APOSTEL 2.0 Recommendations for Reporting Quantitative Optical Coherence Tomography Studies.

OBJECTIVE: To update the consensus recommendations for reporting of quantitative optical coherence tomography (OCT) study results, thus revising the previously published Advised Protocol for OCT Study Terminology and Elements (APOSTEL) recommendations. METHODS: To identify studies reporting quantitative OCT results, we performed a PubMed search for the terms "quantitative" and "optical coherence tomography" from 2015 to 2017. Corresponding authors of the identified publications were invited to provide feedback on the initial APOSTEL recommendations via online surveys following the principle of a modified Delphi method. The results were evaluated and discussed by a panel of experts and changes to the initial recommendations were proposed. A final survey was recirculated among the corresponding authors to obtain a majority vote on the proposed changes. RESULTS: A total of 116 authors participated in the surveys, resulting in 15 suggestions, of which 12 were finally accepted and incorporated into an updated 9-point checklist. We harmonized the nomenclature of the outer retinal layers, added the exact area of measurement to the description of volume scans, and suggested reporting device-specific features. We advised to address potential bias in manual segmentation or manual correction of segmentation errors. References to specific reporting guidelines and room light conditions were removed. The participants' consensus with the recommendations increased from 80% for the previous APOSTEL version to greater than 90%. CONCLUSIONS: The modified Delphi method resulted in an expert-led guideline (evidence Class III; Grading of Recommendations, Assessment, Development and Evaluations [GRADE] criteria) concerning study protocol, acquisition device, acquisition settings, scanning protocol, funduscopic imaging, postacquisition data selection, postacquisition analysis, nomenclature and abbreviations, and statistical approach. It will be essential to update these recommendations to new research and practices regularly.

Long-term effect of natalizumab in patients with RRMS: TYSTEN cohort.

BACKGROUND: Data are needed on long-term effect of natalizumab (NTZ) in relapsing-remitting multiple sclerosis (RRMS). OBJECTIVES: To evaluate the time of onset of secondary progressive phase in patients with an RRMS treated with NTZ and to investigate predictive factors. METHODS: TYSTEN is an observational study. Patients starting NTZ between 2007 and 2012 were included and followed up until October 2018. Relapses, Expanded Disability Status Scale (EDSS) scores, and results of brain magnetic resonance imaging (MRI) were collected each year. Data were used to estimate the cumulative probability of several poor outcomes such as secondary progressive multiple sclerosis (SPMS) conversion, EDSS worsening, EDSS 4.0, and EDSS 6.0. RESULTS: 770 patients were included. The mean follow-up duration was 97 months and the mean time exposure to NTZ was 66 months. At 10 years, the cumulative probability of SPMS was 27.7%. Predictive factors for poor outcomes were a ⩾1-point increase in EDSS score from baseline, new T2 lesion or T1 gadolinium-enhancing lesion, the occurrence of relapse at 1 or 2 years and No Evidence of Disease Activity (NEDA-3; no relapse, no new T2 or T1 gadolinium-enhancing lesions, no progression) was a protective factor. CONCLUSION: In our cohort of patients treated with NTZ, poor outcomes were infrequent and are driven by disease activity.

Asymptomatic optic nerve lesions: An underestimated cause of silent retinal atrophy in MS.

OBJECTIVE: To evaluate the frequency of asymptomatic optic nerve lesions and their role in the asymptomatic retinal neuroaxonal loss observed in multiple sclerosis (MS). METHODS: We included patients with remitting-relapsing MS in the VWIMS study (Analysis of Neurodegenerative Process Within Visual Ways In Multiple Sclerosis) (ClinicalTrials.gov Identifier: 03656055). Included patients underwent optical coherence tomography (OCT), optic nerve and brain MRI, and low-contrast visual acuity measurement. In eyes of patients with MS without optic neuritis (MS-NON), an optic nerve lesion on MRI (3D double inversion recovery [DIR] sequence) was considered as an asymptomatic lesion. We considered the following OCT/MRI measures: peripapillary retinal nerve fiber layer thickness, macular ganglion cell + inner plexiform layer (mGCIPL) volumes, optic nerve lesion length, T2 lesion burden, and fractional anisotropy within optic radiations. RESULTS: An optic nerve lesion was detected in half of MS-NON eyes. Compared to optic nerves without any lesion and independently of the optic radiation lesions, the asymptomatic lesions were associated with thinner inner retinal layers (p < 0.0001) and a lower contrast visual acuity (p ≤ 0.003). Within eyes with asymptomatic optic nerve lesions, optic nerve lesion length was the only MRI measure significantly associated with retinal neuroaxonal loss (p < 0.03). Intereye mGCIPL thickness difference (IETD) was lower in patients with bilateral optic nerve DIR hypersignal compared to patients with unilateral hypersignal (p = 0.0317). For the diagnosis of history of optic neuritis, sensitivity of 3D DIR and of mGCIPL IETD were 84.9% and 63.5%, respectively. CONCLUSIONS: Asymptomatic optic nerve lesions are an underestimated and preponderant cause of retinal neuroaxonal loss in MS. 3D DIR sequence may be more sensitive than IETD measured by OCT for the detection of optic nerve lesions.

A Fully Automatic Method for Optic Radiation Tractography Applicable to Multiple Sclerosis Patients.

The optic radiations (OR) are white matter tracts forming the posterior part of the visual ways. As an important inter-individual variability exists, atlases may be inefficient to locate the OR in a given subject. We designed a fully automatic method to delimitate the OR on a magnetic resonance imaging using tractography. On 15 healthy subjects, we evaluated the validity of our method by comparing the outputs to the Jülich post-mortem histological atlas, and its reproducibility. We also evaluated its feasibility on 98 multiple sclerosis (MS) patients. We correlated different visual outcomes with the inflammatory lesions volume within the OR reconstructed with different methods (our method, atlas, TractSeg). Our method reconstructed the OR bundle in all healthy subjects (< 2 h for most of them), and was reproducible. It demonstrated good classification indexes: sensitivity up to 0.996, specificity up to 0.993, Dice coefficient up to 0.842, and an area under the receiver operating characteristic (ROC) curve of 0.981. Our method reconstructed the OR in 91 of the 98 MS patients (92.9%, < 6 h for most of patients). Compared to an atlas-based approach and the TractSeg method, the inflammatory lesions volume in the OR measured with our method better correlated with the visual cortex volume, visual acuity and mean peripapillar retinal nerve fiber layer thickness. Our method seems to be efficient to reconstruct the OR in healthy subjects, and seems applicable to MS patients. It may be more relevant than an atlas based approach.

Imaging spectrum of Bing-Neel syndrome: how can a radiologist recognise this rare neurological complication of Waldenström's macroglobulinemia?

OBJECTIVES: Bing-Neel syndrome (BNS) is a rare neurological complication of Waldenström's macroglobulinemia. The aim of this study is to describe the spectrum of radiological manifestations of this syndrome and their prevalence in order to facilitate its early diagnosis. METHODS: Twenty-four patients with BNS were diagnosed between 1994 and 2016 in eight centres in France. We retrospectively examined the medical records of these patients as well as the corresponding literature, focusing on imaging studies. Recorded data were statistically analysed and radiological findings described. RESULTS: The mean age of our patients was 62.4 years (35-80 years). The vast majority of patients were men, with a male to female ratio of 9:1. Findings included parenchymal or meningeal involvement or both. The most common finding was leptomeningeal infiltration, either intracranial or spinal, with a prevalence reaching 70.8%. Dural involvement was present in 37.5% of patients. In 41.7% (10/24) of patients, there was parenchymal involvement with a higher prevalence of brain comparing to medullar involvement (33.3% and 23.1% respectively). High T2 signal of the parenchyma was identified in 41.7% of patients and high signal in diffusion was evident in 25% of them. Intraorbital or periorbital involvement was also detected in four cases. A proposition regarding the appropriate imaging protocol completed our study. CONCLUSION: BNS's diagnosis remains challenging. Central nervous system MRI findings in the setting of known or suspected Waldenström's macroglobulinemia appear to be highly suggestive of BNS and appropriate imaging protocols should be implemented for their depiction. KEY POINTS: • Diagnosis of Bing-Neel syndrome (BNS) remains challenging and recent expert recommendations include MRI in the diagnostic criteria for the syndrome. • The most common radiological manifestations of BNS are leptomeningeal/dural infiltration or parenchymal involvement of brain or spinal cord, but many atypical forms may exist with various presentations. • Appropriate imaging protocol for BNS should include enhanced MRI studies of both brain and spine.

Magnetic resonance imaging changes following natalizumab discontinuation in multiple sclerosis patients with progressive multifocal leukoencephalopathy.

BACKGROUND: Detecting early progressive multifocal leukoencephalopathy-immune reconstitution inflammatory syndrome (PML-IRIS) is clinically relevant. OBJECTIVE: Evaluating magnetic resonance imaging (MRI) changes following natalizumab (NTZ) discontinuation and preceding PML-IRIS. METHODS: MRIs (including diffusion-weighted imaging (DWI), T2-weighted fluid-attenuated inversion recovery (T2-FLAIR), post-contrast T1-weighted sequences) were performed every week following PML diagnosis in 11 consecutive NTZ-PML patients. PML expansion, punctate lesions, contrast-enhancement, and mass-effect/edema were evaluated on each MRI sequence, following NTZ discontinuation. RESULTS: PML-IRIS occurred from 26 to 89 days after NTZ discontinuation. MRI changes prior to early PML-IRIS appeared significantly more pronounced using DWI compared to T2-FLAIR imaging (p < 0.003). Two DWI features (marked PML expansion, punctate lesions) systematically preceded contrast-enhancement. CONCLUSION: Subtle changes may occur on DWI preceding contrast-enhancement.

Punctate pattern: A promising imaging marker for the diagnosis of natalizumab-associated PML.

OBJECTIVE: To evaluate the usefulness of the punctate pattern (PP) for the diagnosis and follow-up of patients with progressive multifocal leukoencephalopathy (PML). METHODS: A cohort of 20 consecutive patients with PML, related to natalizumab (NTZ) (n = 14) or not (n = 6), underwent 3T MRI (147 MRI examinations). MRI was available at presymptomatic (n = 9 patients), symptomatic (n = 15), immune reconstitution inflammatory syndrome (IRIS), and chronic stages (n = 20). A pathologic control group of patients without PML (n = 80), with clinically definitive multiple sclerosis or a clinically isolated syndrome suggestive of CNS demyelination, underwent the same MRI protocol. Number and appearance of punctate lesions were assessed by 3 blinded readers using T2-weighted, fluid-attenuated inversion recovery (FLAIR), and postcontrast T1-weighted images. RESULTS: Interobserver agreement was good (κ = 0.79) (0.72-0.87). Of the 20 patients with PML, 18 had PP, including the 14 patients with NTZ-PML; none in the pathologic control group. Of the 9 presymptomatic patients with NTZ-PML, PP was observed in 7 (78% sensitive and 100% specific). Nonenhancing PP on T2-weighted/FLAIR images was detected in 13 patients with PML, exclusively at the presymptomatic or symptomatic stages (including 7 NTZ-PML), whereas enhancing PP occurred in 16 patients with PML, including 13 of the 14 patients with NTZ-PML at the IRIS stage. CONCLUSIONS: PP is a highly specific feature of PML and may be the first imaging feature at the presymptomatic stage with potential implications in patient care. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that a PP on MRI accurately identifies patients with NTZ-PML.

Natalizumab in relapsing-remitting multiple sclerosis.

Natalizumab is the first humanized moclonal antibody indicated in the treatment of relapsing-remitting multiple sclerosis (RRMS). Based on its remarkable efficacy in reducing disease activity and reducing the risk of disability progession in RRMS, and the risk of a serious adverse event (progressive multifocal leukoencephalopathy [PML]), natalizumab was indicated in active RRMS, mostly as a second-line therapy. With natalizumab and other recent anti-inflammatory therapies, the concept of no evidence of disease activity has emerged and may sometimes be achievable. Use of natalizumab in other inflammatory diseases of the nervous system has been less encouraging than in MS. PML remains the main serious adverse event occuring during natalizumab therapy. PML risk stratification according to JCV serology and JCV index is now being applied more often. Other PML risk biomarkers are being evaluated. If stopping natalizumab is planned, the wash-out period needs to be less than 12 weeks and probably closer to 4-8 weeks with efficient validated immunomodulatory or immunosuppressive therapies in RRMS.

Asymptomatic Progressive Multifocal Leukoencephalopathy Associated with Natalizumab: Diagnostic Precision with MR Imaging.

PURPOSE: To determine diagnostic precision with magnetic resonance (MR) imaging of the brain, the most predictive MR imaging features, and the added value of comparison with previous data for the diagnosis of asymptomatic progressive multifocal leukoencephalopathy (PML) associated with natalizumab (NTZ). MATERIALS AND METHODS: This retrospective study was approved by the institutional review board, and written informed consent was obtained. Eleven consecutive patients with multiple sclerosis (MS) who had received a definitive diagnosis of asymptomatic NTZ-associated PML (NTZ PML, 18 brain lesions) underwent 3-T MR imaging. The control group included 40 patients with MS but without PML who were treated with NTZ. Three readers independently performed blinded analysis of MR images. First, the readers were asked to detect NTZ PML lesions without comparing current images with previously obtained MR imaging data by evaluating MR images for the following features: U fiber and/or cortex involvement, lesion signal intensity and borders, and occurrence of punctate lesions. Second, they reassessed NTZ PML lesions with all the previous MR imaging data available. Diagnostic precision with MR imaging was assessed with and without comparison with previously obtained data. Logistic regression analyses were performed to identify the association of MR imaging features with NTZ PML. RESULTS: Overall interobserver agreement was good (κ = 0.76; 95% confidence interval [CI]: 0.71, 0.81). Hyperintensity on diffusion-weighted images and involvement of U fibers were the most predictive features (odds ratio, 33.7; 95% CI: 4.9, 229.7 [P < .0001] and odds ratio, 8.7; 95% CI: 1.2, 61.4 [P = .03], respectively), while punctate lesions were exclusively observed in patients with NTZ PML. Comparison with previous MR imaging data improved specificity of MR imaging for the detection of NTZ PML lesions (from 88% to 100%, P = .05). CONCLUSION: Recognition of the most predictive imaging features and comparison with previous MR imaging data may facilitate the detection of asymptomatic NTZ PML.

JC-virus seroconversion in multiple sclerosis patients receiving natalizumab.

AIM: The objectives of this study were to evaluate the rate of JC virus (JCV) seroconversion/seroreversion in a French cohort of multiple sclerosis (MS) patients receiving natalizumab (NTZ), describe the characteristics of this population, identify risk factors for JCV seropositivity and analyse the additional value of quantitative JCV serology results in this context. METHODS: MS patients from two French MS centres, whose JCV serological status in 2011 while receiving NTZ was known (n=357; first-generation enzyme-linked immunosorbent assay (ELISA) test (Gen1)), were proposed for inclusion in this study. We evaluated the rate of JCV seroconversion over a period of one year with a second-generation ELISA test (Gen2; n=303) and analysed the quantitative results. Multivariate analysis was performed to identify risk factors for JCV seropositivity. RESULTS: Among the patients with Gen2 JCV serology (n=303) that had been JCV-seronegative one year before (n=165), the rate of JCV seroconversion was 26.67% (44/165). We observed a higher proportion of anti-JCV antibody seroconverters (14.5%) than expected (≤3%) but also increasing index values of anti-JCV antibody over time. CONCLUSION: Our data suggest that JCV reactivation occurs during NTZ therapy and leads to an increase in the anti-JCV antibodies titre, thus making them more easily detectable by the second-generation ELISA test.

3D mapping of cerebrospinal fluid local volume changes in patients with hydrocephalus treated by surgery: preliminary study.

OBJECTIVE: To develop automated deformation modelling for the assessment of cerebrospinal fluid (CSF) local volume changes in patients with hydrocephalus treated by surgery. METHODS: Ventricular and subarachnoid CSF volume changes were mapped by calculating the Jacobian determinant of the deformation fields obtained after non-linear registration of pre- and postoperative images. A total of 31 consecutive patients, 15 with communicating hydrocephalus (CH) and 16 with non-communicating hydrocephalus (NCH), were investigated before and after surgery using a 3D SPACE (sampling perfection with application optimised contrast using different flip-angle evolution) sequence. Two readers assessed CSF volume changes using 3D colour-encoded maps. The Evans index and postoperative volume changes of the lateral ventricles and sylvian fissures were quantified and statistically compared. RESULTS: Before surgery, sylvian fissure and brain ventricle volume differed significantly between CH and NCH (P = 0.001 and P = 0.025, respectively). After surgery, 3D colour-encoded maps allowed for the visual recognition of the CSF volume changes in all patients. The amounts of ventricle volume loss of CH and NCH patients were not significantly different (P = 0.30), whereas readjustment of the sylvian fissure volume was conflicting in CH and NCH patients (P < 0.001). The Evans index correlated with ventricle volume in NCH patients. CONCLUSION: 3D mapping of CSF volume changes is feasible providing a quantitative follow-up of patients with hydrocephalus. KEY POINTS: • MRI can provide helpful information about cerebrospinal fluid volumes. • 3D CSF mapping allows quantitative follow-up in communicating and non-communicating hydrocephalus. • Following intervention, fissures and cisterns readjust in both forms of hydrocephalus. • These findings support the hypothesis of suprasylvian block in communicating hydrocephalus. • 3D mapping may improve shunt dysfunction detection and guide valve pressure settings.

Anti-JCV antibody prevalence in a French cohort of MS patients under natalizumab therapy.

To measure the prevalence of JCV-specific antibodies in a French cohort of MS patients treated with natalizumab and to identify risk factor(s) of JCV seropositivity. Progressive multifocal leukoencephalopathy (PML) risk may be stratified by anti-JCV antibody status, duration of natalizumab therapy (≥24 months) and prior exposure to immunosuppressive (IS) drugs. No data are available in France on the prevalence of anti-JCV antibodies and distribution of PML risk factors in patients treated with natalizumab. Sera of 361 patients under natalizumab therapy in two MS centers were analyzed using a previously validated ELISA test. We studied different characteristics: demographic, ethnic, radiological, clinical, prior use of immunomodulatory (IM) or IS drugs and natalizumab exposure duration. The JCV seropositivity rate was 51 % for the whole cohort. Mean natalizumab exposure duration was 27.27 months ± 15.57 (mean ± SD), and prior use of IS drugs was observed in 15.24 % of patients. Twenty-three patients (6.4 %) presented the three PML risk factors. By multivariate analysis, presence of anti-JCV antibodies was significantly linked to age, North African origin and natalizumab exposure duration. Anti-JCV antibody prevalence was similar to previously published data. Anti-JCV antibody status was linked to age. We also suggested that anti-JCV antibody status could be linked to natalizumab exposure duration and ethnic characteristics.

Long-term follow-up of acute partial transverse myelitis.

BACKGROUND: Acute partial transverse myelitis (APTM) may be the first clinical symptom of multiple sclerosis (MS) or may remain a monophasic event. OBJECTIVES: To evaluate the risk of conversion to MS and long-term disability, and to determine prognosis factors for disability. DESIGN: We identified patients with no previous history of neurological disease who experienced APTM between January 1998 and December 2005 and were followed up at 3 university hospitals in France. Data on the patients' demographics and clinical states during follow-up, as well as data on cerebrospinal fluid (CSF) analysis, brain and spinal cord magnetic resonance imaging (MRI), and visual evoked potentials, were analyzed. SETTING: Neurology departments of 3 university hospitals in Lille, Strasbourg, and Rouen, France, respectively. PATIENTS: A total of 85 patients with no previous history of neurological disease who experienced APTM. RESULTS: The mean (SD) follow-up period was 104.8 (29.8) months. There were 57 women (67%) and 28 men (33%), with a mean (SD) age at onset of 36.7 (11.7) years. At the end of follow-up, 53 patients (62%) were classified as having MS with a mean (SD) Expanded Disability Status Scale score of 2.6 (1.8), 1 patient (1%) was classified as having postinfectious myelitis, 1 (1%) as having neuromyelitis optica, 1 (1%) as having Sjögren syndrome, and 29 (34%) still had APTM of undetermined etiology. Oligoclonal bands in CSF were more frequent in patients with MS (92%) than in patients with APTM of undetermined etiology (38%). Brain MRI results were abnormal in 87% of patients with MS and 27% of patients with APTM of undetermined etiology; visual evoked potentials were abnormal in 43% of patients with MS and 4% of patients with APTM of undetermined etiology. Oligoclonal bands in CSF (odds ratio, 15.76 [95% CI, 2.95-84.24]) and at least 1 MRI-detected brain lesion (odds ratio, 7.74 [95% CI, 2.42-24.74]) were independent predictive factors for conversion to MS. CONCLUSION: Our study confirms that abnormal brain MRI results and the presence of oligoclonal bands in CSF are 2 independent predictive factors for conversion to MS. No clinical, biological, or MRI factor at onset was predictive of long-term disability.