A comparative study of transradial versus transfemoral approach for flow diversion.

PURPOSE: Data in neurointerventional literature is extremely limited regarding the safety and efficacy of flow diversion using transradial access (TRA). We aim to demonstrate the safety and efficacy of intracranial aneurysm treatment with the Pipeline Embolization Device (PED) using TRA compared to transfemoral access (TFA). METHODS: We conducted a retrospective analysis of a prospectively maintained database and identified 79 consecutive patients who underwent neuroendovascular embolization for cerebral aneurysms using the PED from April 2018 through October 2019. Patients were divided into 2 groups: TRA (32 patients) and TFA (47 patients). A comparative analysis was performed between the two groups. RESULTS: There was no significant difference in postoperative intracranial hemorrhage (p>.99), symptomatic ischemic stroke (p=.512), access site complications (p=.268), or other complications (p=.512). However, there was a significant increase in overall complications (14.9% vs. 0.0%, p=.038) and procedure duration (71.4 min ± 31.2 vs. 58.5 ± 20.3, p=.018) in the TFA group. There was no significant difference in complete occlusion at latest follow-up (19/25, 76.0% vs. 35/40, 87.5%; p=.311), 6-month follow-up (17/23, 73.9% vs. 33/38, 86.8%; p=.303), or 12-month follow-up (8/8, 100.0% vs. 5/6, 83.3%; p=.429). There was also no significant difference in rate of retreatment (p>.99), morbidity (p=.512), mortality (p>.99), latest follow-up (p=.985), or loss of follow-up (p=.298). CONCLUSIONS: The feasibility and efficacy of flow diversion with the PED via TRA for the treatment of intracranial aneurysms is comparable to TFA. Widespread adoption of this approach may be facilitated by improvements in device navigation and manipulation via radial-specific engineering.

Discordant Effects of Polyamine Depletion by DENSpm and DFMO on ß-cell Cytokine Stress and Diabetes Outcomes in Mice.

Type 1 diabetes (T1D) is an autoimmune disease leading to dysfunction and loss of insulin-secreting ß cells. In ß cells, polyamines have been implicated in causing cellular stress and dysfunction. An inhibitor of polyamine biosynthesis, difluoromethylornithine (DFMO), has been shown to delay T1D in mouse models and preserve ß-cell function in humans with recent-onset T1D. Another small molecule, N1,N11-diethylnorspermine (DENSpm), both inhibits polyamine biosynthesis and accelerates polyamine metabolism and is being tested for efficacy in cancer clinical trials. In this study, we show that DENSpm depletes intracellular polyamines as effectively as DFMO in mouse ß cells. RNA-sequencing analysis, however, suggests that the cellular responses to DENSpm and DFMO differ, with both showing effects on cellular proliferation but the latter showing additional effects on mRNA translation and protein-folding pathways. In the low-dose streptozotocin-induced mouse model of T1D, DENSpm, unlike DFMO, did not prevent or delay diabetes outcomes but did result in improvements in glucose tolerance and reductions in islet oxidative stress. In nonobese diabetic (NOD) mice, short-term DENSpm administration resulted in a slight reduction in insulitis and proinflammatory Th1 cells in the pancreatic lymph nodes. Longer term treatment resulted in a dose-dependent increase in mortality. Notwithstanding the efficacy of both DFMO and DENSpm in reducing potentially toxic polyamine levels in ß cells, our results highlight the discordant T1D outcomes that result from differing mechanisms of polyamine depletion and, more importantly, that toxic effects of DENSpm may limit its utility in T1D treatment.

Inhibition of polyamine biosynthesis preserves ß cell function in type 1 diabetes.

In preclinical models, α-difluoromethylornithine (DFMO), an ornithine decarboxylase (ODC) inhibitor, delays the onset of type 1 diabetes (T1D) by reducing ß cell stress. However, the mechanism of DFMO action and its human tolerability remain unclear. In this study, we show that mice with ß cell ODC deletion are protected against toxin-induced diabetes, suggesting a cell-autonomous role of ODC during ß cell stress. In a randomized controlled trial (ClinicalTrials.gov: NCT02384889) involving 41 recent-onset T1D subjects (3:1 drug:placebo) over a 3-month treatment period with a 3-month follow-up, DFMO (125-1,000 mg/m2) is shown to meet its primary outcome of safety and tolerability. DFMO dose-dependently reduces urinary putrescine levels and, at higher doses, preserves C-peptide area under the curve without apparent immunomodulation. Transcriptomics and proteomics of DFMO-treated human islets exposed to cytokine stress reveal alterations in mRNA translation, nascent protein transport, and protein secretion. These findings suggest that DFMO may preserve ß cell function in T1D through islet cell-autonomous effects.

Growth and development in monogenic forms of neonatal diabetes.

PURPOSE OF REVIEW: Neonatal diabetes mellitus (NDM) is a rare disorder in which 80-85% of infants diagnosed under 6 months of age will be found to have an underlying monogenic cause. This review will summarize what is known about growth and neurodevelopmental difficulties among individuals with various forms of NDM. RECENT FINDINGS: Patients with NDM often have intrauterine growth restriction and/or low birth weight because of insulin deficiency in utero and the severity and likelihood of ongoing growth concerns after birth depends on the specific cause. A growing list of rare recessive causes of NDM are associated with neurodevelopmental and/or growth problems that can either be related to direct gene effects on brain development, or may be related to a variety of co-morbidities. The most common form of NDM results in spectrum of neurological disability due to expression of mutated KATP channels throughout the brain. SUMMARY: Monogenic causes of neonatal diabetes are characterized by variable degree of restriction of growth in utero because of deficiency of insulin that depends on the specific gene cause. Many forms also include a spectrum of neurodevelopmental disability because of mutation-related effects on brain development. Longer term study is needed to clarify longitudinal effects on growth into adulthood.

Decreased KATP Channel Activity Contributes to the Low Glucose Threshold for Insulin Secretion of Rat Neonatal Islets.

Transitional hypoglycemia in normal newborns occurs in the first 3 days of life and has clinical features consistent with hyperinsulinism. We found a lower threshold for glucose-stimulated insulin secretion from freshly isolated embryonic day (E) 22 rat islets, which persisted into the first postnatal days. The threshold reached the adult level by postnatal day (P) 14. Culturing P14 islets also decreased the glucose threshold. Freshly isolated P1 rat islets had a lower threshold for insulin secretion in response to 2-aminobicyclo-(2, 2, 1)-heptane-2-carboxylic acid, a nonmetabolizable leucine analog, and diminished insulin release in response to tolbutamide, an inhibitor of ß-cell KATP channels. These findings suggested that decreased KATP channel function could be responsible for the lower glucose threshold for insulin secretion. Single-cell transcriptomic analysis did not reveal a lower expression of KATP subunit genes in E22 compared with P14 ß cells. The investigation of electrophysiological characteristics of dispersed ß cells showed that early neonatal and cultured cells had fewer functional KATP channels per unit membrane area. Our findings suggest that decreased surface density of KATP channels may contribute to the observed differences in glucose threshold for insulin release.

Lessons Learned After 760 Neurointerventions via the Upper Extremity Vasculature: Pearls and Pitfalls.

BACKGROUND: The radial approach has been gaining more widespread use by neurointerventionalists fueled by data from the cardiology literature showing better safety and overall reduced morbidity. OBJECTIVE: To present our institution's experience with the radial approach for neuroendovascular interventions in 614 consecutive patients who underwent a cumulative of 760 procedures. METHODS: A retrospective analysis was performed and identified neuroendovascular procedures performed via the upper extremity vasculature access site. RESULTS: Amongst 760 procedures, 34.2% (260) were therapeutic, and 65.7% (500) were nontherapeutic angiograms. Access sites were 71.5% (544) via a conventional radial artery, 27.8% (211) via a distal radial artery, 0.5% (4) via an ulnar artery, and 0.1% (1) via the brachial artery. Most of the procedures (96.9%) were performed via the right-sided (737), 2.9% (22) via the left-sided, and 0.1% (1) via a bilateral approach. Major access site complications occurred at a rate of 0.9% (7). The rate of transfemoral conversion was 4.7% (36). There was a statistically higher incidence of transfemoral conversion when repeat procedures were performed using the same access site. Also, there was no significant difference between nontherapeutic procedures performed using the right and left radial access, and conventional versus distal radial access. Procedural metrics improved after completion of 14 procedures, indicating a learning curve that should be surpassed by operators to reach optimal outcomes. CONCLUSION: Radial artery catheterization is a safe and effective means of carrying out a wide range of neuroendovascular procedures associated with excellent clinical outcomes and an overall low rate of periprocedural complications.

Incidence and predictors of ophthalmic artery occlusion in intra-arterial chemotherapy for retinoblastoma.

BACKGROUND: Retinoblastoma is the most common primary intraocular malignancy in children. OBJECTIVE: To determine the incidence of ophthalmic artery (OA) occlusion in patients treated with selective ophthalmic artery catheterization (OAC) for chemotherapy infusion for retinoblastoma. Also, to evaluate technical, anatomical, tumorous, and patient-related factors that are predictors of OA occlusion. METHODS: A retrospective chart review was performed for patients diagnosed with intraocular retinoblastoma and managed with intra-arterial chemotherapy (IAC). RESULTS: The total study cohort included 208 retinoblastoma tumors of 208 eyes in 197 consecutive patients who underwent 688 attempted IAC infusions overall with a total of 624 successful OAC infusions. The total incidence of ophthalmic artery thrombosis was 11.1% (23/208). The numbers of successful OAC procedures before diagnosing OA occlusion were one OAC in six cases (27.3%), two in seven cases (31.8%), three in four cases (18.2%), four in one case (4.5%), five in two cases (9.1%), and six in one case (4.5%). CONCLUSIONS: Local factors relating to the chemotherapy and selective microcatheterization of the OA are essential factors in the development of OA thrombosis, as seen by the association of OA thrombosis with the frequency of IAC.

Cerebral ischemic and hemorrhagic complications of coronavirus disease 2019.

BACKGROUND: The coronavirus disease 2019 is associated with neurological manifestations including stroke. OBJECTIVES: We present a case series of coronavirus disease 2019 patients from two institutions with acute cerebrovascular pathologies. In addition, we present a pooled analysis of published data on large vessel occlusion in the setting of coronavirus disease 2019 and a concise summary of the pathophysiology of acute cerebrovascular disease in the setting of coronavirus disease 2019. METHODS: A retrospective study across two institutions was conducted between 20 March 2020 and 20 May 2020, for patients developing acute cerebrovascular disease and diagnosed with coronavirus disease 2019. We performed a literature review using the PubMed search engine. RESULTS: The total sample size was 22 patients. The mean age was 59.5 years, and 12 patients were female. The cerebrovascular pathologies were 17 cases of acute ischemic stroke, 3 cases of aneurysm rupture, and 2 cases of sinus thrombosis. Of the stroke and sinus thrombosis patients, the mean National Institute of Health Stroke Scale was 13.8 ± 8.0, and 16 (84.2%) patients underwent a mechanical thrombectomy procedure. A favorable thrombolysis in cerebral infarction score was achieved in all patients. Of the 16 patients that underwent a mechanical thrombectomy, the mortality incidence was five (31.3%). Of all patients (22), three (13.6%) patients developed hemorrhagic conversion requiring decompressive surgery. Eleven (50%) patients had a poor functional status (modified Rankin Score 3-6) at discharge, and the total mortality incidence was eight (36.4%). CONCLUSIONS: Despite timely intervention and favorable reperfusion, the mortality rate in coronavirus disease 2019 patients with large vessel occlusion was high in our series and in the pooled analysis. Notable features were younger age group, involvement of both the arterial and venous vasculature, multivessel involvement, and complicated procedures due to the clot consistency and burden.

The Use of Alternative Routes for the Delivery of Intra-Arterial Chemotherapy for Retinoblastoma.

BACKGROUND: The introduction of intra-arterial chemotherapy (IAC) for treatment of retinoblastoma considerably changed the paradigm by which this disease is managed, with event-free survival rates being above 70%. OBJECTIVE: To analyze efficacy of IAC treatment using alternative approaches to ophthalmic artery catheterization (OAC), such as external carotid artery approach or balloon-assisted drug delivery. METHODS: This is a retrospective chart review for subjects receiving IAC for retinoblastoma. The primary approach was OAC. In cases in which selective OAC was not feasible, alternative routes including catheterization of the external carotid artery or use of a balloon-assisted drug infusion were used. RESULTS: This study included 197 consecutive patients with 207 retinoblastomas who underwent 658 IAC procedures overall. The mean age at diagnosis was 24 mo, and 54.5% of the study population was male. Success rate with IAC was 97% (639). Alternative approaches to OAC were, in total, 42 cases (6.4%)-external carotid artery catheterization and use of ICA balloon were performed in 22 (3.3%) and 20 (3%) cases, respectively. A mean of 3.1 IAC cycles were performed for each patient. In total, there were 23 technical failures of the primary OAC technique (3.4%). Periprocedural adverse events occurred in 4 procedures (0.6%). Use of an alternative technique for chemotherapy delivery other than selective OAC in at least one IAC cycle was not a predictor of enucleation. CONCLUSION: IAC is a safe and effective treatment option for retinoblastoma. Chemotherapy delivery using alternative techniques is as effective as selective OAC.

Ophthalmic artery catheterization for retinoblastoma treatment: does reflux affect tumor response?

BACKGROUND: Intra-arterial chemotherapy (IAC) for retinoblastoma (Rb) has been established as a primary treatment for the disease. To determine whether the presence of reflux into the ICA is associated with tumor response or with any other adverse events in pediatric retinoblastoma patients. METHODS: A retrospective chart review was performed for patients diagnosed with Rb and managed with ophthalmic artery catheterization (OAC). RESULTS: The total study cohort included 205 Rb tumors of 205 eyes in 194 consecutive patients who underwent 624 successful intra-arterial chemotherapy infusions using OAC. Of the 205 eyes, 65 eyes (32.7%) underwent 157 OAC procedures constituted group A (no reflux), 64 eyes (31.2%) underwent 236 OAC procedures constituted group B (variable pattern), and 74 eyes (36.1%) underwent 231 OAC procedures constituted group C (reflux). There was no significant difference in baseline characteristics between the three cohorts. Also, there was no significant difference in tumor characteristics between the three groups, except for genetic status. There was no significant difference between the three groups in terms of tumor response at completion of the treatment regimen. Complete tumor response was achieved at 70.2% in Group A, at 83.3% in Group B, and at 78.5% in group C (P=0.39). Similarly, eye enucleation occurred at 38.5% in group A, 31.8% in group B, and 31.5% in group C. None of the patients in both groups had any neurological adverse events or new onset of seizures. CONCLUSIONS: The presence of reflux, which may complicate the procedure and prolong it, was not associated with poor outcomes in our analysis.

Acute ischaemic stroke interventions: large vessel occlusion and beyond.

Care for acute ischaemic stroke is one of the most rapidly evolving fields due to the robust outcomes achieved by mechanical thrombectomy. Large vessel occlusion (LVO) accounts for up to 38% of acute ischaemic stroke and comes with devastating outcomes for patients, families and society in the pre-intervention era. A paradigm shift and a breakthrough brought mechanical thrombectomy back into the spotlight for acute ischaemic stroke; this was because five randomised controlled trials from several countries concluded that mechanical thrombectomy for acute stroke offered overwhelming benefits. This review article will present a comprehensive overview of LVO management, techniques and devices used, and the future of stroke therapy. In addition, we review our institution experience of mechanical thrombectomy for posterior and distal circulation occlusion.