The impact of social distancing measures on anti-JC virus serostatus changes before and during the COVID-19 pandemic in US patients with multiple sclerosis.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic offered an epidemiological opportunity to evaluate if isolation and masking affected John Cunningham (JC) virus transmission. OBJECTIVE: This study aimed to assess the proportion of natalizumab-treated patients who converted to a positive anti-JCV antibody serostatus before and during the pandemic. METHODS: Data from TYSABRI Outreach: Unified Commitment to Health (TOUCH) for 22,375 US patients treated with natalizumab with anti-JCV antibody records were assessed in epochs annually from 2017 to 2022. RESULTS: Pre-pandemic anti-JCV antibody serostatus change was observed for 7.4%-7.7%. During the first and second years of the pandemic, 7.3% and 7.2% of patients' serostatus changed, respectively. CONCLUSION: The proportion of patients with anti-JCV antibody serostatus change did not significantly differ during the first 2 years of the pandemic compared with prior years. In contrast to seasonal influenza, masking and social distancing had no discernable effect on JCV serostatus change.

Depression symptoms and cognition in multiple sclerosis: Longitudinal evidence of a specific link to executive control.

BACKGROUND: Depression symptoms are prevalent in multiple sclerosis (MS) and associated with poorer cognition in cross-sectional studies; it is unknown whether changes in depression symptoms track with cognitive changes longitudinally. OBJECTIVE: Investigate whether changes in depression symptoms correspond with cognitive changes over time in MS, and identify specific cognitive functions related to depression symptoms. METHOD: Persons with early relapse-onset MS (n = 165) completed a depression questionnaire (Beck Depression Inventory FastScreen) and tests of cognitive speed, executive control, and memory at baseline and 3-year follow-up. One-way ANOVAs assessed differences in cognitive change across participants with worsened, stable, or improved depression symptoms from baseline to year 3. RESULTS: Change in depression symptoms was related to change in executive control (p = 0.001, ηp2 = 0.08; worsened mood with worsened executive control; improved mood with improved executive control), even when adjusting for cognitive speed (p = 0.002, ηp2 = 0.08). There were no links to cognitive speed (p = 0.826) or memory (p = 0.243). Regarding individual depression symptoms, executive control was related to loss of pleasure and suicidal thoughts. CONCLUSIONS: Executive control tracks with depression symptoms, raising hope that management of mood may improve executive control. The specific link between executive control and anhedonia implicates dysfunctional reward processing as a key component of MS depression.

MS becomes a treatable disease: 30 years later.

30 years ago the first disease-modifying therapy for relapsing multiple sclerosis was approved for use in the United States and soon thereafter across the globe. Since then the field of MS therapeutics, and studies of immunopathogenesis and genetics, have advanced our understanding of the disease and raised the hope of better addressing the next challenges of treating progressive disease, enhancing repair of the damaged nervous system and, hopefully, of a cure. Thirty years into the MS treatment era, the field continues to debate fundamental aspects of MS, and there exists a widening chasm between the triumphs in relapsing disease and the desolation of MS progression, which remains the principal unmet need. In this Personal Viewpoint, we outline lessons learned from the first era of great therapeutic development, as we look to the future of MS research and therapeutics.

EDSS 0 is not normal: Multiple sclerosis disease burden below the clinical threshold.

Little to no above-threshold deficits may be evident in early multiple sclerosis (MS). The Expanded Disability Status Scale (EDSS) is a standard measure of neurologic function, with an EDSS score of 0 defined as "neurologically normal." The topographical model of MS proposes that sub-threshold disease is compensated for by functional reserve. In this short report, we found that physically high-challenge measures of balance and upper extremity coordination reveal sub-threshold deficits in patients with EDSS score of 0 compared with healthy controls. Challenge task performance was correlated with imaging markers of both lesional burden of disease and a volumetric measure of brain reserve.

Multiple sclerosis diagnosis: Knowledge gaps and opportunities for educational intervention in neurologists in the United States.

BACKGROUND: Few studies have addressed the results of educational efforts concerning proper use of McDonald criteria (MC) revisions outside multiple sclerosis (MS) subspecialty centers. Neurology residents and MS subspecialist neurologists demonstrated knowledge gaps for core elements of the MC in a recent prior study. OBJECTIVE: To assess comprehension and application of MC core elements by non-MS specialist neurologists in the United States who routinely diagnose MS. METHODS: Through a cross-sectional study design, a previously developed survey instrument was distributed online. RESULTS: A total of 222 neurologists completed the study survey. Syndromes atypical for MS were frequently incorrectly considered "typical" MS presentations. Fourteen percent correctly identified definitions of both "periventricular" and "juxtacortical" lesions and 2% correctly applied these terms to 9/9 images. Twenty-four percent correctly identified all four central nervous system (CNS) regions for satisfaction of magnetic resonance imaging (MRI) dissemination in space. In two presented cases, 61% and 71% correctly identified dissemination in time (DIT) was not fulfilled, and 85% and 86% subsequently accepted nonspecific historical symptoms without objective evidence for DIT fulfillment. CONCLUSION: The high rate of knowledge deficiencies and application errors of core elements of the MC demonstrated by participants in this study raise pressing questions concerning adequacy of dissemination and educational efforts upon publication of revisions to MC.

Detection of subtle gait disturbance and future fall risk in early multiple sclerosis.

OBJECTIVE: To test the hypothesis that higher-challenge gait and balance tasks are more sensitive than traditional metrics to subtle patient-reported gait dysfunction and future fall risk in early multiple sclerosis (MS). METHODS: Persons with early MS (n = 185; ≤5 years diagnosed) reported gait function (MS Walking Scale) and underwent traditional disability metrics (Expanded Disability Status Scale [EDSS], Timed 25 Foot Walk). Patients and healthy controls (n = 50) completed clinically feasible challenge tasks of gait endurance (2-Minute Walk Test), standing balance (NIH Toolbox), and dynamic balance (balance boards; tandem walk on 2 ten-foot boards of different widths, 4.5 and 1.5 in). MRI assessed global and regional brain volumes, total T2 lesion volume (T2LV), infratentorial T2LVs and counts, and cervical cord lesion counts. Falls, near falls, and fall-related injuries were assessed after 1 year. We examined links between all tasks and patient-reported gait, MRI markers, and fall data. RESULTS: Patients performed worse on higher challenge balance, but not gait, tasks compared with healthy controls. Worse patient-reported gait disturbance was associated with worse performance on all tasks, but only dynamic balance was sensitive to mild patient-reported gait difficulty. Balance tasks were more correlated with MRI metrics than were walking tasks or EDSS score. Thirty percent of patients reported either a fall or near fall after 1 year, with poor dynamic balance as the only task independently predicting falls. CONCLUSIONS: Balance plays a leading role in gait dysfunction early in MS. Clinically feasible higher-challenge balance tasks were most sensitive to patient-reported gait, MRI disease markers, and risk of future falls, highlighting potential to advance functional outcomes in clinical practice and trials.

The topographical model of MS: Empirical evaluation of the recapitulation hypothesis.

OBJECTIVE: Using the topographical model of multiple sclerosis (MS) to evaluate a longitudinal cohort we (1) test the recapitulation hypothesis, positing that patients' "disease topography" predicts the clinical pattern of disability accumulation; and (2) identify leading indicators of progression. METHODS: 10 patients who transitioned from relapsing-remitting MS to secondary progressive MS (SPMS) were evaluated. Neurologic exams were analyzed from relapses, at time of SPMS diagnosis, and most recent visit. Functional systems (FS), location/laterality, and recovery were recorded. The pyramidal/motor system was the target FS assessing symptom laterality and severity at relapse and SPMS time-points. Each patient's clinical course was mapped using the topographical model software. RESULTS: Cohort was 80% female, age 31.6 ± 8.6 years at diagnosis, followed average 23.8 ± 8.8 years, mean 3.1 relapses before SPMS. 83.3 ± 0.2% of relapse symptoms were present at transition to SPMS, increasing to 91.0 ± 0.2% at most recent visit. This demonstrates concordance between the topographical distribution of relapse symptoms and deficits from subsequent progression. In the topographical model, progression became apparent 7.75 years earlier than SPMS was diagnosed in practice. CONCLUSIONS: We demonstrate the model's utility in depicting patients' disease topography as the loci of clinical progression. This could allow for earlier recognition of progressive disease by identifying leading indicators of progression.

New Insights into Multiple Sclerosis Clinical Course from the Topographical Model and Functional Reserve.

Clinical course in multiple sclerosis (MS) is difficult to predict on group and individual levels. We discuss the topographical model of MS as a new approach to characterizing the clinical course, with the potential to personalize disability progression based on each individual patient's pattern of disease burden (eg, lesion location) and reserve. The dynamic clinical threshold depicted in this visual model may help clinicians to educate patients about clinical phenotype and disease burden, and foster an understanding of the difference between relapses and pseudoexacerbations. There is an emphasis on building reserve against cognitive and physical decline, encouraging agency among patients.

The topographical model of multiple sclerosis: A dynamic visualization of disease course.

Relapses and progression contribute to multiple sclerosis (MS) disease course, but neither the relationship between them nor the spectrum of clinical heterogeneity has been fully characterized. A hypothesis-driven, biologically informed model could build on the clinical phenotypes to encompass the dynamic admixture of factors underlying MS disease course. In this medical hypothesis, we put forth a dynamic model of MS disease course that incorporates localization and other drivers of disability to propose a clinical manifestation framework that visualizes MS in a clinically individualized way. The topographical model encapsulates 5 factors (localization of relapses and causative lesions; relapse frequency, severity, and recovery; and progression rate), visualized utilizing dynamic 3-dimensional renderings. The central hypothesis is that, like symptom recrudescence in Uhthoff phenomenon and pseudoexacerbations, progression clinically recapitulates prior relapse symptoms and unmasks previously silent lesions, incrementally revealing underlying lesion topography. The model uses real-time simulation software to depict disease course archetypes and illuminate several well-described but poorly reconciled phenomena including the clinical/MRI paradox and prognostic significance of lesion location and burden on disease outcomes. Utilization of this model could allow for earlier and more clinically precise identification of progressive MS and predictive implications can be empirically tested.

New Approaches to the Diagnosis, Clinical Course, and Goals of Therapy in Multiple Sclerosis and Related Disorders.

The diagnosis, categorization, and treatment of multiple sclerosis (MS) and other demyelinating diseases have shifted over the past decade, and many of the fundamental principles of MS pathogenesis and clinical course are being rewritten. Fundamental issues include selecting the right disease-modifying therapy for someone with active disease and how, or even if, patients with purely progressive MS should be treated. This article provides an overview and introduction to the current thinking in MS diagnosis and therapy with an emphasis on the data-driven and proactive approach that has come to define the current state of the art.

Homing in on consciousness in the nervous system: An action-based synthesis.

What is the primary function of consciousness in the nervous system? The answer to this question remains enigmatic, not so much because of a lack of relevant data, but because of the lack of a conceptual framework with which to interpret the data. To this end, we have developed Passive Frame Theory, an internally coherent framework that, from an action-based perspective, synthesizes empirically supported hypotheses from diverse fields of investigation. The theory proposes that the primary function of consciousness is well-circumscribed, serving the somatic nervous system. For this system, consciousness serves as a frame that constrains and directs skeletal muscle output, thereby yielding adaptive behavior. The mechanism by which consciousness achieves this is more counterintuitive, passive, and "low level" than the kinds of functions that theorists have previously attributed to consciousness. Passive frame theory begins to illuminate (a) what consciousness contributes to nervous function, (b) how consciousness achieves this function, and (c) the neuroanatomical substrates of conscious processes. Our untraditional, action-based perspective focuses on olfaction instead of on vision and is descriptive (describing the products of nature as they evolved to be) rather than normative (construing processes in terms of how they should function). Passive frame theory begins to isolate the neuroanatomical, cognitive-mechanistic, and representational (e.g., conscious contents) processes associated with consciousness.

Passive frame theory: A new synthesis.

Passive frame theory attempts to illuminate what consciousness is, in mechanistic and functional terms; it does not address the "implementation" level of analysis (how neurons instantiate conscious states), an enigma for various disciplines. However, in response to the commentaries, we discuss how our framework provides clues regarding this enigma. In the framework, consciousness is passive albeit essential. Without consciousness, there would not be adaptive skeletomotor action.

Lhermitte's Sign following VMAT-Based Head and Neck Radiation-Insights into Mechanism.

PURPOSE/OBJECTIVES: We observed a number of patients who developed Lhermitte's sign (LS) following radiation to the head and neck (H/N), since instituting volumetric modulated arc therapy (VMAT). We aimed to investigate the incidence of LS following VMAT-based RT without chemotherapy, and determine the dosimetric parameters that predict its development. We explored whether the role of inhomogeneous dose distribution across the spinal cord, causing a "bath-and-shower" effect, explains this finding. METHODS AND MATERIALS: From 1/20/2010-12/9/2013, we identified 33 consecutive patients receiving adjuvant RT using VMAT to the H/N without chemotherapy at our institution. Patients' treatment plans were analyzed for dosimetric parameters, including dose gradients along the anterior, posterior, right, and left quadrants at each cervical spine level. Institutional Review Board approval was obtained. RESULTS: 5 out of 33 (15.2%) patients developed LS in our patient group, all of whom had RT to the ipsilateral neck only. LS patients had a steeper dose gradient between left and right quadrants across all cervical spine levels (repeated-measures ANOVA, p = 0.030). Within the unilateral treatment group, LS patients received a higher mean dose across all seven cervical spinal levels (repeated-measures ANOVA, p = 0.046). Dose gradients in the anterior-posterior direction and mean doses to the cord were not significant between LS and non-LS patients. CONCLUSIONS: Dose gradients along the axial plane of the spinal cord may contribute to LS development; however, a threshold dose within the high dose region of the cord may still be required. This is the first clinical study to suggest that inhomogeneous dose distributions in the cord may be relevant in humans. Further investigation is warranted to determine treatment-planning parameters associated with development of LS.

Constructing an adaptive care model for the management of disease-related symptoms throughout the course of multiple sclerosis--performance improvement CME.

BACKGROUND: Symptom management remains a challenging clinical aspect of MS. OBJECTIVE: To design a performance improvement continuing medical education (PI CME) activity for better clinical management of multiple sclerosis (MS)-related depression, fatigue, mobility impairment/falls, and spasticity. METHODS: Ten volunteer MS centers participated in a three-stage PI CME model: A) baseline assessment; B) practice improvement CME intervention; C) reassessment. Expert faculty developed performance measures and activity intervention tools. Designated MS center champions reviewed patient charts and entered data into an online database. Stage C data were collected eight weeks after implementation of the intervention and compared with Stage A baseline data to measure change in performance. RESULTS: Aggregate data from the 10 participating MS centers (405 patient charts) revealed performance improvements in the assessment of all four MS-related symptoms. Statistically significant improvements were found in the documented assessment of mobility impairment/falls (p=0.003) and spasticity (p<0.001). For documentation of care plans, statistically significant improvements were reported for fatigue (p=0.007) and mobility impairment/falls (p=0.040); non-significant changes were noted for depression and spasticity. CONCLUSIONS: Our PI CME interventions demonstrated performance improvement in the management of MS-related symptoms. This PI CME model (available at www.achlpicme.org/ms/toolkit) offers a new perspective on enhancing symptom management in patients with MS.

Minimal neuroanatomy for a conscious brain: homing in on the networks constituting consciousness.

There is a consensus that consciousness is constituted by only a subset of all neuroanatomical regions and processes, but no agreement exists regarding which particular subset(s) constitutes it. We propose that a consensus will be reached if investigators (a) pool their knowledge regarding the regions whose non-participation does not in principle render the nervous system devoid of consciousness (e.g., the cerebellum, amygdalae, hippocampi, hemispheric commissures, 'pre-cortical' thalamus, and vast regions of the cortex), and (b) focus on the long-overlooked olfactory system. This 'brutally reductionistic' approach may isolate the physical basis of consciousness; even its falsification would help to illuminate this enigma.

The essence of conscious conflict: subjective effects of sustaining incompatible intentions.

Conflict constitutes one of the fundamental "tuggings and pullings" of the human experience. Yet, the link between the various kinds of conflict in the nervous system and subjective experience remains unexplained. The authors tested a hypothesis that predicts why both the "hot" conflicts involving self-control and motivation and the "cooler" response conflicts of the laboratory lead to changes in subjective experience. From this standpoint, these changes arise automatically from the activation of incompatible skeletomotor intentions, because the primary function of consciousness is to integrate such intentions for adaptive skeletal muscle output. Accordingly, the authors demonstrated for the first time that merely sustaining incompatible intentions (to move right and left) in a motionless state produces stronger subjective effects than sustaining compatible intentions. The results held equally strongly for two different effector systems involving skeletal muscle: arm movements and finger movements. In contrast, no such effects were found with conflict in a smooth muscle effector system. Together, these findings illuminate aspects of the nature of subjective experience and the role of incompatible intentions in affect and failures of self-control.