Purpose: The effect of acute methanol poisoning on the follow-up quality of life of survivors in mass poisoning outbreaks is not known. The objective of this is to study the impact of visual and central nervous system (CNS) sequelae of methanol poisoning on long-term health-related quality of life (QoL) of survivors, its clinical determinants, and dynamics. Materials and methods: A total of 54 patients with confirmed methanol poisoning (mean age 46.7 +/- 13.4 years, 9 females) were examined consequently three times within six-year prospective cohort study and compared to 23 controls with the history of chronic alcohol abuse. The following tests were performed: SF-36 QoL questionnaire, visual evoked potentials (VEP) of optic nerve, ocular examination with retinal nerve fiber layer (RNFL) thickness measurement, brain magnetic resonance imaging (MRI), and biochemical and toxicological tests. Results: Acute methanol poisoning led to significant decrease in physical component summary (PCS) compared to PCS of age-adjusted controls (mean score with SD 46.8 +/- 11.0 versus 52.3 +/- 9.4 points; p = .003). In 17/40 (42.5%) patients with three rounds of examination, signs of severe disability (<= 30 points in at least one score) were present six years after discharge, with negative dynamics of PCS score during the observation period. The patients with abnormal RNFL thickness had lower PCS (mean difference 10.5 points; 95%CI 3.5-17.5, p = .004) and mental component summary score (9.5 points; 95%CI 1.9-17.1, p = .015) compared to the patients with normal RNFL. Signs of physical and mental adaptation to long-term visual sequelae were registered with gradual reduction of difference in most of physical and mental components scores compared to the patients with normal RNFL during six years of observation. Signs of hemorrhagic brain lesions were associated with permanent decrease of PCS score (mean difference 7.4 points; 95%CI 0.6-14.0; p = .033), bodily pain (8.7 points; 95%CI 1.6-17.6; p = .018), and social functioning (8.2 points; 95%CI 3.0-17.4; p = .005) six years after discharge. No effect of type of antidote (fomepizole versus ethanol) and extracorporeal enhanced elimination modality (intermittent hemodialysis versus continuous renal replacement therapy) applied in hospital on long-term QoL was found (all p > .05). Conclusion: Acute methanol poisoning was associated with a significant decrease of health-related quality of life of survivors persisting for at least six years after discharge. The more pronounced decrease in QoL scores was observed in the patients with hemorrhagic brain lesions and visual sequelae of poisoning with abnormal RNFL thickness.

Context: Investigate whether(123)I-ioflupane SPECT (DaT SPECT) has the potential as a marker of basal ganglia damage in acute methanol poisoning. Methods: Prospective, single-centre, cohort study of patients with confirmed methanol poisoning was conducted. DaT SPECT was performed twice with semi-quantification using DaTQUAN and MRI-based volumetry was calculated. Specific binding ratios (SBR) of striatum, caudate nucleus, and putamen were correlated with laboratory parameters of outcome, volumetric data, and retinal nerve fibres layer (RNFL) thickness measurements. Results: Forty-two patients (mean age 46.3 +/- 4.2 years; 8 females), including 15 with MRI-detected putamen lesions (group I) and 27 patients with intact putamen (group II), underwent DaT SPECT. Volumetry was calculated in 35 of the patients assessed. SBR values for the left putamen correlated with putamen volume (r = 0.665;p < 0.001). Decreased bilateral SBR values were determined for the striatum and the putamen, but not for the nucleus caudate, in group I (p < 0.05). Significant correlation was observed between the SBR of the posterior putamen and arterial blood pH (r = 0.574;p < 0.001) and other toxicological parameters of severity of poisoning/outcome including serum lactate, glucose, and creatinine concentrations (p < 0.05). The SBR of the posterior putamen positively correlated with the global RNFL thickness (p < 0.05). ROC analysis demonstrated a significant discriminatory ability of SBR of the posterior putamen with AUC = 0.753 (95%CI 0.604-0.902;p = 0.007). The multivariate regression model demonstrated that arterial blood pH, age, and gender were the most significant factors associated with SBR of the posterior putamen. Conclusion: DaT SPECT demonstrates significant potential for the diagnosis of methanol-induced basal ganglia damage.

Background: Magnetic resonance imaging (MRI) data from multiple sclerosis (MS) patients treated in real-world settings are important for understanding disease-modifying therapy effects, including no evidence of disease activity (NEDA) assessment. This longitudinal, retrospective, single-cohort analysis assessed MRI and clinical disease outcomes in patients with relapsing-remitting MS treated with natalizumab for up to 5 years in Prague, the Czech Republic. Methods: The primary study endpoint was the proportion of patients free of new or enlarging fluid-attenuated inversion recovery (FLAIR) lesions after at least 2 years of natalizumab treatment. Secondary endpoints included percentage brain volume change over time, the number of new T1-hypointense lesions that persisted for >= 6 months, FLAIR and T1-hypointense lesion volume change over time, and the proportion of patients with NEDA-3 (defined as no relapses, no confirmed disability worsening, and no new or enlarging FLAIR lesions). Results: A total of 193 patients were included in the study. During year 1 of natalizumab treatment, 78.9% of patients had no new or enlarging FLAIR lesions and 79.5% had no new T1 lesions. These proportions increased in years 2-5, with >= 98.0% of patients free of new or enlarging FLAIR lesions and >= 98.8% free of new T1 lesions. During year 1 on natalizumab, 52.2% of patients achieved NEDA-3; this proportion increased to >= 69.2% in years 2-5. Conclusion: This study provides additional evidence that long-term MS disease activity, as measured by both MRI activity and NEDA-3, is well-controlled in patients treated with natalizumab in real-world settings.

PurposeInvestigate whether 123I-ioflupane SPECT (DaT SPECT) has the potential as a marker of basal ganglia damage in acute methanol poisoning.MethodsProspective, single-centre, cohort study of patients with confirmed methanol poisoning was conducted. DaT SPECT was performed twice with semi-quantification using DaTQUANTTM and MRI-based volumetry was calculated. Specific binding ratios (SBR) of striatum, caudate nucleus, and putamen were correlated with laboratory parameters of outcome, volumetric data, and retinal nerve fibres layer (RNFL) thickness measurements.ResultsForty-two patients (mean age 46.3±4.2 y; 8 females), including 15 with putamen lesions (Group I) and 27 patients with intact putamen (Group II), underwent DaT SPECT. Volumetry was calculated in 35 of the patients assessed. SBR values for the left putamen correlated with putamen volume (r=0.665; p<0.001). Decreased bilateral SBR values were determined for the striatum and the putamen, but not for the nucleus caudate, in Group I (p<0.05). A strong correlation was observed between the SBR of the posterior putamen and arterial blood pH (r=0.574; p<0.001) and other toxicological parameters of severity of poisoning/outcome including serum lactate, glucose, and creatinine concentrations (p<0.05). The SBR of the posterior putamen positively correlated with the global RNFL thickness (p<0.05). ROC analysis demonstrated a significant discriminatory ability of SBR of the posterior putamen with AUC=0.753 (95%CI 0.604–0.902; p=0.007). The multivariate regression model demonstrated that arterial blood pH, age, and gender were the most significant factors associated with SBR of the posterior putamen.ConclusionDaT SPECT demonstrates significant potential for the diagnosis of methanol-induced basal ganglia damage.

BACKGROUND:Acute methanol poisoning leads to optic neuropathy and necrotic lesions of basal ganglia (BG) and subcortical white matter. Survivors of methanol poisoning exhibit long-term executive and memory deficits. Associations between brain volumetry parameters and cognitive sequelae of methanol poisoning are not known. The aim of our study was to identify long-term associations between the cognitive performance of survivors of methanol poisoning and the volume of the brain structures that are selectively vulnerable to methanol.METHODS:We conducted a cross-sectional follow-up study on a sample of patients (n = 33, age 50 ± 14 years, 82% males) who survived acute methanol poisoning during methanol mass poisoning outbreak from September 2012 till January 2013 in the Czech Republic. A battery of neuropsychological tests and brain magnetic resonance imaging were included in the clinical examination protocol. Specific brain structures (putamen, globus pallidus, nucleus caudatus, and frontal white matter) were selected as regions of interest, and their volumes were estimated using the MorphoBox prototype software.RESULTS:In robust multiple regression models, sustained visual attention performance (as assessed by Trail Making Test and Prague Stroop Test) was positively associated with BG structures and frontal white matter volumes (Wald = 9.03 to 85.50, p < 0.01), sensitivity to interference (as assessed by Frontal Battery Assessment) was negatively associated with frontal white matter volume (Wald = 35.44 to 42.25, p < 0.001), and motor performance (as assessed by Finger Tapping Test) was positively associated with globus pallidus and frontal white matter volumes (Wald = 9.66 to 13.29, p < 0.01).CONCLUSIONS:Our results demonstrate that smaller volumes of elements of BG-thalamocortical circuitry, namely the BG and frontal white matter, relate to attention and motor performance in methanol poisoning from a long-term perspective. Disruption of those functional circuits may underlie specific cognitive deficits observed in methanol poisoning.

Objective: To investigate the ability of serum NfL levels to identify brain MRI activity. Background: Neurofilament light chain (NfL) serum level is associated with disease activity in multiple sclerosis (MS). Its practical value for detecting radiological disease activity as currently assessed by brain MRI has not yet been established. Design/Methods: This longitudinal study included 163 relapsing-remitting MS patients (405 samples) from the SET cohort and 179 relapsing-remitting MS patients (664 samples) from the GeneMSA cohort. Serum NfL levels were evaluated annually using a Single Molecule Array assay. Age-adjusted NfL percentiles were based on normative data from healthy controls. In each cohort, MRI scans were performed annually using single 1.5T scanner and uniform scanning protocol. The accuracy of different NfL cut-offs for the detection of active lesions (new/enlarging lesions compared with MRI in the preceding year or enhancing brain lesions) on annual scans was assessed. Results: NfL levels exceeded 90th percentile in 25.4% of the SET and 26.5% of the GeneMSA samples. 81.6% of the SET (OR=3.4, 95%CI=1.8–6.4) and 48.9% of the GeneMSA cohort (OR=2.6, 95%CI=1.7–3.9) with NfL>90th percentile showed radiological disease activity on their brain MRI. NfL levels Conclusions: Low serum NfL levels help identify MS patients with very low recent radiological disease activity. This result suggests that NfL assessment may help to spare the need for annual brain MRI monitoring in clinically stable patients with very low NfL levels. Disclosure: Dr. Uher has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with T. Uher received financial support for conference travel and honoraria from Biogen Idec, Novartis, Sanofi Genzyme, Roche, and Merck. Dr. Uher has received research support from Biogen Idec. Dr. Hoskova has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Novartis, Sanofi Genzyme and Biogen. Dr. Barro has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva and Novartis. Dr. Bergsland has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with EMD Serono. Dr. Dwyer has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Buffalo Neuroimaging Analysis Center. Dr. Dwyer has received research support from Novartis. Dr. Tyblova has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen Idec, Sanofi, Teva and Merck Serono. Dr. Kucerova has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Novartis and Merck. Dr. Benkert has nothing to disclose. Dr. Michalak has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Novartis Pharma AG, Basel, Switzerland. Dr. Leppert has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Novartis. Dr. Krasensky has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. Seidl has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. Vaneckova has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen Idec, Novartis, Merck, Teva. Dr. Vaneckova has received research support from Czech Ministry of Health, Biogen Idec. Dr. Havrdova has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Actelion, Biogen, Celgene, Merck, Novartis, Sanofi Genzyme and Teva. Dr. Zivadinov has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with EMD Serono, Genzyme-Sanofi, and Novartis. He received financial support for research activities from Teva Pharmaceuticals, Biogen-Idec, Genzyme-Sanofi, Novartis, Claret Medical, Intekrin-Coherus and IMS Health. Dr. Kuhle’s institution has received compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Novartis Pharmaceuticals, Protagen AG, Roche, Teva, Sanofi Genzyme, Swiss MS Society, and Merck Serono,. Dr. Kuhle has received research support from ECTRIMS Research Fellowship Programme, Bayer AG, Biogen, Sanofi Genzyme, Merck, Novartis Pharmaceuticals, Roche, Swiss MS Society, Swiss National Research Foundation, and University of Basel. Dr. Kalincik has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche, Sanofi Genzyme, Novartis Pharmaceuticals, Merck, Biogen, Brain Atrophy Initiative, WebMD Global, Teva, and BioCSL. Dr. Kalincik has received personal compensation in an editorial capacity from Multiple Sclerosis Journal, BMC Neurology and Frontiers in Neurology. Dr. Kalincik has received research support from Biogen. Dr. Horakova has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen Idec, Novartis, Merck, Bayer, Sanofi Genzyme, Roche and Teva.

Context: The influence of co-morbid conditions on the outcome of acute methanol poisoning in mass poisoning outbreaks is not known. Objective: The objective of this is to study the impact of burden of co-morbidities, complications, and methanol-induced brain lesions on hospital, follow-up, and total mortality. Methods: All patients hospitalized with methanol poisoning during a mass poisoning outbreak were followed in a prospective cohort study until death or final follow-up after 6 years. The age-adjusted Charlson co-morbidity index (ACCI) score was calculated for each patient. A multivariate Cox regression model was used to calculate the adjusted hazards ratio (HR) for death. The survival was modeled using the Kaplan-Meier method. Results: Of 108 patients (mean age with SD 50.9 +/- 2.6 years), 24 (54.4 +/- 5.9 years) died during hospitalization (mean survival with SD 8 +/- 4 days) and 84 (49.9 +/- 3.0 years; p = .159) were discharged, including 27 with methanol-induced brain lesions. Of the discharged patients, 15 (56.3 +/- 6.8 years) died during the follow-up (mean survival 37 +/- 11 months) and 69 (48.5 +/- 3.3 years; p = .044) survived. The hospital mortality was 22%, the follow-up mortality was 18%; the total mortality was 36%. Cardiac/respiratory arrest, acute respiratory failure, multiorgan failure syndrome, and arterial hypotension increased the HR for hospital and total (but not follow-up) mortality after adjustment for age, sex, and arterial pH (all p < .05). All patients who died in the hospital had at least one complication. A higher ACCI score was associated with greater total mortality (HR 1.22; 1.00-1.48 95% CI; p = .046). Of those who died, 35 (90%) had a moderate-to-high ACCI. The Kaplan-Meier curve demonstrated that patients with a high ACCI had greater follow-up mortality compared to ones with low (p = .027) or moderate (p = .020) scores. For the patients who died during follow-up, cancers of different localizations were responsible for 7/15 (47%) of the deaths. Conclusions: The character and number of complications affected hospital but not follow-up mortality, while the burden of co-morbidities affected follow-up mortality. Methanol-induced brain lesions did not affect follow-up mortality. Relatively high cancer mortality rate may be associated with acute exposure to metabolic formaldehyde produced by methanol oxidation.

Methyl alcohol intoxication is a global problem with high mortality and long-term visual sequelae and severe brain damage in survivors. The role of neuroinflammation in the mechanisms of methyl alcohol-induced toxic brain damage has not been well studied. We measured the acute concentrations and dynamics of lipoxins LxA4 and LxB4 and the interleukins IL-4, IL-5, IL-9, IL-10, and IL-13 in the serum of patients treated with methyl alcohol poisoning and the follow-up concentrations in survivors two years after discharge from the hospital. A series of acute measurements was performed in 28 hospitalized patients (mean age 54.2 ± 5.2 years, mean observation time 88 ± 20 h) and the follow-up measurements were performed in 36 subjects who survived poisoning (including 12/28 survivors from the acute group). Visual evoked potentials (VEP) and magnetic resonance imaging of the brain (MRI) were performed to detect long-term visual and brain sequelae of intoxication. The acute concentrations of inflammatory mediators were higher than the follow-up concentrations: LxA4, 62.0 ± 6.0 vs. 30.0 ± 5.0 pg/mL; LxB4, 64.0 ± 7.0 vs. 34.0 ± 4.0 pg/mL; IL-4, 29.0 ± 4.0 vs. 15.0 ± 1.0 pg/mL; IL-5, 30.0 ± 4.0 vs. 13.0 ± 1.0 pg/mL; IL-9, 30.0 ± 4.0 vs. 13.0 ± 1.0 pg/mL; IL-10, 38.0 ± 5.0 vs. 16.0 ± 1.0 pg/mL; IL-13, 35.0 ± 4.0 vs. 14.0 ± 1.0 pg/mL (all p < 0.001). The patients with higher follow-up IL-5 concentration had prolonged latency P1 (r = 0.413; p = 0.033) and lower amplitude N1P1 (r = -0.498; p = 0.010) of VEP. The higher follow-up IL-10 concentration was associated with MRI signs of brain necrotic damage (r = 0.533; p = 0.001) and brain hemorrhage (r = 0.396; p = 0.020). Our findings suggest that neuroinflammation plays an important role in the mechanisms of toxic brain damage in acute methyl alcohol intoxication.

BACKGROUND AND PURPOSE: A relatively high intraindividual variability of longitudinal magnetic resonance imaging (MRI) of brain volume loss (BVL) measurements over time renders challenging its application to individual multiple sclerosis (MS) patients. Objective of this study was to investigate if high-frequency brain MRI monitoring affects identification of pathological BVL in an individual patient. METHODS: One hundred fifty-seven relapsing-remitting MS patients had seven MRI scans over 12 months follow-up. All 1,585 MRI scans were performed on the same 1.5T scanner using an identical scanning protocol. Volumetric analysis was performed by ScanView and SIENA software. Linear regression analysis was used for estimation of annualized BVL, with a cutoff greater than.4% defined as pathological. We compared proportions of patients with pathological BVL obtained by analysis of different number of MRI time-points. RESULTS: An analysis of seven MRI scans (months 0, 2, 4, 6, 8, 10, and 12) showed pathological BVL in 105 (65%) of patients. When three MRI scans were included (months 0, 6, and 12), we found 10 (6.4%) false negative and 9 (5.7%) false positive results compared with the analysis of seven MRI scans, used as a reference for assessment of pathological BVL. Analysis of two MRI time-points (months 0 and 12) showed 10 (6.4%) false negative and 13 (8.3%) false positive results compared with analysis of seven MRI time-points. Change in the accuracy of pathological BVL between results obtained by analysis of seven and two time-points was 14.7%. CONCLUSIONS: High-frequency MRI monitoring may have a considerable effect on improving the precision of precisely identifying pathological BVL in individual patients. However, limitations in translation to clinical practice remain.

Abstract Context: Methanol poisoning induces acute optic neuropathy with possible long-term visual damage. Objective: To study the dynamics and key determinants of visual pathway functional changes during 4 years after acute methanol poisoning. Methods: A total of 42 patients with confirmed methanol poisoning (mean age 45.7 ± 4.4 years) were examined 4.9 ± 0.6, 25.0 ± 0.6, and 49.9 ± 0.5 months after discharge. The following tests were performed: visual evoked potential (VEP), retinal nerve fiber layer (RNFL) measurement, brain magnetic resonance imaging (MRI), complete ocular examination, biochemical tests, and apolipoprotein E (ApoE) genotyping. Results: Abnormal VEP P1 latency was registered in 18/42 right eyes (OD) and 21/42 left eyes (OS), abnormal N1P1 amplitude in 10/42 OD and OS. Mean P1 latency shortening during the follow-up was 15.0 ± 2.0 ms for 36/42 (86%) OD and 14.9 ± 2.4 ms for 35/42 (83%) OS, with maximum shortening up to 35.0 ms. No significant change of mean N1P1 amplitude was registered during follow-up. A further decrease in N1P1 amplitude ≥1.0 mcV in at least one eye was observed in 17 of 36 patients (47%) with measurable amplitude (mean decrease −1.11 ± 0.83 (OD)/−2.37 ± 0.66 (OS) mcV versus −0.06 ± 0.56 (OD)/−0.83 ± 0.64 (OS) mcV in the study population; both p < .001). ApoE4 allele carriers had lower global and temporal RNFL thickness and longer initial P1 latency compared to the non-carriers (all p < .05). The odds ratio for abnormal visual function was 8.92 (3.00–36.50; 95%CI) for ApoE4 allele carriers (p < .001). The presence of ApoE4 allele was further associated with brain necrotic lesions (r = 0.384; p = .013) and brain hemorrhages (r = 0.395; p = .011). Conclusions: Improvement of optic nerve conductivity occurred in more than 80% of patients, but evoked potential amplitude tended to decrease during the 4 years of observation. ApoE4 allele carriers demonstrated lower RNFL thickness, longer P1 latency, and more frequent methanol-induced brain damage compared to non-carriers.

April 24, 2018April 10, 2018Free AccessBrain Volume Increase in Multiple Sclerosis Patients (P3.362)Michaela Andelova, Jan Krasensky, Niels Bergsland, Zdenek Seidl, Barbora Benova, Eva Kubala Havrdova, Manuela Vaneckova, Dana Horakova, and Tomas UherAuthors Info & AffiliationsApril 10, 2018 issue90 (15_supplement) Letters to the Editor

April 24, 2018April 10, 2018Free AccessGreat reduction of correlation between global and regional brain volume and spinal cord volume in multiple sclerosis patients with severe disability (P3.349)Manuela Vaneckova, Michaela Andelova, Jan Krasensky, Lukas Sobisek, Zdenek Seidl, Eliska Kusova, Tomas Uher, Eva Havrdova, Barbora Benova, Benedicte Marechal, Tobias Kober, and Dana HorakovaAuthors Info & AffiliationsApril 10, 2018 issue90 (15_supplement) Letters to the Editor

PURPOSE: To study the dynamics and clinical determinants of chronic retinal nerve fiber layer thickness (RNFL) loss after methanol-induced optic neuropathy. DESIGN: Prospective cohort study. METHODS: All patients underwent complete ophthalmic evaluation including spectral-domain optical coherence tomography 3 times during 4 years of observation: 4.9 (+/- 0.6), 25.0 (+/- 0.6), and 49.9 (+/- 0.5) months after discharge. PARTICIPANTS: Eighty-four eyes of 42 survivors of methanol poisoning, mean age (standard deviation) of 45.7 (+/- 4.4) years; and 82 eyes of 41 controls, mean age 44.0 (+/- 4.2) years. MAIN OUTCOME MEASURES: Global and temporal RNFL loss. RESULTS: Abnormal RNFL thickness was registered in 13 of 42 (31%) survivors of methanol poisoning and chronic axonal loss in 10 of 42 (24%) patients. Significant decrease of global/temporal RNFL thickness during the observation period was found in the study population compared to the controls (P < .001). The risk estimate of chronic global RNFL loss for arterial blood pH < 7.3 at admission was 11.65 (95% confidence interval 1.91-71.12) after adjusting for age and sex. The patients with chronic axonal degeneration demonstrated progressive visual loss in 7 of 10 cases. The patients with abnormal RNFL thickness had magnetic resonance signs of brain damage in 10 of 13 vs 8 of 29 cases with normal RNFL thickness (P = .003). Signs of brain hemorrhages were present in 7 of 13 patients with abnormal RNFL thickness vs 5 of 29 cases with normal RNFL thickness (P = .015). CONCLUSIONS: Methanol-induced optic neuropathy may lead to chronic retinal axonal loss during the following years. Arterial blood pH on admission is the strongest predictor of chronic RNFL thickness decrease. Chronic retinal neurodegeneration is associated with the progressive loss of visual functions and necrotic brain lesions. (C) 2018 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license.

CONTEXT:The role of activation of lipid peroxidation in the mechanisms of acute methanol poisoning has not been studied. OBJECTIVE:We measured the concentrations of lipid peroxidation markers in acutely intoxicated patients with known serum concentrations of methanol and leukotrienes. METHODS:Blood serum samples were collected from 28 patients hospitalized with acute intoxication and from 36 survivors 2 years after discharge. In these samples, concentrations of 4-hydroxy-trans-2-hexenal (HHE), 4-hydroxynonenal (HNE), and malondialdehyde (MDA) were measured using the method of liquid chromatography-electrospray ionization-tandem mass spectrometry. RESULTS:The maximum acute serum concentrations of all three lipid oxidative damage markers were higher than the follow-up serum concentrations: HNE 71.7 ± 8.0 ng/mL versus 35.4 ± 2.3 ng/mL; p < .001; HHE 40.1 ± 6.7 ng/mL versus 17.7 ± 4.1 ng/mL; p < .001; MDA 80.0 ± 7.2 ng/mL versus 40.9 ± 1.9 ng/mL; p < .001. The survivors without methanol poisoning sequelae demonstrated higher acute serum concentrations of the markers than the patients with sequelae. A correlation between measured markers and serum leukotrienes was present: HNE correlated with LTC4 (r = 0.663), LTD4 (r = 0.608), LTE4 (r = 0.771), LTB4 (r = 0.717), HHE correlated with LTC4 (r = 0.713), LTD4 (r = 0.676), LTE4 (r = 0.819), LTB4 (r = 0.746), MDA correlated with LTC4 (r = 0.785), LTD4 (r = 0.735), LTE4 (r = 0.814), LTB4 (r = 0.674); all p < .001. Lipid peroxidation markers correlated with anion gap (r= -0.428, -0.388, -0.334; p = .026, .045, .080 for HNE, HHE, MDA, respectively). The follow-up serum concentrations of lipid oxidation markers measured in survivors with and without visual/neurological sequelae 2 years after discharge did not differ. CONCLUSION:Our results demonstrate that lipid peroxidation plays a significant role in the mechanisms of acute methanol poisoning. The acute concentrations of three measured biomarkers were elevated in comparison with the follow-up concentrations. Neuronal membrane lipid peroxidation seems to activate leukotriene-mediated inflammation as a part of the neuroprotective mechanisms. No cases of persistent elevation were registered among the survivors 2 years after discharge.

BACKGROUND AND PURPOSELesion burden and brain volume changes are frequent end points in research but nowadays are becoming important in the clinical practice of multiple sclerosis (MS). The objective of this study was to investigate the correlation between magnetic resonance imaging (MRI) measures obtained by in-house developed ScanView software and commonly used volumetric techniques for assessment of T2 lesion and whole brain volumes and their changes. METHODSTogether 3,340 MRI scans from 209 patients after first demyelinating event suggestive of MS, 181 relapsing-remitting MS patients and 43 controls were analyzed. The average number of MRI scans and follow-up duration was 8.2 and 6.5 years, respectively. All MRI scans were performed in a single center but independently analyzed in two neuroimaging centers. Volumetric analysis by ScanView software was applied in Prague. Commonly used techniques, such as SIENA, SIENAX, and Jim software, were applied in Buffalo. Correlations between MRI measures were evaluated using correlation coefficients. Intraindividual variability of longitudinal MRI data was estimated by mean squared error. RESULTSThe associations of the cross-sectional and longitudinal MRI measures between commonly used techniques and ScanView were significant (r/rho = .83-.95). The associations of cross-sectional MRI measures were stronger (r/rho = .90-.95) compared with longitudinal ones (r = .83). Standardized intraindividual variability of whole brain % volume change was greater in ScanView compared with SIENA (mean squared error .32 vs. .21; P < .001). CONCLUSIONSWe found relatively strong correlations of cross-sectional and longitudinal data obtained by both techniques. However, SIENA showed lower intraindividual variability than the ScanView method in measuring whole brain volume loss over time.

The purpose of this work was to determine whether changes in cholesterol profiles after interferon-β (IFN-β)1a treatment initiation following the first demyelinating event suggestive of multiple sclerosis are associated with clinical and MRI outcomes over 4 years. A group of 131 patients (age: 27.9 ± 7.8 years, 63% female) with serial 3-monthly clinical and 12-monthly MRI follow-ups over 4 years were investigated. Serum cholesterol profiles, including total cholesterol (TC), HDL cholesterol (HDL-C), and LDL cholesterol (LDL-C) were obtained at baseline, 1 month, 3 months, and every 6 months thereafter. IFN-β1a initiation caused rapid decreases in serum HDL-C, LDL-C, and TC within 1 month of IFN-β1a initiation (all P < 0.001) that returned slowly toward baseline. In predictive mixed model analyses, greater percent decreases in HDL-C after 3 months of IFN-β1a treatment initiation were associated with less brain atrophy over the 4 year time course, as assessed by percent brain volume change (P < 0.001), percent gray matter volume change (P < 0.001), and percent lateral ventricle volume change (P = 0.005). Decreases in cholesterol biomarkers following IFN-β1a treatment are associated with brain atrophy outcomes over 4 years. Pharmacological interventions targeting lipid homeostasis may be clinically beneficial for disrupting neurodegenerative processes.

Objective:To investigate whether the strength of the association between magnetic resonance imaging (MRI) metrics and cognitive outcomes differs between various multiple sclerosis subpopulations. Methods:A total of 1052 patients were included in this large cross-sectional study. Brain MRI (T1 and T2 lesion volume and brain parenchymal fraction) and neuropsychological assessment (Brief International Cognitive Assessment for Multiple Sclerosis and Paced Auditory Serial Addition Test) were performed. Results:Weak correlations between cognitive domains and MRI measures were observed in younger patients (age≤30 years; absolute Spearman's rho = 0.05-0.21), with short disease duration (<2 years; rho = 0.01-0.21), low Expanded Disability Status Scale [EDSS] (≤1.5; rho = 0.08-0.18), low T2 lesion volume (lowest quartile; <0.59 mL; rho = 0.01-0.20), and high brain parenchymal fraction (highest quartile; >86.66; rho = 0.01-0.16). Stronger correlations between cognitive domains and MRI measures were observed in older patients (age>50 years; rho = 0.24-0.50), with longer disease duration (>15 years; rho = 0.26-0.53), higher EDSS (≥5.0; rho = 0.23-0.39), greater T2 lesion volume (highest quartile; >5.33 mL; rho = 0.16-0.32), and lower brain parenchymal fraction (lowest quartile; <83.71; rho = 0.13-0.46). The majority of these observed results were confirmed by significant interactions (P ≤ 0.01) using continuous variables. Interpretation:The association between structural brain damage and functional cognitive impairment is substantially weaker in multiple sclerosis patients with a low disease burden. Therefore, disease stage should be taken into consideration when interpreting associations between structural and cognitive measures in clinical trials, research studies, and clinical practice.

OBJECTIVES:To investigate spatial patterns of gray matter (GM) atrophy and their association with disability progression in patients with early relapsing-remitting multiple sclerosis (MS) in a longitudinal setting. METHODS:Brain MRI and clinical neurological assessments were obtained in 152 MS patients at baseline and after 10 years of follow-up. Patients were classified into those with confirmed disability progression (CDP) (n = 85) and those without CDP (n = 67) at the end of the study. An optimized, longitudinal source-based morphometry (SBM) pipeline, which utilizes independent component analysis, was used to identify eight spatial patterns of common GM volume co-variation in a data-driven manner. GM volume at baseline and rates of change were compared between patients with CDP and those without CDP. RESULTS:The identified patterns generally included structurally or functionally related GM regions. No significant differences were detected at baseline GM volume between the sub-groups. Over the follow-up, patients with CDP experienced a significantly greater rate of GM atrophy within two of the eight patterns, after correction for multiple comparisons (corrected p-values of 0.001 and 0.007). The patterns of GM atrophy associated with the development of CDP included areas involved in motor functioning and cognitive domains such as learning and memory. CONCLUSION:SBM analysis offers a novel way to study the temporal evolution of regional GM atrophy. Over 10 years of follow-up, disability progression in MS is related to GM atrophy in areas associated with motor and cognitive functioning.

To evaluate T2-lesion burden assessment in multiple sclerosis (MS) patients followed in clinical routine, based on radiological and quantitative MRI (QMRI) reports.