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Objective To test the current progressive multifocal leukoencephalopathy (PML) diagnostic criteria by applying them to patients previously diagnosed with natalizumab (NTZ)-associated PML in a real-world clinical setting. Methods Patients from the Dutch-Belgian NTZ-PML cohort (n=28) were reviewed at the time of first diagnostic work-up and during follow-up, using the PML diagnostic criteria as proposed in a consensus statement from the American Academy of Neurology. Results At first diagnostic work-up, 18 patients (64.3%) met the criteria for high diagnostic certainty for PML ('definite PML' or 'probable PML'). During follow-up, this increased to 20 patients (71.4%) as JC virus DNA was detected in cerebrospinal fluid of two additional patients. Nonetheless, 28.6% of patients were still classified as 'possible PML' or 'not PML' (6 (21.5%) and 2 (7.1%) patients, respectively) despite a very high suspicion for PML based on lesion evolution and signs of PML-immune reconstitution inflammatory syndrome on MRI, and development of compatible symptoms. Conclusions The current case definition of PML has low sensitivity for diagnosis of NTZ-PML in a real-world clinical setting in which MRI is frequently used for PML screening. This may delay diagnosis and appropriate management of PML, and may complicate a valid estimation of PML incidence during NTZ therapy.

Importance: Therapeutic options for patients with secondary progressive multiple sclerosis (SPMS) are limited. Objective: To analyze disability progression in patients with SPMS treated with rituximab compared with matched control patients never treated with rituximab. Design, Setting, and Participants: This retrospective cohort study analyzed data obtained from patients with SPMS at 3 multiple sclerosis centers located in Basel and Lugano, Switzerland, and Amsterdam, the Netherlands, from 2004 to 2017. Patients were included for analysis if they had received a diagnosis of SPMS, were treated (57 eligible; 54 included) or never treated (504 eligible; 59 included) with rituximab, and had at least 1 follow-up visit. The variables used for propensity score matching were sex, age, Expanded Disability Status Scale (EDSS) score, and disease duration. Follow-up duration was up to 10 years, with a mean (SD) of 3.5 (2.6) years for rituximab-treated patients and 5.4 (2.4) years for controls in the total cohort and a mean (SD) of 3.5 (2.7) years for rituximab-treated patients and 4.8 (2.2) years for controls in the matched cohort. Exposures: Comparing EDSS score progression in patients with SPMS (treated with rituximab vs not treated with rituximab) using propensity score matching. Main Outcomes and Measures: The primary end point was progression of EDSS score after baseline, and the secondary end point was time to confirmed disability progression. Results: After 1:1 propensity score matching, 44 matched pairs (88 patients) were included in the analysis. At baseline, patients treated with rituximab had a mean (SD) age of 49.7 (10.0) years, mean (SD) disease duration of 18.2 (9.4) years, and mean (SD) EDSS score of 5.9 (1.4), and 26 (59%) were women, whereas controls had a mean (SD) age of 51.3 (7.4) years, mean (SD) disease duration of 19.4 (8.7) years, and mean (SD) EDSS score of 5.70 (1.29), and 27 (61%) were women. In the covariate-adjusted analysis of the matched set, pati

Background and objective Natalizumab-associated progressive multifocal leukoencephalopathy (NTZ-PML) patients may show imaging signs suggestive of inflammation at diagnosis ('inflammatory PML'), reminiscent of PML-immune reconstitution inflammatory syndrome (PML-IRIS). We investigated the imaging characteristics of inflammatory NTZ-PML lesions and PML-IRIS to determine differentiating and overlapping features. Methods We scored the presence, localisation and pattern of imaging characteristics of inflammation on brain MRI scans of inflammatory NTZ-PML patients. The imaging characteristics were followed up until the occurrence of PML-IRIS. Results Ten out of the 44 NTZ-PML patients included showed signs suggestive of inflammation at the time of diagnosis. The inflammation pattern at diagnosis was similar to the pattern seen at PML-IRIS, with contrast enhancement representing the most frequent sign of inflammation (90% at diagnosis, 100% at PML-IRIS). However, the severity of inflammation differed, with absence of swelling and low frequency of perilesional oedema (10%) at diagnosis, as compared with the PML-IRIS stage (40%). Conclusion Patterns of inflammation at the time of PML diagnosis and at the PML-IRIS stage overlap but differ in their severity of inflammation. This supports histopathological evidence that the inflammation seen at both stages of the same disease shares a similar underlying pathophysiology, representing the immune response to the JC virus to a variable extend.

IMPORTANCE The JC virus (JCV) was named after the first patient to be described with progressive multifocal leukoencephalopathy (PML), John Cunningham. Detection of JC virus DNA in cerebrospinal fluid (CSF) by polymerase chain reaction (PCR), and of specific lesions by brain magnetic resonance imaging (MRI), are both considered essential for the diagnosis of natalizumab-associated PML (NTZ-PML) in patients with multiple sclerosis. However, strict pharmacovigilance by MRI can result in detection of patients with small lesions and undetectable JCV DNA in CSF. OBJECTIVE To investigate the association of PML lesion characteristics on MRI with both qualitative and quantitative JCV PCR results in CSF of patients with NTZ-PML. DESIGN, SETTING AND PARTICIPANTS This was a retrospective, cross-sectional study conducted from January 2007 to December 2014 in patients considered to have NTZ-PML based on a set of predefined criteria. Follow-up was at least 6 months. Data of patients from the Dutch-Belgian NTZ-PML cohort and patients treated at multiple medical centers in Belgium and the Netherlands and selected for research purposes were included as a convenience sample. MAIN OUTCOMES AND MEASURES Brain MRI scans were analyzed for PML lesion volume, location, dissemination, and signs of inflammation. Associations of the qualitative and quantitative CSF JCV PCR results with PML MRI characteristics were calculated. RESULTS Of the 73 patients screened, 56 were included (37 were women). At inclusion, 9 patients (16.1%) had undetectable JCV DNA in CSF. Patients with a positive PCR had larger total PML lesion volumes than those with undetectable JCV DNA (median volume, 22.9 mL; interquartile range, 9.2-60.4 mL vs median volume, 6.7 mL; interquartile range, 4.9-14.7 mL; P = .008), and logistic regression showed that a lower PML lesion volume significantly increased the probability for undetectable JCV DNA. There was a positive correlation between PML lesion volume and JCV copy numbers (

The 2010 McDonald criteria for the diagnosis of multiple sclerosis are widely used in research and clinical practice. Scientific advances in the past 7 years suggest that they might no longer provide the most up-to-date guidance for clinicians and researchers. The International Panel on Diagnosis of Multiple Sclerosis reviewed the 2010 McDonald criteria and recommended revisions. The 2017 McDonald criteria continue to apply primarily to patients experiencing a typical clinically isolated syndrome, define what is needed to fulfil dissemination in time and space of lesions in the CNS, and stress the need for no better explanation for the presentation. The following changes were made: in patients with a typical clinically isolated syndrome and clinical or MRI demonstration of dissemination in space, the presence of CSF-specific oligoclonal bands allows a diagnosis of multiple sclerosis; symptomatic lesions can be used to demonstrate dissemination in space or time in patients with supratentorial, infratentorial, or spinal cord syndrome; and cortical lesions can be used to demonstrate dissemination in space. Research to further refine the criteria should focus on optic nerve involvement, validation in diverse populations, and incorporation of advanced imaging, neurophysiological, and body fluid markers.

[Background] Mitochondrial dysfunction is increasingly recognized as an important feature of multiple sclerosis (MS) pathology and may be relevant for clinical disease progression. However, it is unknown whether mitochondrial DNA (mtDNA) levels in the cerebrospinal fluid (CSF) associate with disease progression and therapeutic response. [Objectives] To evaluate whether CSF concentrations of mtDNA in MS patients can serve as a marker of ongoing neuropathology and may be helpful to differentiate between MS disease subtypes. To explore the effect of disease-modifying therapies on mtDNA levels in the CSF. [Methods] CSF mtDNA was measured using a digital polymerase chain reaction (PCR) CSF mtDNA in two independent MS cohorts. The cohorts included 92 relapsing-remitting multiple sclerosis (RRMS) patients, 40 progressive multiple sclerosis (PMS) patients (27 secondary progressive and 13 primary progressive), 50 various neurologic disease controls, and 5 healthy controls. [Results] Patients with PMS showed a significant increase in CSF mtDNA compared to non-inflammatory neurologic disease controls. Patients with higher T2 lesion volumes and lower normalized brain volumes showed increased concentration of mtDNA. Patients treated with fingolimod had significantly lower mtDNA copy levels at follow-up compared to baseline. [Conclusion] Our results showed a non-specific elevation of concentration of mtDNA in PMS patients. mtDNA concentrations respond to fingolimod and may be used to monitor biological effect of this treatment

To study the gastric-emptying rate and gut hormonal response of two carbohydrate-rich beverages. A specifically designed carbohydrate-rich beverage is currently used to support the surgical patient metabolically. Fruit-based beverages may also promote recovery, due to natural antioxidant and carbohydrate content. However, gastric emptying of fluids is influenced by its nutrient composition; hence, safety of preoperative carbohydrate loading should be confirmed. Because gut hormones link carbohydrate metabolism and gastric emptying, hormonal responses were studied.

BACKGROUND: The BENEFIT study examined interferon beta (IFNB)-1b treatment in patients with clinically isolated syndrome (CIS) and > or = 2 clinically silent brain MRI lesions. METHODS: Subgroups of 468 patients (IFNB-1b: n = 292; placebo: n = 176) were created for demographics, clinical, laboratory, and MRI findings at onset. The 'natural' risk of clinically definite MS (CDMS) over 2 years was estimated by Kaplan Meier statistics in placebo-treated patients; the IFNB-1b treatment effect was analysed by Cox proportional hazards regression. RESULTS: The risk of CDMS was increased in placebo-treated patients (overall 45 %) if they were younger (< 30 years: 60%), were cerebrospinal fluid (CSF)-positive (49 %), or had received steroid treatment (48 %). MRI parameters implied a higher risk in placebo-treated patients with > or = 9 T2-lesions (48%) or > or = 1 gadolinium (Gd)-enhancing lesions (52 %). The CDMS risk was highest (75 %) in placebo-treated patients with monofocal disease onset displaying MRI disease activity (> or = 1 Gd-lesion) and dissemination (> or = 9 T2-lesions). Treatment effects were significant across almost all subgroups including patients with less disease dissemination/activity at onset (monofocal: 55%; < 9 T2-lesions: 60%; no Gd-lesions: 57%) and patients without steroid treatment for the CIS (62 %). Monofocal patients had greater treatment effects if they had > or = 9 T2-lesions (61 %), Gd-lesions (58 %), or both (65 %). CONCLUSIONS: This study confirms the impact of age of onset, CSF and MRI findings on risk of conversion from CIS to CDMS. IFNB-1b treatment effect was robust across the study population including patients without MRI disease activity and less clinical or MRI disease dissemination at onset and patients not receiving steroids for the CIS.