Stephen Krieger

Diagnostic uncertainty during the transition to secondary progressive multiple sclerosis

Secondary progressive multiple sclerosis (MS) is typically defined as deterioration independent of relapses for ≥ 6 months following an initial relapsing–remitting course; however, this definition is not always easily applied in clinical practice and the declaration of the change in clinical phenotype is often delayed. To identify the length of time required to re-classify relapsing–remitting MS (RRMS) patients whom have clinically transitioned to secondary progressive MS (SPMS) in clinical practice. We reviewed 123 patients with long-term follow-up and identified a sub-group whom transitioned from RRMS to SPMS, then characterized this transition period. There were 14/20 patients who transitioned during the follow-up period that had visits with uncertainty related to the clinical phenotype characterized by possible, but not definitive progression. The mean duration of this period of uncertainty was 2.9 ± 0.8 years. A period of diagnostic uncertainty regarding the transition from RRMS to SPMS existed in many of our patients. Potential reasons included the subtle nature of early progressive disease and caution in applying a progressive label, in light of the lack of evidence-based treatments as well as third-party payer concerns. Delay in definitive identification of an SPMS phenotype has a variety of implications related to patient care and research.

Cognitive and neural components of the phenomenology of agency

A primary aspect of the self is the sense of agency – the sense that one is causing an action. In the spirit of recent reductionistic approaches to other complex, multifaceted phenomena (e.g., working memory; cf. Johnson & Johnson, 2009), we attempt to unravel the sense of agency by investigating its most basic components, without invoking high-level conceptual or ‘central executive’ processes. After considering the high-level components of agency, we examine the cognitive and neural underpinnings of its low-level components, which include basic consciousness and subjective urges (e.g., the urge to breathe when holding ones breath). Regarding urges, a quantitative review revealed that certain inter-representational dynamics (conflicts between action plans, as when holding ones breath) reliably engender fundamental aspects both of the phenomenology of agency and of ‘something countering the will of the self’. The neural correlates of such dynamics, for both primordial urges (e.g., air hunger) and urges elicited in laboratory interference tasks, are entertained. In addition, we discuss the implications of this unique perspective for the study of disorders involving agency.

Association of Deep Gray Matter Damage With Cortical and Spinal Cord Degeneration in Primary Progressive Multiple Sclerosis

IMPORTANCE The investigation of cortical gray matter (GM), deep GM nuclei, and spinal cord damage in patients with primary progressive multiple sclerosis (PP-MS) provides insights into the neurodegenerative process responsible for clinical progression of MS. OBJECTIVE To investigate the association of magnetic resonance imaging measures of cortical, deep GM, and spinal cord damage and their effect on clinical disability. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional analysis of 26 patients with PP-MS (mean age, 50.9 years; range, 31-65 years; including 14 women) and 20 healthy control participants (mean age, 51.1 years; range, 34-63 years; including 11 women) enrolled at a single US institution. Clinical disability was measured with the Expanded Disability Status Scale, 9-Hole Peg Test, and 25-Foot Walking Test. We collected data from January 1, 2012, through December 31, 2013. Data analysis was performed from January 21 to April 10, 2015. MAIN OUTCOMES AND MEASURES Cortical lesion burden, brain and deep GM volumes, spinal cord area and volume, and scores on the Expanded Disability Status Scale (score range, 0 to 10; higher scores indicate greater disability), 9-Hole Peg Test (measured in seconds; longer performance time indicates greater disability), and 25-Foot Walking Test (test covers 7.5 m; measured in seconds; longer performance time indicates greater disability). RESULTS The 26 patients with PP-MS showed significantly smaller mean (SD) brain and spinal cord volumes than the 20 control group patients (normalized brain volume, 1377.81 [65.48] vs 1434.06 [53.67] cm3 [P = .003]; normalized white matter volume, 650.61 [46.38] vs 676.75 [37.02] cm3 [P = .045]; normalized gray matter volume, 727.20 [40.74] vs 757.31 [38.95] cm3 [P = .02]; normalized neocortical volume, 567.88 [85.55] vs 645.00 [42.84] cm3 [P = .001]; normalized spinal cord volume for C2-C5, 72.71 [7.89] vs 82.70 [7.83] mm3 [P < .001]; and normalized spinal cord volume for C2-C3, 64.86 [7.78] vs 72.26 [7.79] mm3 [P =.002]). The amount of damage in deep GM structures, especially with respect to the thalamus, was correlated with the number and volume of cortical lesions (mean [SD] thalamus volume, 8.89 [1.10] cm3; cortical lesion number, 12.6 [11.7]; cortical lesion volume, 0.65 [0.58] cm3; r = -0.52; P < .01). Thalamic atrophy also showed an association with cortical lesion count in the frontal cortex (mean [SD] thalamus volume, 8.89 [1.1] cm3; cortical lesion count in the frontal lobe, 5.0 [5.7]; r = -0.60; P < .01). No association was identified between magnetic resonance imaging measures of the brain and spinal cord damage. CONCLUSIONS AND RELEVANCE In this study, the neurodegenerative process occurring in PP-MS appeared to spread across connected structures in the brain while proceeding independently in the spinal cord. These results support the relevance of anatomical connectivity for the propagation of MS damage in the PP phenotype.

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.

Hydrocephalus in neuromyelitis optica

A majority of patients with neuromyelitis optica (NMO) spectrum disorders (NMOSD) have MRI brain abnormalities, some of which are “NMO-typical” with localization in aquaporin 4 (AQP4)–rich circumventricular and periaqueductal regions.1 Although uncommon in adult patients, symptomatic brain involvement occurs in approximately 50% of NMO–immunoglobulin G (IgG) seropositive children. Here we report the clinical characteristics, type, and frequency of hydrocephalus in NMOSD.

Cerebellar volume as imaging outcome in progressive multiple sclerosis

Background and purpose To assess whether cerebellar volumes changes could represent a sensitive outcome measure in primary-progressive MS. Material and methods Changes in cerebellar volumes over one-year follow-up, estimated in 26 primary-progressive MS patients and 20 controls with Freesurfer longitudinal pipeline, were assessed using Wilcoxon test and tested for their correlation with disability worsening by a logistic regression. Clinical worsening was defined as EDSS score increase or change of >20% for 25-foot walk test or 9-hole peg test scores at follow-up. Sample sizes for given treatment effects and power were calculated. The findings were validated in an independent cohort of 20 primary-progressive MS patients. Results Significant changes were detected in brain T1 lesion volume (p<0.01), cerebellar T2 and T1 lesion volume (p<0.01 and p<0.05), cerebellar volume, cerebellar cortex volume, and cerebellar WM volume (p<0.001). Only cerebellar volume and cerebellar cortex volume percentage change were significantly reduced in clinically progressed patients when compared to patients who did not progress (p<0.01; respectively AUC of 0.91 and 0.96). Cerebellar volume percentage changes were consistent in the exploration and validation cohorts (cerebellar volume -1.90±1.11% vs -1.47±2.30%; cerebellar cortex volume -1.68±1.41% vs -1.56±2.23%). Based on our results the numbers of patients required to detect a 30% effect are 81 per arm for cerebellar volume and 162 per arm for cerebellar cortex volume (90% power, type 1 error alpha = 0.05). Conclusions Our results suggest a role for cerebellar cortex volume and cerebellar volume as potential short-term imaging metrics to monitor treatment effect in primary-progressive MS clinical trials.

Emergency Medical Care of Multiple Sclerosis Patients: Primary Data from the Mount Sinai Resource Utilization in Multiple Sclerosis Project

Background and Purpose There has been no systematic analysis of emergency department (ED) utilization in the multiple sclerosis (MS) population. We investigated the acute-care needs of MS patients using ED as a route for entry into healthcare services. Methods ED visits made by MS patients were identified. Data extracted included demographics, medical/neurological history, and workup/management in the ED. Results The Mount Sinai ED received 569 visits from 224 MS patients during a 3-year period, of whom 33.5% were covered by Medicaid and 12.9% were uninsured. Patients with an Expanded Disability Status Scale score of ≥6 accounted for 54%, 50.5% of relapsing remitting MS patients were being treated with disease-modifying therapies, and 74.5% of the ED visits were non-neurological. Patients with mild-to-moderate MS were more likely to present to the ED for issues directly related to MS such as acute exacerbations, while those with severe MS presented more often due to medical issues indirectly related to MS, such as urinary tract infections (p<0.0001). Conclusions Most MS patients seeking ED care suffer from acute non-neurological problems. The MS patients presenting to the ED tended to be underinsured, had high levels of disability, and were undertreated with disease-modifying therapies. The acute-care needs of MS patients evolve over the disease course, as do the resources that must be utilized in providing emergency care across the spectrum of MS severity. Understanding the characteristics, problems, and needs of MS patients utilizing the ED is an important step in improving care in this population from both clinical and public health perspectives.

Emergency Department visits before the diagnosis of MS

IMPORTANCE Prompt diagnosis and early initiation of disease-modifying treatment improves long-term outcomes in MS patients. This study looks at the path to MS diagnosis from the Emergency Department (ED), a frequent point of access for healthcare. OBJECTIVE To evaluate how patients presenting to the Mount Sinai ED with initial manifestations of MS are ultimately diagnosed with demyelinating disease. DESIGN Retrospective, observational analysis of all patients diagnosed with MS from 2005 to 2009. Part of the Resource Utilization in MS (RESUMS) Study. SETTING Urban, tertiary care center Emergency Department PARTICIPANTS Forty-nine patients were diagnosed with MS during the study period and made a total of 98 ED visits prior to that diagnosis. MAIN OUTCOME MEASURES Outcome measures included percentage of ED visits for neurologic symptoms, percentage that were likely initial manifestations of MS, percentage of visits admitted, mean length of hospital stay of those patients admitted, time until MS diagnosis, and time until initiation of disease modifying agent. Demographic and presentation-specific features correlating with time until MS diagnosis were evaluated. RESULTS 69.4% of patients were female. Mean age was 32.9 years (range 16-56). Hispanics comprised 40.8%, African Americans 28.6%, and Caucasians 18.2%. 59.2% of patients had private insurance, 26.5% Medicaid, and 6.1% Medicare. 50% of ED visits (49) were for neurologic symptoms (sensory symptoms 44.9%, vision changes 26.5%, weakness 24.5%, imbalance 16%, diplopia and vertigo 10.2%). 75.5% of the ED visits for neurologic symptoms were admitted; mean length of stay was 5.7 days (range 1-18). MS or demyelinating disease was diagnosed at the time of the ED visit or admission in 30/49 (61.2%) of neurologic presentations, with 73.5% diagnosed within a week. In the remaining 26.6%, MS diagnosis was delayed. 18.4% were diagnosed within a year of their neurologic ED visit and 8.2% remained undiagnosed at 1 year. Disease modifying agents were started in 71.4% of patients, 77.1% within 6 months. CONCLUSIONS AND RELEVANCE ED presentations for acute neurologic symptoms are an important opportunity to diagnose and treat early MS, and while the majority of the patients studied were appropriately triaged, diagnosed and treated in a timely manner, there exists room for improvement.

Relationship between timed 25-foot walk and diffusion tensor imaging in multiple sclerosis

Objective/Background The majority of multiple sclerosis patients experience impaired walking ability, which impacts quality of life. Timed 25-foot walk is commonly used to gauge gait impairment but results can be broadly variable. Objective biological markers that correlate closely with patients’ disability are needed. Diffusion tensor imaging, quantifying fiber tract integrity, might provide such information. In this project we analyzed relationships between timed 25-foot walk, conventional and diffusion tensor imaging magnetic resonance imaging markers. Design/Methods A cohort of gait impaired multiple sclerosis patients underwent brain and cervical spinal cord magnetic resonance imaging. Diffusion tensor imaging mean diffusivity and fractional anisotropy were measured on the brain corticospinal tracts and spinal restricted field of vision at C2/3. We analyzed relationships between baseline timed 25-foot walk, conventional and diffusion tensor imaging magnetic resonance imaging markers. Results Multivariate linear regression analysis showed a statistically significant association between several magnetic resonance imaging and diffusion tensor imaging metrics and timed 25-foot walk: brain mean diffusivity corticospinal tracts (p = 0.004), brain corticospinal tracts axial and radial diffusivity (P = 0.004 and 0.02), grey matter volume (p = 0.05), white matter volume (p = 0.03) and normalized brain volume (P = 0.01). The linear regression model containing mean diffusivity corticospinal tracts and controlled for gait assistance was the best fit model (p = 0.004). Conclusions Our results suggest an association between diffusion tensor imaging metrics and gait impairment, evidenced by brain mean diffusivity corticospinal tracts and timed 25-foot walk.

Clinical course in multiple sclerosis patients presenting with a history of progressive disease

OBJECTIVES Determine the likelihood of worsening clinical status in the near-term course of progressive MS and evaluate the predictive validity of our diagnostic impression of progressive forms of MS. METHODS Retrospective review of charts from 175 patients seen between 2000 and 2007 who were diagnosed with either primary or secondary progressive multiple sclerosis. Data extracted included demographic factors, neurological examination findings to determine EDSS, timed 25 foot walk (T25FW) when available, duration of symptoms, clinical course as documented on initial visit, and history of disease-modifying agent (DMA) use. Significant change in EDSS was defined as a change of one point or more from initial to final clinical evaluation. Significant change in T25FW was defined as a ±20% difference from baseline. RESULTS Of the 175 charts reviewed, 35 patients met criteria and had sufficient documentation to allow for EDSS abstraction. Twenty-four patients (68.6%) showed no significant change in EDSS from baseline while eleven patients (31.4%) worsened and none improved. For those patients that had T25FW data available, 6 out of 20 (30%) patients worsened while 11 (55%) showed no change. Three patients (15%) improved. CONCLUSION In this observational study at a tertiary care MS center, patients classified as progressive MS did not progress as often, or as rapidly, as previous studies have suggested. Greater than two-thirds of patients in this cohort, did not increase 1 step on the EDSS.