Dynamic Expansion and Contraction of Multiple Sclerosis T2-weighted Hyperintense Lesions are Present Below the Threshold of Visual Perception.

BACKGROUND AND PURPOSE: The study of T2-weighted hyperintense lesions resulting from autoimmune inflammatory injury and associated volumes within the CNS remains fundamental to the diagnosis and disease surveillance of multiple sclerosis (MS). We investigated the dynamic changes of individual T2-weighted hyperintense MS lesions on MRI and hypothesized that variations may be present below the threshold of visual perception when evaluating longitudinal data. MATERIALS AND METHODS: A retrospective study was performed of people with MS, incorporating data from three consecutive MRI time points acquired within a single academic center. All included MRI studies lacked formal imaging interpretations of newly enlarging or contracting T2-weighted hyperintensities. Well defined, non-coalescing, individual T2-weighted hyperintense lesions were targeted. A total of 8-12 lesions were randomly selected in a blinded fashion at MRI time point 1 and 3-dimensional lesion volumes followed over MRI time points 2 and 3. The impact of treatment on lesion expansion and relationship to brain MRI advancement, patient-reported progression of disease, and physician-identified progression was also studied. RESULTS: The study cohort was comprised of 115 people (81 (70.4%) female; mean disease duration of 6.62 years(y) (standard deviation: 6.68y)) who were primarily White (79.1%). A total of 1,426 focal T2-weighted hyperintense MS lesions were identified on MRI time point 1 and longitudinally followed over MRI time points 2 and 3. In the evaluation of raw changes in individual T2-weighted hyperintense lesion volumes from MRI time point 1 to MRI time point 2, a similar number of individuals were observed with predominantly expanding (49/115; 42.6%) or contracting (51/115; 44.3%) lesions. However, the majority of lesions expanded in volume (48/115; 41.7%) versus those that contracted (45/115; 39.1%) when evaluating MRI time point 3 to time point 1. Those individuals not on active treatment had a 67.15% reduction in the odds of more individual lesions predominantly contracting in volume relative to those on low-efficacy disease modifying therapy treatment (95% CI=[-83.89, -33.01], p=0.0008) and 74.02% reduction for those on high-efficacy treatment (95% CI=[-87.37%,-46.56%], p<0.0001). CONCLUSIONS: Dynamic changes in T2-weighted hyperintense lesions are abundant, occurring below the threshold of visual perception and are present more frequently in untreated individuals. ABBREVIATIONS: MS = multiple sclerosis; DMT = disease modifying therapy; 2D = 2-dimensional; 3D = 3-dimensional; LMS = Lambda, Mu, and Sigma.

Generative artificial intelligence versus clinicians: Who diagnoses multiple sclerosis faster and with greater accuracy?

BACKGROUND: Those receiving the diagnosis of multiple sclerosis (MS) over the next ten years will predominantly be part of Generation Z (Gen Z). Recent observations within our clinic suggest that younger people with MS utilize online generative artificial intelligence (AI) platforms for personalized medical advice prior to their first visit with a specialist in neuroimmunology. The use of such platforms is anticipated to increase given the technology driven nature, desire for instant communication, and cost-conscious nature of Gen Z. Our objective was to determine if ChatGPT (Generative Pre-trained Transformer) could diagnose MS in individuals earlier than their clinical timeline, and to assess if the accuracy differed based on age, sex, and race/ethnicity. METHODS: People with MS between 18 and 59 years of age were studied. The clinical timeline for people diagnosed with MS was retrospectively identified and simulated using ChatGPT-3.5 (GPT-3.5). Chats were conducted using both actual and derivatives of their age, sex, and race/ethnicity to test diagnostic accuracy. A Kaplan-Meier survival curve was estimated for time to diagnosis, clustered by subject. The p-value testing for differences in time to diagnosis was accomplished using a general Wilcoxon test. Logistic regression (subject-specific intercept) was used to capture intra-subject correlation to test the accuracy prior to and after the inclusion of MRI data. RESULTS: The study cohort included 100 unique people with MS. Of those, 50 were members of Gen Z (38 female; 22 White; mean age at first symptom was 20.6 years (y) (standard deviation (SD)=2.2y)), and 50 were non-Gen Z (34 female; 27 White; mean age at first symptom was 37.0y (SD=10.4y)). In addition, a total of 529 people that represented digital simulations of the original cohort of 100 people (333 female; 166 White; 136 Black/African American; 107 Asian; 120 Hispanic, mean age at first symptom was 31.6y (SD=12.4y)) were generated allowing for 629 scripted conversations to be analyzed. The estimated median time to diagnosis in clinic was significantly longer at 0.35y (95% CI=[0.28, 0.48]) versus that by ChatGPT at 0.08y (95% CI=[0.04, 0.24]) (p<0.0001). There was no difference in the diagnostic accuracy between ages and by race/ethnicity prior to the inclusion of MRI data. However, prior to including the MRI data, males had a 47% less likely chance of a correct diagnosis relative to females (p=0.05). Post-MRI data inclusion within GPT-3.5, the odds of an accurate diagnosis was 4.0-fold greater for Gen Z participants, relative to non-Gen Z participants (p=0.01) with the diagnostic accuracy being 68% less in males relative to females (p=0.009), and 75% less for White subjects, relative to non-White subjects (p=0.0004). CONCLUSION: Although generative AI platforms enable rapid information access and are not principally designed for use in healthcare, an increase in use by Gen Z is anticipated. However, the obtained responses may not be generalizable to all users and bias may exist in select groups.

Underdosed generic specialty medications: A prescription for patient harm?

The use of generic specialty medications amongst individuals with multiple sclerosis (MS) has expanded due to an increase in the number of available agents. We describe a woman who was denied continued use of brand name teriflunomide (AubagioⓇ), despite being clinically stable for 2.5 years, and switched to generic teriflunomide. She experienced a significant spinal cord exacerbation within a few months of starting treatment. We analyzed 3 generic teriflunomide agents, including the one used for treatment, in addition to AubagioⓇ. The generic teriflunomide used by our patient contained 55.5 % content of the labeled amount, well below U.S. FDA specifications.

Dimethyl fumarate preserves brainstem and cervical spinal cord integrity in radiologically isolated syndrome.

BACKGROUND AND PURPOSE: The first randomized placebo-controlled therapeutic trial in radiologically isolated syndrome (RIS), ARISE, demonstrated that treatment with dimethyl fumarate (DMF) delayed the onset of a first clinical event related to CNS demyelination and was associated with a significant reduction in new and/or newly enlarging T2-weighted hyperintense lesions. The purpose of this study was to explore the effect of DMF on volumetric measures, including whole brain, thalamic, and subcortical gray matter volumes, brainstem and upper cervical spine three-dimensional (3D) volumes, and brainstem and upper cervical spine surface characteristics. METHODS: Standardized 3T MRIs including 3D isotropic T1-weighted gradient echo images were acquired at baseline and end-of-study according to the ARISE study protocol. The acquired data were analyzed using Structural Image Evaluation Using Normalization of Atrophy (SIENA), FreeSurfer v7.3, and an in-house pipeline for 3D conformational metrics. Multivariate mixed models for repeated measures were used to analyze rates of change in whole brain, thalamic, subcortical gray matter, as well as change in the 3D surface curvature of the dorsal pons and dorsal medulla and 3D volume change at the medulla-upper cervical spinal cord. RESULTS: The study population consisted of 64 RIS subjects (DMF:30, placebo:34). No significant difference was seen in whole brain, thalamic, or subcortical gray matter volumes in treated vs. untreated RIS patients. A significant difference was observed in dorsal pons curvature with the DMF group having a lower least squares mean change of - 4.46 (standard estimate (SE): 3.77) when compared to placebo [6.94 (3.71)] (p = 0.036). In individuals that experienced a first clinical event, a greater reduction in medulla-upper cervical spinal cord volume (p = 0.044) and a decrease in surface curvature was observed at the dorsal medulla (p = 0.009) but not at the dorsal pons (p = 0.443). CONCLUSIONS: The benefit of disease-modifying therapy in RIS may extend to CNS structures impacted by neurodegeneration that is below the resolution of conventional volumetric measures.

Gastrointestinal pain: A systematic review of temporal summation of pain paradigms and outcomes.

BACKGROUND AND OBJECTIVE: Since targeted treatment for gastrointestinal pain is elusive, identifying the mechanistic underpinning of this pain type is important. Facilitation of spinal neuronal responses underpins certain pain types, and the psychophysical temporal summation of pain (TSP) paradigm provides a proxy measure of spinal facilitatory processes. Our aim was to systematically review whether facilitated TSP is a feature of gastrointestinal pain in patients with, or pain-free people experiencing experimentally induced, gastrointestinal pain. DATABASES AND DATA TREATMENT: EMBASE, MEDLINE, PsychInfo, CINAHL, and Web of Science were systematically searched, from inception to July 2023, for human studies reporting TSP paradigm outcomes in the context of gastrointestinal pain. The Appraisal tool for Cross-Sectional studies was used for quality assessment and applied independently by two researchers. RESULTS: Fifteen papers consisting of cross-sectional (n = 6), case-control (n = 8), and retrospective cohort (n = 1) studies, were included. Thirteen studies investigated TSP in people with gastrointestinal pain with (n = 5) or without (n = 8) defined pathology. Two studies evoked TSP by repetitive gut stimulation in people undergoing abdominal medical procedures. Preliminary evidence showed that facilitated TSP correlated with the presence of functional gastrointestinal pain in women, and those with a history of trauma. No effect was observed in people with inflammatory bowel disease, although it was often unclear if they experienced pain. CONCLUSIONS: It is not possible to conclude whether facilitated TSP is a feature of gastrointestinal pain. We recommend that subgroup findings are corroborated and that TSP paradigms are standardized in order that direct comparisons between studies may be made. SIGNIFICANCE STATEMENT: Evidence indicated that pain facilitatory processes, as evidenced by a facilitated TSP outcome, contribute to functional gastrointestinal pain in women and those with a history of trauma. However, heterogeneity of study populations and paradigms precluded statistical synthesis and findings would need be corroborated. Studies exploring facilitatory processes in people with inflammatory bowel diseases did not report significant results, but pain is not a given in these conditions and, conversely, may be driven by peripheral inflammation during active disease. This should be taken in consideration in future explorations. REGISTRATION REVIEW: PROSPERO CRD42022341845.

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.

Spatial sorting promotes rapid (mal)adaptation in the red-shouldered soapberry bug after hurricane-driven local extinctions.

Predicting future evolutionary change is a critical challenge in the Anthropocene as geographic range shifts and local extinction emerge as hallmarks of planetary change. Hence, spatial sorting-a driver of rapid evolution in which dispersal-associated traits accumulate along expanding range edges and within recolonized habitats-might be of growing importance in ecology and conservation. We report on the results of a natural experiment that monitored recolonization of host plants by the seed-feeding, red-shouldered soapberry bug, Jadera haematoloma, after local extinctions from catastrophic flooding in an extreme hurricane. We tested the contribution of spatial sorting to generate rapid and persistent evolution in dispersal traits, as well as in feeding traits unrelated to dispersal. Long-winged dispersal forms accumulated in recolonized habitats and due to genetic correlation, mouthparts also became longer and this shift persisted across generations. Those longer mouthparts were probably adaptive on one host plant species but maladaptive on two others based on matching the optimum depth of seeds within their host fruits. Moreover, spatial sorting eroded recently evolved adaptive divergence in mouthpart length among all host-associated biotypes, an outcome pointing to profound practical consequences of the extreme weather event for local adaptation, population resilience and evolutionary futures.

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.

Parent Perception of School Meals in the San Joaquin Valley during COVID-19: A Photovoice Project.

School-based nutrition programs are crucial to reducing food insecurity. The COVID-19 pandemic adversely impacted students' school meal participation. This study seeks to understand parent views of school meals during COVID-19 to inform efforts to improve participation in school meal programs. Photovoice methodology was used to explore parental perception of school meals in San Joaquin Valley, California, a region of predominately Latino farmworker communities. Parents in seven school districts photographed school meals for a one-week period during the pandemic and then participated in focus group discussions and small group interviews. Focus group discussions and small group interviews were transcribed, and data were analyzed using a team-based, theme-analysis approach. Three primary domains emerged: benefits of school meal distribution, meal quality and appeal, and perceived healthfulness. Parents perceived school meals as beneficial to addressing food insecurity. However, they noted that meals were unappealing, high in added sugar, and unhealthy, which led to discarded meals and decreased participation in the school meal program. The transition to grab-and-go style meals was an effective strategy for providing food to families during pandemic school closures, and school meals remain an important resource for families experiencing food insecurity. However, negative parental perceptions of the appeal and nutritional content of school meals may have decreased school meal participation and increased food waste that could persist beyond the pandemic.

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.

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.

Dorsal medulla surface texture: Differentiating neuromyelitis optica spectrum disorder from multiple sclerosis.

BACKGROUND AND PURPOSE: The timely and accurate diagnosis of neuromyelitis optica spectrum disorder (NMOSD) is essential and exposure to multiple sclerosis (MS) disease-modifying therapies may result in permanent neurological disability. METHODS: Standardized 3-Tesla 3-dimensional brain MRI studies were retrospectively studied from people with NMOSD, MS, other CNS neurological diseases, and healthy control subjects. Comparisons of surface texture characteristics at the area postrema involving absolute introverted planar triangle counts, representing more complex and concave tissue topography, along with the spatial dissemination pattern of these triangles were performed cross-sectionally and longitudinally. An ideal introverted planar triangle threshold separating groups with NMOSD and MS was accomplished using the highest Youden's J statistic. For the classification of NMOSD, out-of-sample and in-sample measurements of the following were acquired: sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). RESULTS: The study cohort included 60 people with NMOSD, 100 people with MS, 12 with other neurological diseases, and five healthy controls. Significantly higher cross-sectional median introverted triangle counts were observed when the NMOSD (median [interquartile range]: 100 [23.5]) group was compared to MS (65 [20.25]; p < .0001) and other neurological diseases (66 [13.75]; p < .0001). Distinct spatial dissemination patterns of triangles extending craniocaudally at the region of interest within the dorsal medulla was also seen between groups with NMOSD and MS (p < .0001). For the identification of NMOSD, out-of-sample sensitivity (83%), specificity (100%), PPV (100%), and NPV (60%) were achieved. CONCLUSIONS: Cross-sectional and longitudinal dorsal medulla surface texture differences within selective regions of vulnerability differentiate NMOSD from MS.

Hiding in plain sight: The magnitude of unused disease modifying therapies in multiple sclerosis and strategies for reducing the economic burden of care.

BACKGROUND: The rising costs associated with multiple sclerosis (MS) disease modifying therapies (DMTs) creates challenges for patients and the healthcare system in the United States (U.S.). Within a specialty medicine waste project, we quantified the magnitude of unused medications and corresponding value, the primary factors driving treatment switches, and explored reasons for discontinuations by race and ethnicity. METHODS: Over one calendar year, MS DMTs were recovered from new and existing patients from a single neuroimmunologist within a tertiary MS care center. Baseline demographic and clinical information, including reasons for medication discontinuation or transitions were captured. Patients were stratified into three treatment transition categories: (i) non-medical, (ii) medical, or (iii) tolerability reasons. Cause-specific Cox proportional hazard functions were fit for possible causes for treatment changes. RESULTS: A total of 422 patients (female: 73.2%, median age at diagnosis: 32.9 years (y)) comprised of 86.3% Whites, 11.6% Black or African Americans, 1.4% Asians, and 0.7% Native Americans were included, representing 23% of patients evaluated within 2018, with a mean disease duration of 12.8 years (y) (standard deviation (SD): 8.2) and treatment duration of 2.9y (3.4). Women were more likely to switch due to injection fatigue or desire for an oral DMT when compared to men (95% CI [0.26, 0.78], p = 0.01). Being Black or African American people with MS increased the hazard of switching treatment due to injection fatigue and desire for an oral medication relative to White patients with MS by 91% (95% CI [1.07, 3.42], p = 0.03) and switching to a new DMT based on the subjective report of a perceived lack of efficacy was 221% greater (95% CI [1.04, 4.70], p = 0.04), but not in relation to side effects, being 50% less likely to switch (95% CI [0.28, 0.90], p = 0.02). In the passive recruitment phase over a single calendar year, DMTs with a retail value of $5.2 million (Average Wholesale Price (AWP)) were recovered. In the 1-month active recruitment phase within the same year involving 49 people with MS, unused MS DMTs of $1.1 million (AWP) were acquired. Of the 471 patients studied, 56.2% reported transitions in DMTs for reasons other than adequate disease control and tolerability at one point in their treatment history, underscoring the need for individualized therapy selections that enhance persistence and increase the likelihood of reducing further neurological disability. CONCLUSION: The magnitude of unused and wasted MS DMTs is staggering and these findings allude to a larger, more pervasive problem within the healthcare system with financial resources being applied to therapies that go unused.

Direction and magnitude of displacement differ between slowly expanding and non-expanding multiple sclerosis lesions as compared to small vessel disease.

BACKGROUND AND PURPOSE: Differentiating between multiple sclerosis (MS) and small vessel disease (SVD) lesions represents a key challenge in the day-to-day management of patients. We aimed to distinguish between MS and SVD by identifying the dynamics of lesion movement patterns between enlarging and contracting foci from two MRI time points. METHODS: Standardized 3-Tesla 3-dimensional brain magnetic resonance imaging (MRI) studies were performed at two time points on enrolled MS and SVD patients. Selected supratentorial lesions were segmented and longitudinal changes in the direction of lesion displacement and magnitude along with the evolution of contracting and expanding T1-weighted and T2-weighted MS lesions were quantified based on lesion centroid positioning. Bayesian linear mixed effects regression models were constructed to evaluate associations between changes in lesion transitions and disease state. RESULTS: A total of 420 lesions were analyzed from 35 MS (female (F):22 (62.9%); median age (range):38 years (y) (22-61), median disease duration:7.38y (0.38-20.99)) and 12 SVD patients (F:11 (100%); 54y (40-66)). MS T2-weighted lesions that increased in volume between MRI time points demonstrated movement toward the cortex (p = 0.01), whereas those that decreased in volume moved toward the center (p < 0.0001). Lesion volume changes related to SVD demonstrated no effect on movement direction over time. Both expanding (p = 0.03) and contracting (p = 0.01) MS lesions demonstrated greater distances between centroids when compared to SVD. CONCLUSION: Lesion dynamics may reveal distinct characteristics associated with the biology of disease while providing further insights into the behavior of inflammatory CNS disorders.

Assessment of Somatosensory Function and Self-harm in Adolescents.

Importance: Self-harm is a risk factor for suicide in adolescents, with the prevalence highest in young people in group and residential care programs. Although no established risk factors for self-harm exist, adolescents who self-harm may have decreased pain sensitivity, but this has not been systematically investigated. Objective: To assess somatosensory function using quantitative sensory testing (QST) in children and adolescents living in care grouped by the number of episodes of self-harm in the past year and compare their somatosensory profiles with community control participants to investigate associations with the incidence or frequency of self-harm. Design, Setting, and Participants: Recruitment for this cross-sectional study began January 2019 and ended March 2020. Exclusion criteria included intellectual disability (intelligence quotient <70), autism spectrum disorder, or recent serious injury. Children and adolescents aged 12 to 17 years with no underlying health conditions were recruited from local authority residential care settings in Glasgow, UK, and schools and youth groups in London and Glasgow, UK. The volunteer sample of 64 participants included adolescents ages 13 to 17 years (34 [53%] females; 50 [78%] living in residential care; mean [SD] age, 16.34 [1.01] years) with varying incidents of self-harm in the past year (no episodes, 31 [48%]; 1-4 episodes, 12 [19%]; and ≥5 episodes, 2 [33%]). Exposures: Participants were tested using a standardized QST protocol to establish baseline somatosensory function. Main Outcomes and Measures: Associations between somatosensory sensitivity, incidence and frequency of self-harm, residential status, age, gender, and prescription medication were calculated. Secondary outcomes assessed whether self-harm was associated with specific types of tests (ie, painful or nonpainful). Results: A total of 64 participants ages 13 to 17 years completed testing (mean [SD] age, 16.3 [1.0] years; 34 [53%.] females and 30 [47%] males; 50 [78%] living in group homes). Adolescents with 5 or more self-harm incidences showed significant pain hyposensitivity compared with community control participants after adjusting for age, gender, and prescription drug use (SH group with 5 or more episodes vs control: -1.03 [95% CI, -1.47 to -0.60]; P < .001). Hyposensitivity also extended to nonpainful stimuli, similarly adjusted (SH group with 5 or more episodes vs control: -1.73; 95% CI, -2.62 to -0.84; P < .001). Pressure pain threshold accounted for most of the observed variance (31.1% [95% CI, 10.5% to 44.7%]; P < .001). Conclusions and Relevance: The findings of this study suggest that sensory hyposensitivity is a phenotype of Adolescents who self-harm and that pressure pain threshold has clinical potential as a quick, inexpensive, and easily interpreted test to identify adolescents at increased risk of repeated self-harm.

Towards optimising experimental quantification of persistent pain in Parkinson's disease using psychophysical testing.

People with Parkinson's disease (PD) may live for multiple decades after diagnosis. Ensuring that effective healthcare provision is received across the range of symptoms experienced is vital to the individual's wellbeing and quality of life. As well as the hallmark motor symptoms, PD patients may also suffer from non-motor symptoms including persistent pain. This type of pain (lasting more than 3 months) is inconsistently described and poorly understood, resulting in limited treatment options. Evidence-based pain remedies are coming to the fore but therapeutic strategies that offer an improved analgesic profile remain an unmet clinical need. Since the ability to establish a link between the neurodegenerative changes that underlie PD and those that underlie maladaptive pain processing leading to persistent pain could illuminate mechanisms or risk factors of disease initiation, progression and maintenance, we evaluated the latest research literature seeking to identify causal factors underlying persistent pain in PD through experimental quantification. The majority of previous studies aimed to identify neurobiological alterations that could provide a biomarker for pain/pain phenotype, in PD cohorts. However heterogeneity of patient cohorts, result outcomes and methodology between human psychophysics studies overwhelmingly leads to inconclusive and equivocal evidence. Here we discuss refinement of pain-PD paradigms in order that future studies may enhance confidence in the validity of observed effect sizes while also aiding comparability through standardisation. Encouragingly, as the field moves towards cross-study comparison of data in order to more reliably reveal mechanisms underlying dysfunctional pain processing, the potential for better-targeted treatment and management is high.

Pain in Parkinson's disease: Mechanism-based treatment strategies.

PURPOSE OF REVIEW: Chronic pain, highly prevalent throughout the course of Parkinson's disease (PD), has been ranked as one of the top ten most bothersome symptoms people with Parkinson's (PwP) are experiencing. Yet, robust evidence-based treatment strategies are lacking. This unmet need is partly attributable to the multifaceted nature of PD-related pain, which results in part from a complex and poorly understood interplay involving a range of neurotransmitter pathways. Degeneration of nigrostriatal dopaminergic pathways and alterations of central nervous system extra-striatal dopaminergic, noradrenergic, serotoninergic, glutamatergic, opioidergic and endocannabinoid circuits may all promote a heightened experience of pain in PwP. Thus, the potential targets for mechanism-based pain-relieving strategies in PwP are several. These targets are discussed herein. RECENT FINDINGS: An increasing number of clinical trials and experimental studies in animal models of PD are being designed with the aim of addressing the pathophysiological mechanism(s) underlying PD-related pain. Overall, recent research findings highlight the analgesic effects of dopaminergic and opioidergic medication for certain subtypes of pain in PwP, whereas proposing novel strategies that involve targeting other neurotransmitter pathways. SUMMARY: The origin of pain in PwP remains under investigation. Although our understanding of the mechanisms underpinning persistent pain in PD has improved in recent years, this has not yet translated to clinical alleviation of this most troublesome nonmotor symptom. Patient stratification linked with evidence-based personalized pain-treatment plans for optimal analgesic relief will rely on advances in our understanding of the dopaminergic and nondopaminergic targets outlined in this review.

The impact of paradigm and stringent analysis parameters on measuring a net conditioned pain modulation effect: A test, retest, control study.

BACKGROUND: Reporting in conditioned pain modulation (CPM) studies is not standardised. Here, two CPM protocols were performed in populations of healthy human subjects in order to investigate the influence of the CPM paradigm and stringent analyses parameters on the identification of a net CPM effect. METHODS: A standard thermal or mechanical CPM protocol was carried out on 25 and 17 subjects, respectively. The standard error of measurement (SEM) of the CPM effect was calculated in order to determine a change in pain thresholds greater than that due to measurement error or 'real' change in test scores. In addition, each individual underwent a minimum of two control CPM sessions, which were paired with the CPM test sessions. To quantify a net CPM effect, the intrasession difference between baseline and conditioning was subtracted from the difference calculated at the same time points during the control session. RESULTS: For both protocols, excellent reliability for intrasession repeats of the test stimulus at baseline was demonstrated for thermal and mechanical stimulation (ICC > 0.9). Test-retest subject responses (in terms of experimental Session 1 versus. Session 2) showed excellent reliability for mechanical (ICC > 0.8), compared to thermal stimulation, which ranged from poor to moderate (ICC < 0.4->0.75). However, calculating the net CPM effect using control session data demonstrated poor-fair reliability for both protocols (ICC < 0.4-0.59). CONCLUSION: Calculating the net CPM effect should be optimised and standardised for comparison of CPM data collected from global research groups. Recommendation is made for the performance of a multicentre, test-retest study.

Utility of shape evolution and displacement in the classification of chronic multiple sclerosis lesions.

The accurate recognition of multiple sclerosis (MS) lesions is challenged by the high sensitivity and imperfect specificity of MRI. To examine whether longitudinal changes in volume, surface area, 3-dimensional (3D) displacement (i.e. change in lesion position), and 3D deformation (i.e. change in lesion shape) could inform on the origin of supratentorial brain lesions, we prospectively enrolled 23 patients with MS and 11 patients with small vessel disease (SVD) and performed standardized 3-T 3D brain MRI studies. Bayesian linear mixed effects regression models were constructed to evaluate associations between changes in lesion morphology and disease state. A total of 248 MS and 157 SVD lesions were studied. Individual MS lesions demonstrated significant decreases in volume < 3.75mm3 (p = 0.04), greater shifts in 3D displacement by 23.4% with increasing duration between MRI time points (p = 0.007), and greater transitions to a more non-spherical shape (p < 0.0001). If 62.2% of lesions within a given MRI study had a calculated theoretical radius > 2.49 based on deviation from a perfect 3D sphere, a 92.7% in-sample and 91.2% out-of-sample accuracy was identified for the diagnosis of MS. Longitudinal 3D shape evolution and displacement characteristics may improve lesion classification, adding to MRI techniques aimed at improving lesion specificity.