Flow diverters are increasingly used for the endovascular treatment of cerebral aneurysms. A rare complication from flow diversion is delayed aneurysm rupture, which can lead to carotid-cavernous fistula (CCF) in the setting of cavernous carotid aneurysms (CCAs). Direct CCFs pose unique management challenges, given the lack of transarterial access to the fistula. We present two cases of direct CCFs following treatment of CCAs with the Pipeline embolization device (PED). Case 1 was a middle-aged patient with a symptomatic 10 mm wide-necked left CCA. Six weeks after PED treatment the patient developed diplopia secondary to direct CCF. Case 2 was a middle-aged patient with a symptomatic 17 mm left CCA treated with PED. One-month follow-up angiography demonstrated a direct CCF. Both patients underwent successful coil embolization of the CCF through a transvenous approach. Direct CCF formation following PED deployment for CCA is a rare complication. Parent vessel sacrifice may be avoided with transvenous occlusion of the fistula.

Endovascular treatment of cerebral aneurysm continues to evolve with the development of new technologies. This review provides an overview of the recent major innovations in the neurointerventional space in recent years.

Background

The increasing complexity of modern neurointerventions has necessitated a shift in intracranial access techniques towards more robust distal support platforms. Here we present our experience with the Syphontrak Support Catheter (Codman Neuro, Raynham, MA, USA) in the triaxial platform for the implantation of the second-generation Pipeline Flex embolization device (PED Flex; Medtronic Neurovascular, Irvine, CA, USA).

Methods

We retrospectively identified patients who underwent PED Flex treatment utilizing the Syphontrak at a single institution. The procedural data collected included parent artery tortuosity, patient demographics, aneurysm characteristics, other equipment utilized, and catheter-related complications.

Results

A total of 47 consecutive aneurysm flow diversions were successfully performed using the Syphontrak. The patients' age ranged from 25 to 80 years (mean 57.3 ± 11.6) and 85% were women. The average aneurysm size was 4.8 ± 2.7 mm (range 2-14). All cases were in the anterior circulation, with 6 (12%) aneurysms located beyond the internal carotid artery termination. Significant cervical carotid tortuosity was present in 23% (11/47) of the cases and moderate-to-severe cavernous tortuosity (cavernous grade ≥2) in 51% (24/47) of the cases. The mean fluoroscopy time was 36.6 ± 14.8 min. In 12/47 cases (26%), vasospasm prophylaxis with intra-arterial verapamil infusion was performed. The Syphontrak was tracked to the intended distal position in all cases, with a 100% technical success of PED Flex implantation. Forty-six (98%) of the 47 patients were discharged home after an average length of stay of 1.38 days. No iatrogenic catheter-related vessel injury occurred. Transient, minor neurological morbidity occurred in 3 cases (6%) and 1 patient had a minor ischemic event (NIHSS score < 4) in the periprocedural period.

Conclusion

The Syphontrak is a new large-bore, multi-durometer intermediate catheter (IC) designed for use in modern neurointerventional procedures. We have shown its utility in 47 successful cases of PED Flex flow diversion of a wide range of complexity. The IC provides robust and atraumatic distal intracranial access while also providing an enhanced image quality with its large 0.060″ inner diameter.

Background

Flow diversion with the Pipeline embolization device (PED) is an effective neuro-endovascular method and increasingly accepted for the treatment of cerebral aneurysms. Acute in situ thrombosis is a known complication of PED procedures. There is limited experience in the flow diversion literature on the use of abciximab (ReoPro) for the management of acute thrombus formation in PED cases.

Methods

Data were collected retrospectively on patients who received intra-arterial (IA) ReoPro with or without subsequent intravenous (IV) infusion during PED flow diversion treatment of intracranial aneurysms.

Results

A total of 30 cases in patients with a mean age of 56.7 years (range 36-84) and a mean aneurysm size of 8.6 mm (range 2-25) were identified to have intraprocedural thromboembolic complications during PED treatment. IA ReoPro was administered in all cases, with 20 cases receiving increments of 5-mg boluses and 10 cases receiving a 0.125 mg/kg IA bolus (half cardiac dosing). Complete or partial recanalization was achieved in 100% of the cases. IV ReoPro infusion at 0.125 μg/kg/min for 12 h was administered postprocedurally in 22 cases with a residual thrombus. Postprocedurally, 18 patients were transitioned from clopidogrel (Plavix) to prasugrel (Effient). The majority of the cases (23/30; 77%) were discharged home. Periprocedural intracranial hemorrhage was noted in 2 cases (7%) and radiographic infarct was noted in 4 cases (13%), with an overall mortality of 0% at the time of initial discharge. Clinical follow-up was available for 28/30 patients. The average duration of follow-up was 11.7 months, at which time 23/28 (82%) of the patients had a modified Rankin Scale score of 0.

Conclusions

IA ReoPro administration is an effective and safe rescue strategy for the management of acute intraprocedural thromboembolic complications during PED treatment. Using a dosing strategy of either 5-mg increments or a 0.125 mg/kg IA bolus (half cardiac dosing) can provide high rates of recanalization with low rates of hemorrhagic complications and long-term morbidity.

Cancer-associated isocitrate dehydrogenase (IDH) 1 and 2 mutations gain a new activity of reducing α-KG to produce D-2-hydroxyglutarate (D-2-HG), which is proposed to function as an oncometabolite by inhibiting α-KG dependent dioxygenases. We investigated the function of D-2-HG in tumorigenesis using IDH1 and IDH2 mutant cancer cell lines. Inhibition of D-2-HG production either by specific deletion of the mutant IDH1-R132C allele or overexpression of D-2-hydroxyglutarate dehydrogenase (D2HGDH) increases α-KG and related metabolites, restores the activity of some α-KG-dependent dioxygenases, and selectively alters gene expression. Ablation of D-2-HG production has no significant effect on cell proliferation and migration, but strongly inhibits anchorage independent growth in vitro and tumor growth in xenografted mouse models. Our study identifies a new activity of oncometabolite D-2-HG in promoting tumorigenesis.

Background

Acute in situ thrombosis is an ischaemic phenomenon during Pipeline embolisation device (PED) procedures with potentially high morbidity and mortality. There is controversy regarding the role of platelet function testing with P2Y12 assay as a predictor of intraprocedural thromboembolic events. There is limited knowledge on whether procedural complexity influences these events.

Methods

Data were collected retrospectively on 742 consecutive PED cases at a single institution. Patients with intraprocedural acute thrombosis were compared with patients without these events.

Results

A cohort of 37 PED cases with acute in situ thrombosis (mean age 53.8 years, mean aneurysm size 8.4 mm) was matched with a cohort of 705 PED cases without intraprocedural thromboembolic events (mean age 56.4 years, mean aneurysm size 6.9 mm). All patients with in situ thrombosis received intra-arterial and/or intravenous abciximab. The two groups were evenly matched in patient demographics, previous treatment/subarachnoid hemorrhage (SAH) and aneurysm location. There was no statistical difference in postprocedural P2Y12 reaction unit (PRU) values between the two groups, with a mean of 156 in the in situ thrombosis group vs 148 in the control group (p=0.5894). Presence of cervical carotid tortuosity, high cavernous internal carotid artery grade, need for multiple PED and vasospasm were not significantly different between the two groups. The in situ thrombosis group had statistically significant longer fluoroscopy time (60.4 vs 38.4 min, p<0.0001), higher radiation exposure (3476 vs 2160 mGy, p<0.0001), higher rates of adjunctive coiling (24.3% vs 8.37%, p=0.0010) and higher utilisation of balloon angioplasty (37.8% vs 12.2%, p<0.0001). Clinically, the in situ thrombosis cohort had higher incidence of major and minor stroke, intracerebral haemorrhage and length of stay.

Conclusions

Predictors of procedural complexity (higher radiation exposure, longer fluoroscopy time, adjunctive coiling and need for balloon angioplasty) are associated with acute thrombotic events during PED placement, independent of PRU values.

Background

The prevalence of cerebral aneurysms is increased in fibromuscular dysplasia (FMD). The presence of FMD may serve as discouragement to elective endovascular aneurysm treatment. Outcomes of endovascular intervention for aneurysms through vessels affected by FMD have not been reported.

Methods

A prospectively maintained database of patients undergoing intracranial embolization was reviewed for patients with FMD who underwent endovascular aneurysm treatment.

Results

A total of 1,025 patients were screened and 31 (3.0%) had cerebrovascular FMD. These patients underwent a total of 43 embolization procedures; 27 of these procedures were performed through an affected vessel. All but 1 patient were female and the average age was 62 years. "String-of-pearls"-type FMD was the most common subtype (90%). The internal carotid arteries were more commonly affected (65%) than the vertebral arteries (48%). All patients underwent treatment of cerebral aneurysms, most of which (87%) were incidentally discovered; 6 patients (19%) also had incidental vessel dissection. The average aneurysm size was 7.1 mm. The morphology was saccular in 93% of the cases, and 86% were in the anterior circulation. The most commonly performed treatment was flow diversion (67%), in the majority of cases by pipeline embolization. Other procedures performed were coiling (19%), stent-coiling (12%), and intrasaccular flow disruption (2%). All but 1 procedure (98%) were successful. There were no major complications; 1 patient experienced a transient ischemic attack. Follow-up angiography was performed in 88% of the cases, without evidence for disease progression after treatment. The average time to last angiographic follow-up was 17 months (±13).

Conclusions

Elective embolization of intracranial aneurysms can be performed safely through vessels affected by FMD.

l-2-Hydroxyglutarate aciduria (L-2-HGA) is an autosomal recessive neurometabolic disorder caused by a mutation in the l-2-hydroxyglutarate dehydrogenase (L2HGDH) gene. In this study, we generated L2hgdh knockout (KO) mice and observed a robust increase of l-2-hydroxyglutarate (L-2-HG) levels in multiple tissues. The highest levels of L-2-HG were observed in the brain and testis, with a corresponding increase in histone methylation in these tissues. L2hgdh KO mice exhibit white matter abnormalities, extensive gliosis, microglia-mediated neuroinflammation, and an expansion of oligodendrocyte progenitor cells (OPCs). Moreover, L2hgdh deficiency leads to impaired adult hippocampal neurogenesis and late-onset neurodegeneration in mouse brains. Our data provide in vivo evidence that L2hgdh mutation leads to L-2-HG accumulation, leukoencephalopathy, and neurodegeneration in mice, thereby offering new insights into the pathophysiology of L-2-HGA in humans.

Background

Dual antiplatelet therapy (DAT), most commonly with aspirin and Clopidogrel, is the standard of care for intracranial stenting, including flow diversion. Clopidogrel response varies by individual.

Objective

To investigate the real-world precision of VerifyNow P2Y12 assessment (Accumetrics, San Diego, California) of Clopidogrel response.

Methods

Using a prospectively-collected, IRB-approved cerebral aneurysm database 643 patients were identified who were treated with the Pipeline embolization device from 2011 to 2017. Patients with multiple P2Y12 assays drawn within a 24-h window were identified. A single patient could contribute multiple, independent sets. Levels drawn before a 5-d course of DAT and patients who received alternative antiplatelet agents were excluded. Therapeutic range was defined as platelet reaction units (PRU) 60-200.

Results

A total of 1586 P2Y12 measurements were recorded; 293 (46%) patients had more than one assay. One hundred forty (22%) patients had multiple P2Y12 measurements within 24 h. These patients accounted for 230 independent 24-h sets. The average P2Y12 fluctuation across all sets was 35 points; the 25th, 50th, and 75th percentiles were 12, 26, and 48 points, respectively. Of the 230 24-h sets of P2Y12 assays, 76% remained within their original therapeutic category: 100 (43%) all therapeutic, 54 (23%) all hypo-responsive, and 21 (9%) all hyper-responsive. Twenty-four percent of patients fluctuated between therapeutic categories when multiple P2Y12 assessments were drawn within a 24-h period: 29 (13%) between hypo-response and therapeutic, 23 (10%) between hyper-response and therapeutic, and 3 (1%) between hypo-response and hyper-response.

Conclusion

Our experience suggests P2Y12 is an often-imprecise measure, and this should be considered when utilizing P2Y12 levels for clinical decisions.

Phosphoglycerate kinase 1 (PGK1) catalyzes the reversible transfer of a phosphoryl group from 1, 3-bisphosphoglycerate (1, 3-BPG) to ADP, producing 3-phosphoglycerate (3-PG) and ATP. PGK1 plays a key role in coordinating glycolytic energy production with one-carbon metabolism, serine biosynthesis, and cellular redox regulation. Here, we report that PGK1 is acetylated at lysine 220 (K220), which inhibits PGK1 activity by disrupting the binding with its substrate, ADP. We have identified KAT9 and HDAC3 as the potential acetyltransferase and deacetylase, respectively, for PGK1. Insulin promotes K220 deacetylation to stimulate PGK1 activity. We show that the PI3K/AKT/mTOR pathway regulates HDAC3 S424 phosphorylation, which promotes HDAC3-PGK1 interaction and PGK1 K220 deacetylation. Our study uncovers a previously unknown mechanism for the insulin and mTOR pathway in regulation of glycolytic ATP production and cellular redox potential via HDAC3-mediated PGK1 deacetylation.