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OBJECTIVE: A major challenge in multiple sclerosis (MS) research is the understanding of silent progression and Progressive MS. Using a novel method to accurately capture upper cervical cord area from legacy brain MRI scans we aimed to study the role of spinal cord and brain atrophy for silent progression and conversion to secondary progressive disease (SPMS). METHODS: From a single-center observational study, all RRMS (n = 360) and SPMS (n = 47) patients and 80 matched controls were evaluated. RRMS patient subsets who converted to SPMS (n = 54) or silently progressed (n = 159), respectively, during the 12-year observation period were compared to clinically matched RRMS patients remaining RRMS (n = 54) or stable (n = 147), respectively. From brain MRI, we assessed the value of brain and spinal cord measures to predict silent progression and SPMS conversion. RESULTS: Patients who developed SPMS showed faster cord atrophy rates (-2.19%/yr) at least 4 years before conversion compared to their RRMS matches (-0.88%/yr, p < 0.001). Spinal cord atrophy rates decelerated after conversion (-1.63%/yr, p = 0.010) towards those of SPMS patients from study entry (-1.04%). Each 1% faster spinal cord atrophy rate was associated with 69% (p < 0.0001) and 53% (p < 0.0001) shorter time to silent progression and SPMS conversion, respectively. INTERPRETATION: Silent progression and conversion to secondary progressive disease are predominantly related to cervical cord atrophy. This atrophy is often present from the earliest disease stages and predicts the speed of silent progression and conversion to Progressive MS. Diagnosis of SPMS is rather a late recognition of this neurodegenerative process than a distinct disease phase. ANN NEUROL 2022;91:268-281.
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Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/patología , Médula Espinal/patología , Adulto , Atrofia , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Progresión de la Enfermedad , Femenino , Foramen Magno/diagnóstico por imagen , Foramen Magno/patología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Estudios Prospectivos , Médula Espinal/diagnóstico por imagenRESUMEN
BACKGROUND: Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) and pediatric-onset multiple sclerosis (POMS) share clinical and magnetic resonance imaging (MRI) features but differ in prognosis and management. Early POMS diagnosis is essential to avoid disability accumulation. Central vein sign (CVS), paramagnetic rim lesions (PRLs), and central core lesions (CCLs) are susceptibility-based imaging (SbI)-related signs understudied in pediatric populations that may help discerning POMS from MOGAD. METHODS: T2-FLAIR and SbI (three-dimensional echoplanar imaging (3D-EPI)/susceptibility-weighted imaging (SWI) or similar) were acquired on 1.5T/3T scanners. Two readers assessed CVS-positive rate (%CVS+), and their average score was used to build a receiver operator curve (ROC) assessing the ability to discriminate disease type. PRLs and CCLs were identified using a consensual approach. RESULTS: The %CVS+ distinguished 26 POMS cases (mean age 13.7 years, 63% females, median EDSS 1.5) from 14 MOGAD cases (10.8 years, 35% females, EDSS 1.0) with ROC = 1, p < 0.0001, (cutoff 41%). PRLs were only detectable in POMS participants (mean 2.1±2.3, range 1-10), discriminating the two conditions with a sensitivity of 69% and a specificity of 100%. CCLs were more sensitive (81%) but less specific (71.43%). CONCLUSION: The %CVS+ and PRLs are highly specific markers of POMS. After proper validation on larger multicenter cohorts, consideration should be given to including such imaging markers for diagnosing POMS at disease onset.
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Imagenología Tridimensional , Esclerosis Múltiple , Femenino , Niño , Humanos , Adolescente , Masculino , Glicoproteína Mielina-Oligodendrócito , Venas , Autoanticuerpos , Esclerosis Múltiple/diagnóstico por imagenRESUMEN
BACKGROUND: Remote activity monitoring has the potential to evaluate real-world, motor function, and disability at home. The relationships of daily physical activity with spinal cord white matter and gray matter (GM) areas, multiple sclerosis (MS) disability and leg function, are unknown. OBJECTIVE: Evaluate the association of structural central nervous system pathology with ambulatory disability. METHODS: Fifty adults with progressive or relapsing MS with motor disability who could walk >2 minutes were assessed using clinician-evaluated, patient-reported outcomes, and quantitative brain and spinal cord magnetic resonance imaging (MRI) measures. Fitbit Flex2, worn on the non-dominant wrist, remotely assessed activity over 30 days. Univariate and multivariate analyses were performed to assess correlations between physical activity and other disability metrics. RESULTS: Mean age was 53.3 years and median Expanded Disability Status Scale (EDSS) was 4.0. Average daily step counts (STEPS) were highly correlated with EDSS and walking measures. Greater STEPS were significantly correlated with greater C2-C3 spinal cord GM areas (ρ = 0.39, p = 0.04), total cord area (TCA; ρ = 0.35, p = 0.04), and cortical GM volume (ρ = 0.32, p = 0.04). CONCLUSION: These results provide preliminary evidence that spinal cord GM area is a neuroanatomical substrate associated with STEPS. STEPS could serve as a proxy to alert clinicians and researchers to possible changes in structural nervous system pathology.
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Médula Cervical , Personas con Discapacidad , Trastornos Motores , Esclerosis Múltiple , Adulto , Humanos , Persona de Mediana Edad , Esclerosis Múltiple/patología , Médula Cervical/patología , Médula Espinal/patología , Encéfalo/patología , Imagen por Resonancia Magnética , Caminata , Evaluación de la Discapacidad , Atrofia/patologíaRESUMEN
OBJECTIVE: To assess whether biological aging as measured by leukocyte telomere length (LTL) is associated with clinical disability and brain volume loss in multiple sclerosis (MS). METHODS: Adults with MS/clinically isolated syndrome in the University of California, San Francisco EPIC cohort study were included. LTL was measured on DNA samples by quantitative polymerase chain reaction and expressed as telomere to somatic DNA (T/S) ratio. Expanded Disability Status Scale (EDSS) and 3-dimensional T1-weighted brain magnetic resonance imaging were performed at baseline and follow-up. Associations of baseline LTL with cross-sectional and longitudinal outcomes were assessed using simple and mixed effects linear regression models. A subset (n = 46) had LTL measured over time, and we assessed the association of LTL change with EDSS change with mixed effects models. RESULTS: Included were 356 women and 160 men (mean age = 43 years, median disease duration = 6 years, median EDSS = 1.5 [range = 0-7], mean T/S ratio = 0.97 [standard deviation = 0.18]). In baseline analyses adjusted for age, disease duration, and sex, for every 0.2 lower LTL, EDSS was 0.27 higher (95% confidence interval [CI] = 0.13-0.42, p < 0.001) and brain volume was 7.4mm3 lower (95% CI = 0.10-14.7, p = 0.047). In longitudinal adjusted analyses, those with lower baseline LTL had higher EDSS and lower brain volumes over time. In adjusted analysis of the subset, LTL change was associated with EDSS change over 10 years; for every 0.2 LTL decrease, EDSS was 0.34 higher (95% CI = 0.08-0.61, p = 0.012). INTERPRETATION: Shorter telomere length was associated with disability independent of chronological age, suggesting that biological aging may contribute to neurological injury in MS. Targeting aging-related mechanisms is a potential therapeutic strategy against MS progression. ANN NEUROL 2019;86:671-682.
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Esclerosis Múltiple , Telómero/metabolismo , Adulto , Envejecimiento/fisiología , Senescencia Celular/fisiología , Estudios de Cohortes , Estudios Transversales , Evaluación de la Discapacidad , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/patología , Telómero/patología , Homeostasis del Telómero/fisiologíaRESUMEN
OBJECTIVE: Rates of worsening and evolution to secondary progressive multiple sclerosis (MS) may be substantially lower in actively treated patients compared to natural history studies from the pretreatment era. Nonetheless, in our recently reported prospective cohort, more than half of patients with relapsing MS accumulated significant new disability by the 10th year of follow-up. Notably, "no evidence of disease activity" at 2 years did not predict long-term stability. Here, we determined to what extent clinical relapses and radiographic evidence of disease activity contribute to long-term disability accumulation. METHODS: Disability progression was defined as an increase in Expanded Disability Status Scale (EDSS) of 1.5, 1.0, or 0.5 (or greater) from baseline EDSS = 0, 1.0-5.0, and 5.5 or higher, respectively, assessed from baseline to year 5 (±1 year) and sustained to year 10 (±1 year). Longitudinal analysis of relative brain volume loss used a linear mixed model with sex, age, disease duration, and HLA-DRB1*15:01 as covariates. RESULTS: Relapses were associated with a transient increase in disability over 1-year intervals (p = 0.012) but not with confirmed disability progression (p = 0.551). Relative brain volume declined at a greater rate among individuals with disability progression compared to those who remained stable (p < 0.05). INTERPRETATION: Long-term worsening is common in relapsing MS patients, is largely independent of relapse activity, and is associated with accelerated brain atrophy. We propose the term silent progression to describe the insidious disability that accrues in many patients who satisfy traditional criteria for relapsing-remitting MS. Ann Neurol 2019;85:653-666.
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Progresión de la Enfermedad , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/terapia , Adulto , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
Cortical excitability, as measured by transcranial magnetic stimulation combined with electromyography, is a potential biomarker for the diagnosis and follow-up of epilepsy. We report on long-interval intracortical inhibition data measured in four different centres in healthy controls (n = 95), subjects with refractory genetic generalized epilepsy (n = 40) and with refractory focal epilepsy (n = 69). Long-interval intracortical inhibition was measured by applying two supra-threshold stimuli with an interstimulus interval of 50, 100, 150, 200 and 250 ms and calculating the ratio between the response to the second (test stimulus) and to the first (conditioning stimulus). In all subjects, the median response ratio showed inhibition at all interstimulus intervals. Using a mixed linear-effects model, we compared the long-interval intracortical inhibition response ratios between the different subject types. We conducted two analyses; one including data from the four centres and one excluding data from Centre 2, as the methods in this centre differed from the others. In the first analysis, we found no differences in long-interval intracortical inhibition between the different subject types. In all subjects, the response ratios at interstimulus intervals 100 and 150 ms showed significantly more inhibition than the response ratios at 50, 200 and 250 ms. Our second analysis showed a significant interaction between interstimulus interval and subject type (P = 0.0003). Post hoc testing showed significant differences between controls and refractory focal epilepsy at interstimulus intervals of 100 ms (P = 0.02) and 200 ms (P = 0.04). There were no significant differences between controls and refractory generalized epilepsy groups or between the refractory generalized and focal epilepsy groups. Our results do not support the body of previous work that suggests that long-interval intracortical inhibition is significantly reduced in refractory focal and genetic generalized epilepsy. Results from the second analysis are even in sharper contrast with previous work, showing inhibition in refractory focal epilepsy at 200 ms instead of facilitation previously reported. Methodological differences, especially shorter intervals between the pulse pairs, may have contributed to our inability to reproduce previous findings. Based on our results, we suggest that long-interval intracortical inhibition as measured by transcranial magnetic stimulation and electromyography is unlikely to have clinical use as a biomarker of epilepsy.
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Corteza Cerebral/fisiopatología , Epilepsia/fisiopatología , Potenciales Evocados Motores/fisiología , Inhibición Neural/fisiología , Estimulación Magnética Transcraneal/métodos , Adolescente , Adulto , Biomarcadores , Niño , Electromiografía , Epilepsia/diagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Tiempo , Adulto JovenRESUMEN
PURPOSE: To explore (i) the variability of upper cervical cord area (UCCA) measurements from volumetric brain 3D T1 -weighted scans related to gradient nonlinearity (GNL) and subject positioning; (ii) the effect of vendor-implemented GNL corrections; and (iii) easily applicable methods that can be used to retrospectively correct data. METHODS: A multiple sclerosis patient was scanned at seven sites using 3T MRI scanners with the same 3D T1 -weighted protocol without GNL-distortion correction. Two healthy subjects and a phantom were additionally scanned at a single site with varying table positions. The 2D and 3D vendor-implemented GNL-correction algorithms and retrospective methods based on (i) phantom data fit, (ii) normalization with C2 vertebral body diameters, and (iii) the Jacobian determinant of nonlinear registrations to a template were tested. RESULTS: Depending on the positioning of the subject, GNL introduced up to 15% variability in UCCA measurements from volumetric brain T1 -weighted scans when no distortion corrections were used. The 3D vendor-implemented correction methods and the three proposed methods reduced this variability to less than 3%. CONCLUSIONS: Our results raise awareness of the significant impact that GNL can have on quantitative UCCA studies, and point the way to prospectively and retrospectively managing GNL distortions in a variety of settings, including clinical environments. Magn Reson Med 79:1595-1601, 2018. © 2017 International Society for Magnetic Resonance in Medicine.
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Encéfalo/diagnóstico por imagen , Médula Cervical/diagnóstico por imagen , Interpretación de Imagen Asistida por Computador/métodos , Imagen por Resonancia Magnética/métodos , Esclerosis Múltiple/diagnóstico por imagen , Algoritmos , Médula Cervical/patología , Humanos , Masculino , Persona de Mediana Edad , Dinámicas no Lineales , Fantasmas de ImagenRESUMEN
OBJECTIVE: To characterize the accrual of long-term disability in a cohort of actively treated multiple sclerosis (MS) patients and to assess whether clinical and magnetic resonance imaging (MRI) data used in clinical trials have long-term prognostic value. METHODS: This is a prospective study of 517 actively managed MS patients enrolled at a single center. RESULTS: More than 91% of patients were retained, with data ascertained up to 10 years after the baseline visit. At this last assessment, neurologic disability as measured by the Expanded Disability Status Scale (EDSS) was stable or improved compared to baseline in 41% of patients. Subjects with no evidence of disease activity (NEDA) by clinical and MRI criteria during the first 2 years had long-term outcomes that were no different from those of the cohort as a whole. 25-OH vitamin D serum levels were inversely associated with short-term MS disease activity; however, these levels had no association with long-term disability. At a median time of 16.8 years after disease onset, 10.7% (95% confidence interval [CI] = 7.2-14%) of patients reached an EDSS ≥ 6, and 18.1% (95% CI = 13.5-22.5%) evolved from relapsing MS to secondary progressive MS (SPMS). INTERPRETATION: Rates of worsening and evolution to SPMS were substantially lower when compared to earlier natural history studies. Notably, the NEDA 2-year endpoint was not a predictor of long-term stability. Finally, the data call into question the utility of annual MRI assessments as a treat-to-target approach for MS care. Ann Neurol 2016;80:499-510.
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Progresión de la Enfermedad , Esclerosis Múltiple Crónica Progresiva/diagnóstico por imagen , Esclerosis Múltiple Crónica Progresiva/fisiopatología , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/fisiopatología , Evaluación de Resultado en la Atención de Salud , Índice de Severidad de la Enfermedad , Adulto , Personas con Discapacidad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Crónica Progresiva/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , PronósticoRESUMEN
Epilepsy commonly presents in childhood as part of a syndrome, and some such children may reach adult services without an underlying syndromic diagnosis. For adult neurologists taking over their care, it is often unclear how hard to search for an underlying diagnosis. The diagnostic yield may be small and such a diagnosis may not change management. Young adults with learning difficulties are also challenging to investigate, as they may not tolerate standard epilepsy tests.We present such a case in which simple tests identified a unifying diagnosis. With the new diagnosis came a new treatment that had a significant impact on seizures and quality of life.
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Epilepsia/etiología , Epilepsia/terapia , Guanidinoacetato N-Metiltransferasa/deficiencia , Trastornos del Desarrollo del Lenguaje/complicaciones , Trastornos del Movimiento/congénito , Adulto , Creatina/sangre , Creatina/uso terapéutico , Creatina/orina , Guanidinoacetato N-Metiltransferasa/sangre , Guanidinoacetato N-Metiltransferasa/genética , Guanidinoacetato N-Metiltransferasa/metabolismo , Guanidinoacetato N-Metiltransferasa/orina , Humanos , Trastornos del Desarrollo del Lenguaje/genética , Trastornos del Desarrollo del Lenguaje/metabolismo , Masculino , Trastornos del Movimiento/complicaciones , Trastornos del Movimiento/genética , Trastornos del Movimiento/metabolismo , Mutación/genéticaRESUMEN
A concern for researchers planning multisite studies is that scanner and T1-weighted sequence-related biases on regional volumes could overshadow true effects, especially for studies with a heterogeneous set of scanners and sequences. Current approaches attempt to harmonize data by standardizing hardware, pulse sequences, and protocols, or by calibrating across sites using phantom-based corrections to ensure the same raw image intensities. We propose to avoid harmonization and phantom-based correction entirely. We hypothesized that the bias of estimated regional volumes is scaled between sites due to the contrast and gradient distortion differences between scanners and sequences. Given this assumption, we provide a new statistical framework and derive a power equation to define inclusion criteria for a set of sites based on the variability of their scaling factors. We estimated the scaling factors of 20 scanners with heterogeneous hardware and sequence parameters by scanning a single set of 12 subjects at sites across the United States and Europe. Regional volumes and their scaling factors were estimated for each site using Freesurfer's segmentation algorithm and ordinary least squares, respectively. The scaling factors were validated by comparing the theoretical and simulated power curves, performing a leave-one-out calibration of regional volumes, and evaluating the absolute agreement of all regional volumes between sites before and after calibration. Using our derived power equation, we were able to define the conditions under which harmonization is not necessary to achieve 80% power. This approach can inform choice of processing pipelines and outcome metrics for multisite studies based on scaling factor variability across sites, enabling collaboration between clinical and research institutions.
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Artefactos , Encéfalo/anatomía & histología , Interpretación de Imagen Asistida por Computador/instrumentación , Interpretación de Imagen Asistida por Computador/métodos , Imagen por Resonancia Magnética/instrumentación , Imagen por Resonancia Magnética/métodos , Modelos Estadísticos , Algoritmos , Simulación por Computador , Diseño de Equipo , Análisis de Falla de Equipo , Europa (Continente) , Humanos , Aumento de la Imagen/instrumentación , Aumento de la Imagen/métodos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Estados UnidosRESUMEN
OBJECTIVE: Retinal nerve fibre layer (RNFL) thickness is related to the axonal anterior visual pathway and is considered a marker of overall white matter 'integrity'. We hypothesised that RNFL changes would occur in people with epilepsy, independently of vigabatrin exposure, and be related to clinical characteristics of epilepsy. METHODS: Three hundred people with epilepsy attending specialist clinics and 90 healthy controls were included in this cross-sectional cohort study. RNFL imaging was performed using spectral-domain optical coherence tomography (OCT). Drug resistance was defined as failure of adequate trials of two antiepileptic drugs to achieve sustained seizure freedom. RESULTS: The average RNFL thickness and the thickness of each of the 90° quadrants were significantly thinner in people with epilepsy than healthy controls (p<0.001, t test). In a multivariate logistic regression model, drug resistance was the only significant predictor of abnormal RNFL thinning (OR=2.09, 95% CI 1.09 to 4.01, p=0.03). Duration of epilepsy (coefficient -0.16, p=0.004) and presence of intellectual disability (coefficient -4.0, p=0.044) also showed a significant relationship with RNFL thinning in a multivariate linear regression model. CONCLUSIONS: Our results suggest that people with epilepsy with no previous exposure to vigabatrin have a significantly thinner RNFL than healthy participants. Drug resistance emerged as a significant independent predictor of RNFL borderline attenuation or abnormal thinning in a logistic regression model. As this is easily assessed by OCT, RNFL thickness might be used to better understand the mechanisms underlying drug resistance, and possibly severity. Longitudinal studies are needed to confirm our findings.
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Epilepsia Refractaria/patología , Neuronas Retinianas/patología , Adulto , Anticonvulsivantes/efectos adversos , Anticonvulsivantes/uso terapéutico , Estudios de Cohortes , Estudios Transversales , Femenino , Humanos , Discapacidad Intelectual/complicaciones , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Fibras Nerviosas/patología , Tomografía de Coherencia Óptica , Vigabatrin/efectos adversos , Vigabatrin/uso terapéutico , Campos VisualesRESUMEN
OBJECTIVE: In Jane Austen's Pride and Prejudice, members of the Bennet family are either sensible or silly, and males are under-represented. This study searches for an underlying medical diagnosis that explains these features. DESIGN: Very retrospective literature review. PARTICIPANTS: Mrs Bennet, her five daughters (Jane, Elizabeth, Mary, Kitty and Lydia), her brother (Mr Gardiner) and her sister (Mrs Phillips). MAIN OUTCOME MEASURES: Family tree and associated phenotypes METHODS: The author read Pride and Prejudice. A Bennet family tree was constructed. The number of male and female descendants was analysed using a binomial model. For each character, evidence of behaviour was collected, and members of the Bennet family were categorised as either sensible or silly. RESULTS: Males are under-represented in Mrs Bennet's family. Assuming an equal probability of male or female offspring, this reaches statistical significance (binomial model, P = 0.03). Approximately 50% of females in the family are silly. Silly behaviour is more prevalent during social gatherings. CONCLUSIONS: The family tree suggests an X-linked genetic disorder, fatal in utero or in early life to affected males, explaining the paucity of male offspring. Female carriers survive, but with cognitive difficulties, explaining the approximate 50-50 distribution of sensible and silly females in the family. The exacerbation of silliness during social gatherings may suggest an effect of protein intake, raising suspicions of a disorder of protein metabolism. Ornithine transcarbamylase deficiency is one such condition. Unfortunately, there remain significant challenges in performing genetic testing on fictional characters, so definitive evidence remains elusive. Jane and Elizabeth Bennet do not show signs of the disorder. However, carriers may be asymptomatic; they should be offered genetic counselling before Bingley or Darcy offspring are considered.
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Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Modelos Estadísticos , Enfermedad por Deficiencia de Ornitina Carbamoiltransferasa/diagnóstico , Enfermedad por Deficiencia de Ornitina Carbamoiltransferasa/genética , Personalidad/genética , Proteínas/genética , Emociones/fisiología , Femenino , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Humanos , Masculino , Estudios RetrospectivosRESUMEN
OBJECTIVE: In multiple sclerosis (MS), cerebral gray matter (GM) atrophy correlates more strongly than white matter (WM) atrophy with disability. The corresponding relationships in the spinal cord (SC) are unknown due to technical limitations in assessing SC GM atrophy. Using phase-sensitive inversion recovery (PSIR) magnetic resonance imaging, we determined the association of the SC GM and SC WM areas with MS disability and disease type. METHODS: A total of 113 MS patients and 20 healthy controls were examined at 3T with a PSIR sequence acquired at the C2/C3 disk level. Two independent, clinically masked readers measured the cord WM and GM areas. Correlations between cord areas and Expanded Disability Status Score (EDSS) were determined. Differences in areas between groups were assessed with age and sex as covariates. RESULTS: Relapsing MS (RMS) patients showed smaller SC GM areas than age- and sex-matched controls (p = 0.008) without significant differences in SC WM areas. Progressive MS patients showed smaller SC GM and SC WM areas compared to RMS patients (all p ≤ 0.004). SC GM, SC WM, and whole cord areas inversely correlated with EDSS (rho: -0.60, -0.32, -0.42, respectively; all p ≤ 0.001). The SC GM area was the strongest correlate of disability in multivariate models including brain GM and WM volumes, fluid-attenuated inversion recovery lesion load, T1 lesion load, SC WM area, number of SC T2 lesions, age, sex, and disease duration. Brain and spinal GM independently contributed to EDSS. INTERPRETATION: SC GM atrophy is detectable in vivo in the absence of WM atrophy in RMS. It is more pronounced in progressive MS than RMS and contributes more to patient disability than SC WM or brain GM atrophy.
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Personas con Discapacidad , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/patología , Médula Espinal/patología , Anciano , Atrofia/etiología , Atrofia/patología , Estudios de Casos y Controles , Femenino , Sustancia Gris , Humanos , Procesamiento de Imagen Asistido por Computador , Seguro por Discapacidad , Modelos Lineales , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Curva ROCRESUMEN
PURPOSE: To present and assess a procedure for measurement of spinal cord total cross-sectional areas (TCA) and gray matter (GM) areas based on phase-sensitive inversion recovery imaging (PSIR). In vivo assessment of spinal cord GM and white matter (WM) could become pivotal to study various neurological diseases, but it is challenging because of insufficient GM/WM contrast provided by conventional magnetic resonance imaging (MRI). MATERIALS AND METHODS: We acquired 2D PSIR images at 3T at each disc level of the spinal axis in 10 healthy subjects and measured TCA, cord diameters, WM and GM areas, and GM area/TCA ratios. Second, we investigated 32 healthy subjects at four selected levels (C2-C3, C3-C4, T8-T9, T9-T10, total acquisition time <8 min) and generated normative reference values of TCA and GM areas. We assessed test-retest, intra- and interoperator reliability of the acquisition strategy, and measurement steps. RESULTS: The measurement procedure based on 2D PSIR imaging allowed TCA and GM area assessments along the entire spinal cord axis. The tests we performed revealed high test-retest/intraoperator reliability (mean coefficient of variation [COV] at C2-C3: TCA = 0.41%, GM area = 2.75%) and interoperator reliability of the measurements (mean COV on the 4 levels: TCA = 0.44%, GM area = 4.20%; mean intraclass correlation coefficient: TCA = 0.998, GM area = 0.906). CONCLUSION: 2D PSIR allows reliable in vivo assessment of spinal cord TCA, GM, and WM areas in clinically feasible acquisition times. The area measurements presented here are in agreement with previous MRI and postmortem studies.
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Sustancia Gris/patología , Imagen por Resonancia Magnética , Médula Espinal/patología , Sustancia Blanca/patología , Adulto , Anciano , Estudios de Cohortes , Estudios Transversales , Femenino , Voluntarios Sanos , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Persona de Mediana Edad , Enfermedades del Sistema Nervioso/fisiopatología , Valores de Referencia , Reproducibilidad de los Resultados , Relación Señal-Ruido , Factores de Tiempo , Imagen de Cuerpo EnteroRESUMEN
The oral delivery of peptides and proteins has been hampered by an array of obstacles. However, several promising novel oral delivery systems have been developed. This paper reviews the most advanced oral formulation technologies, and highlights key lessons and implications from studies undertaken to date with these oral formulations. Special interest is given to oral salmon calcitonin (CT), glucagon-like peptide-1 (GLP-1), insulin, PYY-(3-36), recombinant human parathyroid hormone (rhPTH(1-31)-NH2) and PTH(1-34), by different technologies. The issues addressed include (i) interaction with water, (ii) interaction with food, (iii) diurnal variation, (iv) inter- and intra-subject variability, (v) correlation between efficacy and exposure and (vi) key deliverables of different technologies. These key lessons may aid research in the development of other oral formulations.
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Sistemas de Liberación de Medicamentos/métodos , Fragmentos de Péptidos/administración & dosificación , Proteínas Recombinantes/administración & dosificación , Tecnología Farmacéutica/métodos , Administración Oral , Portadores de Fármacos/química , Absorción Gastrointestinal , Humanos , Fragmentos de Péptidos/farmacocinética , Proteínas Recombinantes/farmacocinéticaRESUMEN
INTRODUCTION: Patients with progressive multiple sclerosis (PMS) experience relentless disability worsening. Current approved therapies have very modest effects on disability progression and purely focus on immunomodulation. While some inflammatory processes exist in non-active PMS, other biological processes such as neuronal injury from oxidative stress are likely more critical. N-acetyl cysteine (NAC) directly scavenges free radicals and restores neuronal glutathione, a major endogenous antioxidant. Our group has recently evaluated the safety of high dose NAC in a pilot trial in PMS with no tolerability concerns. We aim now to assess the safety, tolerability, and effect of NAC on progression of several MRI, clinical and biological markers in PMS patients. METHODS: The NACPMS trial is a multi-site, randomized, double-blind, parallel-group, placebo-controlled add-on phase 2 trial. Ninety-eight PMS patients with EDSS 3.0-7.0 and aged 40-70 years will be randomized to NAC 1200 mg TID or matching placebo (1:1) as an add-on to the standard of care stratified by site and disease type during a 15-month intervention period. It is hypothesized that a reduction in oxidative stress injury will lessen brain atrophy estimated by MRI. The primary outcome analysis will compare the percent change over 12 months (Month 15 vs Month 3) between treatment and control arms using multivariable linear regression adjusted by age, sex, and disease duration. ETHICS: This study was approved by the Institutional Review Board at the University of California, San Francisco (IRB21-34143), and an Investigational New Drug approval was obtained from the FDA (IND127184). TRIAL REGISTRATION: NCT05122559.
Asunto(s)
Esclerosis Múltiple Crónica Progresiva , Esclerosis Múltiple , Fármacos Neuroprotectores , Humanos , Fármacos Neuroprotectores/efectos adversos , Acetilcisteína/efectos adversos , Progresión de la Enfermedad , Esclerosis Múltiple Crónica Progresiva/diagnóstico por imagen , Esclerosis Múltiple Crónica Progresiva/tratamiento farmacológico , Método Doble Ciego , Resultado del Tratamiento , Ensayos Clínicos Controlados Aleatorios como Asunto , Ensayos Clínicos Fase II como AsuntoRESUMEN
The lateral-occipital tactile-visual area (LOtv) is activated when objects are recognized by vision or touch. We report here that the LOtv is also activated in sighted and blind humans who recognize objects by extracting shape information from visual-to-auditory sensory substitution soundscapes. Recognizing objects by their typical sounds or learning to associate specific soundscapes with specific objects do not activate this region. This suggests that LOtv is driven by the presence of shape information.
Asunto(s)
Percepción Auditiva/fisiología , Lóbulo Occipital/fisiología , Reconocimiento en Psicología/fisiología , Estereognosis/fisiología , Tacto/fisiología , Estimulación Acústica/métodos , Adolescente , Adulto , Ceguera/fisiopatología , Mapeo Encefálico , Discriminación en Psicología/fisiología , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Oxígeno/sangreRESUMEN
Paediatric inflammatory multisystem syndrome-temporally associated with SARS-CoV-2 (PIMS-TS) is a recently described syndrome. We describe the case of a 17-year-old man presenting with a recent illness consistent with COVID-19 who presented with fever, chest pain and anterior uveitis. He was treated with aspirin, pulsed methylprednisolone and tocilizumab followed by oral steroids. On day 16 from initial presentation, he developed a facial nerve palsy. He was managed with ongoing steroids and the addition of valaciclovir. PIMS-TS is an under-recognised condition among adult physicians and may not be well known in adult neurology. It is important for adult physicians and neurologists to be aware of PIMS-TS and its possible sequelae.