Gabapentin and pregabalin in bipolar disorder, anxiety states, and insomnia: Systematic review, meta-analysis, and rationale.

The gabapentinoids, gabapentin, and pregabalin, target the α2δ subunits of voltage-gated calcium channels. Initially licensed for pain and seizures, they have become widely prescribed drugs. Many of these uses are off-label for psychiatric indications, and there is increasing concern about their safety, so it is particularly important to have good evidence to justify this usage. We conducted a systematic review and meta-analysis of the evidence for three of their common psychiatric uses: bipolar disorder, anxiety, and insomnia. Fifty-five double-blind randomised controlled trials (RCTs) and 15 open-label studies were identified. For bipolar disorder, four double-blind RCTs investigating gabapentin, and no double-blind RCTs investigating pregabalin, were identified. A quantitative synthesis could not be performed due to heterogeneity in the study population, design and outcome measures. Across the anxiety spectrum, a consistent but not universal effect in favour of gabapentinoids compared to placebo was seen (standardised mean difference [SMD] ranging between -2.25 and -0.25). Notably, pregabalin (SMD -0.55, 95% CI -0.92 to -0.18) and gabapentin (SMD -0.92, 95% CI -1.32 to -0.52) were more effective than placebo in reducing preoperative anxiety. In insomnia, results were inconclusive. We conclude that there is moderate evidence of the efficacy of gabapentinoids in anxiety states, but minimal evidence in bipolar disorder and insomnia and they should be used for these disorders only with strong justification. This recommendation applies despite the attractive pharmacological and genetic rationale for targeting voltage-gated calcium channels.

Flow diversion in direct carotid-cavernous fistula refractory to multiple coil embolizations: case report and review of the literature.

OBJECTIVES: Direct carotid-cavernous fistulas are high-flow abnormal connections between the carotid artery and cavernous sinus, which are associated with significant morbidity and mortality if left untreated. In addition to endovascular coil embolization, there is an evolving role for alternative stand-alone or adjunctive treatment approaches. We describe a case of flow diversion as an adjunctive treatment approach in a treatment-resistant direct carotid-cavernous fistula and review the literature on the use of flow diversion in this clinical context. MATERIALS AND METHODS: We describe the clinical course, imaging findings, and outcome of a patient who developed a traumatic carotid-cavernous fistula requiring multiple interventions. We also performed an updated literature review of all published cases of flow diversion use in the treatment of direct CCFs. RESULTS: Our patient achieved angiographic cure and significant improvement in symptoms at 6-month follow-up. A total of 53 cases of flow diversion use in direct carotid-cavernous fistulas were identified from a literature search. In one third of cases, flow diversion was used as a stand-alone treatment modality. Angiographic resolution was achieved in 90% of cases at a median follow-up duration of 6 months. One half of reported cases had complete resolution of symptoms and a further third noted clinical improvement in at least some of their symptoms. CONCLUSIONS: There is an emerging role for flow diversion as a safe and effective stand-alone or adjunctive treatment option for direct carotid-cavernous fistulas. Our case further supports a role for flow diversion in treatment-resistant fistulas with high-risk features. As treatment approaches continue to evolve, prospective, randomized data will be needed to establish the role of flow divertors in the hierarchy of available treatments for carotid-cavernous fistulas.

Endovascular and medical management strategies for carotid-cavernous fistulas: A safety and efficacy analysis.

BACKGROUND: Carotid-cavernous fistulas (CCFs) are complex arteriovenous shunting lesions of the cavernous sinus with diverse clinical presentations. This study aimed to analyze clinical outcomes and differentiate patients treated with conservative observation versus those needing endovascular intervention. METHODS: A retrospective analysis of 84 patients with angiographically confirmed CCF was conducted from 2000 to 2022. Endovascular treatment decisions were made at the discretion of neurointerventionalists. Clinical and angiographic data were collected, including Barrow CCF classification and treatment outcomes. RESULTS: Patients managed conservatively (n = 17) had longer symptom duration (165 vs 42 days) and more indirect CCF (100% vs 68%) compared to those treated with endovascular embolization (n = 67). High-risk clinical symptoms, including proptosis, diplopia, decreased visual acuity, and chemosis, were more common in the embolization group. Cortical venous reflux and ophthalmic venous reflux were more prevalent in the embolization group (39% and 91%, respectively). Overall, 31% of embolized CCFs required retreatment, mainly Barrow type D lesions (65%). Transvenous coil embolization was the primary technique used (78%), followed by feeder artery embolization (16%), and internal carotid artery flow diversion (8%). CONCLUSION: In selected CCF patients without high-risk symptoms or angiographic features, conservative observation is a safe and effective alternative to endovascular embolization. High-risk symptoms and angiographic features favor endovascular intervention. Complications were rare, and most were transient, emphasizing the safety of endovascular management. Longitudinal angiographic and ophthalmologic surveillance is essential for monitoring fistula persistence or recurrence.

Characterizing coma in large vessel occlusion stroke.

BACKGROUND: Coma is an unresponsive state of disordered consciousness characterized by impaired arousal and awareness. The epidemiology and pathophysiology of coma in ischemic stroke has been underexplored. We sought to characterize the incidence and clinical features of coma as a presentation of large vessel occlusion (LVO) stroke. METHODS: Individuals who presented with LVO were retrospectively identified from July 2018 to December 2020. Coma was defined as an unresponsive state of impaired arousal and awareness, operationalized as a score of 3 on NIHSS item 1a. RESULTS: 28/637 (4.4%) patients with LVO stroke were identified as presenting with coma. The median NIHSS was 32 (IQR 29-34) for those with coma versus 11 (5-18) for those without (p < 0.0001). In coma, occlusion locations included basilar (13), vertebral (2), internal carotid (5), and middle cerebral (9) arteries. 8/28 were treated with endovascular thrombectomy (EVT), and 20/28 died during the admission. 65% of patients not treated with EVT had delayed presentations or large established infarcts. In models accounting for pre-stroke mRS, basilar occlusion location, intravenous thrombolysis, and EVT, coma independently increased the odds of transitioning to comfort care during admission (aOR 6.75; 95% CI 2.87,15.84; p < 0.001) and decreased the odds of 90-day mRS 0-2 (aOR 0.12; 95% CI 0.03,0.55; p = 0.007). CONCLUSIONS: It is not uncommon for patients with LVO to present with coma, and delayed recognition of LVO can lead to poor outcomes, emphasizing the need for maintaining a high index of suspicion. While more commonly thought to result from posterior LVO, coma in our cohort was similarly likely to result from anterior LVO. Efforts to improve early diagnosis and care of patients with LVO presenting with coma are crucial.

Vitamin D genetic risk scores in multiple sclerosis.

BACKGROUND: Low serum 25(OH)D3 (vD) is an environmental risk factor for multiple sclerosis (MS). Lower vD levels during early disease may be associated with long-term disability. Determinants of serum vD levels in healthy individuals include supplementation behaviour and genetic factors. These determinants have been less well studied in people with MS (pwMS). METHODS: We developed a vD-weighted genetic risk score (GRS) and validated this in 373,357 UK Biobank participants without MS. We measured serum 25(OH)D3 and genotyped six vD-associated SNPs (rs12785878, rs10741657, rs17216707, rs10745742, rs8018720, rs2282679) in a cohort of pwMS (n = 315) with age and geographically matched controls (n = 232). We then assessed predictors of serum vD concentration in this cohort. RESULTS: The GRS was strongly associated with vD status in the Biobank cohort (p < 2 × 10-16). vD supplementation, having MS, lower BMI, increased age and supplementation dose were associated with higher vD levels (false discovery rate, FDR < 5%). In multivariable models adjusting for supplementation, BMI, age, sex, and MS status, the GRS was strongly associated with vD level (p = 0.004), but not in those who supplemented (p = 0.47). CONCLUSIONS: Our findings suggest that vD supplementation is the major determinant of vD level in pwMS, with genetic determinants playing a far smaller role.

In a hub-and-spoke network, spoke-administered thrombolysis reduces mechanical thrombectomy procedure time and number of passes.

BACKGROUND: The utility of intravenous thrombolysis (IVT) prior to mechanical thrombectomy (MT) in large vessel occlusion stroke (LVO) is controversial. Some data suggest IVT increases MT technical difficulty. Within our hub-and-spoke telestroke network, we examined how spoke-administered IVT affected hub MT procedure time and pass number. METHODS: Patients presenting to 25 spoke hospitals who were transferred to the hub and underwent MT from 2018 to 2020 were identified from a prospectively maintained database. MT procedure time, fluoroscopy time, and pass number were obtained from operative reports. RESULTS: Of 107 patients, 48 received IVT at spokes. Baseline characteristics and NIHSS were similar. The last known well (LKW)-to-puncture time was shorter among IVT patients (4.3 ± 1.9 h vs. 10.5 ± 6.5 h, p < 0.0001). In patients that received IVT, mean MT procedure time was decreased by 18.8 min (50.5 ± 29.4 vs. 69.3 ± 46.7 min, p = 0.02) and mean fluoroscopy time was decreased by 11.3 min (21.7 ± 15.8 vs. 33.0 ± 30.9 min, p = 0.03). Furthermore, IVT-treated patients required fewer MT passes (median 1 pass [IQR 1.0, 1.80] vs. 2 passes [1.0, 2.3], p = 0.0002) and were more likely to achieve reperfusion in ≤2 passes (81.3% vs. 59.3%, p = 0.01). An increased proportion of IVT-treated patients achieved TICI 2b-3 reperfusion after MT (93.9% vs. 83.8%, p = 0.045). There were no associations between MT procedural characteristics and LKW-to-puncture time. CONCLUSION: Within our network, hub MT following spoke-administered IVT was faster, required fewer passes, and achieved improved reperfusion. This suggests spoke-administered IVT does not impair MT, but instead may enhance it.

Spoke-administered thrombolysis improves large vessel occlusion early recanalization: the real-world experience of a large academic hub-and-spoke telestroke network.

Introduction: Intravenous thrombolysis (IVT) prior to mechanical thrombectomy (MT) for large vessel occlusion (LVO) stroke is increasingly controversial. Recent trials support MT without IVT for patients presenting directly to MT-capable "hub" centers. However, bypassing IVT has not been evaluated for patients presenting to IVT-capable "spoke" hospitals that require hub transfer for MT. A perceived lack of efficacy of IVT to result in LVO early recanalization (ER) is often cited to support bypassing IVT, but ER data for IVT in patients that require interhospital transfer is limited. Here we examined LVO ER rates after spoke-administered IVT in our hub-and-spoke stroke network. Methods: Patients presenting to 25 spokes before hub transfer for MT consideration from 2018-2020 were retrospectively identified from a prospectively maintained database. Inclusion criteria were pre-transfer CTA-defined LVO, ASPECTS ≥6, and post-transfer repeat vessel imaging. Results: Of 167 patients, median age was 69 and 51% were female. 76 received spoke IVT (+spokeIVT) and 91 did not (-spokeIVT). Alteplase was the only IVT used in this study. Comorbidities and NIHSS were similar between groups. ER frequency was increased 7.2-fold in +spokeIVT patients [12/76 (15.8%) vs. 2/91 (2.2%), P<0.001]. Spoke-administered IVT was independently associated with ER (aOR=11.5, 95% CI=2.2,99.6, p<0.05) after adjusting for timing of last known well, interhospital transfer, and repeat vessel imaging. Interval NIHSS was improved in patients with ER (median -2 (IQR -6.3, -0.8) vs. 0 (-2.5, 1), p<0.05). Conclusion: Within our network, +spokeIVT patients had a 7.2-fold increased ER relative likelihood. This real-world analysis supports IVT use in eligible patients with LVO at spoke hospitals before hub transfer for MT.

'Drip-and-ship' intravenous thrombolysis and outcomes for large vessel occlusion thrombectomy candidates in a hub-and-spoke telestroke model.

BACKGROUND: Randomized trials have not demonstrated benefit from intravenous thrombolysis among patients undergoing endovascular thrombectomy (EVT). However, these trials included primarily patients presenting directly to an EVT capable hub center. We sought to study outcomes for EVT candidates who presented to spoke hospitals and were subsequently transferred for EVT consideration, comparing those administered alteplase at spokes (i.e., 'drip-and-ship' model) versus those not. METHODS: Consecutive EVT candidates presenting to 25 spokes from 2018 to 2020 with pre-transfer CT angiography defined emergent large vessel occlusion and Alberta Stroke Program CT score ≥6 were identified from a prospectively maintained Telestroke database. Outcomes of interest included adequate reperfusion (Thrombolysis in Cerebral Infarction (TICI) 2b-3), intracerebral hemorrhage (ICH), discharge functional independence (modified Rankin Scale (mRS) ≤2), and 90 day functional independence. RESULTS: Among 258 patients, median age was 70 years (IQR 60-81), median National Institutes of Health Stroke Scale (NIHSS) score was 13 (6-19), and 50% were women. Ninety-eight (38%) were treated with alteplase at spokes and 113 (44%) underwent EVT at the hub. Spoke alteplase use independently increased the odds of discharge mRS ≤2 (adjusted OR 2.43, 95% CI 1.08 to 5.46, p=0.03) and 90 day mRS ≤2 (adjusted OR 3.45, 95% CI 1.65 to 7.22, p=0.001), even when controlling for last known well, NIHSS, and EVT; it was not associated with an increased risk of ICH (OR 1.04, 95% CI 0.39 to 2.78, p=0.94), and there was a trend toward association with greater TICI 2b-3 (OR 3.59, 95% CI 0.94 to 13.70, p=0.06). CONCLUSIONS: Intravenous alteplase at spoke hospitals may improve discharge and 90 day mRS and should not be withheld from EVT eligible patients who first present at alteplase capable spoke hospitals that do not perform EVT. Additional studies are warranted to confirm and further explore these benefits.

Characterizing reasons for stroke thrombectomy ineligibility among potential candidates transferred in a hub-and-spoke network.

Background: Access to endovascular thrombectomy (EVT) is relatively limited. Hub-and-spoke networks seek to transfer appropriate large vessel occlusion (LVO) candidates to EVT-capable hubs. However, some patients are ineligible upon hub arrival, and factors that drive transfer inefficiencies are not well described. We sought to quantify EVT transfer efficiency and identify reasons for EVT ineligibility. Methods: Consecutive EVT candidates presenting to 25 spokes from 2018-2020 with pre-transfer CTA-defined LVO and ASPECTS ≥6 were identified from a prospectively maintained database. Outcomes of interest included hub EVT, reasons for EVT ineligibility, and 90-day modified Rankin Scale (mRS) ≤2. Results: Among 258 patients, the median age was 70 years (IQR 60-81); 50% were female. 56% were ineligible for EVT after hub arrival. Cited reasons were large established infarct (49%), mild symptoms (33%), recanalization (6%), distal occlusion (5%), sub-occlusive lesion (3%), and goals of care (3%). Late window patients [last known well (LKW) >6 hours] were more likely to be ineligible (67% vs 43%, P<0.0001). EVT ineligible patients were older (73 vs 68 years, p=0.04), had lower NIHSS (10 vs 16, p<0.0001), longer LKW-hub arrival time (8.4 vs 4.6 hours, p<0.0001), longer spoke Telestroke consult-hub arrival time (2.8 vs 2.2 hours, p<0.0001), and received less intravenous thrombolysis (32% vs 45%, p=0.04) compared to eligible patients. EVT ineligibility independently reduced the odds of 90-day mRS≤2 (aOR=0.26, 95%CI=0.12,0.56; p=0.001) when controlling for age, NIHSS, and LKW-hub arrival time. Conclusions: Among patients transferred for EVT, there are multiple reasons for ineligibility upon hub arrival, with most excluded for infarct growth and mild symptoms. Understanding factors that drive transfer inefficiencies is important to improve EVT access and outcomes.

Summary-data-based Mendelian randomization prioritizes potential druggable targets for multiple sclerosis.

Multiple sclerosis is a complex autoimmune disease caused by a combination of genetic and environmental factors. Translation of Genome-Wide Association Study findings into therapeutics and effective preventive strategies has been limited to date. We used summary-data-based Mendelian randomization to synthesize findings from public expression quantitative trait locus, methylation quantitative trait locus and Multiple Sclerosis Genome-Wide Association Study datasets. By correlating the effects of methylation on multiple sclerosis, methylation on expression and expression on multiple sclerosis susceptibility, we prioritize genetic loci with evidence of influencing multiple sclerosis susceptibility. We overlay these findings onto a list of 'druggable' genes, i.e. genes which are currently, or could theoretically, be targeted by therapeutic compounds. We use GeNets and search tool for the retrieval of interacting genes/proteins to identify protein-protein interactions and druggable pathways enriched in our results. We extend these findings to a model of Epstein-Barr virus-infected B cells, lymphoblastoid cell lines. We conducted a systematic review of prioritized genes using the Open Targets platform to identify completed and planned trials targeting prioritized genes in multiple sclerosis and related disease areas. Expression of 45 genes in peripheral blood was strongly associated with multiple sclerosis susceptibility (False discovery rate 0.05). Of these 45 genes, 20 encode a protein which is currently targeted by an existing therapeutic compound. These genes were enriched for Gene Ontology terms pertaining to immune system function and leucocyte signalling. We refined this prioritized gene list by restricting to loci where CpG site methylation was associated with multiple sclerosis susceptibility, with gene expression and where expression was associated with multiple sclerosis susceptibility. This approach yielded a list of 15 prioritized druggable target genes for which there was evidence of a pathway linking methylation, expression and multiple sclerosis. Five of these 15 genes are targeted by existing drugs and three were replicated in a smaller expression Quantitative Trait Loci dataset (CD40, MERTK and PARP1). In lymphoblastoid cell lines, this approach prioritized 7 druggable gene targets, of which only one was prioritized by the multi-omic approach in peripheral blood (FCRL3). Systematic review of Open Targets revealed multiple early-phase trials targeting 13/20 prioritized genes in disorders related to multiple sclerosis. We use public datasets and summary-data-based Mendelian randomization to identify a list of prioritized druggable genetic targets in multiple sclerosis. We hope our findings could be translated into a platform for developing targeted preventive therapies.

Abdominal tuberculosis with a Pseudo-Sister Mary Joseph nodule mimicking peritoneal carcinomatosis.

A 46-year-old woman presented in severe abdominal pain on a background of 3 months of weight loss and intermittent vomiting. She had visited East Africa 6 months prior but reported no unwell contacts. On examination, she had generalised abdominal tenderness, distension and a painful paraumbilical swelling. CT scanning confirmed small bowel obstruction and revealed widespread peritoneal nodules, lymphadenopathy, ascites and a soft tissue paraumbilical mass. CA-125 tumour marker was elevated. However, transvaginal ultrasound scanning showed normal-appearing ovaries. She underwent a diagnostic laparoscopy for ascitic fluid analysis and biopsy of omental and peritoneal nodules, which revealed a lymphocytic exudate and caseating granulomas, respectively. Interferon-γ release assay and repeated stains for acid-fast bacilli were negative. She was commenced on antituberculous chemotherapy for a presumed diagnosis of abdominal tuberculosis. Positive culture results 2 weeks later confirmed Mycobacterium tuberculosis infection. The patient experienced a complete resolution of symptoms within 6 weeks of treatment.

Long-term disability in neuromyelitis optica spectrum disorder with a history of myelitis is associated with age at onset, delay in diagnosis/preventive treatment, MRI lesion length and presence of symptomatic brain lesions.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease of the central nervous system (CNS) that preferentially targets the spinal cord and optic nerves. Increasing disability is accrued with each inflammatory attack. Disability has been shown to be an independent predictor of poor quality of life in those with NMOSD. Factors associated with increasing disability need further systematic investigation. METHODS: We performed a multi-center retrospective chart analysis of aquaporin-4 (AQP4) seropositive NMOSD patients with a history of myelitis seen at five large referral centers for patients with NMOSD worldwide for whom thorough records including relapse history and corresponding imaging were available. Potential contributors to long-term disability were extracted including demographics, radiographic findings, and clinical characteristics. Multivariable regression modeling was conducted to determine correlates of disability in patients with NMOSD, as measured by the Expanded Disability Status Scale (EDSS). RESULTS: One hundred eighty-two AQP4 seropositive patients (88% female) were included in this analysis. Multiple regression modeling revealed that older age at disease onset, delay in diagnosis/preventive treatment, length of longest acute myelitis lesion and presence of symptomatic brain/brainstem lesions were associated with increased disability when holding other variables constant. CONCLUSION: While age at onset is a factor that cannot be controlled in NMOSD, we can reduce the delay in diagnosis/preventive treatment and reduce future relapses in the brain/brainstem and spinal cord. Delay in diagnosis/preventive treatment and imaging variables that contributed to increased disability support the need for improved measures for early, accurate diagnosis and management of NMOSD, and aggressive treatment of acute relapses.

Biological rationale and potential clinical use of gabapentin and pregabalin in bipolar disorder, insomnia and anxiety: protocol for a systematic review and meta-analysis.

INTRODUCTION: Gabapentin has been extensively prescribed off-label for psychiatric indications, with little established evidence of efficacy. Gabapentin and pregabalin, a very similar drug with the same mechanism of action, bind to a subunit of voltage-dependent calcium channels which are implicated in the aetiopathogenesis of bipolar disorder, anxiety and insomnia. This systematic review and meta-analysis aims to collect and critically appraise all the available evidence about the efficacy and tolerability of gabapentin and pregabalin in the treatment of bipolar disorder, insomnia and anxiety. METHODS AND ANALYSIS: We will include all randomised controlled trials (RCTs) reported as double-blind and comparing gabapentin or pregabalin with placebo or any other active pharmacological treatment (any preparation, dose, frequency, route of delivery or setting) in patients with bipolar disorder, anxiety or insomnia. For consideration of adverse effects (tolerability), single-blind or open-label RCTs and non-randomised evidence will also be summarised. The main outcomes will be efficacy (measured as dichotomous and continuous outcome) and acceptability (proportion of patients who dropped out of the allocated treatment). Published and unpublished studies will be sought through relevant database searches, trial registries and websites; all reference selection and data extraction will be conducted by at least 2 independent reviewers. We will conduct a random-effects meta-analysis to synthesise all evidence for each outcome. Heterogeneity between studies will be investigated by the I2 statistic. Data from included studies will be entered into a funnel plot for investigation of small-study effects. No subgroup analysis will be undertaken, but we will carry out sensitivity analyses about combination treatment, psychiatric comorbidity, use of rescue medications and fixed versus random-effects model. ETHICS AND DISSEMINATION: This review does not require ethical approval. This protocol has been registered on PROSPERO (CRD42016041802). The results of the systematic review will be disseminated via publication in a peer-reviewed journal.