Reliability, construct and concurrent validity of a smartphone-based cognition test in multiple sclerosis.

BACKGROUND: Early detection and monitoring of cognitive dysfunction in multiple sclerosis (MS) may be enabled with smartphone-adapted tests that allow frequent measurements in the everyday environment. OBJECTIVES: The aim of this study was to determine the reliability, construct and concurrent validity of a smartphone-adapted Symbol Digit Modalities Test (sSDMT). METHODS: During a 28-day follow-up, 102 patients with MS and 24 healthy controls (HC) used the MS sherpa® app to perform the sSDMT every 3 days on their own smartphone. Patients performed the Brief International Cognitive Assessment for MS at baseline. Test-retest reliability (intraclass correlation coefficients, ICC), construct validity (group analyses between cognitively impaired (CI), cognitively preserved (CP) and HC for differences) and concurrent validity (correlation coefficients) were assessed. RESULTS: Patients with MS and HC completed an average of 23.2 (SD = 10.0) and 18.3 (SD = 10.2) sSDMT, respectively. sSDMT demonstrated high test-retest reliability (ICCs > 0.8) with a smallest detectable change of 7 points. sSDMT scores were different between CI patients, CP patients and HC (all ps < 0.05). sSDMT correlated modestly with the clinical SDMT (highest r = 0.690), verbal (highest r = 0.516) and visuospatial memory (highest r = 0.599). CONCLUSION: Self-administered smartphone-adapted SDMT scores were reliable and different between patients who were CI, CP and HC and demonstrated concurrent validity in assessing information processing speed.

Performance validity in outpatients with multiple sclerosis and cognitive complaints.

BACKGROUND: Suboptimal performance during neuropsychological assessment renders cognitive test results invalid. However, suboptimal performance has rarely been investigated in multiple sclerosis (MS). OBJECTIVES: To investigate potential underlying mechanisms of suboptimal performance in MS. METHODS: Performance validity testing, neuropsychological assessments, neuroimaging, and questionnaires were analyzed in 99 MS outpatients with cognitive complaints. Based on performance validity testing patients were classified as valid or invalid performers, and based on neuropsychological test results as cognitively impaired or preserved. Group comparisons and correlational analyses were performed on demographics, patient-reported, and disease-related outcomes. RESULTS: Twenty percent displayed invalid performance. Invalid and valid performers did not differ regarding demographic, patient-reported, and disease-related outcomes. Disease severity of invalid and valid performers with cognitive impairment was comparable, but worse than cognitively preserved valid performers. Lower performance validity scores related to lower cognitive functioning, lower education, being male, and higher disability levels (p < 0.05). CONCLUSION: Suboptimal performance frequently occurs in patients with MS and cognitive complaints. In both clinical practice and in cognitive research, suboptimal performance should be considered in the interpretation of cognitive outcomes. Identification of factors that differentiate between suboptimal and optimal performers with cognitive impairment needs further exploration.

Neuroprotective effects of exercise in people with progressive multiple sclerosis (Exercise PRO-MS): study protocol of a phase II trial.

BACKGROUND: Neurodegeneration, rather than inflammation, plays a key role in the progressive phase of multiple sclerosis (MS). Current disease modifying treatment options for people with progressive MS (PMS) do not specifically target neurodegeneration. Preliminary evidence suggests that exercise therapy might have neuroprotective effects. However, neuroprotective effect studies of exercise interventions in PMS are scarce and the possible mode of action underlying neuroprotective effects of exercise are unknown and need to be elucidated. The main aim of this phase II trial is to assess whether progressive resistance training (PRT) and high intensity interval training (HIIT), can slow down neurodegeneration in people with PMS. METHODS: In a single-blinded phase II clinical trial with an extended baseline period, 60 people with PMS will be randomly assigned to PRT or HIIT. The participants should have had a relapse onset of MS with confirmed disease progression, however still ambulatory. The duration of the study is 48 weeks, consisting of 16 weeks baseline period (no intervention), 16 weeks intervention and 16 weeks follow-up. Patient-tailored training will be performed 3 times per week for one hour in groups, led by an experienced physiotherapist. The primary outcome measure is neurodegeneration, measured as whole brain atrophy on magnetic resonance imaging (MRI). Secondary outcome parameters will include other biomarkers associated with neurodegeneration (i.e. regional brain atrophy, lesion load, white matter integrity, resting state functional connectivity, blood biomarkers (brain derived neurotrophic factor (BDNF) and serum neurofilament light (sNFL)), patient functioning (physical and cognitive) and cardiovascular risk factors. DISCUSSION: Besides the primary outcome measures, this study will examine a large variety of biomarkers associated with neurodegeneration after an exercise intervention. Combining outcome parameters may help to elucidate the mode of action underlying neuroprotective effects of exercise. TRIAL REGISTRATION: This trial is prospectively registered at the Dutch Trial Registry (number NL8265, date 06-01-2020).

Introducing Multiple Screener: An unsupervised digital screening tool for cognitive deficits in MS.

BACKGROUND: Cognitive deficits affect up to 70% of all patients with Multiple Sclerosis (MS) and have a significant impact on quality of life. Cognitive assessments need to be performed by a neuropsychologist and are often time-consuming, hampering timely identification and adequate monitoring of cognitive decline in MS. OBJECTIVE: To develop a time-efficient, unsupervised, digital tool to screen for cognitive deficits in MS. METHODS: A digital (adjusted) version of the Brief International Cognitive Assessment for MS, including the Symbol Digit Modalities Test (SDMT, information processing speed), the California Verbal Learning Test (CVLT-II, verbal memory) and the Spatial Recall Test (SPART, visuospatial memory) was developed: Multiple Screener (intellectual property of Sanofi Genzyme). Firstly, the clarity and feasibility of the tool was confirmed by 16 patients with MS (mean age 50.9 years (SD 9.4, range 37-68). Next, in 60 healthy controls (HCs, mean age 44.5 years (SD 14.0, range 18-67), intraclass correlation coefficients (ICC) were calculated to describe how strongly the digital version resembled the paper and pencil-based assessment. Finally, 236 HCs (mean age 42.8 years (SD 12.8, range 18-69) were included to obtain norm scores for each test. RESULTS: ICCs between digital and paper and pencil-based assessment were excellent to good (SDMT (ICC 0.79, confidence interval (CI) 0.67-0.87); CVLT-II (ICC 0.77, CI 0.64-0.85); SPART (ICC 0.61, CI 0.42-0.75)). For each test, a regression-based correction for the effect of age was applied on the raw scores before converting them to norm Z-scores. Additionally, the SDMT scores needed correction for education and the CVLT-II for education and sex (subgroups were created). CONCLUSIONS: Performance on an adjusted, digital version of the BICAMS correlates highly with the standard paper-and-pencil based test scores in HCs. Multiple Screener is an unsupervised, digital tool, with available norm scores, ultimately allowing for easy monitoring of cognitive decline in patients with MS.

Recommendations for the successful control of a large outbreak of vancomycin-resistant Enterococcus faecium in a non-endemic hospital setting.

BACKGROUND: A large outbreak of three epidemic vancomycin-resistant Enterococcus faecium (VRE) clones affected the study hospital for almost two years. AIM: To describe the strategy to successfully control this outbreak and eradicate VRE from the study hospital. METHODS: Infection control interventions started after detection of VRE in three patients. Hospital-wide surveillance was started after ongoing transmission despite isolation precautions, cleaning and contact tracing. Hygiene education and discipline were enhanced. Despite these interventions, additional measures were required to control the outbreak, such as ward disinfection with hydrogen peroxide vapour and the introduction of a VRE quarantine ward. Ultimately, ciprofloxacin prophylaxis for haematological patients on chemotherapy was abandoned. FINDINGS: Over a 22-month period, 242 VRE carriers were identified. Of these, 128 (53%) patients were detected by hospital-wide surveillance alone. Three epidemic clones were detected: ST494-vanA (N = 160), ST78-vanA (N = 23) and ST117-vanB (N = 32). In total, 5614 possible contacts were identified. VRE transmission occurred on 13 out of 23 wards. VRE was cultured from clinical specimens in 22 patients (seven with bacteraemia). Since January 2014, no further transmission of these VRE clones has been observed. CONCLUSION: Infection control measures according to international guidelines were insufficient to expose the outbreak to its full extent and control it. Its full extent only became apparent after sustained hospital-wide screening. Successful control of this hospital-wide VRE outbreak was feasible, but required great effort. Final containment and eradication of the epidemic clones was achieved by environmental decontamination with hydrogen peroxide vapour, strict isolation precautions, a VRE quarantine ward and antimicrobial stewardship.

Pneumococcal conjugate vaccination response in patients after community-acquired pneumonia, differences in patients with S. pneumoniae versus other pathogens.

OBJECTIVES: The goal of this study is to investigate the immune response to the 13-valent pneumococcal conjugate vaccine (PCV13) in former pneumococcal CAP patients. We hypothesize that an impaired or suboptimal humoral immune response against (specific) pneumococcal serotypes might explain the vulnerability for pneumococcal disease. METHODS: Hospitalised adult CAP patients who participated in two trials (2004-2006 (n=201) and, 2007-2009 (n=304)) were screened. Patients eligible for inclusion had CAP caused by either S. pneumoniae (pneuCAP) or due to another well-defined pathogen (otherCAP). Serotype-specific pneumococcal antibody concentrations (total IgG and IgG2/IgG1) before and 3-4weeks after PCV13 administration were measured (Luminex) and compared between pneuCAP and otherCAP patients. RESULTS: We vaccinated 60 patients:i.e. 34 pneuCAP and 26 otherCAP patients. In the pneuCAP group, 74% of patients were categorized as good responders (≥9/13 serotypes with concentration≥1300ng/ml), versus 77% in the otherCAP group. Significantly fewer full responders (i.e. 13/13 serotypes with a concentration≥1300ng/mL) were identified in the pneuCAP group (15% vs 42% respectively, p=0.02). For serotype 1, total IgG and IgG2/IgG1 subset post-vaccination concentrations were significantly lower among pneuCAP patients. Our additional case-series showed that of 16 pneuCAP patients who were infected by a serotype included in PCV13 three patients did not respond against the serotype originally responsible for their CAP episode, including one former bacteraemic pneumococcal CAP patient who also failed to show a response against the serotype responsible for CAP during infection. Thirteen patients did respond to the previously infecting serotype following PCV13 including three patients who had bacteraemic pneumococcal pneumonia and did not show a response during infection against the serotype responsible for CAP. CONCLUSIONS: Our results confirm the immunogenic properties of PCV13 in former pneumococcal CAP patients including patients previously regarded as potential hyporesponders. A slightly diminished overall humoral response to polysaccharides characterizes the former pneumococcal CAP patients. ClinicalTrials.gov Identifier: NCT02141009.

Functionality of the pneumococcal antibody response in Down syndrome subjects.

We investigated the anti-polysaccharide antibody responses in subjects with Down syndrome (DS) because DS subjects show decreased peripheral B-lymphocyte numbers in all age groups, and a clinical picture of recurrent respiratory tract infections and increased incidence of autoimmune diseases which is reminiscent of common variable immunodeficiency disorders (CVID)-like disease. We determined titers and opsonophagocytosis in response to conjugated and unconjugated pneumococcal serotypes in 18 DS subjects aged 6-24 years. The results show adequate serotype-specific antibody titers in response to all conjugated and almost all unconjugated serotypes used. Opsonophagocytosis activity as measured against pneumococcal serotypes 9N, 19F and 23F was also found to be intact. We conclude that DS subjects do not have a clear defect in their anti-polysaccharide antibody response.

Removal of valproic acid by plasmapheresis in a patient treated for multiple sclerosis.

We present a case of a patient with multiple sclerosis who was treated with plasmapheresis and valproic acid. We used therapeutic drug monitoring to determine whether plasma concentrations of valproic acid were kept within the therapeutic window and to determine the amount of valproic acid that was removed by plasmapheresis.

Acute-phase responsiveness of mannose-binding lectin in community-acquired pneumonia is highly dependent upon MBL2 genotypes.

Mannose-binding lectin (MBL) is a pattern recognition receptor of the complement system and plays an important role in innate immunity. Whether or not MBL acts as an acute-phase response protein in infection has been an issue of extensive debate, because MBL responses have shown a high degree of heterogeneity. Single nucleotide polymorphisms (SNPs) in the promoter (wild-type Y versus X) and exon 1 (A versus 0) of the MBL2 gene can lead to MBL deficiency. This study investigated the influence of SNPs in the promoter and exon 1 of the MBL2 gene on the acute-phase responsiveness of MBL in 143 patients with community-acquired pneumonia. Acute-phase reactivity was observed only in MBL-sufficient genotypes (YA/YA, XA/YA, XA/XA and YA/0). In patients with wild-type exon 1 genotype A/A, positive acute-phase responses were associated with the presence of the YA haplotype and negative responses with its absence. Genotypes YA/0 and XA/XA produced equal levels of MBL in convalescence. In the acute phase, however, patients with genotype XA/XA displayed negative acute-phase responses more often than those with genotype YA/0. Correlation of MBL and C-reactive protein levels in the acute phase of pneumonia also depended upon the MBL2 genotype. In conclusion, acute-phase responsiveness of MBL was highly dependent upon the MBL2 genotype. These data suggest that heterogeneity in protein responses in the acute phase of disease should always be viewed in the light of possible influences of genetic differences in both structural and regulatory parts of the gene.

Autoantibodies to cyclic citrullinated peptides predict progression to rheumatoid arthritis in patients with undifferentiated arthritis: a prospective cohort study.

OBJECTIVE: Rheumatoid arthritis (RA) is a common, severe, chronic inflammatory joint disease. Since the disease may initially be indistinguishable from other forms of arthritis, early diagnosis can be difficult. Autoantibodies seen in RA can be detected years before clinical symptoms develop. In an inception cohort of patients with recent-onset arthritis, we undertook this study to assess the predictive value of RA-specific autoantibodies to cyclic citrullinated peptides (CCPs) in patients with undifferentiated arthritis (UA). METHODS: Anti-CCP2 antibody tests were performed at baseline in 936 consecutive, newly referred patients with recent-onset arthritis. Patients who could not be properly classified 2 weeks after inclusion were categorized as having UA. Patients with UA were followed up for 3 years and evaluated for progression of their disease to RA as defined by the American College of Rheumatology (ACR) 1987 revised criteria. RESULTS: Three hundred eighteen of 936 patients with recent-onset arthritis were classified as having UA and were available for analysis. After 3 years of followup, 127 of 318 UA patients (40%) had been classified as having RA. RA had developed in 63 of 249 patients (25%) with a negative anti-CCP test and in 64 of 69 patients (93%) with a positive anti-CCP test (odds ratio 37.8 [95% confidence interval 13.8-111.9]). Multivariate analysis of the presence of anti-CCP antibodies and parameters from the ACR criteria identified polyarthritis, symmetric arthritis, erosions on radiographs, and anti-CCP antibodies as significant predictors of RA. CONCLUSION: Testing for anti-CCP antibodies in UA allows accurate prediction of a substantial number of patients who will fulfill the ACR criteria for RA.

Orthopaedic sequelae in neurologically recovered obstetrical brachial plexus injury. Case study and literature review.

PURPOSE: Description of shoulder sequelae in obstetrical brachial plexus injury (OBPI) patients who had spontaneous functional recovery, in the context of historical and current conservative methods of treatment. METHOD: Case study of a baby with serious complications, followed by a review of the literature from 1900 until 2001 about conservative treatment of OBPI with respect to the prevention of shoulder complications. RESULTS: Description of contractures and bony deformities did not show important discrepancies over time, other than more detailed images because of new technical possibilities. There is no agreement on the explanation of the development of these deformities. Secondary changes caused by muscular imbalance and longstanding contracture are recognized by all authors. A primary osteoarticular lesion was recognized as a possible cause in the beginning of the twentieth century, then forgotten for a long time and only in the 1980s had gained interest again. The main change in treatment concerns the use of arm braces. This was strongly recommended in the first half of the twentieth century, then advised against and is at this moment not anymore mentioned. CONCLUSIONS: There is no consensus on the cause of contractures and bony deformities in children with OBPI. Conservative methods of treatment have changed over the years, without research on the outcome of these treatment changes.

Evidence for additional genetic risk indicators of relapse-onset MS within the HLA region.

BACKGROUND: Human leukocyte antigen (HLA)-DR2 carriership is associated with an increased risk for MS. Genome searches using microsatellite markers have consistently shown that additional genetic factors contribute to susceptibility for MS. OBJECTIVE: To identify loci within the HLA region that predispose to relapse-onset MS independently of HLA-DR2. METHOD: A case-control study involving 159 patients with definite relapse-onset MS and 273 control subjects was conducted. Six highly polymorphic microsatellite markers encoded within the HLA-C to DR region, that is, D6S1014, D6S273, TNFa, MIB, C1_2_5, and C1_3_2, three single-nucleotide tumor necrosis factor (TNF) promoter gene polymorphisms at positions -238, -308, and -376, and HLA-DR2 carriership were typed. RESULTS: These data confirmed the well-known association between the HLA-DR2 haplotype and relapse-onset MS, yielding an odds ratio (OR) of 3.6 (95% CI: 2.4 to 5.4; p < 0.0001). Multivariate analyses revealed that C1_3_2*354 was also associated with an increased risk for developing relapse-onset MS independently of HLA-DR2 (OR: 2.0; 95% CI: 1.2 to 3.1; p = 0.004). This allele is encoded within an ancestral haplotype that is highly linked to HLA-DR3. The joint effect of this ancestral haplotype and HLA-DR2 resulted in an OR of 8.7 (95% CI: 2.7 to 29; p < 0.0001) to develop relapse-onset MS. In addition, a protective risk factor was found: carriers of TNFa*107 had a 0.5-fold lower risk to develop relapse-onset MS (95% CI: 0.3 to 0.9; p = 0.026). CONCLUSION: Within the HLA region, other loci besides HLA-DR2 haplotype modulate susceptibility for relapse-onset MS.

Polymorphisms in or near tumour necrosis factor (TNF)-gene do not determine levels of endotoxin-induced TNF production.

Innate differences in tumour necrosis factor (TNF) production have been associated with susceptibility for and outcome of inflammatory diseases. Several studies have tried to identify whether polymorphisms in or near the TNF gene or other markers on the short arm of chromosome 6 (6p21) are related to differences in TNF production. Data on these associations are conflicting. Therefore, we conducted a study among 129 healthy individuals in which TNF production was determined upon stimulation with endotoxin in whole blood cultures. TNFa microsatellite, TNF single nucleotide polymorphisms at position +489, -238, -308 and -376 typing was performed. The data revealed that alleles of TNFa microsatellite and carriership of TNF polymorphisms were not related to TNF production. We conclude that the genes determing the differences in endotoxin-induced TNF production have not been yet identified.

On autonomy and participation in rehabilitation.

PURPOSE: To explore the concept of autonomy as a basis for social participation, with particular reference to rehabilitation. METHOD: A study of relevant literature from the field of rehabilitation, building on theory developed in other fields (ethics, social sciences), and deriving important concepts and strategies for rehabilitation practice. RESULTS: The focus of rehabilitation for people with a chronic disabling condition is shifting from a biomedical to a client-centred perspective. Conceptions of autonomy vary among individuals and cultures, but a crucial distinction can be made between decisional autonomy (the ability to make decisions without external restraint) and executional autonomy (the ability to act as one wishes). The liberal-individualist account of autonomy over-emphasizes physical independence and does not sufficiently recognize the inter-dependency of all people, including those with disabilities. An ethic of care, complementary to the principle of respect for autonomy, should guide the development of rehabilitation strategies to enhance individual autonomy and participation in daily living. For rehabilitation, this entails an attentive attitude, maximizing opportunities for informed choices, taking full account of each person's preferences, needs and social contexts. CONCLUSIONS: Autonomy is central to client-centred rehabilitation since it is a pre-requisite for effective participation. It is suggested that autonomy, conceived as a basis for participation, is the ultimate aim of rehabilitation.

Submaximal exercise capacity and maximal power output in polio subjects.

OBJECTIVES: To compare the submaximal exercise capacity of polio subjects with postpoliomyelitis syndrome (PPS) and without (non-PPS) with that of healthy control subjects, to investigate the relationship of this capacity with maximal short-term power and quadriceps strength, and to evaluate movement economy. DESIGN: Cross-sectional survey. SETTING: University hospital. PARTICIPANTS: Forty-three polio subjects (25 PPS, 18 non-PPS) and 12 control subjects. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Power output, oxygen uptake, and heart rate were measured in an incremental submaximal cycle ergometry test. Maximal short-term power was measured in 5-second all-out efforts. Knee extensor strength was measured on a chair dynamometer. RESULTS: The mean submaximal power +/- standard deviation at 80% of heart rate reserve of 83.8 +/- 29.9 watts in the polio subjects was significantly less than the mean submaximal power of 142.1 +/- 30.4 watts in the control group. However, expressed as a percentage of the maximal short-term power, submaximal power did not differ between the groups. Strength and maximal short-term power correlated significantly (p < .005) with submaximal power (r = .64 and .76, respectively). The oxygen uptake was higher than theoretically expected for the given submaximal power output in polio subjects, and appeared to increase with increasing asymmetry in strength and power between legs. No differences were found between PPS and non-PPS subjects. CONCLUSION: The submaximal work capacity of polio subjects was severely reduced, mainly in association with the reduced muscle capacity. And, because of a reduced movement economy, their energy cost was elevated. Although muscle loads in activities such as walking and climbing stairs differ from cycling, they also may require elevated relative levels of effort, predisposing subjects to premature fatigue in sustained activity.

Psychometric properties of the Impact on Participation and Autonomy Questionnaire.

OBJECTIVE: To examine the homogeneity, test-retest reliability, construct validity, and concurrent validity of the Impact on Participation and Autonomy Questionnaire (IPAQ). DESIGN: Cross-sectional study with a test-retest subsample. PATIENTS: One hundred twenty-six persons from 5 diagnostic groups recruited from the outpatients clinics of 2 rehabilitation centers and the rehabilitation department of an academic hospital. INTERVENTIONS: The IPAQ and 3 other self-administered questionnaires (Sickness Impact Profile [68-item version], London Handicap Scale [LHS], Medical Outcome Study Short-Form Health Survey). The IPAQ was completed twice by 75 respondents within approximately 2 weeks. RESULTS: The IPAQ addresses autonomy and participation in 5 domains: autonomy indoors, family role, autonomy outdoors, social relations, and work and educational opportunities. Cronbach's alpha for the several domains ranged between.81 and.91, indicating good homogeneity. On item level, weighted kappas ranged between.56 and.90. On domain level, the test-retest reliability of the IPAQ was good: intraclass correlation coefficients ranged between.83 and.91. Convergent validity was largely supported by the correlations between 4 domains of the LHS and the IPAQ. Discriminant validity was best demonstrated by low correlations between the IPAQ and 2 domains of the LHS representing theoretically different constructs. CONCLUSION: The IPAQ is a reliable and valid instrument for assessing autonomy and participation in chronic disorders. Its responsiveness requires further study.

Secretion of anti-citrulline-containing peptide antibody by B lymphocytes in rheumatoid arthritis.

OBJECTIVE: To understand the regulation of anti-citrulline-containing peptide antibody (anti-CCP) production in rheumatoid arthritis (RA), production of anti-CCP by B cells derived from peripheral blood (PB), bone marrow (BM), and synovial fluid (SF) was examined. METHODS: Purified PB and SF B cells were isolated by negative selection and then cultured in the absence or presence of L-CD40 ligand cells and interleukin-10 or anti-CD3-activated T cells. Total IgM and IgM-anti-CCP were detected after 14 days of culture by enzyme-linked immunosorbent assay. Enzyme-linked immunospot assays were performed to analyze the frequency of cells that spontaneously produced IgM-anti-CCP in BM and SF B cells. RESULTS: IgM-anti-CCP autoantibodies were induced in PB B cells from healthy controls and RA patients following coculture with activated T cells or application of the CD40 activation system, whereas no production could be detected when PB B cells were cultured in the absence of a stimulus. SF and BM B cells from anti-CCP-seropositive RA patients, but not anti-CCP-seronegative patients, actively produced IgM-anti-CCP without stimulation. The frequency of spontaneous production of IgM-anti-CCP among the IgM-secreting cells ranged from 2.2% to 25%. CONCLUSION: These results indicate the presence of B cell precursors for anti-CCP autoantibodies that are able to produce antibodies upon stimulation in the PB B cell repertoire of healthy controls and patients with RA. In contrast, B cells that actively secreted anti-CCP were specifically present in the BM and SF compartment of anti-CCP-seropositive RA patients. The local presence of anti-CCP-secreting cells in the inflamed joints provides evidence for an antigen-driven maturation of CCP-specific B cells at the site of inflammation in RA.

Detection of cerebral involvement in patients with active neuropsychiatric systemic lupus erythematosus by the use of volumetric magnetization transfer imaging.

OBJECTIVE: To determine whether volumetric magnetization transfer imaging (MTI) histogram analysis can detect abnormalities in patients with active neuropsychiatric systemic lupus erythematosus (NPSLE) and to compare the MTI findings in patients with active NPSLE, chronic NPSLE, and multiple sclerosis (MS), as well as in normal control subjects. METHODS: Eight female and 1 male patient with active nonthromboembolic NPSLE (mean +/- SD age 39 +/- 9 years), 10 female patients with chronic NPSLE (age 33 +/- 11 years), 10 female patients with SLE and no history of NPSLE (non-NPSLE; age 34 +/- 11 years), 10 female patients with inactive MS (age 41 +/- 6 years), and 10 healthy control subjects (age 33 +/- 11 years) underwent MTL. Using the MTI scans, histograms were composed from which we derived a variety of parameters that quantitatively reflect the uniformity of the brain parenchyma as well as the ratio of cerebrospinal fluid to intracranial volume, which reflects atrophy. RESULTS: The magnetization transfer ratio (MTR) histograms in the non-NPSLE group and the healthy control group were similar, whereas those in the chronic NPSLE and MS groups were flatter. There was also flattening of the histograms in the active NPSLE group, but with a shift toward higher MTRs. CONCLUSION: Our results indicate that volumetric MTI analysis detects cerebral changes in the active phase of NPSLE. The abnormalities in the brain parenchyma of patients with chronic NPSLE produced MTI values that were the same as those in patients with inactive MS. MTI values in the active phase of NPSLE differed from those in the chronic phase, which might reflect the presence of inflammation. These preliminary results suggest that MTI might provide evidence for the presence of active NPSLE. MTI might also prove to be a valuable technique for monitoring treatment trials.

Innate production of interleukin-10 and tumor necrosis factor affects the risk of multiple sclerosis.

Multiple sclerosis (MS) typically presents with a relapsing-remitting onset. This can be distinguished from primary progressive MS. Typical MS is characterized by a profound inflammatory reaction in which anti-inflammatory cytokine interleukin-10 (IL-10) and pro-inflammatory cytokine tumor necrosis factor (TNF) may play a pivotal role. We tested the hypothesis that patients with MS have a distinct innate cytokine production that contributes to the susceptibility for and outcome of MS. The innate cytokine production of patients was estimated as the average production of cytokines in lipopolysaccharide -stimulated whole-blood cultures of 2 to 5 first-degree healthy family members. A total of 126 family members of 50 patients with typical MS, 61 family members of 25 patients with primary progressive MS, and 129 control subjects of 54 families were enrolled in this study. We found that members of families with low IL-10 and high TNF production had a fourfold increased risk of developing typical MS compared with members of families with high IL-10 and low TNF production. Patients with MS were eightfold more likely to develop typical MS than primary progressive MS when they belonged to families with low IL-10 and high TNF production. The presence of human leukocyte antigen-DR2 was associated with MS but not with TNF production. This study shows that typical MS is associated with an innate pro-inflammatory cytokine profile in contrast to primary progressive MS.