Tunable Action Potential Repolarization Governed by Kv3.4 Channels in Dorsal Root Ganglion Neurons.

The Kv3.4 channel regulates action potential (AP) repolarization in nociceptors and excitatory synaptic transmission in the spinal cord. We hypothesize that this is a tunable role governed by protein kinase-C-dependent phosphorylation of the Kv3.4 cytoplasmic N-terminal inactivation domain (NTID) at four nonequivalent sites. However, there is a paucity of causation evidence linking the phosphorylation status of Kv3.4 to the properties of the AP. To establish this link, we used adeno-associated viral vectors to specifically manipulate the expression and the effective phosphorylation status of Kv3.4 in cultured dorsal root ganglion (DRG) neurons from mixed-sex rat embryos at embryonic day 18. These vectors encoded GFP (background control), wild-type (WT) Kv3.4, phosphonull (PN) Kv3.4 mutant (PN = S[8,9,15,21]A), phosphomimic (PM) Kv3.4 mutant (PM = S[8,9,15,21]D), and a Kv3.4 nonconducting dominant-negative (DN) pore mutant (DN = W429F). Following viral infection of the DRG neurons, we evaluated transduction efficiency and Kv3.4 expression and function via fluorescence microscopy and patch clamping. All functional Kv3.4 constructs induced current overexpression with similar voltage dependence of activation. However, whereas Kv3.4-WT and Kv3.4-PN induced fast transient currents, the Kv3.4-PM induced currents exhibiting impaired inactivation. In contrast, the Kv3.4-DN abolished the endogenous Kv3.4 current. Consequently, Kv3.4-DN and Kv3.4-PM produced APs with the longest and shortest durations, respectively, whereas Kv3.4-WT and Kv3.4-PN produced intermediate results. Moreover, the AP widths and maximum rates of AP repolarization from these groups are negatively correlated. We conclude that the expression and effective phosphorylation status of the Kv3.4 NTID confer a tunable mechanism of AP repolarization, which may provide exquisite regulation of pain signaling in DRG neurons.SIGNIFICANCE STATEMENTThe AP is an all-or-none millisecond-long electrical impulse that encodes information in the frequency and patterns of repetitive firing. However, signaling may also depend on the plasticity and diversity of the AP waveform. For instance, the shape and duration of the AP may regulate nociceptive synaptic transmission between a primary sensory afferent to a secondary neuron in the spinal cord. Here, we used mutants of the Kv3.4 voltage-gated potassium channel to manipulate its expression and effective phosphorylation status in dorsal root ganglion neurons and directly show how the expression and malleable inactivation properties of Kv3.4 govern the AP duration and repolarization rate. These results elucidate a mechanism of neural AP plasticity that may regulate pain signaling.

Fundamental Neurochemistry Review: The role of enteroendocrine cells in visceral pain.

While visceral pain is commonly associated with disorders of the gut-brain axis, underlying mechanisms are not fully understood. Dorsal root ganglion (DRG) neurons innervate visceral structures and undergo hypersensitization in inflammatory models. The characterization of peripheral DRG neuron terminals is an active area of research, but recent work suggests that they communicate with enteroendocrine cells (EECs) in the gut. EECs sense stimuli in the intestinal lumen and communicate information to the brain through hormonal and electrical signaling. In that context, EECs are a target for developing therapeutics to treat visceral pain. Linaclotide is an FDA-approved treatment for chronic constipation that activates the intestinal membrane receptor guanylyl cyclase C (GUCY2C). Clinical trials revealed that linaclotide relieves both constipation and visceral pain. We recently demonstrated that the analgesic effect of linaclotide reflects the overexpression of GUCY2C on neuropod cells, a specialized subtype of EECs. While this brings some clarity to the relationship between linaclotide and visceral analgesia, questions remain about the intracellular signaling mechanisms and neurotransmitters mediating this communication. In this Fundamental Neurochemistry Review, we discuss what is currently known about visceral nociceptors, enteroendocrine cells, and the gut-brain axis, and ongoing areas of research regarding that axis and visceral pain.

A machine learning approach to predict quality of life changes in patients with Parkinson's Disease.

OBJECTIVE: Parkinson disease (PD) is a progressive neurodegenerative disorder with an annual incidence of approximately 0.1%. While primarily considered a motor disorder, increasing emphasis is being placed on its non-motor features. Both manifestations of the disease affect quality of life (QoL), which is captured in part II of the Unified Parkinson's Disease Rating Scale (UPDRS-II). While useful in the management of patients, it remains challenging to predict how QoL will change over time in PD. The goal of this work is to explore the feasibility of a machine learning algorithm to predict QoL changes in PD patients. METHODS: In this retrospective cohort study, patients with at least 12 months of follow-up were identified from the Parkinson's Progression Markers Initiative database (N = 630) and divided into two groups: those with and without clinically significant worsening in UPDRS-II (n = 404 and n = 226, respectively). We developed an artificial neural network using only UPDRS-II scores, to predict whether a patient would clinically worsen or not at 12 months from follow-up. RESULTS: Using UPDRS-II at baseline, at 2 months, and at 4 months, the algorithm achieved 90% specificity and 56% sensitivity. INTERPRETATION: A learning model has the potential to rule in patients who may exhibit clinically significant worsening in QoL at 12 months. These patients may require further testing and increased focus.

Enteroendocrine cell regulation of the gut-brain axis.

Enteroendocrine cells (EECs) are an essential interface between the gut and brain that communicate signals about nutrients, pain, and even information from our microbiome. EECs are hormone-producing cells expressed throughout the gastrointestinal epithelium and have been leveraged by pharmaceuticals like semaglutide (Ozempic, Wegovy), terzepatide (Mounjaro), and retatrutide (Phase 2) for diabetes and weight control, and linaclotide (Linzess) to treat irritable bowel syndrome (IBS) and visceral pain. This review focuses on role of intestinal EECs to communicate signals from the gut lumen to the brain. Canonically, EECs communicate information about the intestinal environment through a variety of hormones, dividing EECs into separate classes based on the hormone each cell type secretes. Recent studies have revealed more diverse hormone profiles and communication modalities for EECs including direct synaptic communication with peripheral neurons. EECs known as neuropod cells rapidly relay signals from gut to brain via a direct communication with vagal and primary sensory neurons. Further, this review discusses the complex information processing machinery within EECs, including receptors that transduce intraluminal signals and the ion channel complement that govern initiation and propagation of these signals. Deeper understanding of EEC physiology is necessary to safely treat devastating and pervasive conditions like irritable bowel syndrome and obesity.

Intestinal neuropod cell GUCY2C regulates visceral pain.

Visceral pain (VP) is a global problem with complex etiologies and limited therapeutic options. Guanylyl cyclase C (GUCY2C), an intestinal receptor producing cyclic GMP(cGMP), which regulates luminal fluid secretion, has emerged as a therapeutic target for VP. Indeed, FDA-approved GUCY2C agonists ameliorate VP in patients with chronic constipation syndromes, although analgesic mechanisms remain obscure. Here, we revealed that intestinal GUCY2C was selectively enriched in neuropod cells, a type of enteroendocrine cell that synapses with submucosal neurons in mice and humans. GUCY2Chi neuropod cells associated with cocultured dorsal root ganglia neurons and induced hyperexcitability, reducing the rheobase and increasing the resulting number of evoked action potentials. Conversely, the GUCY2C agonist linaclotide eliminated neuronal hyperexcitability produced by GUCY2C-sufficient - but not GUCY2C-deficient - neuropod cells, an effect independent of bulk epithelial cells or extracellular cGMP. Genetic elimination of intestinal GUCY2C amplified nociceptive signaling in VP that was comparable with chemically induced VP but refractory to linaclotide. Importantly, eliminating GUCY2C selectively in neuropod cells also increased nociceptive signaling and VP that was refractory to linaclotide. In the context of loss of GUCY2C hormones in patients with VP, these observations suggest a specific role for neuropod GUCY2C signaling in the pathophysiology and treatment of these pain syndromes.

Perioperative Outcomes of a Hydrocortisone Protocol after Endonasal Surgery for Pituitary Adenoma Resection.

Introduction In pituitary adenomas (PAs), the use of postoperative steroid supplementation remains controversial, as it reduces peritumoral edema and sinonasal complaints but disrupts the detection of adrenal insufficiency (AI). It is unclear whether postoperative cortisol supplementation has a measurable effect on improving outcomes in patients with pituitary adenoma undergoing endoscopic transsphenoidal surgery (ETS). The objective of the study was to evaluate a postoperative steroid treatment protocol on various surgical outcomes in patients with PA undergoing ETS. Methods A retrospective cohort study was performed for patients undergoing ETS from 2005 to 2020 for PA at a single tertiary academic center. Patients were divided into two groups: those managed by a routine postoperative glucocorticoid supplementation protocol (steroid protocol) and those who received supplementation based on postoperative cortisol laboratory assessment (steroid sparing protocol). Management was otherwise the same between groups. Evaluation of length of stay (LOS), sinonasal outcomes, 30-day readmission, and perioperative complications, including AI, were performed. Results Among 535 patients, 21% ( n = 111) received postoperative steroids, while the remainder ( n = 424) did not. There were no differences in mean LOS (3 vs. 3 days, p = 0.72), sinonasal complaints (27 vs. 19%, p = 0.12), 30-day readmission (5% vs. 5%, p = 0.44), and perioperative complications (5 vs. 5%, p = 0.79) between both the groups. A multivariate model supported that both groups were comparable in predicting LOS, 30-day readmission, and complications. No reduction in readmission for AI was seen. Conclusion Routine administration of postoperative glucocorticoids did not significantly improve patient outcomes in patients with PA who underwent ETS.

Serious Illness Communication Practices in Glioblastoma: An Institutional Perspective.

Background: Early, high-quality advance care planning discussions are essential for supporting goal-concordant care among glioblastoma (GBM) patients. Objective: Using mixed methods, we sought to characterize current serious illness (SI) communication practices at our institution. Methods: The electronic medical records of 240 deceased GBM patients cared for at the Abramson Cancer Center in Philadelphia, PA between 2017 and 2019 were systematically reviewed for documented SI conversations about four domains: prognosis, goals, end-of-life planning, and code status. Patient outcomes and SI conversation characteristics were analyzed using descriptive statistics. Standardized interviews about GBM care were held with five clinicians. Interview transcripts were analyzed using grounded-theory coding to identify emergent themes. Results: Nearly all patients (96%) had at least one documented SI conversation (median: 4, interquartile range [IQR] 2-7), mostly outpatient with medical oncology physicians. Median timing of first SI conversation was 360 days before death. SI conversations were not significantly associated with patient outcomes, including inpatient death and hospice enrollment. Seven themes emerged from clinician interviews: balancing hope and reality, anticipatory guidance, neglect of the "big picture," need for earlier conversations, care coordination, the role of clinical expertise, and communication training. Conclusion: SI conversations were documented early and often in our sample, but their quality was difficult to assess. Contrary to our quantitative findings, interviewees reported that SI conversations were late, infrequent, inadequate, and fragmented across specialties, failing to explore critical issues such as prognosis and functional decline.

Surgical Outcomes of Endoscopic Transsphenoidal Pituitary Adenoma Resection in Elderly Versus Younger Patients.

Introduction Pituitary adenomas (PAs) are one of the most common types of intracranial neoplasm with increased incidence in elderly patients. The outcomes of endoscopic transsphenoidal surgery (ETS) specifically on elderly patients remain unclear. Methods We performed a retrospective cohort study to compare elderly patients (age ≥65 years) with nonelderly patients (age <65 years) who underwent ETS for PA from January 2005 to December 2020. Surgical outcomes, including extent of resection, complication profile, length of stay, and endocrinopathy rates, were compared between elderly and nonelderly patients. Results A total of 690 patients were included, with 197 (29%) being elderly patients. Elderly patients showed higher rates of hypertension ( p < 0.05), myocardial infarction ( p < 0.01), and atrial fibrillation ( p = 0.01) but not other comorbidities. Elderly patients also had more frequent optic nerve involvement (72 vs. 61% of cases, p = 0.01). Tumor characteristics and other patient variables were otherwise similar between younger and elderly patients. Postoperative cerebrospinal fluid (CSF) leaks (2 vs. 2%, p = 0.8), 30-day readmission, reoperation, postoperative complications, and postoperative endocrinopathies were similar between younger and older patients. Subdividing patients into age <65, 65 to 79, and >80 years also did not demonstrate a worsening of surgical outcomes with age. Conclusion For well-selected elderly patients in experienced endoscopic skull base centers, good surgical outcomes similarly to younger patients may be achieved.

Machine Learning Using Multiparametric Magnetic Resonance Imaging Radiomic Feature Analysis to Predict Ki-67 in World Health Organization Grade I Meningiomas.

BACKGROUND: Although World Health Organization (WHO) grade I meningiomas are considered "benign" tumors, an elevated Ki-67 is one crucial factor that has been shown to influence tumor behavior and clinical outcomes. The ability to preoperatively discern Ki-67 would confer the ability to guide surgical strategy. OBJECTIVE: In this study, we develop a machine learning (ML) algorithm using radiomic feature analysis to predict Ki-67 in WHO grade I meningiomas. METHODS: A retrospective analysis was performed for a cohort of 306 patients who underwent surgical resection of WHO grade I meningiomas. Preoperative magnetic resonance imaging was used to perform radiomic feature extraction followed by ML modeling using least absolute shrinkage and selection operator wrapped with support vector machine through nested cross-validation on a discovery cohort (n = 230), to stratify tumors based on Ki-67 <5% and ≥5%. The final model was independently tested on a replication cohort (n = 76). RESULTS: An area under the receiver operating curve (AUC) of 0.84 (95% CI: 0.78-0.90) with a sensitivity of 84.1% and specificity of 73.3% was achieved in the discovery cohort. When this model was applied to the replication cohort, a similar high performance was achieved, with an AUC of 0.83 (95% CI: 0.73-0.94), sensitivity and specificity of 82.6% and 85.5%, respectively. The model demonstrated similar efficacy when applied to skull base and nonskull base tumors. CONCLUSION: Our proposed radiomic feature analysis can be used to stratify WHO grade I meningiomas based on Ki-67 with excellent accuracy and can be applied to skull base and nonskull base tumors with similar performance achieved.

The Prevalence and Management of Stingers in College and Professional Collision Athletes.

PURPOSE OF REVIEW: Particularly common in collision sports such as American football or rugby, stingers are a traumatic transient neuropraxia of a cervical nerve root(s) or brachial plexus that may last anywhere from minutes to hours. This review summarizes the knowledge on the diagnosis and management of stingers in college and professional collision athletes by providing an overview of their epidemiology and pathophysiology, followed by a discussion on current treatment guidelines and return-to-play recommendations. RECENT FINDINGS: Despite modifications to tackling technique, increasing awareness, and various equipment options, American football continues to have a high rate of cervical spine injuries, the majority of which occur in preseason and regular season competition settings. The incidence of stingers has slowly increased among collision athletes, and nearly half of all players report sustaining at least one stinger in their career. Recent studies have shown certain anatomical changes in the cervical spine are related to acute and reoccurring stingers. Most players who experience stingers do not miss practices or games. Despite their prevalence, literature highlighting the impact of stingers on college and professional collision athletes is limited. Advances in imaging modalities and novel radiographic parameters have provided tools for screening athletes and can guide return-to-play decisions. Future research regarding appropriate screening practices for athletes with reoccurring stingers, use of protective equipment, and rehabilitation strategies are needed to identify predisposing factors, mitigate the risk of injury, and restore full functional strength and ability.

Mechanical Thrombectomy in Acute Ischemic Stroke Patients Greater than 90 Years of Age: Experience in 26 Patients in a Large Tertiary Care Center and Outcome Comparison with Younger Patients.

BACKGROUND: Several independent randomized controlled trials have shown superior efficacy of mechanical thrombectomy (MT) for management of acute ischemic stroke (AIS). However, elderly patients have been underrepresented or excluded in these trials. The aim of this study was to investigate the feasibility and safety of MT in patients with AIS ≥90 years old. METHODS: A retrospective review was performed of patients ≥90 years old presenting with AIS who underwent MT between 2010 and 2018. RESULTS: Of 453 patients with AIS, 5.74% (n = 26) were ≥90 years old, and 69.32% (n = 314) were 60-89 years old. Of baseline characteristics between both groups, there was a significant difference in age, sex, body mass index, smoking, hyperlipidemia, atrial fibrillation, and diabetes mellitus. Mean National Institutes of Health Stroke Scale score on admission was higher in the nonagenarians (17 vs. 15). Similar proportions of both groups received tissue plasminogen activator, 57.69% (n = 15) versus 42.68% (n = 134), P = 0.14). There was no difference in periprocedural and postprocedural complications, good Thrombolysis In Cerebral Infarction scores (88.46% [n = 23] vs. 87.58% [n = 275], P = 1.00), good modified Rankin Scale scores (34.62% [n = 4] vs. 49.36% [n = 155], P = 0.40), or mortality (11.54% [n = 3] vs. 13.06% [n = 41], P = 0.82). CONCLUSIONS: Age is a factor that affects functional outcome following MT. Advancements in catheter techniques, technical experience, and great outcomes with MT allow for pushing the boundaries to consider age as one factor, rather than an exclusion criterion. Our results show that MT is safe and feasible in nonagenarians.

Predictors of Complications, Functional Outcome, and Morbidity in a Large Cohort Treated With Flow Diversion.

BACKGROUND: A dramatic improvement in obliteration rates of large, wide-necked aneurysms has been observed after the FDA approved the Pipeline Embolization Device (PED) in 2011. OBJECTIVE: To assess the predictors of complications, morbidity, and unfavorable outcomes in a large cohort of patients with aneurysms treated with PED. METHODS: A retrospective chart review of a prospectively maintained database for subjects treated with flow diversion from 2010 to 2019. RESULTS: A total of 598 aneurysms were treated during a period extending from 2010 to 2019 (84.28% females, mean age 55.5 yr, average aneurysm size 8.49 mm). Morbidity occurred at a rate of 5.8% and mortality at a rate of 2.2%. Ischemic stroke occurred at a rate of 3%, delayed aneurysmal rupture (DAR) at 1.2%, and distal intraparenchymal hemorrhage (DIPH) at 1.5%. On multivariate analysis, the predictor of stroke was aneurysm size >15 mm. Predictors of DAR were previous subarachnoid hemorrhage (SAH), increasing aneurysm size, and posterior circulation aneurysm. Predictors of DIPH were using more than 1 PED and baseline P2Y12 value. Predictors of in-stent stenosis were the increasing year of treatment and balloon angioplasty, whereas increasing age and previous treatment were negatively associated with in-stent stenosis. Predictors of morbidity were posterior circulation aneurysms, increasing aneurysm size, and hypertension, and incidental aneurysm diagnosis was protective for morbidity. CONCLUSION: Flow diversion is a safe and effective treatment option for aneurysms. A better understanding of predictive factors of complications, morbidity, and functional outcomes is of high importance for a more accurate risk assessment.

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.

Predictors of ventriculostomy infection in a large single-center cohort.

OBJECTIVE: External ventricular drain (EVD) placement is a common neurosurgical procedure. While this procedure is simple and effective, infection is a major limiting factor. Factors predictive of infection reported in the literature are not conclusive. The aim of this retrospective, single-center large series was to assess the rate and independent predictors of ventriculostomy-associated infection (VAI). METHODS: The authors performed a retrospective chart review of consecutive patients who underwent EVD placement between January 2012 and January 2018. RESULTS: A total of 389 patients were included in the study. The infection rate was 3.1% (n = 12). Variables that were significantly associated with VAI were EVD replacement (OR 10, p = 0.001), bilateral EVDs (OR 9.2, p = 0.009), duration of EVD placement (OR 1.1, p = 0.011), increased CSF output/day (OR 1.0, p = 0.001), CSF leak (OR 12.9, p = 0.001), and increased length of hospital stay (OR 1.1, p = 0.002). Using multivariate logistic regression, independent predictors of VAI were female sex (OR 7.1, 95% CI 1.1-47.4; p = 0.043), EVD replacement (OR 8.5, 95% CI 1.44-50.72; p = 0.027), increased CSF output/day (OR 1.01, 95% CI 1.0-1.02; p = 0.023), and CSF leak (OR 15.1, 95% CI 2.6-87.1; p = 0.003). CONCLUSIONS: The rate of VAI was 3.1%. Routine CSF collection (every other day or every 3 days) and CSF collection when needed were not associated with VAI. The authors recommend CSF collection when clinically needed rather than routinely.

Association of state-level CPR training initiatives with layperson CPR knowledge in the United States.

STUDY AIM: Recent work has demonstrated low rates of layperson CPR training across the US. In an attempt to increase rates, some states passed legislation that requires CPR training before high school graduation. We hypothesized laypeople in states with required training would exhibit a greater likelihood of being currently trained in CPR when compared with laypeople in states without required CPR training. METHODS: We used a previously conducted nationwide cross-sectional random-digit dial survey of the US adult population (09/2015-11/2015). Survey weighted descriptive statistics and logistic regression were used to assess the primary association of likelihood of CPR training and required CPR training by graduation. RESULTS: Of the 9022 participants, 677 healthcare workers were excluded. Among those living in states with required training, 17% of laypersons were currently trained, while 14% of laypersons in states without required training were currently trained (p < 0.01). Amongst younger individuals (18-24), 29% were currently trained in states with required CPR training compared with 19% currently trained in states without required training (p < 0.01). Those in required training states were 34% more likely to be currently trained than individuals in states without required training (OR: 1.34, 95%CI: 1.20-1.50, p < 0.01). In a secondary analysis, younger laypersons in required training states were almost two times more likely to be currently trained (OR: 1.81, 95% CI: 1.18-2.78, p = 0.01). CONCLUSIONS: Individuals were more likely to be currently trained in CPR in states with mandatory CPR training for high school graduation, suggesting a need for additional research on this public policy.

Mechanical Thrombectomy in Distal Vessels: Revascularization Rates, Complications, and Functional Outcome.

INTRODUCTION: Pivotal trials have shown the tremendous efficacy of mechanical thrombectomy in proximal occlusions. However distal occlusions involving second-order branches of the middle cerebral artery and beyond, anterior cerebral and posterior cerebral arteries were not represented. In this study, we investigated the feasibility and safety of distal circulation mechanical thrombectomy. METHODS: A retrospective review of patients presenting with distal circulation acute ischemic stroke who underwent mechanical thrombectomy 2010 and 2018. RESULTS: Of 453 patients who underwent mechanical thrombectomy for acute ischemic stroke, 76 had a distal occlusion. The mean National Institute Health Stroke Scale on admission was 12. Vessels involved included second-order branches of the middle cerebral artery (89%), third- and fourth-order branches of the middle cerebral artery (5%), second-order branch of the anterior cerebral artery (3%), and posterior cerebral artery (3%). Most procedures required 1 pass to recanalize the vessel (55%, n = 42). Thrombolysis in Cerebral Infarction score ≥IIb was achieved in 89% of subjects. Mortality rate was 8% and independent functional outcome of m Rankin score ≤2 at 3 months was seen in 64.7% with clinical follow-up. On multivariate analysis, distal circulation had a significantly shorter length of stay by about 2 days, compared with proximal circulation. Subjects with proximal occlusion were more than 5 times more likely to have a good Thrombolysis in Cerebral Infarction score compared with the distal group. There was no significant difference in periprocedural and postprocedural complications, good functional outcome at 3 months, and mortality between both groups. CONCLUSIONS: Mechanical thrombectomy procedure for distal circulation strokes is as effective and safe as a proximal group. Though distal vessels supply smaller brain area; however, when symptoms are pronounced, the benefit of the procedure outweighs the risks.

Safety and Efficacy of Bilateral Flow Diversion for Treatment of Anterior Circulation Cerebral Aneurysms.

BACKGROUND: Nearly 20% of individuals with an aneurysm will have multiple aneurysms-these individuals are at increased risk of subarachnoid hemorrhage. Treatment of bilateral aneurysms with flow diverters (FDs), or Pipeline embolization device, has not yet been established as an effective therapy. We evaluated the safety and efficacy of a 2-stage treatment of bilateral aneurysms with Pipeline embolization devices placed 6 months apart. METHODS: We performed a retrospective review to analyze the clinical and angiographic outcomes of 16 individuals with bilateral aneurysms treated with 2-stage flow diversion at a tertiary referral center from January 2010 to July 2018. RESULTS: Of the 16 patients with 33 aneurysms treated with bilateral flow diversion, 1 had 2 aneurysms treated with a single FD on the contralateral side. The aneurysms treated were ophthalmic, superior hypophyseal, posterior communicating, or cavernous segment aneurysms, with an average size of 6.5 mm. No major complications, such as in-stent stenosis, thromboembolic events, distal intraparenchymal hemorrhage, rerupture, stent migration, or neurological death, were recorded. All the patients had good functional outcomes. At the 24-month follow-up examination, 81% of aneurysms showed complete occlusion. No aneurysm required repeat treatment. CONCLUSIONS: The results from the present study have demonstrated that 2-stage treatment of bilateral aneurysms with FDs is both safe and efficacious. The timing of contralateral FD stent placement is critical. We found that 6 months allows for adequate neurological recovery and stent endothelialization.