 4 doses and four patients received 2. One patient (who received 2 doses), suffered a fatal recurrent stroke on D9 due to a known complete acute internal carotid artery occlusion, assessed as unrelated to the study drug. There were no other local or major systemic TEAEs recorded. In all surviving patients, the median NIHSS improved from 6 to 2 on D7. The median Tmax volume on D0 was 23 mL which was reduced to a FLAIR volume of 10 mL on D3 and 4 mL on D9. CONCLUSIONS: Afamelanotide was well tolerated and safe in our small sample of AIS patients. It also appears to be associated with good recovery and radiological improvement of salvageable tissue which needs to be tested in randomized studies. GOV IDENTIFIER: NCT04962503, First posted 15/07/2021.

Local hero: A phase II study of local therapy only (stereotactic radiosurgery and / or surgery) for treatment of up to five brain metastases from HER2+ breast cancer. (TROG study 16.02).

Introduction, A decade ago, stereotactic radiosurgery (SRS) without whole brain radiotherapy (WBRT) was emerging as preferred treatment for oligometastatic brain metastases. Studies of cavity SRS after neurosurgery were underway. Data specific to metastatic HER2 breast cancer (MHBC), describing intracranial, systemic and survival outcomes without WBRT, were lacking. A Phase II study was designed to address this gap. Method, Adults with MHBC, performance status 0-2, ≤ five BrM, receiving/planned to receive HER2-targeted therapy were eligible. Exclusions included leptomeningeal disease and prior WBRT. Neurosurgery allowed ≤6 weeks before registration and required for BrM >4 cm. Primary endpoint was 12-month requirement for WBRT. Secondary endpoints; freedom from (FF-) local failure (LF), distant brain failure (DBF), extracranial disease failure (ECDF), overall survival (OS), cause of death, mini-mental state examination (MMSE), adverse events (AE). Results, Twenty-five patients accrued Decembers 2016-2020. The study closed early after slow accrual. Thirty-seven BrM and four cavities received SRS. Four cavities and five BrM were observed. At 12 months: one patient required WBRT (FF-WBRT 95 %, 95 % CI 72-99), FFLF 91 % (95 % CI 69-98), FFDBF 57 % (95 % CI 34-74), FFECDF 64 % (95 % CI 45-84), OS 96 % (95 % CI 74-99). Two grade 3 AE occurred. MMSE was abnormal for 3/24 patients at baseline and 1/17 at 12 months. Conclusion, At 12 months, SRS and/or neurosurgery provided good control with low toxicity. WBRT was not required in 95 % of cases. This small study supports the practice change from WBRT to local therapies for MHBC BrM.

Factors Affecting Selection of TraineE for Neurointervention (FASTEN).

BACKGROUND AND IMPORTANCE: Neurointervention is a very competitive specialty in the United States due to the limited number of training spots and the larger pool of applicants. The training standards are continuously updated to ensure solid training experiences. Factors affecting candidate(s) selection have not been fully established yet. Our study aims to investigate the factors influencing the selection process. METHODS: A 52-question survey was distributed to 93 program directors (PDs). The survey consisted of six categories: (a) Program characteristics, (b) Candidate demographics, (c) Educational credentials, (d) Personal traits, (e) Research and extracurricular activities, and (f) Overall final set of characteristics. The response rate was 59.1%. As per the programs' characteristics, neurosurgery was the most involved specialty in running the training programs (69%). Regarding demographics, the need for visa sponsorship held the greatest prominence with a mean score of 5.9 [standard deviation (SD) 2.9]. For the educational credentials, being a graduate from a neurosurgical residency and the institution where the candidate's residency training is/was scored the highest [5.4 (SD = 2.9), 5.4 (SD = 2.5), respectively]. Regarding the personal traits, assessment by faculty members achieved the highest score [8.9 (SD = 1)]. In terms of research/extracurricular activities, fluency in English had the highest score [7.2 (SD = 1.9)] followed by peer-reviewed/PubMed-indexed publications [6.4 (SD = 2.2)]. CONCLUSION: Our survey investigated the factors influencing the final decision when choosing the future neurointerventional trainee, including demographic, educational, research, and extracurricular activities, which might serve as valuable guidance for both applicants and programs to refine the selection process.

Rare Presentation of Acute Myeloid Leukemia With TP53 Mutation and Dermatologic Manifestations.

Acute myeloid leukemia (AML) is a complex and aggressive malignancy that occurs due to genetic mutations and subsequent stem cell overproduction. We report a case of a patient with AML and a highly fatal, uncommon TP53 mutation who developed dermatologic manifestations. This report serves to highlight the importance of dermatologic findings in underlying leukemia and educate healthcare providers on the diagnosis and treatment of a rare TP53 mutation in AML.

The Brain Tumor Segmentation (BraTS-METS) Challenge 2023: Brain Metastasis Segmentation on Pre-treatment MRI.

Clinical monitoring of metastatic disease to the brain can be a laborious and timeconsuming process, especially in cases involving multiple metastases when the assessment is performed manually. The Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) guideline, which utilizes the unidimensional longest diameter, is commonly used in clinical and research settings to evaluate response to therapy in patients with brain metastases. However, accurate volumetric assessment of the lesion and surrounding peri-lesional edema holds significant importance in clinical decision-making and can greatly enhance outcome prediction. The unique challenge in performing segmentations of brain metastases lies in their common occurrence as small lesions. Detection and segmentation of lesions that are smaller than 10 mm in size has not demonstrated high accuracy in prior publications. The brain metastases challenge sets itself apart from previously conducted MICCAI challenges on glioma segmentation due to the significant variability in lesion size. Unlike gliomas, which tend to be larger on presentation scans, brain metastases exhibit a wide range of sizes and tend to include small lesions. We hope that the BraTS-METS dataset and challenge will advance the field of automated brain metastasis detection and segmentation.

Aspirin for the prevention of cognitive decline in the elderly: rationale and design of a neuro-vascular imaging study (ENVIS-ion).

BACKGROUND: This paper describes the rationale and design of the ENVIS-ion Study, which aims to determine whether low-dose aspirin reduces the development of white matter hyper-intense (WMH) lesions and silent brain infarction (SBI). Additional aims include determining whether a) changes in retinal vascular imaging (RVI) parameters parallel changes in brain magnetic resonance imaging (MRI); b) changes in RVI parameters are observed with aspirin therapy; c) baseline cognitive function correlates with MRI and RVI parameters; d) changes in cognitive function correlate with changes in brain MRI and RVI and e) whether factors such as age, gender or blood pressure influence the above associations. METHODS/DESIGN: Double-blind, placebo-controlled trial of three years duration set in two Australian academic medical centre outpatient clinics. This study will enrol 600 adults aged 70 years and over with normal cognitive function and without overt cardiovascular disease. Subjects will undergo cognitive testing, brain MRI and RVI at baseline and after 3 years of study treatment. All subjects will be recruited from a 19,000-patient clinical outcome trial conducted in Australia and the United States that will evaluate the effects of aspirin in maintaining disability-free longevity over 5 years. The intervention will be aspirin 100 mg daily versus matching placebo, randomized on a 1:1 basis. DISCUSSION: This study will improve understanding of the mechanisms at the level of brain and vascular structure that underlie the effects of aspirin on cognitive function. Given the limited access and high cost of MRI, RVI may prove useful as a tool for the identification of individuals at high risk for the development of cerebrovascular disease and cognitive decline. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01038583.

Low-dose, once-daily, intraclot injections of alteplase for treatment of acute deep venous thrombosis.

PURPOSE: To evaluate the safety and efficacy of once-daily intraclot injections of low doses (≤ 10 mg) of tissue plasminogen activator (tPA) for thrombolysis of venous thrombosis. MATERIALS AND METHODS: In prospective studies, 33 patients with subclavian, jugular, and central venous thrombosis (SJ-CVT) (all but two cases associated with central catheters) were treated once a day with ≤ 4 mg/day of tPA, and 30 patients with acute deep vein thrombosis of the lower extremity (DVT-LE) < 14 days old were treated once a day with ≤ 10 mg/leg/day of tPA by intraclot "lacing" of thrombus without continuous infusions of tPA. RESULTS: Patency was restored in 26 (79%) of 33 patients with SJ-CVT using an average total dose of 7.1 mg of tPA/per patient and average of 2.1 treatments or days of therapy. Five patients received thrombolytic therapy for SJ-CVT as outpatients. Initial patency was restored in 29 (97%) of 30 patients with acute DVT-LE using an average total dose of 20 mg of tPA per patient over an average of 2.7 treatments/or days per patient. Follow-up imaging examinations at 6 months showed continued patency in 27 (96%)/of 28 patients. There were no major bleeding complications, and no patient required a blood transfusion. CONCLUSIONS: Intraclot injection of low doses of alteplase is effective for acute venous thrombosis, and pharmacokinetic data suggest potentially greater safety.

Coaxial Access for Microcatheter Stabilization During Aneurysm Coiling: 2-Dimensional Operative Video.

Coaxial support is a fundamental technique utilized by neurointerventionalists to optimize distal catheter control within the intracranial circulation. Here we present a 41-yr-old woman with a previously coiled ruptured anterior communicating artery aneurysm with progressive recurrence harboring tortuous internal carotid anatomy to demonstrate the utility of coaxial support. Raymond-Roy classification of initial aneurysm coiling of class 1 resulted as class 3b over the 21 mo from initial treatment.1 The patient consented to stent-assisted coiling for retreatment of this aneurysm. Coaxial support was advanced as distally as possible in the proximal vasculature to improve catheter control, reducing dead space within which the microcatheter could move, decreasing angulations within proximal vasculature, limiting the movement of the native vessels, and providing a surface of lower friction than the endothelium. As the risk of recurrent subarachnoid hemorrhage in previously treated coiled aneurysms approaches 3%, retreatment occurs in 16.4% within 6 yr2 and in 17.4% of patients within 10 yr.3 Rerupture is slightly higher in patients who underwent coiling vs clipping, with the rerupture risk inversely proportional to the degree of aneurysm occlusion,4 further substantiating that coaxial support provides technical advantage in selected patients where additional microcatheter control is necessary for optimal occlusion. Pitfalls of this technique include vasospasm and vascular injury, which can be ameliorated by pretreatment of the circulation with vasodilators to prevent catheter-induced vasospasm. This case and model demonstration illustrates the technique of coaxial access in the stent-assisted coiling of a recurrent anterior communicating artery aneurysm and identification and management of catheter-induced vasospasm.

Sinonasal inverted papilloma mimicking a pituitary macroadenoma.

We report the rare entity of an inverted papilloma arising from the sphenoid sinus that we expected to be a pituitary tumour on the basis of history, examination and pre-operative investigations, especially MRI appearance. Inverted sinonasal papilloma should be considered in the differential diagnosis of pituitary macroadenoma invading the sphenoid sinus.

Deep vein thrombosis of lower extremity: direct intraclot injection of alteplase once daily with systemic anticoagulation--results of pilot study.

PURPOSE: To prospectively evaluate the outcome of patients with acute deep vein thrombosis (DVT) of the lower extremity treated with "lacing" of the thrombus with alteplase (recombinant tissue plasminogen activator, or rTPA). MATERIALS AND METHODS: This HIPAA-compliant study was approved by the Institutional Review Board of the National Heart, Lung, and Blood Institute and was funded by the National Institutes of Health. After giving written consent, 20 patients with first-onset acute DVT were treated with direct intraclot lacing of the thrombus with alteplase (maximum daily dose, 50 mg per leg per day; maximum of four treatments) and full systemic anticoagulation. Alteplase was chosen because its high fibrin affinity obviates continuous infusion of this thrombolytic agent. Ventilation-perfusion (V/Q) scans were performed for evaluation of embolic risks, and clinical and imaging examinations were supplemented with pharmacokinetic studies to enable further assessment of treatment outcomes. RESULTS: The 20 patients included 13 men and seven women aged 18-79 years. Antegrade blood flow was restored throughout the deep venous system in 16 patients (80%) during thrombolytic therapy, with complete resolution of symptoms in 18 patients (90%) after 6 months of anticoagulation. Pharmacokinetic studies showed rapid clearance of circulating alteplase and recovery of plasminogen activator inhibitor-1 levels within 2 hours after termination of alteplase treatment. V/Q scans revealed a 40% incidence of pulmonary embolism before treatment and a 15% incidence of asymptomatic pulmonary embolism during thrombolytic therapy. There were no cases of clinically important pulmonary embolism or serious bleeding during thrombolytic therapy. During a mean follow-up period of 3.4 years, no patient developed a postthrombotic syndrome or recurrent thromboembolism. CONCLUSION: Intraclot injection or lacing of the thrombus with a fibrin-binding thrombolytic agent such as alteplase is an alternative to continuous-infusion thrombolytic regimens and minimizes the duration of systemic exposure to thrombolytic agents.

Bing-Neel syndrome - Bilateral cavernous sinus lymphoma causing visual failure.

We report the case of a 68-year-old male with right eye vision loss secondary to a compressive optic neuropathy from Waldenstrom macroglobulinaemia relapse in both cavernous sinuses. Central nervous system involvement is extremely uncommon in lymphoplasmacytic lymphoma. Known as Bing-Neel syndrome, this has not been previously reported to present simultaneously in bilateral cavernous sinuses. We discuss the pathophysiology, diagnostic and neuroradiological features of Bing-Neel syndrome. In this case, there was marked clinical and radiological response to chemotherapy. As outcomes following treatment for Waldenstrom macroglobulinaemia improve, greater awareness of its less common manifestations becomes important. Neurosurgical intervention may be indicated to obtain histological diagnosis or decompress critical structures.

Deterministic Tractography of the Descending Tract of the Spinal Trigeminal Nerve Using Diffusion Tensor Imaging.

BACKGROUND AND PURPOSE: Pain information from the face enters the pons via the trigeminal nerve before creating an anatomical "elbow" that turns caudally into the spinal trigeminal tract (SpTV). Visualization of the descending tract of the trigeminal nerve as it begins its descent from the nerve root entry zone (NREZ) in the pons would improve the accuracy of current procedures aimed at altering or lesioning the trigeminal nerve within the brainstem. The focus of this study was to develop a standardized protocol using diffusion tensor imaging (DTI) and deterministic tractography methods to image the SpTV. There are currently no standard techniques used to visualize the trigeminal nerve using DTI. METHODS: DTI and tractography were performed on 20 patients: 17 with trigeminal neuralgia (TN), 1 with hemifacial spasm, 1 with a facial nerve tumor, and 1 with an arteriovenous malformation. A standardized protocol was developed using regions of interest (ROIs) located at the SpTV, as determined by a brainstem atlas, and the NREZ. RESULTS: Using our standardized protocol, the descending tract of the trigeminal nerve was successfully visualized in all 20 patients. Trigeminal fibers entered the pons at the NREZ and descended through the SpTV. The accuracy of the visualized tract was confirmed through coregistration with a stereotactic atlas and anatomical scan. CONCLUSION: A successful, robust DTI imaging and postprocessing protocol of the SpTV contributes to our understanding of its anatomical distribution within the brainstem and is a potentially new neurosurgical planning tool.

Optimizing the Definitions of Stroke, Transient Ischemic Attack, and Infarction for Research and Application in Clinical Practice.

BACKGROUND AND PURPOSE: Until now, stroke and transient ischemic attack (TIA) have been clinically based terms which describe the presence and duration of characteristic neurological deficits attributable to intrinsic disorders of particular arteries supplying the brain, retina, or (sometimes) the spinal cord. Further, infarction has been pathologically defined as death of neural tissue due to reduced blood supply. Recently, it has been proposed we shift to definitions of stroke and TIA determined by neuroimaging results alone and that neuroimaging findings be equated with infarction. METHODS: We examined the scientific validity and clinical implications of these proposals using the existing published literature and our own experience in research and clinical practice. RESULTS: We found that the proposals to change to imaging-dominant definitions, as published, are ambiguous and inconsistent. Therefore, they cannot provide the standardization required in research or its application in clinical practice. Further, we found that the proposals are scientifically incorrect because neuroimaging findings do not always correlate with the clinical status or the presence of infarction. In addition, we found that attempts to use the proposals are disrupting research, are otherwise clinically unhelpful and do not solve the problems they were proposed to solve. CONCLUSION: We advise that the proposals must not be accepted. In particular, we explain why the clinical focus of the definitions of stroke and TIA should be retained with continued sub-classification of these syndromes depending neuroimaging results (with or without other information) and that infarction should remain a pathological term. We outline ways the established clinically based definitions of stroke and TIA, and use of them, may be improved to encourage better patient outcomes in the modern era.

Phase I study of hepatic arterial melphalan infusion and hepatic venous hemofiltration using percutaneously placed catheters in patients with unresectable hepatic malignancies.

PURPOSE: We conducted a phase I study of a 30-minute hepatic artery infusion of melphalan via a percutaneously placed catheter and hepatic venous hemofiltration using a double balloon catheter positioned in the retrohepatic inferior vena cava to shunt hepatic venous effluent through an activated charcoal filter and then to the systemic circulation. The purpose of the study was to demonstrate feasibility in an initial cohort and subsequently determine the maximum tolerated dose and dose-limiting toxicity of melphalan. PATIENTS AND METHODS: The initial cohort (n = 12) was treated with 2.0 mg/kg of melphalan before dose escalation to 3.5 mg/kg (n = 16). Total hepatic drug delivery, systemic levels, and percent filter efficiency were determined. Patients were assessed for hepatic and systemic toxicity and response. RESULTS: A total of 74 treatments were administered to 28 patients. Twelve patients with primary and metastatic hepatic tumors received 30 treatments (mean, 2.5 per patient) at an initial melphalan dose of 2.0 mg/kg. At 3.5 mg/kg, a dose-limiting toxicity (neutropenia and/or thrombocytopenia) was observed in two of six patients. Transient grade 3/4 hepatic and systemic toxicity was seen after 19% and 66% of treatments, respectively. An overall radiographic response rate of 30% was observed in treated patients. In the 10 patients with ocular melanoma, a 50% overall response rate was observed, including two complete responses. CONCLUSION: Delivery of melphalan via this system is feasible, with limited, manageable toxicity and evidence of substantial antitumor activity; 3 mg/kg is the maximum safe tolerated dose of melphalan administered via this technique.

Treatment of post-traumatic carotid-cavernous fistulas using pipeline embolization device assistance.

This report describes two cases of post-traumatic, high flow carotid-cavernous fistulas that demonstrated residual shunting after initial embolization with coils and Onyx, and that were successfully closed with pipeline embolization devices. Following their combined endovascular treatments, the patients experienced clinical improvement of symptoms with durable obliteration of the fistulous communications.

Treatment of post-traumatic carotid-cavernous fistulas using pipeline embolization device assistance.

This report describes two cases of post-traumatic, high flow carotid-cavernous fistulas that demonstrated residual shunting after initial embolization with coils and Onyx, and that were successfully closed with pipeline embolization devices. Following their combined endovascular treatments, the patients experienced clinical improvement of symptoms with durable obliteration of the fistulous communications.

Hirayama disease.

This article discusses three patients with likely Hirayama disease. They have no other significant past medical history and no personal or family history of other neurological disorders. Hirayama disease is a form of cervical myelopathy attributed to forward displacement of the posterior cervical dural sac on neck flexion with resultant cord compression and/or venous congestion. It is characterized by a pure motor focal amyotrophy in the distribution of C7, C8 and T1 spinal segmental-innervated muscles and differs from other motor neuron diseases by virtue of its ultimately non-progressive course.

Mechanisms of upper limb amyotrophy in spinal disorders.

Upper limb amyotrophy may occur as an indirect consequence of various spinal disorders, including ventral longitudinal intraspinal fluid collection, Hirayama disease and high cervical cord compression. We present patients who suffer from each of these and review the literature on the three conditions with emphasis on the pathogenesis of amyotrophy. We propose that pathology some distance from the lower cervical spinal cord may affect normal venous drainage, resulting in venous congestion and reduced perfusion pressure which, in turn, could result in anterior horn cell dysfunction in all three disorders.

Case report of multiple sclerosis diagnosis in an 82-year old male.

An 82-year old male, with no significant past medical history, presented with a subacute right foot drop in the setting of a 14-month history of generalised weakness, highly-responsive to steroids. Temporal artery and vastus lateralis biopsies were normal. Vasculitic screen and inflammatory markers were normal. Lumbar puncture revealed elevated cerebrospinal fluid (CSF) protein without oligoclonal bands. Visual evoked response (VER) was normal. Magnetic resonance imaging (MRI) of his lumbar spine showed compression of exiting L5 nerve root. He had three cerebral MRI scans spaced over the 12 month period, which showed a progressive increase of T2 and fluid attenuated inversion recovery (FLAIR) hyperintense lesions consistent with active demyelinating plaques. He was treated with intravenous methylprednisolone 1g daily for three days with a weaning regimen of oral prednisolone, resulting in a full return of power and a resolution of his right foot drop. He was diagnosed with late-onset multiple sclerosis (LOMS), and was treated with monthly natalizumab. A literature review of LOMS is discussed.