Faculty Bibliography

BACKGROUND:Prospective data on maintenance therapy with bevacizumab for persons with NF2-related schwannomatosis (NF2-SWN) is lacking. In this prospective multicenter phase II study, we evaluated the efficacy, safety, and tolerability of bevacizumab for maintenance therapy in children and adults with NF2-SWN and hearing loss due to vestibular schwannomas (VS). METHODS:Following induction therapy, participants received bevacizumab 5 mg/kg every 3 weeks for 18 months. Participants were monitored for changes in hearing, tumor size, and quality of life (QOL), and for adverse events. Hearing loss was defined as a statistically significant decline in word recognition score (WRS) or pure-tone average compared to the study baseline; tumor growth was defined as >20% increase in volume compared to baseline. RESULTS:Twenty participants with NF2-SWN (median age 23.5 years; range, 12.5-62.5 years) with hearing loss in the target ear (median WRS 70%, range 2%-94%) received maintenance bevacizumab. Freedom from hearing loss in the target ear was 95% after 48 weeks, 89% after 72 weeks, and 70% after 98 weeks. Freedom from tumor growth in the target VS was 94% after 48 weeks, 89% after 72 weeks, and 89% after 98 weeks. NF2-related QOL remained stable for 98 weeks whereas tinnitus-related distress decreased. Maintenance bevacizumab was well tolerated, with 3 participants (15%) discontinuing treatment due to adverse events. CONCLUSIONS:Maintenance bevacizumab (5 mg/kg every 3 weeks) is associated with high rates of hearing and tumor stability during 18 months of follow-up. No new unexpected adverse events related to bevacizumab were identified in this population.

According to a Bayesian framework, visual perception requires active interpretation of noisy sensory signals in light of prior information. One such mechanism, serial dependence, is thought to promote perceptual stability by assimilating current percepts with recent stimulus history. Combining a delayed orientation-adjustment paradigm with predictable (study 1) or unpredictable (study 2) task structure, we test two key predictions of this account in a novel context: first, that serial dependence should persist even in variable environments, and, second, that, within a given observer and context, this behavioral bias should be stable from one occasion to the next. Relying on data of 41 human volunteers and two separate experimental sessions, we confirm both hypotheses. Group-level, attractive serial dependence remained strong even in the face of volatile settings with multiple, unpredictable types of tasks, and, despite considerable interindividual variability, within-subject patterns of attractive and repulsive stimulus-history biases were highly stable from one experimental session to the next. In line with the hypothesized functional role of serial dependence, we propose that, together with previous work, our findings suggest the existence of a more general individual-specific fingerprint with which the past shapes current perception. Congruent with the Bayesian account, interindividual differences may then result from differential weighting of sensory evidence and prior information.

The cannabidiol (CBD) Expanded Access Program (EAP), initiated in 2014, provided CBD (Epidiolex) to patients with treatment-resistant epilepsy (TRE). In the final pooled analysis of 892 patients treated through January 2019 (median exposure = 694 days), CBD treatment was associated with a 46%-66% reduction in median monthly total (convulsive plus nonconvulsive) seizure frequency. CBD was well tolerated, and adverse events were consistent with previous findings. We used pooled EAP data to investigate the effectiveness of add-on CBD therapy for individual convulsive seizure types (clonic, tonic, tonic-clonic, atonic, focal to bilateral tonic-clonic), nonconvulsive seizure types (focal with and without impaired consciousness, absence [typical and atypical], myoclonic, myoclonic absence), and epileptic spasms. CBD treatment was associated with a reduction in the frequency of convulsive seizure types (median percentage reduction = 47%-100%), and nonconvulsive seizure types and epileptic spasms (median percentage reduction = 50%-100%) across visit intervals through 144 weeks of treatment. Approximately 50% of patients had ≥50% reduction in convulsive and nonconvulsive seizure types and epileptic spasms at nearly all intervals. These results show a favorable effect of long-term CBD use in patients with TRE, who may experience various convulsive and nonconvulsive seizure types. Future controlled trials are needed to confirm these findings.

OBJECTIVE/UNASSIGNED:Since motor nerve conduction slowing can occur due to loss of large axons, we investigate the conduction slowing profile in amyotrophic lateral sclerosis (ALS) and identify the limits beyond which the diagnosis of exclusive axonal loss is unlikely. METHODS/UNASSIGNED:First, using linear regression analysis, we established the range of motor conduction slowing in 76 chronic inflammatory demyelinating polyneuropathy (CIDP) patients. Demyelinating range confidence intervals were defined by assessing conduction velocity (CV), distal latency (DML), and F-wave latency (F) in relation to distal compound muscle action potential (CMAP) amplitude of median, ulnar, fibular, and tibial nerves. Results were subsequently validated in 38 additional CIDP patients. Then, the newly established demyelination confidence intervals were used to investigate the profile of conduction slowing in 95 ALS patients. RESULTS/UNASSIGNED:CV slowing, prolonged DML, and abnormal F were observed in 22.2%, 19.6%, and 47.1% of the studied nerves respectively in ALS patients. When slowing occurred, it affected more than one segment of the motor nerve, suggesting that CMAP amplitude dependent conduction slowing caused by an exclusive loss of large axons is the main mechanism of slowing. No ALS patient had more than 2 nerves with CV slowing in the confidence interval defined by the regression equations or the American Academy of Neurology (AAN) research criteria for CIDP diagnosis. CONCLUSIONS/UNASSIGNED:The presence of more than two motor nerves with CV slowing in the demyelinating range defined by the regression analysis or AAN criteria in ALS patients suggests the contribution of acquired demyelination or other additional mechanisms exist in the electrodiagnostic profile of ALS.

BACKGROUND:Transophthalmic artery embolization of intracranial meningiomas is thought to be associated with a high complication risk. PURPOSE:With advances in endovascular techniques, we systematically reviewed the current literature to improve our understanding of the safety and efficacy of transophthalmic artery embolization of intracranial meningiomas. DATA SOURCES:We performed a systematic search using PubMed from inception until August 3, 2022. STUDY SELECTION:Twelve studies with 28 patients with intracranial meningiomas embolized through the transophthalmic artery were included. DATA ANALYSIS:Baseline and technical characteristics and clinical and safety outcomes were collected. No statistical analysis was conducted. DATA SYNTHESIS:-BCA in 6 (23%), Onyx in 6 (23%), Gelfoam in 5 (19%), and coils in 1 patient (4%). Complete embolization of the target meningioma feeders was reported in 8 (47%) of 17 patients; partial embolization, in 6 (32%); and suboptimal embolization, in 3 (18%). The endovascular complication rate was 16% (4 of 25), which included visual impairment in 3 (12%) patients. LIMITATIONS:Selection and publication biases were limitations. CONCLUSIONS:Transophthalmic artery embolization of intracranial meningiomas is feasible but is associated with a non-negligible complication rate.

OBJECTIVE:Friedreich ataxia (FRDA) is an inherited condition caused by a GAA triplet repeat (GAA-TR) expansion in the FXN gene. Clinical features of FRDA include ataxia, cardiomyopathy, and in some, vision loss. In this study, we characterize features of vision loss in a large cohort of adults and children with FRDA. METHODS:Using optical coherence tomography (OCT), we measured peripapillary retinal nerve fiber layer (RNFL) thickness in 198 people with FRDA, and 77 controls. Sloan letter charts were used to determine visual acuity. RNFL thickness and visual acuity were compared to measures of disease severity obtained from the Friedreich Ataxia Clinical Outcomes Measures Study (FACOMS). RESULTS:The majority of patients, including children, had pathologically thin RNFLs (mean = 73 ± 13 μm in FRDA; 98 ± 9 μm in controls) and low-contrast vision deficits early in the disease course. Variability in RNFL thickness in FRDA (range: 36 to 107 μm) was best predicted by disease burden (GAA-TR length X disease duration). Significant deficits in high-contrast visual acuity were apparent in patients with an RNFL thickness of ≤68 μm. RNFL thickness decreased at a rate of -1.2 ± 1.4 μm/year and reached 68 μm at a disease burden of approximately 12,000 GAA years, equivalent to disease duration of 17 years for participants with 700 GAAs. INTERPRETATION/CONCLUSIONS:These data suggest that both hypoplasia and subsequent degeneration of the RNFL may be responsible for the optic nerve dysfunction in FRDA and support the development of a vision-directed treatment for selected patients early in the disease to prevent RNFL loss from reaching the critical threshold.

OBJECTIVE:Interventions for carotid occlusions are infrequently undertaken and the outcomes are poorly defined. We sought to study patients undergoing urgent carotid revascularization for symptomatic occlusions. METHODS:The Society for Vascular Surgery Vascular Quality Initiative database was queried from 2003 to 2020 to identify patients with carotid occlusions undergoing carotid endarterectomy (CEA). Only symptomatic patients undergoing urgent interventions within 24 hours of presentation were included. Patients were identified based on CT and MRI imaging. This cohort was compared to symptomatic patients undergoing urgent intervention for severe stenosis (≥80%). Primary endpoints were perioperative stroke, death, myocardial infarction (MI) and composite outcomes as defined by the SVS reporting guidelines. Patient characteristics were analyzed to determine predictors of perioperative mortality and neurological events. RESULTS:inhibitor (32.0%), aspirin (77.9%) and renin-angiotensin inhibitor (43.7%) preoperatively. When compared to patients undergoing urgent endarterectomy for severe stenosis (≥80%), those with symptomatic occlusion were well matched with regards to risk factors, but the severe stenosis cohort appeared better medically managed and less likely to present with cortical stroke symptoms. Perioperative outcomes were significantly worse for the carotid occlusion cohort, primarily driven by higher perioperative mortality (2.8% vs 0.9%, P<.001). The composite endpoint of stroke/death/MI was also significantly worse in the occlusion cohort (7.7% vs 4.9%, P=.014). On multivariate analysis, carotid occlusion was associated with increased mortality (OR, 3.028; 95% CI, 1.362-6.730; P=.007) and composite outcome of stroke, death, or MI (OR, 1.790; 95% CI, 1.135-2.822, P=.012). CONCLUSIONS:Revascularization for symptomatic carotid occlusion constitutes approximately 2% of carotid interventions captured in the VQI, affirming the rarity of this undertaking. These patients have acceptable rates of perioperative neurologic events but are at an elevated risk of overall perioperative adverse events, primarily driven by higher mortality, compared to those with severe stenosis. Carotid occlusion appears to be the most significant risk factor for the composite endpoint of perioperative stroke, death, or MI. While intervention for a symptomatic carotid occlusion may be performed with acceptable rate of perioperative complications, judicious patient selection is warranted in this high-risk cohort.

Approximately half of the brain's circuits are involved in vision and control of eye movements. Therefore, visual dysfunction is a common symptom of concussion, the mildest form of traumatic brain injury (TBI). Photosensitivity, vergence dysfunction, saccadic abnormalities, and distortions in visual perception have been reported as vision-related symptoms following concussion. Impaired visual function has also been reported in populations with a lifetime history of TBI. Consequently, vision-based tools have been developed to detect and diagnose concussion in the acute setting, and characterize visual and cognitive function in those with a lifetime history of TBI. Rapid automatized naming (RAN) tasks have provided widely accessible and quantitative measures of visual-cognitive function. Laboratory-based eye tracking approaches demonstrate promise in measuring visual function and validating results from RAN tasks in patients with concussion. Optical coherence tomography (OCT) has detected neurodegeneration in patients with Alzheimer's disease and multiple sclerosis and may provide critical insight into chronic conditions related to TBI, such as traumatic encephalopathy syndrome. Here, we review the literature and discuss the future directions of vision-based assessments of concussion and conditions related to TBI.

BACKGROUND:Treatment of pediatric-onset multiple sclerosis (POMS) is challenging given the lack of safety and efficacy data in the pediatric population for many of the disease-modifying treatments (DMTs) approved for use in adults with MS. Our objective was to describe the demographic features and clinical and radiologic course of patients with POMS treated with the commonly used newer DMTs within the US Network of Pediatric MS Centers (NPMSC). METHODS:This is an analysis of prospectively collected data from patients who initiated treatment before age 18 with the DMTs listed below at the 12 regional pediatric MS referral centers participating in the NPMSC. RESULTS:One hundred sixty-eight patients on dimethyl fumarate, 96 on fingolimod, 151 on natalizumab, 166 on rituximab, and 37 on ocrelizumab met criteria for analysis. Mean age at DMT initiation ranged from 15.2 to 16.5 years. Disease duration at the time of initiation of index DMT ranged from 1.1 to 1.6 years with treatment duration of 0.9-2.0 years. Mean annualized relapse rate (ARR) in the year prior to initiating index DMT ranged from 0.4 to 1.0. Mean ARR while on index DMT ranged from 0.05 to 0.20. New T2 and enhancing lesions occurred in 75%-88% and 55%-73% of the patients, respectively, during the year prior to initiating index DMT. After initiating index DMT, new T2 and enhancing lesions occurred in 0%-46% and 11%-34% patients, respectively. Rates of NEDA-2 (no evidence of disease activity) ranged from 76% to 91% at 6 months of treatment with index DMTs and 66% to 84% at 12 months of treatment with index DMTs. CONCLUSIONS:Though limited by relatively short treatment duration with the index DMTs, our data suggest clinical and MRI benefit, as well as high rates of NEDA-2, in a large number of POMS patients, which can be used to guide future studies in this population.