Contingent Negative Variation Is Associated with Cognitive Dysfunction and Secondary Progressive Disease Course in Multiple Sclerosis

Background: Cognitive dysfunction as a predictor of clinical progression and mortality in multiple sclerosis (MS) is still a matter of debate. Objective: The aim of this study was to explore the long-term outcome associated with neuropsychological performance in a cohort of patients with MS. Methods: A series of 408 MS patients had previously undergone a comprehensive neuropsychological assessment and a contemporaneous neurological evaluation (T1). A retrospective review of the clinical records was conducted 102–192 months after T1. Demographic and clinical data regarding the last clinical appointment with EDSS measurement (T2) were collected and the date of the last clinical contact or death (TS) was recorded. Results: This review revealed that cognitive dysfunction (T1) was associated with higher odds of transitioning from relapsing–remitting course to a progressive disease course (adjusted odds ratio (OR) = 2.29, p = 0.043) and higher hazard of death in the total sample (adjusted hazard ratio (HR) = 3.07, p = 0.006) and the progressive disease course subgroup (adjusted HR = 3.68, p = 0.007), even when adjusting for other covariates. Discussion: The study results demonstrate that cognitive dysfunction in MS is predictive of poorer prognosis and mortality.

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Late-onset multiple sclerosis presenting with cognitive dysfunction and severe cortical/infratentorial atrophy

Multiple Sclerosis Journal ◽

10.1177/1352458514542363 ◽

2014 ◽

Vol 21 (5) ◽

pp. 580-589 ◽

Cited By ~ 11

Author(s):

Massimiliano Calabrese ◽

Alberto Gajofatto ◽

Francesca Gobbin ◽

Giulia Turri ◽

Silvia Richelli ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cognitive Dysfunction ◽

Progressive Disease ◽

Late Onset ◽

Disease Onset ◽

Reference Population ◽

Healthy Controls ◽

Cognitively Normal ◽

Midbrain Tegmentum ◽

Symptoms And Signs

Objective: Although cognitive dysfunction is a relevant aspect of multiple sclerosis (MS) from the earliest disease phase, cognitive onset is unusual thus jeopardizing early and accurate diagnosis. Here we describe 12 patients presenting with cognitive dysfunction as primary manifestation of MS with either mild or no impairment in non-cognitive neurological domains. Methods: Twelve patients with cognitive onset who were subsequently diagnosed with MS (CI-MS) were included in this retrospective study. Twelve cognitively normal MS patients (CN-MS), 12 healthy controls and four patients having progressive supranuclear palsy (PSP) served as the reference population. Results: Ten CI-MS patients had progressive clinical course and all patients had late disease onset (median age = 49 years; range = 40–58 years). Among cognitive functions, frontal domains were the most involved. Compared to CN-MS and healthy controls, significant cortical and infratentorial atrophy characterized CI-MS patients. Selective atrophy of midbrain tegmentum with relative sparing of pons, known as “The Hummingbird sign,” was observed in eight CI-MS and in three PSP patients. Discussion: Our observation suggests that MS diagnosis should be taken into consideration in case of cognitive dysfunction, particularly when associated with slowly progressive disease course and severe cortical, cerebellar and brainstem atrophy even in the absence of other major neurological symptoms and signs.

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Cognitive dysfunction in patients with clinically isolated syndromes or newly diagnosed multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458507077943 ◽

2007 ◽

Vol 13 (8) ◽

pp. 1004-1010 ◽

Cited By ~ 112

Author(s):

BI Glanz ◽

CM Holland ◽

SA Gauthier ◽

EL Amunwa ◽

Z. Liptak ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cognitive Impairment ◽

Disease Severity ◽

Cognitive Dysfunction ◽

Grey Matter Volume ◽

Lesion Volume ◽

Disease Course ◽

Newly Diagnosed ◽

Matter Volume ◽

Clinically Isolated Syndromes

Cognitive dysfunction is common in patients with multiple sclerosis (MS), and has been associated with MRI measures of lesion burden and atrophy. Little is known about the prevalence of cognitive impairment in patients with early MS. The associations between cognitive impairment and MRI measures of disease severity early in the disease course are also unclear. This study used a brief battery of cognitive tests to determine the prevalence and pattern of cognitive impairment in patients with clinically isolated syndromes or newly diagnosed MS. The associations between cognitive impairment and MRI measures of disease severity early in the disease course were also examined. Ninety-two patients with clinically isolated syndromes or the diagnosis of MS within the last 3 years participating in the CLIMB study underwent a neurologic examination, neuropsychological evaluation and MRI at 1.5T. Forty-nine percent of patients were impaired on one or more cognitive measures. There were no significant correlations between cognitive scores and MRI measures of disease severity including total T2 lesion volume, normal appearing white matter volume, grey matter volume, and brain parenchymal fraction. These findings suggest that cognitive impairment may predate the appearance of gross structural abnormalities on MRI and serve as an early marker of disease activity in MS. Multiple Sclerosis 2007; 13: 1004—1010. http://msj.sagepub.com

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121. Smoking is associated with progressive disease course and increased progression in clinical disability in a prospective cohort of people with multiple sclerosis

Journal of Clinical Neuroscience ◽

10.1016/j.jocn.2008.07.020 ◽

2009 ◽

Vol 16 (3) ◽

pp. 467

Author(s):

Fotini Pittas ◽

Anne-Louise Ponsonby ◽

Ingrid van der Mei ◽

Bruce V. Taylor ◽

Leigh Blizzard ◽

...

Keyword(s):

Multiple Sclerosis ◽

Prospective Cohort ◽

Progressive Disease ◽

Disease Course

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Multiple sclerosis: BAFF and CXCL13 in cerebrospinal fluid

Multiple Sclerosis Journal ◽

10.1177/1352458511398887 ◽

2011 ◽

Vol 17 (7) ◽

pp. 819-829 ◽

Cited By ~ 60

Author(s):

Samia Ragheb ◽

Yanfeng Li ◽

Kirk Simon ◽

Stephen VanHaerents ◽

Daniela Galimberti ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

B Cell ◽

Progressive Disease ◽

Inverse Correlation ◽

Enzyme Linked Immunosorbent Assay ◽

Cell Homeostasis ◽

Secondary Progressive ◽

Igg Index ◽

B Cell Homeostasis

Background: There is increasing evidence of B-cell involvement in the pathogenesis of multiple sclerosis (MS). B-cell activating factor (BAFF) has an essential role in B-cell homeostasis. The chemokine CXCL13 has an important role in the formation and maintenance of B-cell follicles. Objective: To measure BAFF and CXCL13 levels in the cerebrospinal fluid (CSF) of patients with MS compared to patients with other neurological diseases. Methods: Cytokine/chemokine levels were measured by an enzyme-linked immunosorbent assay (ELISA). Results: In MS patients, BAFF levels were highest in patients with secondary progressive disease, and were higher during relapse in patients with relapsing–remitting and secondary progressive disease. CXCL13 levels were also higher during relapse. There was a positive correlation between CXCL13 and the IgG index, and an inverse correlation between BAFF and the IgG index. The implications of this finding are discussed. Conclusion: During relapse, we found various positive correlations between BAFF, CXCL13 and the cytokines IL-6 and IL-10. These findings show that molecules that are essential for B-cell recruitment, survival, maturation and function may be working in concert to affect B-cell homeostasis in MS and contribute to the pathophysiology of the disease.

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Poor early relapse recovery affects onset of progressive disease course in multiple sclerosis

Neurology ◽

10.1212/wnl.0000000000001856 ◽

2015 ◽

Vol 85 (8) ◽

pp. 722-729 ◽

Cited By ~ 46

Author(s):

Martina Novotna ◽

M. Mateo Paz Soldán ◽

Nuhad Abou Zeid ◽

Nilufer Kale ◽

Melih Tutuncu ◽

...

Keyword(s):

Multiple Sclerosis ◽

Progressive Disease ◽

Disease Course ◽

Early Relapse

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Secondary Progressive Multiple Sclerosis: New Insights

Neurology ◽

10.1212/wnl.0000000000012323 ◽

2021 ◽

pp. 10.1212/WNL.0000000000012323

Author(s):

Bruce Anthony Campbell Cree ◽

Douglas L Arnold ◽

Jeremy Chataway ◽

Tanuja Chitnis ◽

Robert J. Fox ◽

...

Keyword(s):

Multiple Sclerosis ◽

Progressive Disease ◽

Progressive Multiple Sclerosis ◽

Secondary Progressive Multiple Sclerosis ◽

Response To Treatment ◽

Disability Progression ◽

Long Term Outcomes ◽

Secondary Progressive ◽

Relapsing Remitting

In most cases, multiple sclerosis (MS) begins with a relapsing–remitting course followed by insidious disability worsening that is independent from clinically apparent relapses and is termed secondary progressive multiple sclerosis (SMPS). Major differences exist between relapsing–remitting MS (RRMS) and SPMS, especially regarding therapeutic response to treatment. This review provides an overview of the pathology, differentiation, and challenges in the diagnosis and treatment of SPMS. We emphasize the criticality of conversion from a relapsing–remitting to a secondary progressive disease course not only because such conversion is evidence of disability progression, but also because, until recently, treatments that effectively reduced disability progression in relapsing MS were not proven to be effective in SPMS. Clear clinical, imaging, immunological, or pathological criteria marking the transition from RRMS to SPMS have not yet been established. Early identification of SPMS will require tools which, together with the use of appropriate treatments, may result in better long-term outcomes for the population of patients with SPMS.

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Epidemiology of Pediatric-Onset Multiple Sclerosis: A Systematic Review of the Literature

Journal of Child Neurology ◽

10.1177/0883073819845827 ◽

2019 ◽

Vol 34 (12) ◽

pp. 705-712 ◽

Cited By ~ 4

Author(s):

Anna Jeong ◽

Denise M. Oleske ◽

Joan Holman

Keyword(s):

Multiple Sclerosis ◽

Systematic Review ◽

Confidence Interval ◽

Progressive Disease ◽

Pediatric Population ◽

Population Based ◽

Disease Course ◽

Relapsing Remitting ◽

Pediatric Neurologist ◽

Pediatric Onset

Multiple sclerosis onset in youth is increasingly recognized. A systematic review was conducted to assess incidence and prevalence of pediatric-onset multiple sclerosis, focusing on occurrence by age subgroups and disease course. A literature search for the period 1965-2018 was carried out, selecting population-based studies of multiple sclerosis in individuals aged 19 years and younger. Nineteen studies met inclusion criteria. One pediatric neurologist extracted the data. Overall incidence ranged from 0.05 (95% confidence interval 0.03-0.08) to 2.85 (95% confidence interval 2.83-2.86) per 100 000 children and overall prevalence from 0.69 (95% confidence interval 0.58-0.80) to 26.92 (95% confidence interval 26.61-27.23) per 100 000 children. Incidence increased with age. The female-male ratio increased from 1.2:1 in children <12 years old to 2.8:1 in children ≥12 years old. Ten studies (n=521 children) reported disease course. Seven studies found only relapsing-remitting disease and 3 studies found primary-progressive disease in 3.0% to 6.7%. Two secondary-progressive disease cases were identified. Epidemiologic data aid in understanding the magnitude of multiple sclerosis and its clinical phenotypes, for planning for new disease-modifying therapies in the pediatric population.

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Cortical grey matter sodium accumulation is associated with disability and secondary progressive disease course in relapse-onset multiple sclerosis

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2018-319634 ◽

2019 ◽

Vol 90 (7) ◽

pp. 755-760 ◽

Cited By ~ 6

Author(s):

Wallace J Brownlee ◽

Bhavana Solanky ◽

Ferran Prados ◽

Marios Yiannakas ◽

Patricia Da Mota ◽

...

Keyword(s):

Multiple Sclerosis ◽

Grey Matter ◽

Disease Onset ◽

Healthy Controls ◽

Disease Course ◽

Cross Sectional ◽

Sodium Accumulation ◽

Secondary Progressive ◽

Cortical Grey Matter

ObjectiveSodium (23Na)-MRI is an emerging imaging technique to investigate in vivo changes in tissue viability, reflecting neuroaxonal integrity and metabolism. Using an optimised 23Na-MRI protocol with smaller voxel sizes and improved tissue contrast, we wanted to investigate whether brain total sodium concentration (TSC) is a biomarker for long-term disease outcomes in a cohort of patients with relapse-onset multiple sclerosis (MS), followed from disease onset.MethodsWe performed a cross-sectional study in 96 patients followed up ~ 15 years after a clinically isolated syndrome (CIS) and 34 healthy controls. Disease course was classified as CIS, relapsing-remitting MS or secondary progressive MS (SPMS). We acquired 1H-MRI and 23Na-MRI and calculated the TSC in cortical grey matter (CGM), deep grey matter, normal-appearing white matter (WM) and WM lesions. Multivariable linear regression was used to identify independent associations of tissue-specific TSC with physical disability and cognition, with adjustment for tissue volumes.ResultsTSC in all tissues was higher in patients with MS compared with healthy controls and patients who remained CIS, with differences driven by patients with SPMS. Higher CGM TSC was independently associated with Expanded Disability Status Scale (R2=0.26), timed 25-foot walk test (R2=0.23), 9-hole peg test (R2=0.23), Paced Auditory Serial Addition Test (R2=0.29), Symbol Digit Modalities Test (R2=0.31) and executive function (R2=0.36) test scores, independent of grey matter atrophy.ConclusionsSodium accumulation in CGM reflects underlying neuroaxonal metabolic abnormalities relevant to disease course heterogeneity and disability in relapse-onset MS. TSC and should be considered as an outcome measure in future neuroprotection trials.

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Anti-MOG and anti-MBP antibody subclasses in multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/135245850100700503 ◽

2001 ◽

Vol 7 (5) ◽

pp. 285-289 ◽

Cited By ~ 58

Author(s):

R Egg ◽

M Reindl ◽

F Deisenhammer ◽

C Linington ◽

T Berger

Keyword(s):

Multiple Sclerosis ◽

Significant Relationship ◽

Progressive Disease ◽

Basic Protein ◽

Intravenous Immunoglobulins ◽

Myelin Oligodendrocyte Glycoprotein ◽

Disease Course ◽

Mog Antibodies ◽

Demyelinating Process ◽

Myelin Antigens

In a subset of multiple sclerosis (MS) patients antibodies against myelin antigens seem to be important in the demyelinating process. In this study we investigated IgM, IgA and IgG serum antibodies against the myelin oligodendrocyte glycoprotein (MOG) and the myelin basic protein (MBP) in 261 MS patients. Seventy-two per cent had anti-MOG antibodies, 59% were anti-MBP seropositive. The dominating antibody was anti-MOG IgM. A significant relationship between IgA and a progressive disease course was found. The predominance of IgG1 together with the significantly associated occurrence of IgG3 against MOG corresponds to the prevailing IgG1 and IgG3 isotypes in other autoimmune diseases. Patients who actually suffered from a relapse were significant more often anti-MOG and anti-MBP IgG3 seropositive than those in remission. However, patients treated either with intravenous immunoglobulins or interferon-b showed a significant reduction of anti-MOG IgG3 antibodies.

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