Identification of the NRF2 transcriptional network as a therapeutic target for trigeminal neuropathic pain.

Trigeminal neuralgia, historically dubbed the "suicide disease," is an exceedingly painful neurologic condition characterized by sudden episodes of intense facial pain. Unfortunately, the only U.S. Food and Drug Administration (FDA)-approved medication for trigeminal neuralgia carries substantial side effects, with many patients requiring surgery. Here, we identify the NRF2 transcriptional network as a potential therapeutic target. We report that cerebrospinal fluid from patients with trigeminal neuralgia accumulates reactive oxygen species, several of which directly activate the pain-transducing channel TRPA1. Similar to our patient cohort, a mouse model of trigeminal neuropathic pain also exhibits notable oxidative stress. We discover that stimulating the NRF2 antioxidant transcriptional network is as analgesic as inhibiting TRPA1, in part by reversing the underlying oxidative stress. Using a transcriptome-guided drug discovery strategy, we identify two NRF2 network modulators as potential treatments. One of these candidates, exemestane, is already FDA-approved and may thus be a promising alternative treatment for trigeminal neuropathic pain.

Timing of Revascularization in Ischemic Moyamoya Disease: Association of Early Versus Delayed Surgery with Perioperative and Long-Term Outcomes.

OBJECTIVE: Patients with nmoyamoya disease (MMD) who present primarily with ischemic stroke are known to have greater rates of perioperative strokes as compared with those who present with nonstroke symptoms. The optimal timing for revascularization for these patients remains unclear. METHODS: From 1994 to 2015, 91 patients with MMD presented with signs and symptoms of an acute ischemic stroke with diffusion restriction correlate on magnetic resonance imaging, and these patients were subdivided into those who underwent early revascularization (<90 days from last stroke), versus those who underwent delayed revascularization (≥90 days after last stroke), based on evidence that most neurological recovery after stroke occurs during the first three months. Perioperative and long-term outcomes were compared between the 2 surgical cohorts. RESULTS: In total, 27 patients underwent early revascularization, and 64 patients underwent delayed revascularization. Patients who underwent early revascularization had a statistically greater rate of perioperative stroke (P = 0.04) and perioperative mortality (P = 0.03), and overall complication rate (P = 0.049). At last follow-up of 5.2 ± 4.3 years, patients who underwent delayed revascularization had a lower mortality rate (P = 0.01) and a lower overall postoperative stroke incidence (P = 0.002). As a function of time, patients with MMD undergoing delayed revascularization had a statistically higher length of stroke-free survival (P = 0.005). CONCLUSIONS: Patients with MMD who present with ischemic stroke are more likely to have perioperative strokes, overall perioperative complications, worse long-term mortality rates, and lower rates of stroke-free survival if revascularization surgery occurred within 90 days of last stroke.

Revascularization of Hemorrhagic Moyamoya Disease in a North American Cohort: The Role of Timing in Perioperative and Long-Term Outcomes.

BACKGROUND: Several East Asian studies have examined the role of revascularization in the context of hemorrhagic moyamoya disease (MMD) and found a decrease in postoperative rehemorrhage rates. To date, no data exist comparing revascularization with conservative management in North American patients with hemorrhagic MMD. OBJECTIVE: To compare the clinical outcomes of conservative management vs surgical revascularization for North American patients with hemorrhagic MMD and investigate the effect of revascularization timing. METHODS: We retrospectively studied the mortality and stroke-free survival of patients with MMD presenting with hemorrhagic stroke between 1994 and 2015. RESULTS: The diagnosis of hemorrhagic MMD was established in 38 patients. Seventeen patients were managed conservatively, and 21 were surgically revascularized. Twelve patients underwent revascularization within 6 months of hemorrhage, and 9 underwent surgery in a delayed fashion. Six conservatively managed patients (35.3%) died within the follow-up period compared with 0 (0%) surgically revascularized patients, P = .004. Conservatively managed patients also experienced an increased number of postoperative strokes, P = .037, and shorter stroke-free survival compared with patients undergoing revascularization, P = .047. On multivariate analysis, increased age, worse baseline modified Rankin score, and conservative management were independently associated with worse neurological outcomes, P < .05. Early revascularization was associated with higher rates of postoperative seizures, P = .033, and wound complications, P = .031, compared with those who underwent delayed surgery. CONCLUSION: Conservative management in a North American patient cohort was associated with greater mortality and worsened neurological outcomes compared with those undergoing revascularization. Early revascularization was associated with higher rates of postoperative seizures and wound complications, although these risks must be balanced against the risk of rehemorrhage.

Moyamoya disease versus moyamoya syndrome: comparison of presentation and outcome in 338 hemispheres.

OBJECTIVE: Phenotypic differences between moyamoya disease (MMD) and moyamoya syndrome (MMS) remain unclear. The purpose of this study was to evaluate whether such differences exist when presentation, procedure-related, and outcome variables are compared quantitatively. METHODS: The study cohort included 185 patients with moyamoya presenting to the Johns Hopkins Medical Institutions between 1994 and 2015. Baseline demographic, angiographic, and clinical characteristics were compared between patients with MMS and MMD, in addition to procedure-related complications and length of stay (LOS) after surgery. Stroke-free survival was compared between both disease variants after diagnosis. Kaplan-Meier analysis and Cox proportional hazards regression were used to compare stroke-free survival between surgically treated and conservatively managed hemispheres in both types of disease, while evaluating interaction between disease variant and management. RESULTS: The cohort consisted of 137 patients with MMD (74%) with a bimodal age distribution and 48 patients with MMS (26%) who were mostly under 18 years of age (75%). Underlying diseases included sickle cell disease (48%), trisomy 21 (12%), neurofibromatosis (23%), and other disorders (17%). Patients with MMS were younger (p < 0.001) and less likely to be female (p = 0.034). Otherwise, baseline characteristics were statistically comparable. The rate of surgical complications was 33% in patients with MMD and 16% in patients with MMS (p = 0.097). Both groups of patients had a similar LOS after surgery (p = 0.823). Survival analysis (n = 330 hemispheres) showed similar stroke-free survival after diagnosis (p = 0.856) and lower stroke hazard in surgically managed patients in both MMD (hazard ratio [HR] 0.29, p = 0.028) and MMS (HR 0.62, p = 0.586). The disease variant (MMD vs MMS) did not affect the relationship between management approach (surgery vs conservative) and stroke hazard (p = 0.787). CONCLUSIONS: MMD and MMS have largely comparable clinical and angiographic phenotypes with analogously favorable responses to surgical revascularization.

Racial phenotypes in moyamoya disease: a comparative analysis of clinical presentation and natural history in a single multiethnic cohort of 250 hemispheres.

OBJECTIVE: The authors aimed to determine whether differences exist in presentation and natural history when comparing Asian patients with moyamoya disease (MMD) to those of other ethnicities in North America. METHODS: A database of 137 patients with MMD presenting to their institution between 1994 and 2015 was reviewed. Baseline characteristics and outcome variables, including stroke and functional outcome, were compared between Asian and non-Asian patients. Unadjusted Kaplan-Meier survival analysis and adjusted Cox regression models were used to compare stroke-free survival and stroke hazard after diagnosis among hemispheres of both racial groups. The analysis was stratified by age group, and censoring was performed until last follow-up or at the time of surgery. Because the relative rate of stroke changed between Asian and non-Asian adults after 1.5 years of follow-up, a time-segmented analysis focusing on the period 1.5 years after diagnosis was performed. RESULTS: The cohort comprised 23% (31/137) Asian and 77% (106/137) non-Asian patients with MMD with a bimodal age distribution. Non-Asian patients had a higher prevalence of increased BMI (p = 0.02) and smoking (p = 0.04). Among patients who presented with stroke (n = 90), hemorrhage was significantly more common among Asians (p = 0.02). The natural history analysis included 250 hemispheres: 67 pediatric and 183 adult hemispheres. The overall mean follow-up duration since diagnosis was 3.3 years. Among adults, Asian patients had a higher incidence of stroke (8.0 per 100 person-years vs 3.0 per 100 person-years) over a mean follow-up of 3.3 years, but results were not statistically significant (p = 0.45). In the period beginning 1.5 years after diagnosis, Asian adults had a significantly higher hazard of stroke over a mean follow-up of 7.7 years, while controlling for sex, hypertension, and stroke before diagnosis (hazard ratio 8.8, p = 0.02). Among pediatric patients, Asians also had a higher stroke incidence (10.0 per 100 person-years vs 3.5 per 100 person-years) over a mean follow-up of 3.2 years; however, results did not reach statistical significance (p = 0.40). Functional outcome was similar between both ethnic groups at last follow-up (p = 0.57). CONCLUSIONS: This study suggests a comparatively more progressive course of MMD in Asians. Further studies are required to fully characterize the phenotypic distinctions between different races and underlying pathophysiological mechanisms.

Differing Surgical Outcomes in a Multiethnic Cohort Suggest Racial Phenotypes in Moyamoya Disease.

BACKGROUND: Variable Moyamoya disease (MMD) genotypes and phenotypes between different races have been suggested previously. This study investigates differences in surgical complications and response to revascularization among Asian patients with MMD compared with other ethnicities in North America. METHODS: From a database of 185 patients with moyamoya presenting to our institution between 1994 and 2015, 85 patients with MMD underwent surgery and constituted the study cohort. Baseline characteristics before surgery, procedure-related complications, length of hospital stay, and outcome variables including stroke and functional outcome were compared between Asian and non-Asian patients. Kaplan-Meier survival analyses were used to compare time to ipsilateral stroke and any cerebrovascular event after bypass. RESULTS: Our surgical cohort consisted of 27% (23/85) Asian and 73% (62/85) non-Asian patients with MMD with a bimodal age distribution. Among the subset of patients who presented with stroke (n = 55), hemorrhage was significantly more common among Asian patients (P = 0.007). In 120 revascularization procedures, per-operative complication rates were greater among Asian patients while controlling for age, type of surgery, and stroke history (odds ratio 2.94; 95% confidence interval 1.16-7.48; P = 0.02). The mean follow-up time after surgery was 4.57 years. Ipsilateral cerebrovascular event rates were 4.77 per 100 person-years in non-Asian patients and 6.51 per 100 person-years in Asians (P = 0.66). Unfavorable modified Rankin Scale scores (>2) were found in 22% of Asian patients and 8% of non-Asian patients on last follow-up (P = 0.13). CONCLUSIONS: Asian patients with MMD may be more susceptible to surgical complications and may differ from other races in their response to revascularization. Further long-term prospective studies are needed to investigate these findings.