Anxiety and dysautonomia symptoms in patients with a NaV1.7 mutation and the potential benefits of low-dose short-acting guanfacine.

PURPOSE: Guanfacine is an α2A-adrenergic receptor agonist, FDA-approved to treat attention-deficit hyperactivity disorder and high blood pressure, typically as an extended-release formulation up to 7 mg/day. In our dysautonomia clinic, we observed that off-label use of short-acting guanfacine at 1 mg/day facilitated symptom relief in two families with multiple members presenting with severe generalized anxiety. We also noted anecdotal improvements in associated dysautonomia symptoms such as hyperhidrosis, cognitive impairment, and palpitations. We postulated that a genetic deficit existed in these patients that might augment guanfacine susceptibility. METHODS: We used whole-exome sequencing to identify mutations in patients with shared generalized anxiety and dysautonomia symptoms. Guanfacine-induced changes in the function of voltage-gated Na+ channels were investigated using voltage-clamp electrophysiology. RESULTS: Whole-exome sequencing uncovered the p.I739V mutation in SCN9A in the proband of two nonrelated families. Moreover, guanfacine inhibited ionic currents evoked by wild-type and mutant NaV1.7 encoded by SCN9A, as well as other NaV channel subtypes to a varying degree. CONCLUSION: Our study provides further evidence for a possible pathophysiological role of NaV1.7 in anxiety and dysautonomia. Combined with off-target effects on NaV channel function, daily administration of 1 mg short-acting guanfacine may be sufficient to normalize NaV channel mutation-induced changes in sympathetic activity, perhaps aided by partial inhibition of NaV1.7 or other channel subtypes. In a broader context, expanding genetic and functional data about ion channel aberrations may enable the prospect of stratifying patients in which mutation-induced increased sympathetic tone normalization by guanfacine can support treatment strategies for anxiety and dysautonomia symptoms.

The predictive value of preoperative apparent diffusion coefficient (ADC) for facial nerve outcomes after vestibular schwannoma resection: clinical study.

OBJECT: Diffusion MRI has been used to predict intraoperative consistency of tumors. Apparent diffusion coefficient (ADC) has shown predictive value as an imaging biomarker in many CNS tumors but has not been studied in a large cohort of patients with vestibular schwannoma. In this study, we examine the utility of ADC as a predictive biomarker for intraoperative tumor characteristics and postoperative facial nerve outcome. METHODS: A retrospective review of patients who underwent vestibular schwannoma resection at our institution from 2008 to 2018 yielded 87 patients, of which 72 met inclusion criteria. Operative reports and clinical records were reviewed for clinical data; MRI data were interpreted in a blinded fashion for qualitative and quantitative biomarkers, including tumor ADC. RESULTS: Mean tumor ADC values did not predict intraoperative consistency or adherence (p = 0.63). Adherent tumors were associated with worse facial nerve outcomes (p = 0.003). Regression tree analysis identified 3 ADC categories with statistically different facial nerve outcomes. The categories identified were ADC < 1006.04 × 10-6 mm2/s; ADC 1006.04-1563.93 × 10-6 mm2/s and ADC ≥ 1563.94 × 10-6 mm2/s. Postoperative and final House-Brackmann (HB) scores were significantly higher in the intermediate ADC group (2.3, p = 0.0038). HB outcomes were similar between the group with ADC < 1006.04 × 10-6 mm2/s and ≥ 1563.94 × 10-6 mm2/s (1.3 vs 1.3). CONCLUSIONS: Middle-range preoperative ADC in vestibular schwannoma suggests a less favorable postoperative HB score. Preoperative measurement of ADC in vestibular schwannoma may provide additional information regarding prognostication of facial nerve outcomes.

Acute Sigmoid Sinus Compromise Following Skull Base Procedures: Is a "Laissez-Faire" Approach Best?

Objective Venous sinus compromise (VSC) of the sigmoid sinus can manifest as either venous sinus thrombosis, stenosis, or a combination of the two. It may occur following retro and presigmoid craniotomy, even in the absence of overt intraoperative sinus injury. Currently, the optimal management of VSC in the perioperative period is not well established. We report our incidence and management of VSC following skull base surgery around the sigmoid sinus. Patients and Methods A retrospective chart review of all patients undergoing presigmoid, retrosigmoid, or combined approach by the senior author from 2014 to 2019 was performed. Main Outcome Measures Charts were reviewed for patient demographics, surgical details, details of venous sinus compromise, and patient outcomes. Statistical analyses were performed using R 3.6.0 (R Project). Results A 115 surgeries were found with a total of 13 cases of VSC (overall incidence of 11.3%). Nine cases exhibited thrombosis and four stenosis. There were no statistically significant differences between the groups with (group 1) or without (group 2) VSC. Operation on the side of the dominant sinus did not predispose to postoperative VSC. Five patients received antiplatelet medication in the perioperative period. There was no difference in outcomes in the group that did not receive antiplatelet medication versus those who did. Conclusion Acute iatrogenic sigmoid sinus compromise can be managed expectantly. We believe that the treatment for each instance of VSC must be individualized, considering the symptoms of the patient, rather than applying a universal algorithm.