Faculty Bibliography

BACKGROUND:Tocilizumab (TCZ), a humanized monoclonal antibody against the interleukin-6 receptor, is approved for treatment of rheumatoid arthritis and several other immune-mediated disorders. Off-label use of the intravenous formulation of tocilizumab for Neuromyelitis Optica Spectrum Disorder (NMOSD) decreased relapse rates in two small case series. However, treatment protocol that requires frequent intravenous infusions may adversely affect adherence to therapy, especially in the more disabled patients, thereby reducing effectiveness. A subcutaneous formulation of tocilizumab was shown to be noninferior to the IV formulation for approved rheumatologic diseases. The effectiveness of subcutaneous TCZ for NMOSD is unknown. METHODS:We retrospectively reviewed clinical, radiological and serological data on all NMOSD patients who received subcutaneous TCZ in two tertiary referral centers between 2014-2019. RESULTS:Twelve NMOSD patients who received at least 6 months of subcutaneous TCZ were identified. Eleven were female; mean age was 46.9 ± 14.5 years and mean disease duration was 6.6 ± 4.6 years. Seven patients were seropositive for AQP-4 antibodies, two - for MOG-IgG antibodies, and three were doubly seronegative. During subcutaneous TCZ treatment, eight patients (66.6%) were relapse-free, one patient (8.3%) experienced 1 relapse, two patients (16.6%) - 2 relapses, and one patient (8.3%) - 3 relapses. The median relapse rate within 1 year after starting subcutaneous TCZ - 0 (interquartile range =1.75-0) - was significantly lower than in the year prior to treatment initiation (2, interquartile range = 4.0-0.25; p = 0.04). Overall, the annual relapse rate (ARR) decreased from a median of 2 (interquartile range = 5.75-1.29) prior to subcutaneous TCZ to 0 (interquartile range= = 1.0-0) on treatment (p = 0.0015). One TCZ-treated patient died following a severe myelitis attack. CONCLUSIONS:Effectiveness of subcutaneous TCZ in NMOSD appears to be similar to that reported for the IV formulation and has an advantage of at-home administration. Prospective, comparative studies of subcutaneous TCZ for NMOSD are warranted.

Spinal cord lesions detected on MRI hold important diagnostic and prognostic value for multiple sclerosis. Previous attempts to correlate lesion burden with clinical status have had limited success, however, suggesting that lesion location may be a contributor. Our aim was to explore the spatial distribution of multiple sclerosis lesions in the cervical spinal cord, with respect to clinical status. We included 642 suspected or confirmed multiple sclerosis patients (31 clinically isolated syndrome, and 416 relapsing-remitting, 84 secondary progressive, and 73 primary progressive multiple sclerosis) from 13 clinical sites. Cervical spine lesions were manually delineated on T2- and T2*-weighted axial and sagittal MRI scans acquired at 3 or 7 T. With an automatic publicly-available analysis pipeline we produced voxelwise lesion frequency maps to identify predilection sites in various patient groups characterized by clinical subtype, Expanded Disability Status Scale score and disease duration. We also measured absolute and normalized lesion volumes in several regions of interest using an atlas-based approach, and evaluated differences within and between groups. The lateral funiculi were more frequently affected by lesions in progressive subtypes than in relapsing in voxelwise analysis (P < 0.001), which was further confirmed by absolute and normalized lesion volumes (P < 0.01). The central cord area was more often affected by lesions in primary progressive than relapse-remitting patients (P < 0.001). Between white and grey matter, the absolute lesion volume in the white matter was greater than in the grey matter in all phenotypes (P < 0.001); however when normalizing by each region, normalized lesion volumes were comparable between white and grey matter in primary progressive patients. Lesions appearing in the lateral funiculi and central cord area were significantly correlated with Expanded Disability Status Scale score (P < 0.001). High lesion frequencies were observed in patients with a more aggressive disease course, rather than long disease duration. Lesions located in the lateral funiculi and central cord area of the cervical spine may influence clinical status in multiple sclerosis. This work shows the added value of cervical spine lesions, and provides an avenue for evaluating the distribution of spinal cord lesions in various patient groups.

The spinal cord is frequently affected by atrophy and/or lesions in multiple sclerosis (MS) patients. Segmentation of the spinal cord and lesions from MRI data provides measures of damage, which are key criteria for the diagnosis, prognosis, and longitudinal monitoring in MS. Automating this operation eliminates inter-rater variability and increases the efficiency of large-throughput analysis pipelines. Robust and reliable segmentation across multi-site spinal cord data is challenging because of the large variability related to acquisition parameters and image artifacts. In particular, a precise delineation of lesions is hindered by a broad heterogeneity of lesion contrast, size, location, and shape. The goal of this study was to develop a fully-automatic framework - robust to variability in both image parameters and clinical condition - for segmentation of the spinal cord and intramedullary MS lesions from conventional MRI data of MS and non-MS cases. Scans of 1042 subjects (459 healthy controls, 471 MS patients, and 112 with other spinal pathologies) were included in this multi-site study (n = 30). Data spanned three contrasts (T₁-, T₂-, and T₂^∗-weighted) for a total of 1943 vol and featured large heterogeneity in terms of resolution, orientation, coverage, and clinical conditions. The proposed cord and lesion automatic segmentation approach is based on a sequence of two Convolutional Neural Networks (CNNs). To deal with the very small proportion of spinal cord and/or lesion voxels compared to the rest of the volume, a first CNN with 2D dilated convolutions detects the spinal cord centerline, followed by a second CNN with 3D convolutions that segments the spinal cord and/or lesions. CNNs were trained independently with the Dice loss. When compared against manual segmentation, our CNN-based approach showed a median Dice of 95% vs. 88% for PropSeg (p ≤ 0.05), a state-of-the-art spinal cord segmentation method. Regarding lesion segmentation on MS data, our framework provided a Dice of 60%, a relative volume difference of -15%, and a lesion-wise detection sensitivity and precision of 83% and 77%, respectively. In this study, we introduce a robust method to segment the spinal cord and intramedullary MS lesions on a variety of MRI contrasts. The proposed framework is open-source and readily available in the Spinal Cord Toolbox.

The prevalence of nocturia in patients with multiple sclerosis (MS) is high, ranging from 20.9% to 48.8% in this population. Its underlying pathophysiology is complex and different from the non-neurogenic population. In the MS population, the pathophysiology may involve neurogenic lower urinary tract dysfunction (NLUTD) such as detrusor overactivity (NDO), detrusor-sphincter dyssynergia, or detrusor underactivity resulting in reduced bladder capacity. Nocturnal polyuria is also a significant contributor to the pathogenesis of nocturia in MS patients and may be the result of specific mechanisms such as nocturnal hypertension through autonomic cardiovascular dysfunction or lack of diurnal variation of antidiuretic hormone production (ADH) due to demyelinating lesions of the spinal cord. Nocturia might be particularly burdensome in MS patients by contributing to fatigue, a common and highly debilitating symptom in this population. There is likely a complex and multidirectional relationship between nocturia, other sleep disorders, and fatigue in the MS population that has yet to be explored. The assessment of nocturia in MS should rely upon a thorough history and physical examination. Urinalysis should be done to rule out urinary tract infection, a frequency-volume chart might help elucidating the underlying mechanisms, and post-void residual volume may be of interest to screen for urinary retention that could be asymptomatic in MS patients. Other tests such as urodynamics or polysomnography are indicated in selected patients. The treatment should be tailored to the underlying cause. The first steps involve behavioral interventions and treatment of cofactors. When possible, the predominant mechanism should be addressed first. In case of predominant NDO, antimuscarinics and beta-3 agonists should be offered as a first-line treatment and intradetrusor injections of botulinum toxin as a second-line treatment. In cases of incomplete bladder emptying, clean-intermittent self-catheterization is often used as part of multiple other interventions. In cases of nocturnal polyuria, desmopressin may be offered, inclusive of use of newer formulations (desmopressin acetate nasal spray, desmopressin orally disintegrated tablet) in countries where they are approved.

INTRODUCTION: Quantitative T2 mapping may provide an objective biomarker for occult nervous tissue pathology in relapsing-remitting multiple sclerosis (RRMS). We applied a novel echo modulation curve (EMC) algorithm to identify T2 changes in normal-appearing brain regions of subjects with RRMS (N = 27) compared to age-matched controls (N = 38). METHODS: The EMC algorithm uses Bloch simulations to model T2 decay curves in multi-spin-echo MRI sequences, independent of scanner, and scan-settings. T2 values were extracted from normal-appearing white and gray matter brain regions using both expert manual regions-of-interest and user-independent FreeSurfer segmentation. RESULTS: Compared to conventional exponential T2 modeling, EMC fitting provided more accurate estimations of T2 with less variance across scans, MRI systems, and healthy individuals. Thalamic T2 was increased 8.5% in RRMS subjects (p < 0.001) and could be used to discriminate RRMS from healthy controls well (AUC = 0.913). Manual segmentation detected both statistically significant increases (corpus callosum & temporal stem) and decreases (posterior limb internal capsule) in T2 associated with RRMS diagnosis (all p < 0.05). In healthy controls, we also observed statistically significant T2 differences for different white and gray matter structures. CONCLUSIONS: The EMC algorithm precisely characterizes T2 values, and is able to detect subtle T2 changes in normal-appearing brain regions of RRMS patients. These presumably capture both axon and myelin changes from inflammation and neurodegeneration. Further, T2 variations between different brain regions of healthy controls may correlate with distinct nervous tissue environments that differ from one another at a mesoscopic length-scale.

Currently used classification schemes for multiple sclerosis (MS) have not taken into account disease severity, instead focusing on disease phenotype (ie, relapsing vs. progressive). In this article, we argue that disease severity adds a crucial dimension to the clinical picture and may help guide treatment decisions. We outline a practical, easy-to-implement, and comprehensive scheme for severity grading in MS put forward by our mentor, Professor Joseph Herbert. We believe that severity grading may help to better prognosticate individual disease course, formulate and test rational treatment algorithms, and enhance research efforts in MS.