Histopathology of the cerebellar cortex in essential tremor and other neurodegenerative motor disorders: comparative analysis of 320 brains.

In recent years, numerous morphologic changes have been identified in the essential tremor (ET) cerebellar cortex, distinguishing ET from control brains. These findings have not been fully contextualized within a broader degenerative disease spectrum, thus limiting their interpretability. Building off our prior study and now doubling the sample size, we conducted comparative analyses in a postmortem series of 320 brains on the severity and patterning of cerebellar cortex degenerative changes in ET (n = 100), other neurodegenerative disorders of the cerebellum [spinocerebellar ataxias (SCAs, n = 47, including 13 SCA3 and 34 SCA1, 2, 6, 7, 8, 14); Friedreich's ataxia (FA, n = 13); multiple system atrophy (MSA), n = 29], and other disorders that may involve the cerebellum [Parkinson's disease (PD), n = 62; dystonia, n = 19] versus controls (n = 50). We generated data on 37 quantitative morphologic metrics, grouped into 8 broad categories: Purkinje cell (PC) loss, heterotopic PCs, PC dendritic changes, PC axonal changes (torpedoes), PC axonal changes (other than torpedoes), PC axonal changes (torpedo-associated), basket cell axonal hypertrophy, and climbing fiber-PC synaptic changes. Principal component analysis of z scored raw data across all diagnoses (11,651 data items) revealed that diagnostic groups were not uniform with respect to pathology. Dystonia and PD each differed from controls in only 4/37 and 5/37 metrics, respectively, whereas ET differed in 21, FA in 10, SCA3 in 10, MSA in 21, and SCA1/2/6/7/8/14 in 27. Pathological changes were generally on the milder end of the degenerative spectrum in ET, FA and SCA3, and on the more severe end of that spectrum in SCA1/2/6/7/8/14. Comparative analyses across morphologic categories demonstrated differences in relative expression, defining distinctive patterns of changes in these groups. In summary, we present a robust and reproducible method that identifies somewhat distinctive signatures of degenerative changes in the cerebellar cortex that mark each of these disorders.

Selective vulnerability of brainstem and cervical spinal cord regions in people with non-progressive multiple sclerosis of Black or African American and European ancestry.

BACKGROUND: We evaluated imaging features suggestive of neurodegeneration within the brainstem and upper cervical spinal cord (UCSC) in non-progressive multiple sclerosis (MS). METHODS: Standardized 3-Tesla three-dimensional brain magnetic resonance imaging (MRI) studies were prospectively acquired. Rates of change in volume, surface texture, curvature were quantified at the pons and medulla-UCSC. Whole and regional brain volumes and T2-weighted lesion volumes were also quantified. Independent regression models were constructed to evaluate differences between those of Black or African ancestry (B/AA) and European ancestry (EA) with non-progressive MS. RESULTS: 209 people with MS (pwMS) having at least two MRI studies, 29% possessing 3-6 timepoints, resulted in 487 scans for analysis. Median follow-up time between MRI timepoints was 1.33 (25th-75th percentile: 0.51-1.98) years. Of 183 non-progressive pwMS, 88 and 95 self-reported being B/AA and EA, respectively. Non-progressive pwMS demonstrated greater rates of decline in pontine volume (p < 0.0001) in B/AA and in medulla-UCSC volume (p < 0.0001) for EA pwMS. Longitudinal surface texture and curvature changes suggesting reduced tissue integrity were observed at the ventral medulla-UCSC (p < 0.001), dorsal pons (p < 0.0001) and dorsal medulla (p < 0.0001) but not the ventral pons (p = 0.92) between groups. CONCLUSIONS: Selectively vulnerable regions within the brainstem-UCSC may allow for more personalized approaches to disease surveillance and management.

Improving the efficiency of clinical trials in multiple sclerosis.

BACKGROUND: Phase 3 clinical trials for disease-modifying therapies in relapsing-remitting multiple sclerosis (RRMS) have utilized a limited number of conventional designs with a high degree of success. However, these designs limit the types of questions that can be addressed, and the time and cost required. Moreover, trials involving people with progressive multiple sclerosis (MS) have been less successful. OBJECTIVE: The objective of this paper is to discuss complex innovative trial designs, intermediate and composite outcomes and to improve the efficiency of trial design in MS and broaden questions that can be addressed, particularly as applied to progressive MS. METHODS: We held an international workshop with experts in clinical trial design. RESULTS: Recommendations include increasing the use of complex innovative designs, developing biomarkers to enrich progressive MS trial populations, prioritize intermediate outcomes for further development that target therapeutic mechanisms of action other than peripherally mediated inflammation, investigate acceptability to people with MS of data linkage for studying long-term outcomes of clinical trials, use Bayesian designs to potentially reduce sample sizes required for pediatric trials, and provide sustained funding for platform trials and registries that can support pragmatic trials. CONCLUSION: Novel trial designs and further development of intermediate outcomes may improve clinical trial efficiency in MS and address novel therapeutic questions.

Antipyretic Efficacy of Bromocriptine in Central Fever: an Exploratory Analysis.

BACKGROUND: 'Central' fevers are thought to result from disruption of hypothalamic thermoregulatory pathways following severe brain injuries. Bromocriptine, due to its central dopamine receptor agonism, has been hypothesized to have antipyretic effect in this setting. However, clinical evidence for this off-label use is limited to a few case reports. In this retrospective cohort study, we analyzed the effect of bromocriptine administration on body temperature in acute brain injury patients with suspected central fever. METHODS: We screened a cohort of adult patients that received bromocriptine in the neurologic-intensive care unit of a tertiary care hospital between January 2018 and December 2021. Indication of central fever was ascertained by review of clinical documentation. A generalized additive mixed model (GAMM) was used to model temperature as a function of time relative to bromocriptine initiation. We adjusted for potential confounding due to the following covariates: temperature recording method (invasive vs surface), concurrent antipyretic administration within 8 h, and surface cooling device use within 4 h of temperature measurement. Temperature-time function was modeled using a cubic spline with k = 10 knots. RESULTS: A total of 33 patients were included in the analysis (14 women; mean age: 50 y, standard deviation 14 y). Median dose of bromocriptine was 7.5 mg (range 2.5-40) for a median of 13 d (range 5-160). Age and sex did not impact the function of temperature over time. Predicted temperatures were significantly (p < 0.05) higher by 0.4 °C with invasive compared to surface recording methods, lower by 0.2 °C in the presence of cooling device use and lower by 0.1 °C with concurrent antipyretic use. On adjusted analysis with the GAMM, there was decline (p < 0.05) in temperature following bromocriptine initiation by - 0.3 °C at 24 h, - 0.5 °C at 48 h, and - 0.7 °C at 72 h. CONCLUSIONS: Bromocriptine use was associated with modest but statistically significant decline in temperature, with nadir at 72 h post initiation. The findings provide a data driven basis for prospective evaluation.

Effects of psychiatric comorbidities in persons with epilepsy on recurrent emergency department visits.

BACKGROUND: Coexisting mental health disorders in persons with epilepsy present as substantial burdens to patients and healthcare systems. STUDY DESIGN AND METHODS: In this retrospective study, we reviewed 160 patients presenting to a safety net hospital Emergency Department (ED) with seizures to investigate whether differences in clinical workup, follow-ups, and ED visit recurrence existed between epilepsy patients with epilepsy with and without a coexisting psychiatric disorder. RESULTS: Patients with epilepsy with a psychiatric comorbidity had more subsequent ED visits (45 % vs 26 %, p = 0.01) and fewer outpatient follow-up opportunities (74 % vs 87 %, p = 0.042) compared to patients with epilepsy without psychiatric comorbidities, highlighting a healthcare gap that needs to be addressed. INTERPRETATION: Our findings suggest a need for ED providers to shift their clinical practice in favor of offering more outpatient follow-up opportunities, to ensure long-term management of seizures in patients with epilepsy with comorbid psychiatric disorders.

Responsiveness of UMSARS and other clinical measures in a longitudinal structured care clinic for multiple system atrophy.

PURPOSE: As understanding of multiple system atrophy (MSA) pathophysiology improves, clinical trials of disease-modifying therapies are starting. Outcome measures responsive to disease progression will be critical, but the United MSA Rating Scale (UMSARS) has limitations. The MSA multidisciplinary clinic at the University of Texas Southwestern is a longitudinal clinic with structured assessments performed at fixed time intervals. The objective of this study was to evaluate the performance of clinical measures in assessing MSA progression over time. METHODS: Data from 73 subjects with clinically diagnosed MSA were analyzed using repeated measures correlation models. Observations were made every 4 months, with up to 3 years of data included for each patient. RESULTS: UMSARS-I and UMSARS-II correlated positively with the MSA Quality of Life (QOL) scale. The rate of change was 3.12 points per year (ppy) for UMSARS-I and 5.55 ppy for UMSARS-II. Some individual UMSARS questions contributed more significantly than others to overall UMSARS rate of change. Based on this finding, and using repeated measures correlations between question combinations and QOL, an optimization of UMSARS parts I and II was curated. The amended UMSARS-I included 8 of the 12 subquestions, and the amended UMSARS-II included 10 of the 14 subquestions. CONCLUSIONS: Data from a longitudinal MSA clinic allows better characterization of the performance of UMSARS as a clinical outcome measure. A curated set of UMSARS questions appears more responsive to change and accounts for correlation with QOL, and could be the starting point for an improved MSA outcome measure.

Application of the International Interocular Difference Thresholds into Practice: Localising the Patient Experience.

Demyelinating diseases of the central nervous system (CNS) often have neuro-ophthalmological manifestations, and retinal examination can be helpful in making the diagnosis. The latest iteration of optical coherence tomography (OCT)-based criteria for optic neuritis in multiple sclerosis has been developed in the research realm, but its application to clinical practice, and to the more uncommon demyelinating diseases requires further study. The ability to use OCT data to distinguish between various CNS demyelinating disorders could provide additional paraclinical tools to accurately diagnose patients. Furthermore, neuro-ophthalmological testing can define the extent of inflammatory damage in the CNS, independent of patient-reported history. New referrals for OCT at a tertiary multiple sclerosis and neuro-immunology referral centre (n = 167) were analysed retrospectively for the self-reporting of optic neuritis, serological test results, and diagnosis. Only approximately 30% of patients with a clinical history of unilateral optic neuritis solely had a unilateral optic neuropathy, nearly 40% of those subjects actually having evidence of bilateral optic neuropathies. Roughly 30% of patients reporting a history of bilateral optic neuritis did not have any evidence of structural disease, with 20% of these patients having a separate, intervenable diagnosis noted on macular scans. OCT is a useful adjunct diagnostic tool in the evaluation of demyelinating disease and has the ability to aid in a more accurate diagnosis for patients. Application of the international interocular difference thresholds to a clinical patient population generally reproduces the original results, emphasising their appropriateness. The analysis distinguishing the demyelinating diseases needs to be replicated in a blinded, multi-centre setting.

Utilization of Visual Acuity Retroilluminated Charts for the Assessment of Afferent Visual System Dysfunction in a Pediatric Neuroimmunology Population.

BACKGROUND: Visual acuity has been a significant outcome measure in clinical trials for patients suffering from neuro-ophthalmological diseases and multiple sclerosis; however, there are limited data on the comparison of various testing strategies in pediatric patients with these disorders. Clinical trials using vision as an outcome could include a variety of tools to assess the acuity, including 2-m and 4-m standardized retroilluminated charts. METHODS: We investigated the difference in Early Treatment Diabetic Retinopathy Study (ETDRS) scores obtained using 2-m and 4-m charts, as well as the impact of optic neuritis, use of vision correction, age, and gender on visual acuity data from 71 patients with pediatric neuroimmunological conditions in a cross-sectional study. RESULTS: We determine that the ETDRS letter scores obtained using 4-m charts are on average 3.43 points less (P = 0.0034) when testing monocular ETDRS letter scores and on average 4.14 points less (P = 0.0008) when testing binocular ETDRS letter scores, relative to that obtained using the 2-m charts. However, we find that when performing monocular testing, optic neuritis in the eye being tested did not result in a statistically significant difference between 2-m and 4-m ETDRS letter scores. CONCLUSIONS: Although visual acuity charts are formatted by the distance, there are significant differences in the number of letters correctly identified between 2-m and 4-m charts. Although the differences may not impact the clinical acuity, research protocols should consider these differences before collapsing data across disparate studies.

Post-gadolinium 3-dimensional spatial, surface, and structural characteristics of glioblastomas differentiate pseudoprogression from true tumor progression.

PURPOSE: Pseudoprogression is often indistinguishable from true tumor progression on conventional 2-dimensional (2D) MRI in glioblastoma multiforme (GBM) patients. The aim of this study was to determine the association between post-gadolinium 3-dimensional (3D) characteristics and clinical state in GBM patients. METHODS: Standardized 3D brain MRI studies were performed, and contrast enhancing portions of each tumor were segmented and analyzed, blinded to clinical state, using principal component analysis (PCA), medial axis transformation (MAT), and coverage analysis. Associations between the 3D characteristics of the post-gadolinium enhanced regions and the clinical status of patients were performed. RESULTS: A total of 15 GBM patients [male: 11 (73%); median age (range): 62 years (36-72)] with a median disease duration of 6 months (range 2-24 months) were studied cross-sectionally with 6 (40%) patients identified with tumor progression. Post-gadolinium features corresponding to the group with progressive disease exhibited a more spherical and symmetric shape relative to their stable counterparts (p = 0.005). The predictive value of a more uniformly full post-gadolinium enhanced shell to clinical progression was determined with a sensitivity of 66.7% (95% CI 29.9-92.5), specificity of 100% (54.1-100), and PPV of 100% (p = 0.028, 2-tailed Fisher's exact test). There did not appear to be an association between the thickness of the contrast enhanced shell to clinical state. CONCLUSIONS: The application of 3D technology with post-gadolinium imaging data may inform healthcare providers with new insights into disease states based on spatial, surface, and structural patterns.

Pathologically based criteria to distinguish essential tremor from controls: analyses of the human cerebellum.

OBJECTIVE: Essential tremor is among the most prevalent neurological diseases. Diagnosis is based entirely on neurological evaluation. Historically, there were few postmortem brain studies, hindering attempts to develop pathologically based criteria to distinguish essential tremor from control brains. However, an intensive effort to bank essential tremor brains over recent years has resulted in postmortem studies involving >200 brains, which have identified numerous degenerative changes in the essential tremor cerebellar cortex. Although essential tremor and controls have been compared with respect to individual metrics of pathology, there has been no overarching analysis to derive a combination of metrics to distinguish essential tremor from controls. We asked whether there is a constellation of pathological findings that separates essential tremor from controls, and how well that constellation performs. METHODS: Analyses included 100 essential tremor brains from the essential tremor centralized brain repository and 50 control brains. A standard tissue block from the cerebellar cortex was used to quantify 11 metrics of pathological change. Three supervised classification algorithms were investigated, with data divided into training and validation samples. RESULTS: Using three different algorithms, we illustrate the ability to correctly predict a diagnosis of essential tremor, with sensitivity and specificity >87%, and in the majority of situations, >90%. We also provide a web-based application that uses these metric values, and based on specified cutoffs, determines the likely diagnosis. INTERPRETATION: These analyses set the stage for use of pathologically based criteria to distinguish clinically diagnosed essential tremor cases from controls, at the time of postmortem.

Reduced Bergmann glial process terminations and lateral appendages in essential tremor.

OBJECTIVE: Postmortem examination of the essential tremor cerebellum has revealed a variety of pathological changes centered in and around Purkinje cells. Studies have predominantly focused on cerebellar neuronal connections. Bergmann glial morphology has not yet been studied in essential tremor. Among their many roles, Bergmann glia in the cerebellar cortex ensheath Purkinje cell synapses and provide neuroprotection. Specifically, the complex radial processes and lateral appendages of Bergmann glia are structural domains that modulate Purkinje cell synaptic transmission. In this study, we investigate whether Bergmann glia morphology is altered in the essential tremor cerebellum. METHODS: We applied the Golgi-Kopsch method and used computerized three-dimensional cell reconstruction to visualize Bergmann glia in the postmortem cerebellum of 34 cases and 17 controls. We quantified morphology of terminal structures (number of terminations and lateral appendage density) and morphology of radial processes (total process length, branch length, branch order, and branch volume) in each glial cell. We quantified number of branches and volume as well. RESULTS: Essential tremor cases had a 31.9% decrease in process terminations and a 35.7% decrease in lateral appendage density in Bergmann glia. Total process length and branch length did not differ between essential tremor cases and controls. We found also a reduction in number of secondary and tertiary branches and tertiary branches volume. INTERPRETATION: These findings suggest that Bergmann glia in essential tremor cases have more alterations in their terminal structures, with a relative preservation of radial processes, and highlight a potential role for these astrocytes in the disease pathophysiology.

Characterization of potentially avoidable neurological emergency department visits at a large urban public hospital.

This study characterized potentially avoidable neurological emergency department (ED) visits at a large urban public hospital. This was a retrospective review of Parkland Health (Dallas, TX) data from May 15, 2021, to July 15, 2021. The study population included encounters discharged home from the ED with any of the following: a primary neurological ED diagnosis, a neurological consultation in the ED, or a neurology clinic referral placed during the ED encounter. Neurovascular, strokelike, acute trauma, and nonneurological cases were excluded. The primary outcome was the number of ED visits by diagnosis category. A total of 965 ED discharge encounters met study criteria as potentially avoidable neurological ED visits, far higher than total neurology-related admissions over the same 2-month period. Headache (66%) and seizure/epilepsy (18%) syndromes were the most common. Thirty-five percent of all cases had neurology involvement in either the ED or the outpatient setting. This was lowest for headache (19%). The revisit rate within 3 months of the index ED visit was 29%, and it was highest for seizures/epilepsy (48%). Potentially avoidable nonvascular neurological ED visits occur frequently, especially for headache and seizure disorders. This study highlights the need for quality improvement and delivery innovation initiatives to optimize the site of care for patients with chronic neurological conditions.

Quality of Life in Patients With Confirmed and Suspected Spinal CSF Leaks.

BACKGROUND AND OBJECTIVES: Spontaneous intracranial hypotension (SIH) is a debilitating condition typically producing orthostatic headache limiting upright time. SIH is often difficult to diagnose and treat, negatively affecting quality of life (QoL) in patients with the disorder. We studied QoL in patients with confirmed and suspected SIH using standardized instruments, including suicidality. METHODS: We performed a cross-sectional survey of adult patients with confirmed and clinically suspected SIH evaluated in our Headache and Facial Pain Program from 2016 to 2022. Using an online data collection tool (REDCap V 11.2.2), participants completed validated questionnaires assessing general well-being (SF-36), depression (PHQ-9), generalized anxiety disorder-7 (GAD-7), spiritual well-being during chronic illness therapy (FACIT-Sp-12), and headache impact (HIT-6). Subsequently, we interviewed willing participants to administer the Columbia-Suicide Severity Rating Scale (C-SSRS) assessing suicidal behavior and ideation. RESULTS: A total of 234 patients met inclusion criteria and were invited to participate in the study, and 95 patients (59 confirmed and 36 clinically suspected) completed the questionnaires. The average age of the cohort was 51.1 years (SD: 15.5), predominantly female (69.5%), White (91.6%), and married (69.5%). Three-quarters (74.5%) scored within the most severe headache category (HIT-6). SF-36 scores were significantly inferior (p < 0.0001) to the general population and lower than reported values for patients with multiple sclerosis and idiopathic intracranial hypertension. Almost half (49.1%) of respondents scored in the moderate depression range or worse (>10), and 25.4% scored with moderate anxiety or worse (>10). FACIT-Sp-12 scores were significantly worse (p < 0.0001) in symptomatic participants than in the validation cohorts of patients with AIDS and cancer. Of the 67 respondents who completed the C-SSRS, more than half (64.2%) endorsed a wish to be dead, and 22.4% had demonstrated suicidal behavior. Patients with symptom-free SIH (n = 22) scored significantly better than symptomatic patients, comparable with the general population. DISCUSSION: Based on our single-center cohort, SIH is associated with severe headache pain and high rates of depression, anxiety, and disability, affecting basic activities of daily living. Individuals with confirmed and suspected spinal CSF leaks scored similarly on these measures including suicidality. Outcomes were comparable with the general population after successful treatment or spontaneous remission. Improved identification and treatment of SIH are imperative to improve patients' QoL.

Reasons and predictors for early termination of pediatric polysomnography: one children's hospital's experience.

STUDY OBJECTIVES: We sought to identify reasons for early polysomnography termination in pediatric patients. METHODS: We retrospectively reviewed all studies conducted at the Pediatric Sleep Center at UT Southwestern Medical Center from January 1, 2017, through December 31, 2019, that were terminated before study completion. We investigated reasons for early termination and gathered characteristics such as age, sex, presence of neurocognitive impairment, payor status, seasonal variability, and testing site location. RESULTS: There were 137 patients who terminated their studies before completion, comprising 1.05% of all patients who arrived for their scheduled polysomnographies during that time frame. The 3 main categories of reasons were equipment intolerance (47%), acute illness (33%), and parental refusal (20%). Parental refusal reasons included the patient's becoming combative, a lack of specialized equipment, patient's inability to fall asleep, forgetting the patient's nighttime medications, and the parent's inability to stay the night. Males represented a greater proportion of those who terminated due to intolerance of equipment (75%). Patients who terminated early due to equipment intolerance consisted of more neurologically impaired patients compared with those who terminated due to acute illness (56% vs 24%). Termination due to acute illness occurred more during the wintertime (44%) than in the summer (7%). In those who terminated due to parental refusal, there was a greater proportion of children under 6 years of age (75%). CONCLUSIONS: Determining factors that are associated with early polysomnography termination is an important step to help identify at-risk groups and implement strategies to improve study completion. CITATION: Luong S, Culp M, McCreary M, Wani A, Caraballo M. Reasons and predictors for early termination of pediatric polysomnography: one children's hospital's experience. J Clin Sleep Med. 2023;19(10):1711-1716.

Factors associated with the misdiagnosis of neuromyelitis optica spectrum disorder.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune condition that is associated with severe disability. Approximately 40% of individuals are misdiagnosed with multiple sclerosis (MS) or other diseases. We aimed to define factors that influence the misdiagnosis of people with NMOSD and provide strategies for reducing error rates. METHODS: A retrospective study was performed involving all people with a confirmed diagnosis of NMOSD within a single academic institution. Comprehensive clinical timelines were constructed for each individual that included presenting symptoms, provider type and timing of evaluations, aquaporin 4-IgG (AQP4) results, and MRI scans. Two-sample comparisons of continuous and categorial variables were performed for people accurately diagnosed with NMOSD and those originally misdiagnosed with another medical condition. A subanalysis of only AQP4-IgG positive people was also performed. RESULTS: The study cohort included 199 people fulfilling International Panel criteria for NMOSD with 71 people (62 female; mean age at first symptom presentation (standard deviation (SD)) = 32.8 years (y) (SD 16.1)) being initially misdiagnosed and 128 people (106 female; 41.14y (SD 15.41)) who were accurately diagnosed. Of the 199 people with NMOSD, 166 had a positive serostatus. Identified factors associated with misdiagnosis, regardless of AQP4-IgG serostatus, were the presence of protracted nausea/vomiting/hiccups without any accompanying neurological symptoms, 23 (32.4%) versus 16 (12.5%) (p = 0.001), a longer median (range) time to see a neuroimmunology specialist 4.2y (0.14-31.8) versus 0.5y (0.0-21.2) (p<0.0001), and a delay in acquiring an MRI study, 4.7y (0.0-27.3) versus 0.3y (0.0-20.2) (p<0.0001). A greater proportion of people misdiagnosed were identified with a negative live-cell based AQP4-IgG serum test result, 13/13 (100%) versus 22/114 (19.3%) (p<0.0001). Additionally, the mean (SD) time between a first negative and successive live-cell based AQP4-IgG positive test result was greater for people misdiagnosed with another condition, 3.9y (SD 5.0) versus 1.5y (SD 2.1) (p = 0.01). Although not significant between groups, a rash was also reported in 63/199 people with NMOSD, with 31/63 having an anti-nuclear antibody titer ≥ 1:160. CONCLUSION: Defined factors can help guide both generalists and specialists in the pursuit of strategies aimed at efficiently diagnosing those with NMOSD such that effective care can be delivered.

High-efficacy therapies reduce clinical and radiological events more effectively than traditional treatments in neuromyelitis optica spectrum disorder.

BACKGROUND: People with neuromyelitis optica spectrum disorder (pwNMOSD) experience debilitating neurological attacks, resulting in permanent disability. OBJECTIVE: To evaluate if high-efficacy treatment was better than traditional agents at preventing disease advancement in pwNMOSD. METHODS: A retrospective study of pwNMOSD at one academic center was performed. Timelines were created for treatments subjects were exposed to along with clinical/radiological events related to disease worsening. High-efficacy treatments included eculizumab, inebilizumab, satralizumab, rituximab, ocrelizumab, tocilizumab, and sarilumab while therapies such as azathioprine, methotrexate, cyclophosphamide, and mycophenolate mofetil were classified as traditional agents. Poisson regression and mixed effects logistics models were constructed, and a subject-specific random intercept was used for intrasubject correlation. RESULTS: Of 189 pwNMOSD identified, 161 were aquaporin-4 IgG positive (AQP4 +) with 92 (77 female; median disease duration (MDD) (range) of 6.6 years (y) (1.2-18.6)) exposed only to high-efficacy therapy, 33 (28 female; 10.4 y (0.8-32.7)) only to traditional therapy, and 64 (54 female; 10.8 y (0.7-20.2)) to both. High-efficacy treatments reduced the rate of MRI advancement by 62.4% (95% CrI = [- 86.9%, - 16.8%]), relapses by 99.8% (95% CrI = [- 99.9%, - 99.6%]), and hospitalizations by 99.3% (95% CrI = [- 99.6%, - 98.8%]) when compared to traditional treatments. For AQP4 + subjects, a 655.7-fold increase in the odds of new spinal cord lesion development (95% CrI = [+ 37.4-fold, + 3239.5-fold]) was observed with traditional agents (p < 0.0001). CONCLUSION: High-efficacy treatments maximize opportunity for preventing disease advancement in newly diagnosed and established pwNMOSD.

Treatment transitions in neuromyelitis optica spectrum disorder increase risk for disease advancement.

BACKGROUND: People with neuromyelitis optica spectrum disorder (PwNMOSD) commonly switch between disease modifying therapies, yet the consequence of transitions remains unknown. We aimed to understand if treatment transitions due to medical, non-medical, and tolerability reasons were related to disease progression. METHODS: A retrospective study of medical records for PwNMOSD was performed between 2008 and 2022. A comprehensive clinical timeline was created for each person including details related to treatment history and associated clinical and radiological outcomes (i.e., hospital admission, relapses, and MRI advancement). If a transition occurred, the reason for the switch was categorized as being due to medical, non-medical, or tolerability issues. A proportional hazards model was created, and the assumptions were tested based on weighted residuals. RESULTS: The cohort included 164 aquaporin-4 IgG positive NMOSD subjects with 89 (79 female; median disease duration (range) = 10.1 years (y) (1.7-32.8)) people switching therapies at least once (once: 42; twice: 26; three times: 12; four times: 6; 5 or more times: 3). A similar amount of higher efficacy therapies was used by PwNMOSD that switched due to a non-medical/tolerability or a medical-related reason. The results of the recurrent event survival analysis revealed that after an initial transition due to non-medical/tolerability reasons, the risk of a hospital admission, relapse, and MRI advancement decreases by 40.3 % (p = 0.005), 53.1 % (p = 0.002), and 65.9 % (p = 0.005), respectively. However, with each additional discontinuation due to non-medical/tolerability reasons, the risk of hospitalization increased by 25.2 % (p = 0.0003) and risk for MRI advancement increased by 41.9 % (p = 0.03). For transitions due to medical reasons, a significant increased risk of MRI advancement by 32.2 % (p = 0.005) for the first switch was identified with no associated observed risk with each additional discontinuation (p = 0.33). Within the first six months after stopping a medication due to non-medical/tolerability reasons, the rate of starting a new medication was less (p<0.0001) when compared to a discontinuation due to a medical-related event. CONCLUSIONS: The risk associated with the time course of treatment transitions for people with NMOSD may assist in transforming the way healthcare providers bridge the gap between therapies and the approach to the timing of a switch. These data highlight additional factors that may be equatable to the efficacy of prescribed treatments in the prevention of acute neurological events.

Pupillary light reflex measured with quantitative pupillometry has low sensitivity and high specificity for predicting neuroworsening after traumatic brain injury.

BACKGROUND: Triage and neurological assessment of the 1.7 million traumatic brain injuries occurring annually is often done by nurse practitioners and physician assistants in the emergency department. Subjective assessments, such as the neurological examination that includes evaluation of the pupillary light reflex (PLR), can contain bias. Quantitative pupillometry (QP) standardizes and objectifies the PLR examination. Additional data are needed to determine whether QP can predict neurological changes in a traumatic brain injury (TBI) patient. PURPOSE: This study examines the effectiveness of QP in predicting neurological decline within 24 hours of admission following acute TBI. METHODOLOGY: This prospective, observational, clinical trial used pragmatic sampling to assess PLR in TBI patients using QP within 24 hours of ED admission. Chi-square analysis was used to determine change in patient status, through Glasgow Coma Scale (GCS), at baseline and within 24 hours of admission, to the QP. RESULTS: There were 95 participants included in the analysis; of whom 35 experienced neuroworsening, defined by change in GCS of >2 within the first 24 hours of admission. There was a significant association between an abnormal Neurological Pupil index (NPi), defined as NPi of <3, and neuroworsening (p < .0001). The sensitivity (51.43%) and specificity (91.67%) of abnormal NPi in predicting neuroworsening were varied. CONCLUSION: There is a strong association between abnormal NPi and neuroworsening in the sample of TBI patients with high specificity and moderate sensitivity. IMPLICATIONS: NPi may be an early indicator of neurological changes within 24 hours of ED admission in patients with TBI.

Structural MRI Ratios Fail to Distinguish Progressive Supranuclear Palsy From Parkinson Disease in Individual Patients.

Background and Objectives: Parkinson disease (PD) and progressive supranuclear palsy (PSP) are often difficult to differentiate in the clinic. The MR parkinsonism index (MRPI) has been recommended to assist in making this distinction. We aimed to assess the usefulness of this tool in our real-world practice of movement disorders. Methods: We prospectively obtained MRI scans on consecutive patients with movement disorders with a clinical indication for imaging and obtained measures of MRI regions of interest (ROIs) from our neuroradiologists. The authors reviewed all MRI scans and corrected any errors in the original ROI drawings for this analysis. We retrospectively assigned diagnoses using established consensus criteria from progress notes stored in our electronic medical record. We analyzed the data using multinomial logistic regression models and receiver operating curve analysis to determine the predictive accuracy of the MRI ratios. Results: MRI measures and consensus diagnoses were available on 130 patients with PD, 54 with PSP, and 77 diagnosed as other. The out-of-sample prediction error rate of our 5 regression models ranged from 45% to 59%. The average sensitivity and specificity of the 5 models in the testing sample were 53% and 80%, respectively. The positive predictive value of an MRPI ≥13.55 (the published cutoff) in our patients was 79%. Discussion: These results indicate that MRI measures of brain structures were not effective at predicting diagnosis in individual patients. We conclude that the search for a biomarker that can differentiate PSP from PD must continue.

Disease associations of excessive daytime sleepiness in multiple sclerosis: A prospective study.

Background: Excessive daytime sleepiness (EDS) in multiple sclerosis (MS) can be a significant source of disability. Despite this, its prevalence as a patient-reported outcome in this condition has not been well established, and its causes are not well understood. Methods: We prospectively assessed EDS as part of an observational study for patients referred for diagnostic neuro-ophthalmological testing. EDS was evaluated by the Epworth Sleepiness Scale (ESS), and visual data were also collected as part of a research protocol. Analysis with patient data was performed following the exclusion of patients with known primary sleep disorders. Results: A total of 69 patients with MS were included in the analysis. The mean ESS was 6.5 with a SD of 4.3. ESS ≥ 10 was present in 23% of the cohort even in the presence of minimal mean neurological disability (Patient Determined Disease Steps (PDDS) = 1.5). The ESS score was not associated with age, sex, disease-related disability, retinal nerve fiber layer (RNFL), or optic neuritis (ON), but displayed an association with visual dysfunction. Conclusions: There is an increased prevalence of EDS in MS. The increased values of the ESS are not explained by other sleep disorders, suggesting separate mechanisms. Further study of the underlying mechanisms is warranted.