Safety and efficacy of MD1003 (high-dose biotin) in patients with progressive multiple sclerosis (SPI2): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: There is an unmet need to develop therapeutic interventions directed at the neurodegeneration that underlies progression in multiple sclerosis. High-dose, pharmaceutical-grade biotin (MD1003) might enhance neuronal and oligodendrocyte energetics, resulting in improved cell function, repair, or survival. The MS-SPI randomised, double-blind, placebo-controlled study found that MD1003 improved disability outcomes over 12 months in patients with progressive multiple sclerosis. The SPI2 study was designed to assess the safety and efficacy of MD1003 in progressive forms of multiple sclerosis in a larger, more representative patient cohort. METHODS: SPI2 was a randomised, double-blind, parallel-group, placebo-controlled trial done at 90 academic and community multiple sclerosis clinics across 13 countries. Patients were aged 18-65 years, had a diagnosis of primary or secondary progressive multiple sclerosis fulfilling the revised International Panel criteria and Lublin criteria, a Kurtzke pyramidal functional subscore of at least 2 (defined as minimal disability), an expanded disability status scale (EDSS) score of 3·5-6·5, a timed 25-foot walk (TW25) of less than 40 s, evidence of clinical disability progression, and no relapses in the 2 years before enrolment. Concomitant disease-modifying therapies were allowed. Patients were randomly assigned (1:1) by an independent statistician using an interactive web response system, with stratification by study site and disease history, to receive MD1003 (oral biotin 100 mg three times daily) or placebo. Participants, investigators, and assessors were masked to treatment assignment. The primary endpoint was a composite of the proportion of participants with confirmed improvement in EDSS or TW25 at month 12, confirmed at month 15, versus baseline. The primary endpoint was assessed in the intention-to-treat analysis set, after all participants completed the month 15 visit. Safety analyses included all participants who received at least one dose of MD1003. This trial is registered with ClinicalTrials.gov (NCT02936037) and the EudraCT database (2016-000700-29). FINDINGS: From Feb 22, 2017, to June 8, 2018, 642 participants were randomly assigned MD1003 (n=326) or placebo (n=316). The double-blind, placebo-controlled phase of the study ended when the primary endpoint for the last-entered participant was assessed on Nov 15, 2019. The mean time in the placebo-controlled phase was 20·1 months (SD 5·3; range 15-27). For the primary outcome, 39 (12%) of 326 patients in the MD1003 group compared with 29 (9%) of 316 in the placebo group improved at month 12, with confirmation at month 15 (odds ratio 1·35 [95% CI 0·81-2·26]). Treatment-emergent adverse events occurred in 277 (84%) of 331 participants in the MD1003 group and in 264 (85%) of 311 in the placebo group. 87 (26%) of 331 participants in the MD1003 group and 82 (26%) of 311 participants in the placebo group had at least one serious treatment-emergent adverse event. One (<1%) person died in the MD1003 group and there were no deaths in the placebo group. Despite use of mitigation strategies, MD1003 led to inaccurate laboratory results for tests using biotinylated antibodies. INTERPRETATION: This study showed that MD1003 did not significantly improve disability or walking speed in patients with progressive multiple sclerosis and thus, in addition to the potential of MD1003 for deleterious health consequences from interference of laboratory tests, MD1003 cannot be recommended for treatment of progressive multiple sclerosis. FUNDING: MedDay Pharmaceuticals.

Clopidogrel responsiveness in stroke patients on a chronic aspirin regimen.

This study evaluated the antiplatelet effects of clopidogrel (CPG) in patients sustaining acute ischemic stroke who were already receiving chronic outpatient aspirin therapy (81-325 mg/day). Platelet function was measured using 3 different "point-of-care" platelet function analyzers: the Thrombelastograph hemostasis system, the Accumetrics VerifyNow system, and the Chronolog 570VS impedance aggregometer. Platelet function was assessed before administration of a 300-mg CPG loading dose and again at 26 hours and 64 hours after this loading dose along with a 75-mg daily maintenance dose. All 3 instruments detected marked inhibition of platelet function at 26 hours and 64 hours after CPG administration. There were significant variations among the 3 instruments in monitoring antiplatelet responses to aspirin and CPG; however, these variations were eliminated when the platelet function results were corrected for baseline platelet variability. The percentage of patients who were poor responders to CPG after switching from aspirin depended on the measurement instrument used, but was higher at 26 hours after CPG administration than at 64 hours after CPG administration. Our findings indicate that poor response to antiplatelet agents in general, and to CPG in particular, is a function of the measuring instrument. The correction for baseline platelet variability results in similar levels of platelet inhibition measured by the 3 platelet function analyzers. Future studies are warranted to examine the association between ex vivo CPG-induced platelet inhibition and clinical outcomes in patients with ischemic stroke.

Lp-PLA2: inflammatory biomarker of vascular risk in multiple sclerosis.

A member of the A2 phospholipase superfamily, the enzyme lipoprotein-associated phospholipase A2 (Lp-PLA2), is involved in atherogenic processes. Lp-PLA2 mass and activity were measured by the enzyme-linked immunosorbent assay and by a colorimetric method, respectively, and compared among 63 multiple sclerosis (MS) patients and 47 age-matched healthy controls (HCs). Lp-PLA2 plasma levels were significantly higher in MS patients (236.7 ± 10 ng/ml) compared to HCs (197.0 ± 7 ng/ml) (p = 0.003), but LP-PLA2 activity did not differ between the two groups. Both Lp-PLA2 plasma mass and activity were higher in secondary progressive (mass 247.0 ±15.5 ng/ml, p = 0.05; activity 156.1 ±6 nmol/min/ml, p = 0.003) compared to relapsing-remitting MS patients (mass 227.0 ± 16 ng/ml; activity 128.8 ± 5 nmol/min/ml) and compared to HCs. Lp-PLA2 plasma activity was associated with measures of MS clinical disability. However, this association was attenuated after adjustment for the components of lipid profiles.

Sustained improvement in Expanded Disability Status Scale as a new efficacy measure of neurological change in multiple sclerosis: treatment effects with natalizumab in patients with relapsing multiple sclerosis.

BACKGROUND: Validated measures of sustained improvements in neurological function have not been established for multiple sclerosis (MS) clinical studies. OBJECTIVE: To evaluate sustained Expanded Disability Status Scale (EDSS) change as a potential indicator of neurological improvement and as an outcome measure in MS clinical studies. METHODS: Analyses were performed on patients (n = 620) from the pivotal natalizumab study AFFIRM with baseline EDSS scores ≥2.0. Cumulative probabilities of neurological improvement, defined as a 1.0-point decrease in EDSS score sustained for ≥12 weeks, were estimated by Kaplan-Meier analysis. A Cox proportional hazards model identified associated baseline factors and examined treatment effects. RESULTS: Sustained improvement (as well as sustained worsening) in neurological disability was seen in AFFIRM patients. Sustained EDSS changes correlated well with quality of life measurements (SF36 and VAS). Natalizumab increased the cumulative probability of improvement over 2 years by 69% versus placebo (HR = 1.69; 95% CI 1.16-2.45; p = 0.006). Sensitivity analyses showed consistent benefits of natalizumab with variations in improvement magnitude and duration, and baseline disease activity. CONCLUSION: These analyses demonstrate that sustained EDSS improvement is an additional measure that is sensitive to treatment effects over 2 years and correlates with quality of life. Further research is warranted to validate its use as an MS study clinical outcome.

MRI characteristics of patients with antiphospholipid syndrome and multiple sclerosis.

MRI findings of primary anti-phospholipid antibody syndrome (PAPLS) are difficult to distinguish from those of multiple sclerosis (MS). Only a few previous studies have compared conventional and non-conventional MRI findings in MS and PAPLS patients. In addition, MRI differences between anti-phospholipid antibody (APLA) positive (+) and APLA negative (-) MS patients have not been reported. Therefore, the aim of this study was to investigate the differences in MRI measures among patients with PAPLS, MS and normal control (NC) subjects. We also explored non-conventional MRI measures in APLA+ and APLA- MS patients. Forty-nine (49) consecutive MS patients among whom 39 had relapsing-remitting (RR) and 10 secondary-progressive (SP) disease course, 30 patients with PAPLS and 49 NC were enrolled. Twenty-eight (28) MS patients were APLA+. MRI measures of T1- and T2-lesion volumes (LV) and brain atrophy, including fractions of whole brain (BPF), gray matter (GMF) and white matter (WMF), were evaluated. The magnetization transfer ratio (MTR) of T2- and T1-LVs and different normal-appearing brain tissue (NABT) compartments as well as diffusion-weighted imaging of whole brain mean parenchyma diffusivity (MPD) were obtained. MS patients differed significantly from NC in all MRI measures. PAPLS patients differed from NC in their T2-LV, in MTR measures and in MPD. When MS patients were compared to PAPLS patients, they showed significantly higher T2- and T1-LVs and T2-LV MTR, lower BPF and GMF and higher MPD. APLA+ RR and SPMS (all APLA+) patients showed significantly higher T2-LV, lower GMF, lower normal-appearing gray matter MTR and higher MPD when compared to APLA- patients. The results indicate that brain abnormalities can be detected in PAPLS patients with non-conventional MRI. MRI reveals more profound injury in patients with MS versus PAPLS. APLA mediates heterogeneous cerebral pathology that remains to be further investigated.

The effects of L-amphetamine sulfate on cognition in MS patients: results of a randomized controlled trial.

Defects in processing speed and memory are common in multiple sclerosis (MS) patients. In other populations, amphetamines have been shown to enhance cognition, but their use is limited by adverse behavioral effects. The L-isomer may have equivalent cognition enhancement with less adverse effects due to decreased potency in subcortical areas. The aim of this study was to assess the safety and efficacy of L-amphetamine sulfate in the treatment of cognitive dysfunction in MS. This was a 2:1 randomized, placebo-controlled, double-blind trial, involving 33 MS clinics across the USA. One hundred and fifty-one clinically definite MS patients with documented cognitive dysfunction who were relapse free for >or=90 days, with an Expanded Disability Status Scale (EDSS)

Clinical efficacy, effects on MRI and tolerability of weekly intramuscular interferon-beta-1a in patients with MS and CIS.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Interferon (IFN) beta products are potent antiinflammatory and immunomodulatory agents that interfere with the autoimmune processes in MS and reduce CNS damage. Once-weekly intramuscular IFN beta-1a slows the progression of neurologic and cognitive disability, reduces the frequency of relapses and inflammatory lesion burden, and preserves cognitive function. It has a positive effect on both conventional and nonconventional measures of magnetic resonance imaging (MRI) and reduces the progression of brain atrophy, predominantly due to reduced grey matter atrophy. Early initiation of disease-modifying therapy after the diagnosis of relapsing-remitting MS or after a single demyelinating event (and evidence of lesions on MRI) allows patients the opportunity to obtain maximal long-term benefits.

Use of perfusion- and diffusion-weighted imaging in differential diagnosis of acute and chronic ischemic stroke and multiple sclerosis.

OBJECTIVE: To investigate differences in lesions and surrounding normal appearing white matter (NAWM) by perfusion-weighted imaging (PWI) and diffusion-weighted imaging (DWI) in patients with acute and chronic ischemic stroke and multiple sclerosis (MS). METHODS: Study subjects included 45 MS patients, 22 patients with acute ischemic stroke and 20 patients with chronic ischemic stroke. All subjects underwent T2-weighted imaging (WI), flair attenuated inversion recovery (FLAIR), DWI and dynamic contrast enhanced PWI. Apparent diffusion coefficient (ADC) and mean transit time (MTT) maps were generated and values were calculated in the acute and chronic ischemic and demyelinating lesions, and in NAWM for distances of 5, 10 and 15 mm. Fifty-three acute ischemic and 33 acute demyelinating lesions, and 775 chronic ischemic and 998 chronic demyelinating lesions, were examined. Univariate, multivariate and data mining analyses were used to examine the feasibility of a prediction model between different lesion types. Correctly and incorrectly classified lesions, true positive (TP), false positive (FP) and precision rates were calculated. RESULTS: Patients with acute ischemic lesions presented more prolonged mean MTT values in lesions (p=0.002) and surrounding NAWM for distances of 5, 10 and 15 mm (all p<0.0001) than those with acute demyelinating lesions. In multinomial logistic regression analysis, 65 of 86 acute lesions were correctly classified (75.6%). The TP rates were 81.1% for acute ischemic lesions and 66.7% for acute demyelinating lesions. The FP rates were 33.3% for acute ischemic and 18.9% for acute demyelinating lesions. The precision was 79.6% for classification of acute ischemic lesions and 68.8% for prediction of acute demyelinating lesions. The logistic model tree decision algorithm revealed that prolonged MTT of surrounding NAWM for a distance of 15 mm (> or =7459.2 ms) was the best classifier of acute ischemic versus acute demyelinating lesions. Patients with chronic ischemic lesions presented higher mean ADC (p<0.0001) and prolonged MTT (p=0.013) in lesions, and in surrounding NAWM for distances of 5, 10 and 15 mm (all p<0.0001), compared to the patients with chronic demyelinating lesions. Data mining analyses did not show reliable predictability for correctly discerning between chronic ischemic and chronic demyelinating lesions. The precision was 56.7% for classification of chronic ischemic and 58.9% for prediction of chronic demyelinating lesions. DISCUSSION: We found prolonged MTT values in lesions and surrounding NAWM of patients with acute and chronic ischemic stroke when compared to MS patients. The use of PWI is a promising tool for differential diagnosis between acute ischemic and acute demyelinating lesions. The results of this study contribute to a better understanding of the extent of hemodynamic abnormalities in lesions and surrounding NAWM in patients with MS.

Application of hidden Markov random field approach for quantification of perfusion/diffusion mismatch in acute ischemic stroke.

The perfusion/diffusion 'mismatch model' in acute ischemic stroke provides the potential to more accurately understand the consequences of thrombolytic therapy on an individual patient basis. Few methods exist to quantify mismatch extent (ischemic penumbra) and none have shown a robust ability to predict infarcted tissue outcome. Hidden Markov random field (HMRF) approaches have been used successfully in many other applications. The aim of the study was to develop a method for rapid and reliable identification and quantification of perfusion/diffusion mismatch using an HMRF approach. An HMRF model was used in combination with automated contralateral identification to segment normal tissue from non-infarcted tissue with perfusion abnormality. The infarct was used as a seed point to initialize segmentation, along with the contralateral mirror tissue. The two seeds were then allowed to compete for ownership of all unclassified tissue. In addition, a novel method was presented for quantifying tissue salvageability by weighting the volume with the degree of hypoperfusion, allowing the penumbra voxels to contribute unequal potential damage estimates. Simulated and in vivo datasets were processed and compared with results from a conventional thresholding approach. Both simulated and in vivo experiments demonstrated a dramatic improvement in accuracy with the proposed technique. For the simulated dataset, the mean absolute error decreased from 171.9% with conventional thresholding to 2.9% for the delay-weighted HMRF approach. For the in vivo dataset, the mean absolute error decreased from 564.6% for thresholding to 34.2% for the delay-weighted HMRF approach. The described method represents a significant improvement over thresholding techniques.

Cortical atrophy and personality in multiple sclerosis.

Although the cognitive disorder of multiple sclerosis (MS) is well characterized, little is known about personality changes that may occur in this disease. There are reliable personality tests available for research in neurological disease, based on the well-known Five Factor Model. Preliminary research suggests that cognitively impaired MS patients exhibit elevation in Neuroticism, and diminution in Extraversion, Agreeableness, and Conscientiousness, as do patients with Alzheimer's disease. We predicted that these characteristics would be associated with lower neocortical volume. We studied 44 patients using brain MRI and the NEO Five-Factor Inventory. Regression models controlling for T2 lesion volume, depression, and cognitive dysfunction revealed significant correlation between cortical atrophy and reduction in Extraversion and Conscientiousness. Discrepancies between patient- and informant-reports were found, and overreporting of high Openness and Conscientiousness among patients was associated with lower neocortical volume. A final regression model accounting for depression, cognitive function, and personality accounted for 38% of the variance in neocortical volume. These findings suggest that cortical atrophy in MS is associated with adverse impact on personality, although longitudinal research is needed to test this hypothesis.

Diffusion-weighted imaging predicts cognitive impairment in multiple sclerosis.

Following a previous study with diffusion tensor imaging, we investigated the correlation between diffusion-weighted imaging (DWI) and cognitive dysfunction in multiple sclerosis (MS). We studied 60 MS patients (mean age 45.8+/-9.0 years) using 1.5-T MRI. Disease course was RR=40 and SP = 20. Mean disease duration was 12.8+/-8.7 years. Mean EDSS was 3.4+/-1.7. Whole brain, gray and white matter normalized volumes were calculated on 3D SPGR T1-WI using a fully automated Hybrid SIENAX method. Parenchymal mean diffusivity (PMD) maps were created after automated segmentation of the brain parenchyma and cerebrospinal fluid using T2-WI and DW images. Histogram analysis was performed and DWI indices of peak position (PP), peak height (PH), mean parenchymal diffusivity (MPD) and entropy were obtained. Neuropsychological (NP) evaluation emphasized auditory/verbal and visual/spatial memory, as well as processing speed and executive function. We found significant correlations between DWI and performance in all cognitive domains. Overall, stronger correlations emerged for MPD and entropy than other DWI measures, although all correlations were in the expected direction. The strongest association was between DWI entropy and performance on the Symbol Digit Modalities Test, which assesses processing speed and working memory (r = -0.54). Fisher r to z transformations revealed that DWI, gray matter (GMF) and whole brain (BPF) atrophy, T1-lesion volume (LV) and T2-LV all accounted for similar amounts of variance in NP testing. Stepwise regression models determined whether multiple MRI measures predicted unique additive variance in test performance. GMF (R2 = 0.35, F =30.82, P <0.01) and entropy (DeltaR2 =0.06, DeltaF=5.47, P <0.05) both accounted for unique variance in processing speed. Our data make a stronger case for the clinical validity of DWI in MS than heretofore reported. DWI has very short acquisition times, and the segmentation method applied in the present study is reliable and fully automated. Given its overall simplicity and moderate correlation with cognition, DWI may offer several logistic advantages over more traditional MRI measures when predicting the presence of NP impairment.

Quantitative diffusion weighted imaging measures in patients with multiple sclerosis.

Diffusion-weighted imaging (DWI) has been proposed as a sensitive measure of disease severity capable of detecting subtle changes in gray matter and white matter brain compartments in patients with multiple sclerosis (MS). However, DWI has been applied to the study of MS clinical subtypes in only a few studies. The objective of this study was to demonstrate the validity of a novel, fully automated method for the calculation of quantitative DWI measures. We also wanted to assess the correlation between whole brain (WB)-DWI variables and clinical and MRI measures of disease severity in a large cohort of MS patients. For this purpose we studied 432 consecutive MS patients (mean age 44.4+/-10.2 years), 16 patients with clinically isolated syndrome (CIS) and 38 normal controls (NC) using 1.5 T brain MRI. Clinical disease subtypes were as follows: 294 relapsing-remitting (RR), 123 secondary-progressive (SP) and 15 primary-progressive (PP). Mean disease duration was 12+/-10 years. Mean Expanded Disability Status Scale (EDSS) was 3.3+/-2.1. Brain parenchymal fraction (BPF), gray matter fraction (GMF) and white matter fraction (WMF) were calculated using a fully automated method. Mean parenchymal diffusivity (MPD) maps were created. DWI indices of peak position (PP), peak height (PH), MPD and entropy (ENT) were obtained. T2- and T1-lesion volumes (LV), EDSS, ambulation index (AI) and nine-hole peg test (9-HPT) were also assessed. MS patients had significantly lower BPF (d=1.26; p<0.001) and GMF (d=0.61; p=0.003), and higher ENT (d=1.2; p<0.0001), MPD (d=1.04; p<0.0001) and PH (d=0.47; p=0.045) than NC subjects. A GLM analysis, adjusted for age and multiple comparisons, revealed significant differences between different clinical subtypes for BPF, GMF, ENT, PH, PP, T2-LV and T1-LV (p<0.0001), WMF (p=0.001) and MPD (p=0.023). In RR and SP MS patients, ENT showed a more robust correlation with other MRI (r=0.54 to 0.67, p<0.0001) and clinical (r=0.31 to 0.36, p<0.0001) variables than MPD (r=0.23 to 0.41, p<0.001 for MRI and r=0.13 to 0.18; p=0.006 to p<0.001 for clinical variables). The GMF and BPF showed a slightly stronger relationship with all clinical variables (r=0.33 to 0.48; p<0.0001), when compared to both lesion and DWI measures. ENT (R2=0.28; p<0.0001) and GMF (R2=0.26; p<0.001) were best related with SP disease course. This study highlights the validity of DWI in discerning differences between NC and MS patients, as well as between different MS subtypes. ENT is a sensitive marker of overall brain damage that is strongly related to clinical impairment in patients with SP MS.

Clinical and MRI correlates of autoreactive antibodies in multiple sclerosis patients.

BACKGROUND: Autoreactive antibodies (ARAB) occur more frequently in patients with multiple sclerosis (MS) than in general population and the presence of these antibodies often causes uncertainty regarding the disease course, response to therapy and the diagnosis of MS. METHODS: Retrospective analyses of the ARAB, clinical and MRI data of a consecutive patient cohort of MS and clinically isolated syndrome (CIS) patients were conducted. The patients were evaluated for an extensive panel that included various subtypes of antiphospholipid antibody (APLA) including anti-phosphatidylethanolamine (APE), anti-phosphatidylserine (APS), anti-beta-2-glycoprotein-1 (ABGP), anti-cardiolipin (ACA), and several other ARAB such as antinuclear antibody (ANA), anti-neutrophilic cytoplasmic antibodies (ANCA), anti-thyroid peroxidase antibodies (ATA), anti-SS-A, and anti-SS-B antibodies. Quantitative MRI analysis was performed in a subgroup of MS patients measuring T2-lesion volume (LV), T1 black hole LV and brain parenchymal fraction (BPF). RESULTS: A total of 137 patients (mean age 44.7, 84% female) with either MS (n=111; age: mean 46.5+/-S.D. 10.3 years; disease duration: mean 13.0+/-S.D. 10.4 years; EDSS: mean 3.2+/-S.D. 1.9) or CIS (n=26; age: mean 37.7+/-S.D. 7.8 years; disease duration: mean 1.3+/-S.D. 1.1 years; EDSS: mean 1.0+/-S.D. 0.7) were enrolled. Among MS patients, 82 were RRMS, 26 SPMS, and 3 had PPMS. Seventy-seven (69%) of MS patients showed presence of one or more ARAB. The proportion of MS patients with APLA was 55% (61 patients); IgM subtype was most frequent. Co-occurrence of ACA and APE was more frequent in SPMS as compared to RRMS (15.4% vs. 1.2%, p=0.012). The proportion of CIS patients with ARAB was 75% with IgM subtype being the most frequent. However, the ARAB in majority of CIS patients (9 out of 14, 64%) were transient on repeated testing. In a subgroup of 62 MS patients, quantitative MRI analysis showed significantly higher T2-LV in patients with positive APLA (15.1 ml for APLA positive vs. 6.75 ml for APLA negative) after correcting for the disease duration (p=0.048). The patients with ATA also had significantly higher T2-LV after correction for disease duration (19.0 ml vs.8.5, p=0.044). CONCLUSIONS: ARAB were present in more than two thirds of MS and CIS patients although most of APLA in CIS were transient. The presence of APLA in MS patients was associated with higher T2-LV.

Faith-placed cardiovascular health promotion: a framework for contextual and organizational factors underlying program success.

The objective of this study was to assess the literature on faith-placed cardiovascular health promotion in order to construct a framework of factors meant to facilitate effective program design. Data source was empirical studies on the contextual and organizational factors underlying faith-placed cardiovascular program performance. Study inclusion criteria were papers reported from 1984 to 2003 that include contextual and organizational variables. Success factors identified in the literature fall under the following clusters: faith support, secular support, partnership (and obstacles to it), faith organization capabilities, secular organization capabilities and caring intervention. Each cluster consists of several factors, whose relative weights cannot be ascertained from the present state of the literature. These clusters of factors can be interrelated through a simple framework that is useful in program design.

Geographical variation of cerebrovascular disease in New York State: the correlation with income.

BACKGROUND: Income is known to be associated with cerebrovascular disease; however, little is known about the more detailed relationship between cerebrovascular disease and income. We examined the hypothesis that the geographical distribution of cerebrovascular disease in New York State may be predicted by a nonlinear model using income as a surrogate socioeconomic risk factor. RESULTS: We used spatial clustering methods to identify areas with high and low prevalence of cerebrovascular disease at the ZIP code level after smoothing rates and correcting for edge effects; geographic locations of high and low clusters of cerebrovascular disease in New York State were identified with and without income adjustment. To examine effects of income, we calculated the excess number of cases using a non-linear regression with cerebrovascular disease rates taken as the dependent variable and income and income squared taken as independent variables. The resulting regression equation was: excess rate = 32.075-1.22 x 10(-4)(income)+ 8.068x10(-10)(income2), and both income and income squared variables were significant at the 0.01 level. When income was included as a covariate in the non-linear regression, the number and size of clusters of high cerebrovascular disease prevalence decreased. Some 87 ZIP codes exceeded the critical value of the local statistic yielding a relative risk of 1.2. The majority of low cerebrovascular disease prevalence geographic clusters disappeared when the non-linear income effect was included. For linear regression, the excess rate of cerebrovascular disease falls with income; each 10,000 dollars increase in median income of each ZIP code resulted in an average reduction of 3.83 observed cases. The significant nonlinear effect indicates a lessening of this income effect with increasing income. CONCLUSION: Income is a non-linear predictor of excess cerebrovascular disease rates, with both low and high observed cerebrovascular disease rate areas associated with higher income. Income alone explains a significant amount of the geographical variance in cerebrovascular disease across New York State since both high and low clusters of cerebrovascular disease dissipate or disappear with income adjustment. Geographical modeling, including non-linear effects of income, may allow for better identification of other non-traditional risk factors.

Prediction of longitudinal brain atrophy in multiple sclerosis by gray matter magnetic resonance imaging T2 hypointensity.

BACKGROUND: Gray matter magnetic resonance imaging T2 hypointensity, a marker of iron deposition, is associated with clinical impairment and brain atrophy in cross-sectional studies of multiple sclerosis. Treatment with intramuscular interferon beta-1a limits brain atrophy in the second year of treatment. OBJECTIVE: To test whether T2 hypointensity predicts brain atrophy and whether interferon affects this relationship. DESIGN: Post hoc analysis. SETTING: A multicenter treatment trial conducted at tertiary care comprehensive multiple sclerosis centers. Patients Patients with multiple sclerosis who took part in a 2-year clinical trial in which they received intramuscular interferon beta-1a (30 mug/wk) or placebo. MAIN OUTCOME MEASURES: Deep gray matter T2 hypointensity, brain parenchymal fraction (BPF), and total T2, gadolinium-enhancing, and T1 lesion volumes. RESULTS: T2 hypointensity in various gray matter areas correlated with baseline BPF (r = 0.19-0.39; P = .001-.03). In placebo-treated patients (n = 68), baseline T2 hypointensity predicted the change in BPF in the first year and throughout 2 years (r = 0.26-0.42; P<.001-.03). T2 hypointensity was chosen in regression modeling as the best predictor of BPF change at the 1-year (R(2) = 0.23; P = .002) and 2-year (R(2) = 0.33; P<.001) time points after accounting for all magnetic resonance imaging variables. In the interferon group (n = 65), no relationship existed between baseline T2 hypointensity and BPF change. CONCLUSIONS: Gray matter T2 hypointensity predicts the progression of brain atrophy in placebo- but not interferon beta-1a-treated patients. This predictive effect is seen as early as the first year. We hypothesize that interferon beta may exert its effect on brain atrophy in part by reducing a cascade of events that involve iron deposition as a mediator of neurotoxicity or as a disease epiphenomenon.

Eight-year immunogenicity and safety of interferon beta-1a-Avonex treatment in patients with multiple sclerosis.

An open-label extension study of the phase III trial of intramuscular interferon beta-1a (IFNbeta-1a-Avonex) was conducted to evaluate the immunogenicity and safety of IFNbeta-1a-Avonex over six years in patients with relapsing multiple sclerosis (MS). Patients who participated in the pivotal phase III study were offered enrolment; entry was also open to patients who had not participated. All patients received IFNbeta-1a-Avonex 30 microg intramuscularly once weekly for six years, for a treatment duration of up to eight years in patients who received IFNbeta-1a-Avonex in the phase III trial. Serum levels of IFNbeta antibodies were measured every six months using a screening enzyme-linked immunosorbent assay (ELISA) followed by an antiviral cytopathic effect assay to detect neutralizing antibodies (NAbs) in serum samples positive on ELISA. The incidence of adverse events and laboratory test results assessed safety. Of 382 total patients, 218 had participated in the phase III study (103 placebo, 115 IFNbeta-1a-Avonex) and 164 had not participated; 24 of the 164 were IFNbeta-naïve. At baseline, 281 patients were negative for IFNbeta antibodies (NAb-). NAbs (titre > or = 20) developed at any time over six years in 5% of these patients. Of 140 patients who had been on IFNbeta-1b-Betaseron, 49 were positive for NAbs (NAb+) at baseline; 11 of 115 who had been on IFNbeta-1a-Avonex were NAb+ at baseline. Thirty-nine of 49 patients who had been on Betaseron and were NAb+ had titres < 100; 36 of these 39 seroconverted to NAb- while on IFNbeta-1a-Avonex, with a median time of approximately six months. Ten patients who had been on Betaseron had NAb titres > or = 100; five remained NAb+ during six years on IFNbeta-1a-Avonex and five seroconverted to NAb-, but only after at least two years. Five patients who had been on IFNbeta-1a-Avonex during the clinical trial were NAb+ with titres < 100 at baseline; four seroconverted to NAb-, with a median time of two to three years. Six patients who had been on IFNbeta-1a-Avonex had NAb titres > or = 100; five of these remained NAb+ at six years. No patient with a NAb titre > 1000 seroconverted to NAb-, whether initially treated with IFNbeta-1a-Avonex or -Betaseron. Adverse events were similar to those observed in the pivotal phase III trial. Results from this trial indicated that IFNbeta-1a-Avonex was associated with a low incidence of NAbs and was well tolerated for up to eight years. Further, the results indicate that persistence of NAbs is dependent on titre and IFNbeta product.

Assessment and management of neutralizing antibodies in patients with multiple sclerosis.

The development of neutralizing antibodies (NAbs) to interferon beta (IFNbeta) products during treatment of MS poses a challenge for clinicians. Given the impact of NAbs on the clinical efficacy of IFNbetas, the immunogenicity of different IFNbeta products should be one of the factors that neurologists consider in the treatment of patients with MS. However, no clear guidelines are available for the practicing neurologist concerning which patients should be tested for NAbs and how to clinically manage patients who develop NAbs. This article summarizes the content of this supplement, discusses issues related to measuring NAbs in clinical practice, and gives practical alternatives for managing MS in patients who develop NAbs during IFNbeta therapy.

Whole-brain atrophy in multiple sclerosis measured by automated versus semiautomated MR imaging segmentation.

BACKGROUND AND PURPOSE: Semiautomated and automated methods are used to measure whole-brain atrophy in multiple sclerosis (MS), but their comparative reliability, sensitivity, and validity are unknown. METHODS: Brain parenchymal fraction (BPF) was measured in patients with MS (n = 52) and healthy control subjects (n = 17) by four methods: semiautomated or automated segmentation and 2D or 3D pulse sequences. Linear measures of atrophy, whole-brain lesion volumes, and clinical data were used to explore validity. RESULTS: The 2D automated method yielded unreliable segmentation and was discarded. The three other BPF methods produced data that were highly intercorrelated and indistinguishable by analysis of variance. In the MS group, semiautomated (2D: 0.84 +/- 0.04, P <.001; 3D: 0.84 +/- 0.05, P =.04) and automated 3D (0.83 +/- 0.05, P =.002) BPFs were lower than controls (semiautomated 2D: 0.88 +/- 0.02; 3D: 0.88 +/- 0.03; automated 3D: 0.88 +/- 0.03). In the MS group, the semiautomated (r = -.79 to -.82) and automated 3D (r = -.81) BPFs inversely correlated with third ventricular width and showed similarly robust correlations with the bicaudate ratio (all r = -.74). The semiautomated and automated BPFs showed similar, moderate correlations with T1 hypointense and FLAIR hyperintense lesion volume, physical disability (Expanded Disability Status Scale) score, and disease duration and similar differences between secondary progressive and relapsing-remitting patients. The intraobserver, interobserver, and test-retest reliability was somewhat higher for the automated than for the semiautomated methods. CONCLUSION: These automated and semiautomated measures of whole-brain atrophy provided similar and nearly interchangeable data regarding MS. They discriminated MS from healthy individuals and showed similar relationships to established disease variables.

A community education program on atrial fibrillation: implications of pulse self-examination on awareness and behavior.

OBJECTIVES: We postulated that community groups with older demographics could be taught to find and characterize their pulse rhythm for the presence of an irregular pulse (IP), which may indicate atrial fibrillation, a major risk factor for stroke. METHODS: We conducted 281 community group education sessions involving 6203 attendees. Awareness objectives were to demonstrate that: (1) group education was effective in establishing awareness that an IP may indicate atrial fibrillation; and (2) this message was retained at follow-up. Behavioral objectives were to: (1) assess ability of participants to find and characterize their pulse rhythm; (2) regularly monitor pulse rhythm; and (3) act with medical appropriateness upon detecting an IP. RESULTS: Of 6203 attendees, 4322 were older than 50 years and consented to participate. Of these consenting participants, 73.2% found their radial pulse and 91% characterized the rhythm (regular, 72.1%; irregular, 11%; undetermined, 7.9%). Telephone follow-ups on 1839 participants were performed at 30 to 60 days to assess durability of message and action taken. At follow-up, 89.1% remembered that an IP is potentially a risk factor for stroke, and 70.3% had taken their pulse since the program. Of those who discovered a new IP, 38% sought medical assessment. CONCLUSION: Community education programs focusing on pulse self-examination are effective in improving awareness that an IP may be a surrogate indicator of stroke risk. Such programs may lead to improved awareness of atrial fibrillation, subsequent behavioral changes, and stroke prevention.