Imaging chronic active lesions in multiple sclerosis: a consensus statement.

Chronic active lesions (CAL) are an important manifestation of chronic inflammation in multiple sclerosis and have implications for non-relapsing biological progression. In recent years, the discovery of innovative MRI and PET-derived biomarkers has made it possible to detect CAL, and to some extent quantify them, in the brain of persons with multiple sclerosis, in vivo. Paramagnetic rim lesions on susceptibility-sensitive MRI sequences, MRI-defined slowly expanding lesions on T1-weighted and T2-weighted scans, and 18-kDa translocator protein-positive lesions on PET are promising candidate biomarkers of CAL. While partially overlapping, these biomarkers do not have equivalent sensitivity and specificity to histopathological CAL. Standardization in the use of available imaging measures for CAL identification, quantification and monitoring is lacking. To fast-forward clinical translation of CAL, the North American Imaging in Multiple Sclerosis Cooperative developed a consensus statement, which provides guidance for the radiological definition and measurement of CAL. The proposed manuscript presents this consensus statement, summarizes the multistep process leading to it, and identifies the remaining major gaps in knowledge.

Paramagnetic rim lesions are associated with pathogenic CSF profiles and worse clinical status in multiple sclerosis: A retrospective cross-sectional study.

BACKGROUND: Paramagnetic rims have been observed as a feature of some multiple sclerosis (MS) lesions on susceptibility-sensitive magnetic resonance imaging (MRI) and indicate compartmentalized inflammation. OBJECTIVE: To investigate clinical, MRI, and intrathecal (cerebrospinal fluid, CSF) associations of paramagnetic rim lesions (PRLs) using 3T MRI in MS. METHODS: This is a retrospective, cross-sectional analysis. All patients underwent 3T MRI using a T2*-weighted sequence with susceptibility postprocessing (susceptibility-weighted angiography (SWAN) protocol, GE). SWAN-derived filtered-phase maps and corresponding T2-FLAIR images were manually reviewed to determine PRL. Descriptive statistics, t-tests, and regression determined demographic, clinical, MRI, and CSF associations with PRL. RESULTS: A total of 147 MS patients were included; 79 of whom had available CSF. Forty-three percent had at least one PRL. PRL status (presence/absence) did not vary by sex or Expanded Disability Status Scale (EDSS) but was associated with younger age, shorter disease duration, worse disease severity, high-efficacy therapy use, and poorer dexterity, as well as lower age-adjusted brain volumes and cognitive processing speeds. PRL status was moreover associated with blood-brain barrier disruption as determined by pathologically elevated albumin quotient. Sensitivity analyses remained supportive of these findings. CONCLUSION: PRLs, an emerging noninvasive biomarker of chronic neuroinflammation, are confirmed to be associated with greater disease severity and newly shown to be preliminarily associated with blood-brain barrier disruption.

Paramagnetic Rim Lesions in Multiple Sclerosis: Comparison of Visualization at 1.5-T and 3-T MRI.

BACKGROUND. Multiple sclerosis (MS) is characterized by both acute and chronic intrathecal inflammation. A subset of MS lesions show paramagnetic rims on susceptibility-weighted MRI sequences, reflecting iron accumulation in microglia. These para-magnetic rim lesions have been proposed as a marker of compartmentalized smoldering disease. Paramagnetic rim lesions have been shown at 7 T and, more recently, at 3 T. As susceptibility effects are weaker at lower field strength, it remains unclear if paramagnetic rim lesions are visible at 1.5 T. OBJECTIVE. The purpose of our study was to compare visualization of paramagnetic rim lesions using susceptibility-weighted imaging at 1.5-T and 3-T MRI in patients with MS. METHODS. This retrospective study included nine patients (five women, four men; mean age, 46.8 years) with MS who underwent both 1.5-T and 3-T MRI using a comparable susceptibility-weighted angiography (SWAN) sequence from the same manufacturer. Lesions measuring greater than 3 mm were annotated. Two reviewers independently assessed images at each field strength in separate sessions and classified the annotated lesions as isointense, diffusely paramagnetic, or paramagnetic rim lesions. Discrepancies were discussed at consensus sessions including a third reviewer. Agreement was assessed using kappa coefficients. RESULTS. Based on the 3-T consensus readings, 115 of 140 annotated lesions (82%) were isointense lesions, 16 (11%) were diffusely paramagnetic lesions, and nine (6%) were paramagnetic rim lesions; based on the 1.5-T consensus readings, 115 (82%) were isointense lesions, 14 (10%) were diffusely paramagnetic lesions, and 11 (8%) were para-magnetic rim lesions. The mean lesion diameter was 11.9 mm for paramagnetic rim lesions versus 6.4 mm for diffusely paramagnetic lesions (p = .006) and 7.8 mm for iso-intense lesions (p = .003). Interrater agreement for lesion classification as a paramagnetic rim lesion was substantial at 1.5 T (κ = 0.65) and 3 T (κ = 0.70). Agreement for paramagnetic rim lesions was also substantial between the consensus readings at the two field strengths (κ = 0.79). CONCLUSION. We show comparable identification of paramagnetic rim lesions at 1.5-T and 3-T MRI with substantial interrater agreement at both field strengths and substantial consensus agreement between the field strengths. CLINICAL IMPACT. Paramagnetic rim lesions may be an emerging marker of chronic neuroinflammation in MS. Their visibility at 1.5 T supports the translational potential of paramagnetic rim lesion identification to more widespread clinical settings, where 1.5-T scanners are prevalent.

The neutrophil-to-lymphocyte and monocyte-to-lymphocyte ratios are independently associated with neurological disability and brain atrophy in multiple sclerosis.

BACKGROUND: Serum hematological indices such as the neutrophil-lymphocyte ratio (NLR) or monocyte-lymphocyte ratio (MLR) have been used as biomarkers of pathogenic inflammation and prognostication in multiple areas of medicine; recent evidence shows correlation with psychological parameters as well. OBJECTIVES/AIMS: To characterize clinical, neuroimaging, and psycho-neuro-immunological associations with NLR and MLR in persons with multiple sclerosis (MS). METHODS: We identified a large cohort of clinically well-defined patients from our longitudinal database that included MS-related outcomes, disease-modifying therapy, patient-reported outcome (PRO) measures, and quantified cerebral MRI at 1.5 T. We queried hospital records for complete blood counts within 2 months of each clinic visit and excluded those obtained during clinical relapses. Four hundred eighty-three patients, with a mean of 3 longitudinal observations each, were identified who met these criteria. Initial analyses assessed the association between NLR and MLR as the outcomes, and psychological and demographic predictors in univariable and multivariable models controlling for age, gender and treatment. The second set of analyses assessed the association between clinical and MRI outcomes including whole brain atrophy and T2-hyperintense lesion volume, with NLR and MLR as predictors in univariable and multivariable models. All analyses used a mixed effects linear or logistic regression model with repeated measures. RESULTS: Unadjusted analyses demonstrated significant associations between higher (log-transformed) NLR (but not MLR) and PRO measures including increasing depression (p = 0.01), fatigue (p < 0.01), and decreased physical quality of life (p < 0.01). Higher NLR and MLR strongly predicted increased MS-related disability as assessed by the Expanded Disability Status Scale, independent of all demographic, clinical, treatment-related, and psychosocial variables (p < 0.001). Lastly, higher NLR and MLR significantly discriminated progressive from relapsing status (p ≤ 0.01 for both), and higher MLR correlated with increased whole-brain atrophy (p < 0.05) but not T2 hyperintense lesion volume (p > 0.05) even after controlling for all clinical and demographic covariates. Sensitivity analyses using a subset of untreated patients (N = 146) corroborated these results. CONCLUSIONS: Elevated NLR and MLR may represent hematopoetic bias toward increased production and pro-inflammatory priming of the myeloid innate immune system (numerator) in conjunction with dysregulated adaptive immune processes (denominator), and consequently reflect a complementary and independent marker for severity of MS-related neurological disability and MRI outcomes.

Human herpesvirus 6 associated post-transplant acute limbic encephalitis: Clinical observations of biomarkers for risk of seizure in a pediatric population.

BACKGROUND: Human herpesvirus 6 (HHV6) is a cause of post-transplant acute limbic encephalitis (PALE). Seizures are associated with this disorder yet no predictive biomarkers have been identified. The objective of this study was to evaluate lab and neurodiagnostic biomarkers in patients with HHV6 associated PALE. METHODS: A retrospective chart review was performed at our institutions between 2000 and 2017. Patients were identified through a clinical database. Inclusion criteria included: age less than 18 years, HHV6 (quantitative real-time PCR or meningoencephalitis panel) tested in CSF and serum. Biomarkers of serum and CSF viral load, EEG, and MRI were reviewed along with clinical data. RESULTS: In total, 11 patients met inclusion criteria. All patients had undergone hematopoietic stem cell transplantation. Five of 11 patients had seizures as part of their clinical course, all being controlled with antiepileptic monotherapy. Seizure semiology was focal-onset in three cases and generalized in two. Neuroimaging was normal in all patients within seven days but six patients developed T2 signal intensities in the temporal lobes on repeat imaging between 14-28 days. The median CSF HHV6 viral load for all patients was 47 300 copies/mL although the median viral load was 2586 copies/mL in patients who had seizure compared to 473 969 copies/mL in those who had not (P = 0.02). Those with seizures tended to be younger (median 6.5 years compared to 11 years, P = 0.27). All patients with seizures had an EEG with 80% demonstrating abnormalities. CONCLUSION: In patients with post-hematopoietic stem cell transplant HHV6 associated PALE, lower CSF viral load may be associated with a higher likelihood to have seizures. This may indicate a primary infection as opposed to secondary reactivation phenomenon.

Evaluating the Clinical Utility of Epstein-Barr Virus Antibodies as Biomarkers in Multiple Sclerosis: A Systematic Review.

BACKGROUND: EBV is a necessary but not sufficient factor in the pathophysiology of multiple sclerosis (MS). EBV antibodies to the nuclear antigen (EBNA1) and viral capsid antigen (VCA) rise rapidly prior to MS disease manifestations, and their absence has clinical utility with a high negative predictive value. It remains unclear whether EBV levels act as prognostic, monitoring, or pharmacodynamic/response biomarkers. Substantial literature on this topic exists but has not been systematically reviewed. We hypothesized that EBV levels against EBNA1 and VCA are potential prognostic and monitoring biomarkers in MS, and that patient population, MS clinical phenotype, and EBV assay method may play important roles in explaining variation among study outcomes. METHODS: We systematically searched PubMed and EMBASE from inception to April 1, 2022. After removal of duplicates, records were screened by abstract. Remaining full-text articles were reviewed. Clinical and MRI data were extracted from full-text articles for comparison and synthesis. RESULTS: Searches yielded 696 unique results; 285 were reviewed in full, and 36 met criteria for data extraction. Heterogeneity in sample population, clinical outcome measures, assay methods and statistical analyses precluded a meta-analysis. EBV levels were not consistently associated with clinical disease markers including conversion from CIS to RRMS, neurological disability, or disease phenotype. Studies using repeated-measures design suggest that EBNA1 levels may temporarily reflect inflammatory disease activity as assessed by gadolinium-enhancing Magnetic Resonance Imaging (MRI) lesions. Limited data also suggest a decrease in EBV levels following initiation of certain disease-modifying therapies. CONCLUSION: Heterogeneous methodology limited generalization and meta-analysis. EBV antibody levels are unlikely to represent prognostic biomarkers in MS. The areas of highest ongoing promise relate to diagnostic exclusion and pharmacodynamic/disease response. Use of EBV antibodies as biomarkers in clinical practice remains additionally limited by lack of methodological precision, reliability, and validation.

New Imaging Markers in Multiple Sclerosis and Related Disorders: Smoldering Inflammation and the Central Vein Sign.

Concepts of multiple sclerosis (MS) biology continue to evolve, with observations such as "progression independent of disease activity" challenging traditional phenotypic categorization. Iron-sensitive, susceptibility-based imaging techniques are emerging as highly translatable MR imaging sequences that allow for visualization of at least 2 clinically useful biomarkers: the central vein sign and the paramagnetic rim lesion (PRL). Both biomarkers demonstrate high specificity in the discrimination of MS from other mimics and can be seen at 1.5 T and 3 T field strengths. Additionally, PRLs represent a subset of chronic active lesions engaged in "smoldering" compartmentalized inflammation behind an intact blood-brain barrier.

A single-arm, open-label pilot study of neuroimaging, behavioral, and peripheral inflammatory correlates of mindfulness-based stress reduction in multiple sclerosis.

Multiple sclerosis (MS) is a chronic neurological disease frequently associated with significant fatigue, anxiety, depression, and stress. These symptoms are difficult to treat, and prominently contribute to the decreases in quality of life observed with MS. The underlying mechanisms of these "silent" symptoms are not well understood and include not just the psychological responses to a chronic disease, but also biological contributions from bidirectional psycho-neuro-immune (dys)regulation of systemic inflammatory biology. To address these issues, we conducted a prospective, observational pilot study to investigate the psychological, biological, and neuroarchitecture changes associated with a mindfulness-based stress reduction (MBSR) program in MS. The overarching hypothesis was that MBSR modulates systemic and central nervous system inflammation via top-down neurocognitive control over forebrain limbic areas responsible for the neurobiological stress response. 23 patients were enrolled in MBSR and assessed pre/post-program with structural 3 T MRI, behavioral measures, hair cortisol, and blood measures of peripheral inflammation, as indexed by the Conserved Transcriptional Response to Adversity (CTRA) profile. MBSR was associated with improvements across a variety of behavioral outcomes, as well as on-study enlargement of the head of the right hippocampus. The CTRA analyses revealed that greater inflammatory gene expression was related to worse patient-reported anxiety, depression, stress, and loneliness, in addition to lower eudaimonic well-being. Hair cortisol did not significantly change from pre- to post-MBSR. These results support the use of MBSR in MS and elucidate inflammatory mechanisms related to key patient-reported outcomes in this population.

Targeted proteomics of cerebrospinal fluid in treatment naïve multiple sclerosis patients identifies immune biomarkers of clinical phenotypes.

Multiple sclerosis (MS) is an inflammatory demyelinating disease with heterogeneous clinical presentations and variable long-term disability accumulation. There are currently no standard criteria to accurately predict disease outcomes. In this study we investigated the cross-sectional relationship between disease phenotype and immune-modulating cytokines and chemokines in cerebrospinal fluid (CSF). We analyzed CSF from 20 DMT-naïve MS patients using Olink Proteomics' Target 96 Inflammation panel and correlated the resulting analytes with respect to (1) disease subtype, (2) patient age and sex, (3) extent of clinical disability, and (4) MRI segmental brain volumes. We found that intrathecal IL-4 correlated with higher Expanded Disability Status Scale (EDSS) scores and longer 25-foot walk times, and CD8A correlated with decreased thalamic volumes and longer 9-hole peg test times. Male sex was associated with higher FGF-19 expression, and Tumefactive MS with elevated CCL4. Several inflammatory markers were correlated with older age at the time of LP. Finally, higher intrathecal IL-33 correlated with increased MS lesion burden and multi-compartment brain atrophy. This study confirms immune heterogeneity underlying CSF profiles in MS, but also identifies several inflammatory protein biomarkers that may be of use for predicting clinical outcomes in future algorithms.

Serum Albumin Modifies the Effect of Peripheral Blood Monocytes on Severity of Diabetic Nephropathy in an Adult Population.

BACKGROUND: Our aim in this study was to characterize clinical associations between peripheral blood immune populations and diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus. METHODS: We queried hospital records from an outpatient diabetes primary care clinic between 2018 and 2019 for clinical and laboratory data, including complete blood counts with differentials, serum albumin and globulin, glycated hemoglobin (A1C) and urine albumin-to-creatinine ratio. One hundred ninety-eight patients had complete cross-sectional data with temporally proximate complete blood counts and urine albumin-to-creatinine ratios. After univariable correlation assessment, we used a forward multivariable linear regression model to test the hypothesis that higher numbers of circulating innate immune populations would be associated with DKD, while accounting for known demographic, clinical and laboratory risk factors. We defined DKD as an albumin-to-creatinine ratio of >3 mg/mmol or an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2 from the Chronic Kidney Disease Epidemiology Collaboration. RESULTS: Adjusted analyses demonstrated significant (p<0.01) associations between higher urine albumin-to-creatinine ratio and peripheral circulating monocytes, independent of other established significant risk factors, including blood pressure, A1C, age and sex. We also identified serum albumin as a potentially important modifying factor of albuminuric kidney disease, which interacts with monocytes in more advanced disease. In contrast, the variable most strongly predictive of eGFR was age. CONCLUSIONS: Circulating monocytes and serum albumin are significantly associated with albuminuria, but not eGFR in DKD. These results support the potential role of the innate immune system in diabetic microvascular end-organ damage and urinary protein loss, and may be readily translatable clinical markers to incorporate into risk-assessment models for prognostication in diabetes.

The impact of socioeconomic status on mental health and health-seeking behavior across race and ethnicity in a large multiple sclerosis cohort.

BACKGROUND: Psychiatric symptoms are common in multiple sclerosis (MS) and may contribute to worse MS outcomes. Previous studies suggest the burden of symptoms may vary by race, ethnicity and socioeconomic status (SES). Our objective was to expand upon this previous work and explore the associations between SES, race, and ethnicity, as predictors of psychiatric symptoms, mental health attitudes, and health-seeking behavior in patients with MS. METHODS: Persons with MS answered a national web-based survey including demographic characteristics (including race, ethnicity and measures of SES), mental health attitudes, the Patient Health Questionnaire-9 (PHQ-9), the Generalized Anxiety Disorder 7-item (GAD-7) scale, the Modified Fatigue Impact Scale 5-item version (MFIS-5), and the Alcohol Use Disorders Identification Test (AUDIT). The survey also queried mental health availability and perceptions of care. We measured neighborhood-level SES (nSES) of each participant using the Agency for Healthcare Research and Quality (AHRQ) index that was calculated from 5-digit postal codes. Other indicators of participant-level SES included education level and self-reported household income. We assessed the association between race, ethnicity, and neighborhood/participant-level SES indicators and affective symptom burden using generalized linear models that were adjusted for age, sex, and MS characteristics. RESULTS: 2095 participants answered the survey (mean AHRQ index 54.6 ± 5.4, age 51.3 ± 12.2 years, 7% Black/African American, 5.4% Hispanic/Latino, and 81.8% female). Those in the lowest quartile of nSES (most disadvantaged) were more likely to be either Black/African American or Hispanic/Latino as compared to those in highest quartile (least disadvantaged). Those in the lowest quartile of nSES had higher mean MFIS-5 (1.02 points; 95% CI: 0.39, 1.43), PHQ-9 (1.24 points; 95% CI: 0.49, 1.98), and GAD-7 (0.69 points; 95% CI: -0.01, 1.38) scores relative to those in the highest quartile. Of those who consumed alcohol (n = 1489), participants in the lowest AHRQ quartile had lower mean AUDIT scores (-0.73 points; 95% CI: -1.18, -0.29) as compared to those in higher quartiles. Race and ethnicity were not associated with self-reported psychiatric symptom burden in this cohort. SES was also associated with self-reported improvement of symptoms after receiving mental health care. A higher proportion of Black/African American (44.1% vs 30.2%, p = 0.003) and Hispanic/Latino (49.1% vs 30.6%, p<0.001) participants were more likely to report they would "definitely go" receive mental health care if services were co-located with their MS care as compared to white and Non-Hispanic/Latino participants, respectively. CONCLUSION: Higher SES was associated with a lower burden of psychiatric symptoms and with a higher likelihood of self-reported symptom recovery after receiving mental health treatment. Attitudes regarding mental health care delivery in MS varied according to racial and ethnic background. Future longitudinal studies in more diverse populations should assess whether co-location of mental health services with MS care helps to reduce the gap between access and need of mental health care in MS.

A distraction can impair or enhance motor performance.

Humans have a prodigious capacity to perform multiple tasks simultaneously. Being distracted while, for example, performing a complex motor skill adds complexity to a task and thus leads to a performance impairment. Yet, it may not be just the presence or absence of a distraction that affects motor performance. Instead, the characteristics of the distraction may play a critical role in affecting human motor performance. Here, we show that performance of a motor sequence can be substantially enhanced by simultaneously learning an independent color sequence. In contrast, performance of the same motor sequence was impaired by concurrently counting the number of red cues that were in the color sequence. The color and motor sequences had different lengths (10 vs 12 items), different numbers of elements (five vs four elements), and different temporal patterns (randomly intermittent vs continuous) and thus were independent of one another. These observations show that distracting information does not always impair motor performance, and so is not a sufficient explanation for the impaired performance. Instead, the influence that a distraction exerts upon performance is mediated by the type of processes engaged: when similar core processes are engaged, motor performance is enhanced, whereas when very different processes are engaged (i.e., counting and sequence performance), performance is impaired. Thus, these observations deepen our understanding of how a distraction, depending on its characteristics, can either impair or enhance performance and may offer novel approaches to optimizing human cognition.

Shape conveyed by visual-to-auditory sensory substitution activates the lateral occipital complex.

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.

Exacerbation of Multiple Sclerosis by BRAF/MEK Treatment for Malignant Melanoma: The Central Vein Sign to Distinguish Demyelinating Lesions From Metastases.

The emergence of immunomodulators as effective cancer treatments has been an important advance in cancer therapy. The combination therapy of BRAF/MEK inhibition with or without anti-CTLA-4 treatment causes an immunostimulatory effect that has greatly reduced death from melanoma. In this article, we present the case of a patient with prior multiple sclerosis (MS) and who later developed metastatic malignant melanoma, had a marked increase of magnetic resonance imaging (MRI) findings after treatment with the combination of trametinib (MEK) and dabrafenib (BRAF), diagnostic question of metastatic disease versus new MS lesions without brain biopsy is discussed. A healthy 49-year-old man was diagnosed with MS in October 2012. He was stable with an oral disease modifying drug until March of 2016 when the patient discovered a lump in his right groin. Biopsy was positive for S100 and BRAF V600 mutation. Combination MEK/BRAF was given and after immunotherapy an MRI showed 25 new gadolinium-enhancing lesions thought to be metastases. A brain biopsy was recommended but neurology and neuroimaging consultation showed that the MRI was consistent with demyelination (oval/ovoid, homogeneous and open-ring enhancement, and predominance of the central vein sign within lesions) rather than metastasis. Treatment for MS has been successful and there has been no return of his melanoma in 4 years. New immunotherapies are lifesaving but the modulation of the immune system can cause unpredictable events such are markedly increased MS activity. The awareness of the diagnostic value of the central vein sign provided a better outcome for this patient and could be a model in the future for others.

A real-world cohort analysis of alemtuzumab outcomes in relapsing multiple sclerosis.

Multiple sclerosis (MS) is a chronic and progressive neurological disease characterized by recurrent episodes of inflammatory demyelination of the brain and spinal cord. Alemtuzumab has been previously shown in large phase III trials to be an effective therapy in reducing MS clinical flares as well as new radiological activity and atrophy rates. The purpose of this study was to examine real-world effectiveness and safety data from a large cohort of people treated with alemtuzumab at an academic medical center, including those who failed B-cell depletion therapy. Over an average of 2.6 years follow-up, there were small but significant improvements in neurological disability scores, and a 61% rate of the composite "No Evidence of Disease Activity" (NEDA-3) outcome at 2-year follow-up. There were no substantial safety issues encountered in our review; rates of adverse events were similar or below those reported in Phase III trials. We compare and contrast our results to other available real-world data using alemtuzumab in multiple sclerosis.

HHV-6-Associated Neurological Disease in Children: Epidemiologic, Clinical, Diagnostic, and Treatment Considerations.

Human herpesviruses 6A and 6B, often referred to collectively as human herpesvirus 6, are a pair of beta-herpesviruses known to cause a variety of clinical syndromes in both immunocompetent and immunocompromised individuals. Most humans are infected with human herpesvirus 6B, and many with human herpesvirus 6A. Primary infection typically occurs in early childhood, although large-scale reviews on the topic are limited. Herein, the authors explore the clinical manifestations of human herpesvirus 6-associated disease in both immunocompetent and immunocompromised pediatric patients, the risk factors for development of human herpesvirus 6-associated neurological disease, the risk of autoimmunity associated with development of active or latent infection, the relevance of human herpesvirus 6-specific diagnostic tests, and the medications used to treat human herpesvirus 6. The goal of this review is to improve the current understanding of human herpesvirus 6 in pediatric populations and to examine the most effective diagnostic and therapeutic interventions in this disease state.

Cervical spondylosis is a risk factor for localized spinal cord lesions in multiple sclerosis.

OBJECTIVES: To answer the question whether cervical spondylosis would increase the incidence of cord lesions in MS patients, we investigated the statistical association between the two pathologies. METHODS: We extracted demographics, basic disease characteristics and MRI data of a cohort of 304 consecutive MS patients. For a subset of 176 patients, a detailed analysis independently assessed for each cervical level the co-existence of spinal canal narrowing from spondylosis and corresponding cord signal abnormalities. RESULTS: The cohort had typical demographics and in over 80 % of cases there was at least one cord lesion. EDSS correlated with age, disease duration, cerebral lesion burden and spinal cord lesions. After adjusting for either age, disease duration, central lesion burden, or EDSS, the presence of spinal spondylosis was not significantly associated with spinal cord lesions (p > 0.05). In the subset of 176 subjects with the level-by-level spine data, we found a highly statistically significant association (Pearson's χ2 = 23.7, p < 0.001) between canal narrowing and cord lesion at the level directly above or below. This association remained highly significant in both univariable and multivariable logistic regression models adjusting for age, disease duration, MS treatment, cerebral lesion burden and disability scores (p < 0.001). CONCLUSIONS: The data from our cohort of MS patients suggest an indirect contribution of cervical spondylosis to disability by increasing the risk of developing localized cord lesions. While further studies are needed to confirm the findings and clarify disease mechanisms, closer attention should be paid to worsening spondylosis in patients with MS.

Placebos in chronic pain: evidence, theory, ethics, and use in clinical practice.

Despite their ubiquitous presence, placebos and placebo effects retain an ambiguous and unsettling presence in biomedicine. Specifically focused on chronic pain, this review examines the effect of placebo treatment under three distinct frameworks: double blind, deception, and open label honestly prescribed. These specific conditions do not necessarily differentially modify placebo outcomes. Psychological, clinical, and neurological theories of placebo effects are scrutinized. In chronic pain, conscious expectation does not reliably predict placebo effects. A supportive patient-physician relationship may enhance placebo effects. This review highlights "predictive coding" and "bayesian brain" as emerging models derived from computational neurobiology that offer a unified framework to explain the heterogeneous evidence on placebos. These models invert the dogma of the brain as a stimulus driven organ to one in which perception relies heavily on learnt, top down, cortical predictions to infer the source of incoming sensory data. In predictive coding/bayesian brain, both chronic pain (significantly modulated by central sensitization) and its alleviation with placebo treatment are explicated as centrally encoded, mostly non-conscious, bayesian biases. The review then evaluates seven ways in which placebos are used in clinical practice and research and their bioethical implications. In this way, it shows that placebo effects are evidence based, clinically relevant, and potentially ethical tools for relieving chronic pain.