Background and purpose
John Cunningham virus (JCV) seropositivity is a risk factor for the development of natalizumab‐associated progressive multifocal leukoencephalopathy (PML) in multiple sclerosis ...(MS) patients. When JCV seronegative patients seroconvert, their risk of developing PML increases. Limited longitudinal data exist about the seroconversion rate amongst natalizumab‐treated relapsing−remitting MS (RRMS) patients. Our objective was to evaluate the seroconversion rate in a large Dutch cohort of natalizumab‐treated RRMS patients. Seroconversion was defined as at least two consecutive seropositive serum samples (or cessation of therapy after a single seropositive sample because of seropositivity) after initial seronegative testing.
Methods and results
In our study of 179 patients for whom longitudinal blood samples were available over a long period (median 4.2 years), anti‐JCV antibody indices were measured in 933 available samples. Eighty‐six patients (48.0%) tested seronegative initially. Of these 86 seronegative patients, 23 patients (26.7%) seroconverted during follow‐up. The annualized seroconversion rate was 7.1%. Seroconversion occurred between 9 and 90 months (median 43 months) of treatment. The rate of seroconversion was independent of follow‐up duration. No significant increase was seen in the anti‐JCV antibody index in the non‐converting patients during the follow‐up.
Conclusion
The annualized seroconversion rate of 7.1% in patients using natalizumab, cumulatively leading to more than 25% of seronegative patients becoming seropositive in 4 years, is of clinical relevance and should be taken into account in the risk assessment when considering the start of natalizumab therapy.
Suspected central nervous system (CNS) infections may pose a diagnostic challenge, and often concern severely ill patients. We aim to identify predictors of unfavourable outcome to prioritize ...diagnostics and treatment improvements. Unfavourable outcome was assessed on the Glasgow Outcome Scale at hospital discharge, defined by a score of 1 to 4. Of the 1152 episodes with suspected CNS infection, from two Dutch prospective cohorts, the median age was 54 (IQR 37-67), and 563 episodes (49%) occurred in women. The final diagnoses were categorized as CNS infection (N = 358 episodes, 31%), CNS inflammatory disease (N = 113, 10%), non-infectious non-inflammatory neurological disorder (N = 388, 34%), non-neurological infection (N = 252, 22%), and other systemic disorder (N = 41, 4%). Unfavourable outcome occurred in 412 of 1152 (36%), and 99 died (9%). Predictors for unfavourable outcomes included advanced age, absence of headache, tachycardia, altered mental state, focal cerebral deficits, cranial nerve palsies, low thrombocytes, high CSF protein, and the final diagnosis of CNS inflammatory disease (odds ratio 4.5 95% confidence interval 1.5-12.6). Episodes suspected of having a CNS infection face high risk of experiencing unfavourable outcome, stressing the urgent need for rapid and accurate diagnostics. Amongst the suspected CNS infection group, those diagnosed with CNS inflammatory disease have the highest risk.
Background:
Cholesterol homeostasis is important for formation and maintenance of myelin and axonal membranes in the central nervous system (CNS). The concentrations of the brain specific cholesterol ...metabolite 24S-hydroxycholesterol (24OHC) and cholesterol precursors have been shown to be altered in multiple sclerosis (MS). However, how changes in sterol levels relate to the pathological processes in MS is not clear.
Methods:
In this study, we compared serum and cerebrospinal fluid (CSF) sterol levels between 105 MS (51 relapsing–remitting (RR); 39 secondary progressive (SP) and 15 primary progressive (PP)) and 49 control patients. Sterol levels were correlated to magnetic resonance imaging (MRI) markers of disease activity.
Results:
We found decreased serum 24OHC and 27-hydroxycholesterol (27OHC) and increased CSF lathosterol in MS patients compared to control patients (p=0.018, p=0.002 and p=0.002, respectively). Subgroup analysis showed that serum 24OHC levels were negatively correlated to normalized brain volume measurements in relapse-onset MS patients (r= −0.326, p=0.004).
Conclusions:
These results confirm that cholesterol homeostasis is disturbed in MS and suggest that changes in cholesterol synthesis are related to neurodegenerative pathological processes as seen on the MRI. The data seem to be in line with the recently reported observation that high dose statins may have a positive effect on clinical disability in secondary progressive MS.
Atrophy of the spinal cord is known to occur in multiple sclerosis (MS). The mean upper cervical cord area (MUCCA) can be used to measure this atrophy. Currently, several (semi-)automated methods for ...MUCCA measurement exist, but validation in clinical magnetic resonance (MR) images is lacking.
Five methods to measure MUCCA (SCT-PropSeg, SCT-DeepSeg, NeuroQLab, Xinapse JIM and ITK-SNAP) were investigated in a predefined upper cervical cord region. First, within-scanner reproducibility and between-scanner robustness were assessed using intra-class correlation coefficient (ICC) and Dice's similarity index (SI) in scan-rescan 3DT1-weighted images (brain, including cervical spine using a head coil) performed on three 3 T MR machines (GE MR750, Philips Ingenuity, Toshiba Vantage Titan) in 21 subjects with MS and 6 healthy controls (dataset A). Second, sensitivity of MUCCA measurement to lesions in the upper cervical cord was assessed with cervical 3D T1-weighted images (3 T GE HDxT using a head-neck-spine coil) in 7 subjects with MS without and 14 subjects with MS with cervical lesions (dataset B), using ICC and SI with manual reference segmentations.
In dataset A, MUCCA differed between MR machines (p < 0.001) and methods (p < 0.001) used, but not between scan sessions. With respect to MUCCA values, Xinapse JIM showed the highest within-scanner reproducibility (ICC absolute agreement = 0.995) while Xinapse JIM and SCT-PropSeg showed the highest between-scanner robustness (ICC consistency = 0.981 and 0.976, respectively). Reproducibility of segmentations between scan sessions was highest in Xinapse JIM and SCT-PropSeg segmentations (median SI ≥ 0.921), with a significant main effect of method (p < 0.001), but not of MR machine or subject group. In dataset B, SI with manual outlines did not differ between patients with or without cervical lesions for any of the segmentation methods (p > 0.176). However, there was an effect of method for both volumetric and voxel wise agreement of the segmentations (both p < 0.001). Highest volumetric and voxel wise agreement was obtained with Xinapse JIM (ICC absolute agreement = 0.940 and median SI = 0.962).
Although MUCCA is highly reproducible within a scanner for each individual measurement method, MUCCA differs between scanners and between methods. Cervical cord lesions do not affect MUCCA measurement performance.
•Mean upper cervical cord area (MUCCA) was obtained with five different methods.•MUCCA was determined in a unique scan-rescan multi-vendor MR study.•Reproducibility: MUCCA did not differ between scan-rescan images for any method.•Robustness: MUCCA differed between methods and between scanners.•Performance of MUCCA methods was not affected by the presence of lesions.
Background Neurofilament light is a neuronal protein detectable in serum (sNfL), with high potential as disease activity biomarker in multiple sclerosis (MS). To date, little is known about sNfL ...fluctuations between 2 consecutive measurements in healthy controls (HC) and MS patients. Yet this information is critical, as it will help define a clinically significant variation.
Methods sNfL was measured at 2 consecutive time points in a cohort of 90 MS patients (untreated relapsing remitting MS (uRRMS), n=35; treated relapsing remitting MS (tRRMS), n= 21; secondary progressive MS, SPMS, n=21; primary progressive MS, PPMS, n=13), and 90 age-matched HC, using the Simoa NfL light® assay.
Results Mean sNfL was elevated in all MS subtypes compared to HC (p<0.0001), and positively associated with age in HC (r=0.70, p<0.001), confirming previous reports. Mean sNfL was higher at follow-up compared to baseline in HC (p<0.001), and lower in uRRMS(p=0.036) and tRRMS (p=0.008). At follow-up, a similar proportion of HC (50.0%), untreated RRMS (51.4%), treated RRMS (33.3%), SPMS (45.0%) and PPMS (46.2%) had variations in sNfL levels exceeding 20% of baseline levels.
Conclusions Our data suggest variations in sNfL occur both in HC and MS populations to a similar extent and magnitude. Variations between two consecutive sNfL measurements may reflect natural variations and not necessarily variations in inflammatory disease activity.
•Effect of high efficacy therapy on brain atrophy was investigated on clinical MRI.•Natalizumab slowed ventricular growth the most (1.1 %/year).•Patients treated with moderate efficacy DMT had a ...ventricular growth of 2.4 %/year.•Whole-brain and regional volumes were most strongly related to 9HPT and EDSS.
The long-term effect of high efficacy disease modifying therapy (DMT) on neurodegeneration in people with multiple sclerosis (pwMS) is largely unknown. The aim of this study was to evaluate the long-term effect of natalizumab (NTZ) or fingolimod (FTY) therapy on the evolution of brain atrophy compared to moderate efficacy DMT in a real-world clinical setting.
A total of 438 pwMS with 2,439 MRI exams during treatment were analyzed: 252 pwMS treated with moderate efficacy DMT, 130 with NTZ and 56 with FTY. Evolution of brain atrophy was analyzed over an average follow-up of 6.6 years after treatment initiation. Brain segmentation was performed on clinical 3D-FLAIRs using SynthSeg and regional brain volume changes over time were compared between the treatment groups.
Total brain, white matter and deep gray matter atrophy rates did not differ between moderate efficacy DMTs, NTZ and FTY. Annualized ventricle growth rates were lower in pwMS treated with NTZ (1.1 %/year) compared with moderate efficacy DMT (2.4 %/year, p < 0.001) and similar to FTY (2.0 %/year, p = 0.051). Cortical atrophy rates were lower in NTZ (-0.08 %/year) compared with moderate efficacy DMT (-0.16 %/year, p = 0.048).
In a real-world clinical setting, pwMS treated with NTZ had slower ventricular expansion and cortical atrophy compared to those treated with moderate efficacy DMT.
Background:
The heterogeneity of the disease course in multiple sclerosis (MS) remains a challenge for patient management and clinical trials.
Objective:
The objective of this paper is to investigate ...the relationship between disease course heterogeneity and retinal layer thicknesses in MS.
Methods:
A total of 230 MS patients and 63 healthy control subjects were included. Spectral-domain OCT scanning of the peripapillary and macular regions was performed, followed by automated eight-layer segmentation. Generalised estimation equations were used for comparisons. Receiver operating characteristic (ROC) curves were calculated for distinguishing a benign from a typical disease course.
Results:
Primary progressive patients showed relative preservation of inner retinal layers, compared to the relapsing onset MS types. Only in MS eyes without optic neuritis did patients with typical MS show more severe thinning of the inner retinal layers (RNFL to INL) compared to patients with a benign disease course, even after an average disease course of 20 years.
Conclusion:
The thicknesses, particularly of the innermost retinal layers (RNFL, GCC), were significantly related to the heterogeneous disease course in MS. The relative preservation of these layers in primary progressive and benign MS suggests rather limited susceptibility of the retina to neurodegeneration, which may be relevant for future neurodegenerative treatment trials employing OCT as a secondary outcome measure in primary progressive MS.
Abstract
Background
Seizures can be part of the clinical presentation of central nervous system (CNS) infections. We describe patients suspected of a neurological infection who present with a seizure ...and study diagnostic accuracy of clinical and laboratory features predictive of CNS infection in this population.
Methods
We analyzed all consecutive patients presenting with a seizure from two prospective Dutch cohort studies, in which patients were included who underwent cerebrospinal fluid (CSF) examination because of the suspicion of a CNS infection.
Results
Of 900 episodes of suspected CNS infection, 124 (14%) presented with a seizure. The median age in these 124 episodes was 60 years (IQR 45–71) and 53% of patients was female. CSF examination showed a leukocyte count ≥ 5/mm
3
in 41% of episodes. A CNS infection was diagnosed in 27 of 124 episodes (22%), a CNS inflammatory disorder in 8 (6%) episodes, a systemic infection in 10 (8%), other neurological disease in 77 (62%) and in 2 (2%) episodes another systemic disease was diagnosed. Diagnostic accuracy of clinical and laboratory characteristics for the diagnosis of CNS infection in this population was low. CSF leukocyte count was the best predictor for CNS infection in patients with suspected CNS infection presenting with a seizure (area under the curve 0.94, 95% CI 0.88 – 1.00).
Conclusions
Clinical and laboratory features fail to distinguish CNS infections from other causes of seizures in patients with a suspected CNS infection. CSF leukocyte count is the best predictor for the diagnosis of CNS infection in this population.
Although the relationships among physical disability, mood disorders, and pain are well described in multiple sclerosis (MS), little is known about whether those symptoms are associated with sleep ...disturbances.
Forty-six patients with MS experiencing pain participated. Sleep was indirectly measured by assessing rest-activity rhythm via actigraphy: interdaily stability, intradaily variability, and relative amplitude. Pain was assessed using visual and verbal analog scales, mood by the Beck Depression Inventory and Symptom Checklist-90, and physical disability by the Expanded Disability Status Scale.
Incorporating mood, pain, and physical disability into 1 regression model resulted in a significant association with interdaily stability.
Compared with intradaily variability and relative amplitude, interdaily stability seems to be the most vulnerable actigraphy variable for mood disturbances, pain, and physical disabilities.
Background and purpose
Infection with the John Cunningham virus (JCV) is required for the development of progressive multifocal leukoencephalopathy, the feared complication of natalizumab treatment ...in multiple sclerosis patients. The JCV seroconversion rate seems higher in natalizumab treated patients than in the normal population, with an unknown cause.
Methods
Natalizumab concentration was correlated to JCV antibody status and seroconversion in a large cohort of multiple sclerosis patients.
Results
One hundred and thirty‐five patients were included. No correlation was found between natalizumab concentration and JCV status, JCV seroconversion or JCV index.
Conclusions
Higher natalizumab concentrations do not explain the increased JCV seroconversion rate in natalizumab treated patients.
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