Frontiers in Neurology

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ISSN / EISSN : 1664-2295 / 1664-2295
Published by: Frontiers Media SA (10.3389)
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, Patricia C. Heyn, Alex Tagawa, Christina Coughlan, James J. Carollo
Published: 27 June 2022
Frontiers in Neurology, Volume 13; https://doi.org/10.3389/fneur.2022.748015

Abstract:
Objective: Adults with cerebral palsy (CP) often have impaired cognitive functions. CP also has deteriorations in multiple quality-of-life (QoL) domains. The bio-psycho-social health psychology model posits that biological factor interacts with social and psychological functions. However, the biological determinant of psycho-social and functional outcomes in CP has been scarcely examined. Circulating Insulin-like growth factor-1 (IGF-1) is associated with cognitive deficits in older adults, we thus aimed to examine the associations of circulating IGF-1 with: (1) objectively measured cognitive functions, (2) self-reported cognitive functions, and (3) QoL measures in adults diagnosed with CP. Methods: Seventy-two adults with CP and varying degrees of cognitive functions were recruited from an accredited clinical motion analysis laboratory at a regional Children's Hospital. Circulating IGF-1 was measured using post-fasting serum. The Wechsler Adult Intelligence Scale (WAIS) tests were administered to assess multiple cognitive functions, whereas the Patient-Reported Outcomes Measurement Information System (PROMIS) was used to measure multiple domains of self-reported health, including cognitive complaints and eight QoL domains. Results: Sixty-eight participants had complete data [mean age = 25 (SD = 5.3), female = 52.8%]. Controlling for covariates, circulating IGF-1 was associated with multiple cognitive domains, including positively with declarative memory and executive function and inversely with visual-spatial and motor skills, and processing speed, while no association with subjective memory complaint was detected. Circulating IGF-1 was also inversely associated with four QoL domains, including depressive symptoms, executive function, physical function, and social roles and activities. Conclusions: In CP, circulating IGF-1 might be a useful biological determinant of objective cognitive functions and several quality-of-life domains commonly impaired in CP.
Zhiqiang Li, Sijie Cai, Jing Wang, Rui Chen
Published: 27 June 2022
Frontiers in Neurology, Volume 13; https://doi.org/10.3389/fneur.2022.911996

Abstract:
Objective: The main aim of this meta-analysis was to evaluate the predictors of the efficacy of continuous positive airway pressure (CPAP) in ameliorating excessive daytime sleepiness (EDS) in patients with obstructive sleep apnea (OSA).Methods: Randomized controlled trials (RCTs) published between January 1994 and October 2021 were searched in the PubMed, EMBASE, and Cochrane Library databases. The weighted mean differences (WMDs) for the Epworth Sleepiness Scale (ESS) scores, the Multiple Sleep Latency Test (MSLT), and the Maintenance of Wakefulness Test (MWT) were pooled in STATA.Results: A total of 41 RCTs involving 7,332 patients were included. CPAP therapy was found to be significantly associated with changes in ESS (WMD = −2.14, P < 0.001), MSLT (WMD = 1.23, P < 0.001), and MWT (WMD = 1.6, P < 0.001). Meta-regression analysis and subgroup analysis indicated that in mild OSA, the efficacy of CPAP therapy for subjective EDS was limited to patients <50 years of age, with a baseline body mass index (BMI) of ≥30 kg/m2, baseline ESS score of ≥11, therapy adherence for ≥3 h/night, and treatment duration of ≥2 months. In moderate OSA, significant differences were observed in the changes in ESS among groups stratified by baseline ESS score (P = 0.005), adherence (P < 0.001), treatment duration (P = 0.009), and trial design type (P = 0.001). In severe OSA, this difference was observed among groups stratified by baseline BMI (P = 0.028), baseline ESS score (P = 0.001), and adherence (P = 0.047). Patients with moderate-severe OSA but not mild OSA showed significant improvements in MSLT. Patients with the age <50 years or BMI ≥33 kg/m2 had a more significant increase in MWT.Conclusion: Continuous positive airway pressure therapy improved subjective and objective sleepiness in patients with OSA. Age, baseline BMI, baseline ESS score, adherence, and duration of treatment may predict the effects of CPAP on EDS in patients with OSA. Notably, the baseline ESS scores and adherence were stable predictors regardless of OSA severity.
Atul Kumar, Yasheng Chen, Aaron Corbin, Ali Hamzehloo, Amin Abedini, Zeynep Vardar, Grace Carey, Kunal Bhatia, Laura Heitsch, Jamal J. Derakhshan, et al.
Published: 27 June 2022
Frontiers in Neurology, Volume 13; https://doi.org/10.3389/fneur.2022.898728

Abstract:
Quantifying the extent and evolution of cerebral edema developing after stroke is an important but challenging goal. Lesional net water uptake (NWU) is a promising CT-based biomarker of edema, but its measurement requires manually delineating infarcted tissue and mirrored regions in the contralateral hemisphere. We implement an imaging pipeline capable of automatically segmenting the infarct region and calculating NWU from both baseline and follow-up CTs of large-vessel occlusion (LVO) patients. Infarct core is extracted from CT perfusion images using a deconvolution algorithm while infarcts on follow-up CTs were segmented from non-contrast CT (NCCT) using a deep-learning algorithm. These infarct masks were flipped along the brain midline to generate mirrored regions in the contralateral hemisphere of NCCT; NWU was calculated as one minus the ratio of densities between regions, removing voxels segmented as CSF and with HU outside thresholds of 20–80 (normal hemisphere and baseline CT) and 0–40 (infarct region on follow-up). Automated results were compared with those obtained using manually-drawn infarcts and an ASPECTS region-of-interest based method that samples densities within the infarct and normal hemisphere, using intraclass correlation coefficient (ρ). This was tested on serial CTs from 55 patients with anterior circulation LVO (including 66 follow-up CTs). Baseline NWU using automated core was 4.3% (IQR 2.6–7.3) and correlated with manual measurement (ρ = 0.80, p < 0.0001) and ASPECTS (r = −0.60, p = 0.0001). Automatically segmented infarct volumes (median 110-ml) correlated to manually-drawn volumes (ρ = 0.96, p < 0.0001) with median Dice similarity coefficient of 0.83 (IQR 0.72–0.90). Automated NWU was 24.6% (IQR 20–27) and highly correlated to NWU from manually-drawn infarcts (ρ = 0.98) and the sampling-based method (ρ = 0.68, both p < 0.0001). We conclude that this automated imaging pipeline is able to accurately quantify region of infarction and NWU from serial CTs and could be leveraged to study the evolution and impact of edema in large cohorts of stroke patients.
, Stephan Richter, Mathias Mäurer, Mathias Buttmann, Boris Kreusel, Anne-Maria Poehler, Maren Lampl, Ralf A. Linker
Published: 27 June 2022
Frontiers in Neurology, Volume 13; https://doi.org/10.3389/fneur.2022.913616

Abstract:
Background: Ozanimod, a sphingosine 1-phosphate receptor 1 and 5 modulator, was approved as a disease-modifying therapy for active relapsing-remitting multiple sclerosis (RRMS) in 2020 and for active ulcerative colitis in 2021. Long-term, real-world studies in a nonselective population are needed. OzEAN is an ongoing study to assess the real-world persistent use, effectiveness, and safety of ozanimod and its impact on quality of life (QoL) in patients with RRMS over a 5-year period. Methods: This prospective, noninterventional, postmarketing authorization study will enroll ~1,300 patients (≥18 years of age) with active RRMS. The decision to initiate ozanimod must have been made before and independent from study participation. Enrollment began in March 2021. Recruitment is ongoing and will last for 36 months across 140 sites in Germany. Treatment-naive patients or those having prior experience with a disease-modifying therapy receive oral ozanimod 0.92 mg/day after an initial dose escalation, per the summary of product characteristics recommendations, for up to 60 months. Persistence with ozanimod treatment (primary endpoint) is assessed at month 60. Secondary endpoints include additional physician-reported outcomes [persistence at earlier time points, annualized relapse rate, Expanded Disability Status Scale score, cognition (Symbol Digit Modalities Test), and incidence of adverse events], and patient-reported outcomes assessing patient satisfaction, adherence, and treatment modalities (Treatment Satisfaction Questionnaire for Medication, v1.4), disability (United Kingdom Neurological Disability Rating Scale), QoL (MSQOL-54 questionnaire), fatigue (Fatigue Scale for Motor and Cognitive Functions), and health economics [Work Productivity and Activity Impairment Questionnaire for Multiple Sclerosis (German v2.1); Multiple Sclerosis Health Resource Survey, v3.0]. A Multiple Sclerosis Documentation System with an internet-based e-health portal allows patients to view files and complete questionnaires. A safety follow-up will occur 3–8 months after the last ozanimod dose for patients who discontinue treatment early. Long-term results are anticipated after study completion in 2029. Yearly interim analyses are planned after enrollment has reached 25%. Conclusion: This is the first long-term, real-world study of ozanimod in patients with RRMS and, to our knowledge, the first noninterventional study utilizing a patient portal. These data will add to the safety/efficacy profile of ozanimod demonstrated in phase 3 trials. Clinical Trial Registration: Clinicaltrials.gov, identifier: NCT05335031.
, James Soileau, Bradley Shore
Published: 27 June 2022
Frontiers in Neurology, Volume 13; https://doi.org/10.3389/fneur.2022.879149

Abstract:
Objective: This report is a case series of patients with findings suspicious for a labyrinthine dehiscence syndrome not previously described in the medical literature. We describe the clinical and test findings in 16 patients with CT findings suspicious for dehiscence of the ampullated end of the horizontal semicircular canal at the tympanic segment of the facial nerve. Study Design: Observational case series. Setting: Neurotology vestibular referral center. Patients: To be included in this study the patients were seen at our center in 2019 and had a high-resolution CT scan with a collimation of 0.6 mm. Patients who were identified as having findings suspicious for dehiscence of bone where the facial nerve crosses the ampullated end of the horizontal semicircular canal (HSC-FND) were identified and further analyzed. Interventions: Case series retrospective record review of patient symptoms, physical findings, audiometry, vestibular testing, and CT scans was performed. CT findings of other dehiscent sites were noted. A comparison to surgically treated perilymph fistula (PLF) patients of the same period was performed. Main Outcome Measures: History and physical exam were reviewed for auditory symptoms, vestibular symptoms, and exacerbating factors. and. Audiometry and vestibular testing were reviewed to determine which tests were most likely to be abnormal. CT scans were independently graded according to degree of suspicion for HSC-FND. Finally, patients with HSC-FND as the sole dehiscence identified were compared to those who had HSC-FND plus other dehiscent sites (HSC-FND+O) and to the group of surgically treated PLF patients. Results: Of 18 patients, 16 met inclusion criteria. Nine (56%) of those suspicious for HSC-FND had dehiscences in other parts of the labyrinth. Additional dehiscent sites included: six superior semicircular canal dehiscences (SSCD), two cochlear facial dehiscences and one cochlear carotid dehiscence. The most common auditory symptoms were autophony followed by tinnitus and aural fullness. The most common vestibular symptoms were pulsion sensation (feeling of being pushed to one side) followed by vertigo spells. The most common exacerbating factors for vertigo were straining, and sound. The most commonly abnormal vestibular test was nasal Valsalva testing, which was positive in all but one patient. Anamnesis and examination observations were similar in both groups, but the HSC-FND group were less likely to demonstrate a caloric weakness or an abnormal ECOG compared to the HSC-FND+O group. Of note, cVEMP was more often found to have lower thresholds in the HSC-FND group compared to the HSC-FND+O group. An example case is highlighted. Comparison to the PLF patients revealed statistically significant difference in the presenting symptoms of autophony, fullness and pulsion sensation. When comparing testing, HSC-FND patients were more likely to have an abnormal cVEMP and PLF patients were more likely to have asymmetric hearing. The incidence of bilateral disease was also more common among the HSC-FND patients than the PLF patients. Conclusions: A new labyrinthine dehiscence has been described to occur where the tympanic segment of the facial nerve crosses over the ampullated end of the horizontal semicircular canal. HSC-FND patients can present in a similar manner as HSC-FND+O patients with similar test findings except as mentioned above. The identification of one dehiscence such as SSCD does not preclude the presence of another dehiscence such as HSC-FND. HSC-FND could be the source of persistent symptoms post SSCD surgery as illustrated in the case presented. HSC-FND patients seem to identify themselves compared to PLF patients by a much more likely presenting symptoms of autophony, fullness, pulsion, abnormal cVEMP, bilaterality of disease, and symmetric hearing.
, Janet E. Sowden, Joshua Burns, Michael P. McDermott, Jeffrey Krischer, John Thornton, Davide Pareyson, Steven S. Scherer, Michael E. Shy, Mary M. Reilly, et al.
Published: 27 June 2022
Frontiers in Neurology, Volume 13; https://doi.org/10.3389/fneur.2022.930435

Abstract:
With therapeutic trials on the horizon for Charcot-Marie-Tooth type 1A (CMT1A), reliable, valid, and responsive clinical outcome assessments and biomarkers are essential. Accelerate Clinical Trials in CMT (ACT-CMT) is an international study designed to address important gaps in CMT1A clinical trial readiness including the lack of a validated, responsive functional outcome measure for adults, and a lack of validated biomarkers for multicenter application in clinical trials in CMT1A. The primary aims of ACT-CMT include validation of the Charcot-Marie-Tooth Functional Outcome Measure, magnetic resonance imaging of intramuscular fat accumulation as a lower limb motor biomarker, and in-vivo reflectance confocal microscopy of Meissner corpuscle sensory receptor density, a sensory biomarker. Initial studies have indicated that these measures are feasible, reliable and valid. A large prospective, multi-site study is necessary to fully validate and examine the responsiveness of these outcome measures in relation to existing outcomes for use in future clinical trials involving individuals with CMT1A. Two hundred 15 adults with CMT1A are being recruited to participate in this prospective, international, multi-center study. Serial assessments, up to 3 years, are performed and include the CMT-FOM, CMT Exam Score-Rasch, Overall Neuropathy Limitations Scale, CMT-Health Index, as well as nerve conduction studies, and magnetic resonance imaging and Meissner corpuscle biomarkers. Correlations using baseline data will be examined for validity. Longitudinal analyses will document the changes in function, intramuscular fat accumulation, Meissner corpuscle sensory receptor density. Lastly, we will use anchor-based and other statistical methods to determine the minimally clinically important change for these clinical outcome assessments and biomarkers in CMT1A. Reliable, and responsive clinical outcome assessments of function and disease progression biomarkers are urgently needed for application in early and late phase clinical trials in CMT1A. The ACT-CMT study protocol will address this need through the prospective, longitudinal, multicenter examination in unprecedented detail of novel and existing clinical outcome assessments and motor and sensory biomarkers, and enhance international clinical trial infrastructure, training and preparedness for future therapeutic trials in CMT and related neuropathies.
, Luca Sclabas, Marco Caversaccio, Stefan Weder
Published: 27 June 2022
Frontiers in Neurology, Volume 13; https://doi.org/10.3389/fneur.2022.886171

Abstract:
Introduction and Objectives: Among cochlear implant candidates, an increasing number of patients are presenting with residual acoustic hearing. To monitor the postoperative course of structural and functional preservation of the cochlea, a reliable objective biomarker would be desirable. Recently, impedance telemetry has gained increasing attention in this field. The aim of this study was to investigate the postoperative course of the residual acoustic hearing and clinical impedance in patients with long electrode arrays and to explore the applicability of impedance telemetry for monitoring residual hearing.Methods: We retrospectively analyzed records of 42 cochlear implant recipients with residual hearing covering a median postoperative follow-up of 25 months with repeated simultaneous pure tone audiometry and impedance telemetry. We used a linear mixed-effects model to estimate the relation between clinical electrode impedance and residual hearing. Besides the clinical impedance, the follow-up time, side of implantation, gender, and age at implantation were included as fixed effects. An interaction term between impedance and follow-up time, as well as subject-level random intercepts and slopes, were included.Results: Loss of residual hearing occurred either during surgery or within the first 6 post-operative months. Electrode contacts inserted further apically (i.e., deeper) had higher impedances, independent of residual hearing. The highest impedances were measured 1 month postoperatively and gradually decreased over time. Basal electrodes were more likely to maintain higher impedance. Follow-up time was significantly associated with residual hearing. Regardless of the time, we found that a 1 kΩ increase in clinical impedance was associated with a 4.4 dB deterioration of residual hearing (p < 0.001).Conclusion: Pure tone audiometry is the current gold standard for monitoring postoperative residual hearing. However, the association of clinical impedances with residual hearing thresholds found in our study could potentially be exploited for objective monitoring using impedance telemetry. Further analysis including near-field related impedance components could be performed for improved specificity to local immune responses.
Qian-Rong Huang, Jian-Wen Li, Ping Yan, Qian Jiang, Fang-Zhou Guo, Yin-Nong Zhao,
Published: 27 June 2022
Frontiers in Neurology, Volume 13; https://doi.org/10.3389/fneur.2022.861438

Abstract:
Background: The prognosis of lower-grade glioma (LGG) is highly variable, and more accurate predictors are still needed. The aim of our study was to explore the prognostic value of ferroptosis-related long non-coding RNAs (lncRNAs) in LGG and to develop a novel risk signature for predicting survival with LGG. Methods: We first integrated multiple datasets to screen for prognostic ferroptosis-related lncRNAs in LGG. A least absolute shrinkage and selection operator (LASSO) analysis was then utilized to develop a risk signature for prognostic prediction. Based on the results of multivariate Cox analysis, a prognostic nomogram model for LGG was constructed. Finally, functional enrichment analysis, single-sample gene set enrichment analysis (ssGSEA), immunity, and m6A correlation analyses were conducted to explore the possible mechanisms by which these ferroptosis-related lncRNAs affect survival with LGG. Results: A total of 11 ferroptosis-related lncRNAs related to the prognosis of LGG were identified. Based on prognostic lncRNAs, a risk signature consisting of 8 lncRNAs was constructed and demonstrated good predictive performance in both the training and validation cohorts. Correlation analysis suggested that the risk signature was closely linked to clinical features. The nomogram model we constructed by combining the risk signature and clinical parameters proved to be more accurate in predicting the prognosis of LGG. In addition, there were differences in the levels of immune cell infiltration, immune-related functions, immune checkpoints, and m6A-related gene expression between the high- and low-risk groups. Conclusion: In summary, our ferroptosis-related lncRNA signature exhibits good performance in predicting the prognosis of LGG. This study may provide useful insight into the treatment of LGG.
Yasuhisa Tamura, Masanori Yamato,
Published: 27 June 2022
Frontiers in Neurology, Volume 13; https://doi.org/10.3389/fneur.2022.890217

Abstract:
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic disease of unknown etiology and without effective treatment options. The onset of ME/CFS is often associated with neuroinflammation following bacterial or viral infection. A positron emission tomography imaging study revealed that the degree of neuroinflammation was correlated with the severity of several symptoms in patients with ME/CFS. In animal studies, lipopolysaccharide- and polyinosinic-polycytidylic acid-induced models are thought to mimic the pathological features of ME/CFS and provoke neuroinflammation, characterized by increased levels of proinflammatory cytokines and activation of microglia. In this review, we described the anti-inflammatory effects of three compounds on neuroinflammatory responses utilizing animal models. The findings of the included studies suggest that anti-inflammatory substances may be used as effective therapies to ameliorate disease symptoms in patients with ME/CFS.
Jie Zhang, Yingqi Xing,
Published: 27 June 2022
Frontiers in Neurology, Volume 13; https://doi.org/10.3389/fneur.2022.814972

Abstract:
Background and Objective: Patients with symptomatic vertebral artery stenosis are at high risk of stroke recurrence, especially ≥70% stenosis. Revascularization may be considered for extracranial vertebral artery stenosis in patients with recurrent ischemic events despite optimal medical management. Currently, there is a lack of consensus on the ultrasonic evaluation of extracranial vertebral artery stenosis in clinical practice. This study aimed to validate the efficiency of duplex ultrasonography and assess the optimal sonographic thresholds for predicting extracranial vertebral artery stenosis. Methods: This is a prospective study of all patients with symptomatic posterior circulation stroke/transient ischemic attack who were scheduled to undergo digital subtraction angiography from April 2020 to October 2021. A total of 544 vertebral arteries with a normal lumen or extracranial stenosis confirmed with digital subtraction angiography were included in the study. The peak systolic velocity at the V1 segment (PSVv1) and the V2 segment (PSVv2) were measured and the PSVv1/PSVv2 and PSVv2/PSVv1 ratios were calculated. The cutoff values were determined using receiver operating characteristic analysis. Results: The areas under the receiver operating characteristic curve of all the velocity parameters to predict extracranial vertebral artery stenosis were >0.80. The cutoff values for predicting ≥50% and ≥70% V1 segment stenosis were PSVv1 ≥146 cm/s (sensitivity 76.2%, specificity 86.3%) and PSVv1/PSVv2 ratio ≥2.2 (sensitivity 84.3%, specificity 77.6%), and PSVv1 ≥184 cm/s (sensitivity 80.8%, specificity 87.1%) and PSVv1/PSVv2 ratio ≥3.5 (sensitivity 79.5%, specificity 90.5%), respectively. The cutoff values for predicting ≥50% and ≥70% V2 segment stenosis were PSVv2 ≥80 cm/s (sensitivity 75.0%, specificity 91.0%) and PSVv2/PSVv1 ratio ≥1.2 (sensitivity 75.0%, specificity 94.8%), and PSVv2 ≥111 cm/s (sensitivity 81.0%, specificity 95.0%) and PSVv2/PSVv1 ratio ≥1.7 (sensitivity 81.0%, specificity 96.6%), respectively. Conclusion: Symptomatic patients with the ultrasonic parameters of PSVv1 ≥146 cm/s and PSVv1/PSVv2 ratio ≥2.2 at V1 segment or PSVv2 ≥80 cm/s and PSVv2/PSVv1 ratio ≥1.2 at V2 segment need to be considered for further verification by digital subtraction angiography to seek revascularization. If the parameters increase to PSVv1 ≥184 cm/s and PSVv1/PSVv2 ratio ≥3.5 at the V1 segment or PSVv2 ≥111 cm/s and PSVv2/PSVv1 ratio ≥1.7 at the V2 segment, these patients have an increased risk of recurrent stroke and are more likely to need revascularization. The results can be used as a reference for the assessment and long-term management of patients with extracranial VA stenosis.
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