Identifying highly sensitive and reliable neurological exam components are crucial in recognizing clinical deficiencies. This study aimed to investigate finger tapping performance differences between ...patients with CNS demyelinating lesions and healthy control subjects.
Twenty-three patients with multiple sclerosis or clinically isolated syndrome with infratentorial and/or cervical cord lesions on MRI, and 12 healthy controls were videotaped while tapping the tip of the index finger against the tip and distal crease of the thumb using both the dominant and non-dominant hand. Videos were assessed independently by 10 evaluators (three MS neurologists, four neurology residents, three advanced practice providers). Sensitivity and inter-evaluator reliability of finger tapping interpretations were calculated.
A total of 1400 evaluations (four videos per each of the 35 subjects evaluated by 10 independent providers) were obtained. Impairments in finger tapping against the distal thumb crease of the non-dominant hand, identified by neurologists, had the greatest sensitivity (84%, p < 0.001) for detecting impairment. Finger tapping against the thumb crease was more sensitive than the thumb tip across all categories of providers. The best inter-evaluator reliability was associated with neurologists' evaluations for the thumb crease of the non-dominant hand (kappa = 0.83, p < 0.001).
Impaired finger tapping against the distal thumb crease of the non-dominant hand was a more sensitive technique for detecting impairments related to CNS demyelinating lesions. Our findings highlight the importance of precise examinations of the non-dominant side where impaired fine motor control secondary to an upper motor injury might be detectable earlier than the dominant side.
A prodrome is an early set of signs or symptoms that indicate the onset of a disease before more typical symptoms develop. Prodromal stages are well recognized in some neurological and ...immune-mediated diseases such as Parkinson disease, schizophrenia, type 1 diabetes mellitus and rheumatoid arthritis. Emerging evidence indicates that a prodromal stage exists in multiple sclerosis (MS), raising the possibility of intervention at this stage to delay or prevent the development of classical MS. However, much remains unclear about the prodromal stage of MS and considerable research is needed to fully characterize the prodrome and develop standardized criteria to reliably identify individuals with prodromal MS who are at high risk of progressing to a diagnosis of MS. In this Roadmap, we draw on work in other diseases to propose a disease framework for MS that incorporates the prodromal stage, and set out key steps and considerations needed in future research to fully characterize the MS prodrome, identify early disease markers and develop standardized criteria that will enable reliable identification of individuals with prodromal MS, thereby facilitating trials of interventions to slow or stop progression beyond the prodrome.
Key unmet needs in multiple sclerosis (MS) include detection of early pathology, disability worsening independent of relapses, and accurate monitoring of treatment response. Collaborative approaches ...to address these unmet needs have been driven in part by industry-academic networks and initiatives such as the Grant for Multiple Sclerosis Innovation (GMSI) and Multiple Sclerosis Leadership and Innovation Network (MS-LINK
) programs. We review the application of recent advances, supported by the GMSI and MS-LINK
programs, in neuroimaging technology to quantify pathology related to central pathology and disease worsening, and potential for their translation into clinical practice/trials. GMSI-supported advances in neuroimaging methods and biomarkers include developments in magnetic resonance imaging, positron emission tomography, ocular imaging, and machine learning. However, longitudinal studies are required to facilitate translation of these measures to the clinic and to justify their inclusion as endpoints in clinical trials of new therapeutics for MS. Novel neuroimaging measures and other biomarkers, combined with artificial intelligence, may enable accurate prediction and monitoring of MS worsening in the clinic, and may also be used as endpoints in clinical trials of new therapies for MS targeting relapse-independent disease pathology.
Introduction
S1P
1
receptor modulators (S1P
1
-RM) are oral disease-modifying therapies (DMTs) for multiple sclerosis (MS). Several authorities have raised doubts that S1P
1
-RM are responsible for ...an increased risk of melanoma in patients with MS. We studied the in vitro effects of S1P
1
-RM on different melanoma cell lines to compare the effect of available S1P
1
-RM on the proliferation of human melanoma cells.
Methods
Four S1P
1
-RM were studied which are currently approved for managing MS, namely fingolimod (Gilenya
®
), siponimod (Mayzent
®
), ozanimod (Zeposia
®
), and ponesimod (Ponvory
®
). We tested these four drugs at different concentrations, including therapeutic doses (0.5, 1.6, 5.5, 18, and 60 µM), on human melanoma cell lines (501Mel cells, 1205LU cells, and M249R cells) to analyze in vitro cell proliferation monitored with the IncuCyte ZOOM live cell microscope (Essen Bioscience).
Results
At therapeutic doses, median confluence increased overall for all lineages: + 122% for ozanimod (
p
< 0.001), + 71% for ponesimod (
p
< 0.001), + 67% for siponimod (NS), and + 41% for fingolimod (
p
= 0.094). Ozanimod- and ponesimod-treated cells increased confluency in 501Mel, 1205LU, and M249R cell lines (
p
< 0.001).
Conclusion
These data suggest an increased proliferation of various melanoma cell lines with S1P
1
-RM treatments used at therapeutic concentrations for patients with MS and should raise the question of increased dermatologic surveillance.
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.BACKGROUND AND PURPOSEThe 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.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.METHODSStandardized 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.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).RESULTSThe 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).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.CONCLUSIONSThe benefit of disease-modifying therapy in RIS may extend to CNS structures impacted by neurodegeneration that is below the resolution of conventional volumetric measures.
The average age of onset of multiple sclerosis (MS) is between 20 and 40 years of age. Therefore, most new patients diagnosed with MS within the next 10 to 15 years will be from the millennial ...generation, representing those born between 1982 and 2000. Certain preferences and trends of this contemporary generation will present new challenges to the MS physician and effective MS care. By first understanding these challenges, relevant and successful solutions can be created to craft a system of care that best benefits the millennial patient with MS.
The neural mechanisms underlying motor impairment in multiple sclerosis (MS) remain unknown. Motor cortex dysfunction is implicated in blood-oxygen-level-dependent (BOLD) functional magnetic ...resonance imaging (fMRI) studies, but the role of neural–vascular coupling underlying BOLD changes remains unknown. We sought to independently measure the physiologic factors (i.e., cerebral blood flow (ΔCBF), cerebral metabolic rate of oxygen (ΔCMRO2), and flow–metabolism coupling (ΔCBF/ΔCMRO2), utilizing dual-echo calibrated fMRI (cfMRI) during a bilateral finger-tapping task. We utilized cfMRI to measure physiologic responses in 17 healthy volunteers and 32 MS patients (MSP) with and without motor impairment during a thumb-button-press task in thumb-related (task-central) and surrounding primary motor cortex (task-surround) regions of interest (ROIs). We observed significant ΔCBF and ΔCMRO2 increases in all MSP compared to healthy volunteers in the task-central ROI and increased flow–metabolism coupling (ΔCBF/ΔCMRO2) in the MSP without motor impairment. In the task-surround ROI, we observed decreases in ΔCBF and ΔCMRO2 in MSP with motor impairment. Additionally, ΔCBF and ΔCMRO2 responses in the task-surround ROI were associated with motor function and white matter damage in MSP. These results suggest an important role for task-surround recruitment in the primary motor cortex to maintain motor dexterity and its dependence on intact white matter microstructure and neural–vascular coupling.
The hemodynamic response function (HRF), a model of brain blood-flow changes in response to neural activity, reflects communication between neurons and the vasculature that supplies these neurons in ...part by means of glial cell intermediaries (e.g., astrocytes). Intact neural-vascular communication might play a central role in optimal cognitive performance. This hypothesis can be tested by comparing healthy individuals to those with known white-matter damage and impaired performance, as seen in Multiple Sclerosis (MS). Glial cell intermediaries facilitate the ability of neurons to adequately convey metabolic needs to cerebral vasculature for sufficient oxygen and nutrient perfusion. In this study, we isolated measurements of the HRF that could quantify the extent to which white-matter affects neural-vascular coupling and cognitive performance. HRFs were modeled from multiple brain regions during multiple cognitive tasks using piecewise cubic spline functions, an approach that minimized assumptions regarding HRF shape that may not be valid for diseased populations, and were characterized using two shape metrics (peak amplitude and time-to-peak). Peak amplitude was reduced, and time-to-peak was longer, in MS patients relative to healthy controls. Faster time-to-peak was predicted by faster reaction time, suggesting an important role for vasodilatory speed in the physiology underlying processing speed. These results support the hypothesis that intact neural-glial-vascular communication underlies optimal neural and cognitive functioning.
•Intact neural-vascular communication may play a central role in cognitive performance.•Patients with Multiple Sclerosis (MS) are known to have white-matter damage and impaired cognitive performance.•Hemodynamic response function (HRF) shapes of healthy individuals were compared to those of MS patients.•Spline interpolation (minimizing shape assumptions) revealed group differences in both HRF amplitude and time-to-peak (TTP).•Faster performance predicted faster HRF TTP, implicating vasodilatory speed in the physiology underlying cognitive speed.
Differentiating multiple sclerosis (MS) from other relapsing inflammatory autoimmune diseases of the central nervous system such as neuromyelitis optica spectrum disorder (NMOSD) and myelin ...oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is crucial in clinical practice. The differential diagnosis may be challenging but making the correct ultimate diagnosis is critical, since prognosis and treatments differ, and inappropriate therapy may promote disability. In the last two decades, significant advances have been made in MS, NMOSD, and MOGAD including new diagnostic criteria with better characterization of typical clinical symptoms and suggestive imaging (magnetic resonance imaging MRI) lesions. MRI is invaluable in making the ultimate diagnosis. An increasing amount of new evidence with respect to the specificity of observed lesions as well as the associated dynamic changes in the acute and follow-up phase in each condition has been reported in distinct studies recently published. Additionally, differences in brain (including the optic nerve) and spinal cord lesion patterns between MS, aquaporin4-antibody-positive NMOSD, and MOGAD have been described. We therefore present a narrative review on the most relevant findings in brain, spinal cord, and optic nerve lesions on conventional MRI for distinguishing adult patients with MS from NMOSD and MOGAD in clinical practice. In this context, cortical and central vein sign lesions, brain and spinal cord lesions characteristic of MS, NMOSD, and MOGAD, optic nerve involvement, role of MRI at follow-up, and new proposed diagnostic criteria to differentiate MS from NMOSD and MOGAD were discussed.
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.
PDF
