Longitudinal Development of Peripapillary Hyper-Reflective Ovoid Masslike Structures Suggests a Novel Pathological Pathway in Multiple Sclerosis.

OBJECTIVE: Peripapillary hyper-reflective ovoid masslike structures (PHOMS) are a new spectral domain optical coherence tomography (OCT) finding. METHODS: This prospective, longitudinal study included patients (n = 212) with multiple sclerosis (MS; n = 418 eyes), 59 healthy controls (HCs; n = 117 eyes), and 267 non-MS disease controls (534 eyes). OCT and diffusion tensor imaging were used. RESULTS: There were no PHOMS in HC eyes (0/117, 0%). The prevalence of PHOMS was significantly higher in patients with MS (34/212, p = 0.001) and MS eyes (45/418, p = 0.0002) when compared to HCs (0/59, 0/117). The inter-rater agreement for PHOMS was 97.9% (kappa = 0.951). PHOMS were present in 16% of patients with relapsing-remitting, 16% of patients with progressive, and 12% of patients with secondary progressive disease course (2% of eyes). There was no relationship of PHOMS with age, disease duration, disease course, disability, or disease-modifying treatments. The fractional anisotropy of the optic radiations was lower in patients without PHOMS (0.814) when compared to patients with PHOMS (0.845, p = 0.03). The majority of PHOMS remained stable, but increase in size and de novo development of PHOMS were also observed. In non-MS disease controls, PHOMS were observed in intracranial hypertension (62%), optic disc drusen (47%), anomalous optic discs (44%), isolated optic neuritis (19%), and optic atrophy (12%). INTERPRETATION: These data suggest that PHOMS are a novel finding in MS pathology. Future research is needed to determine whether development of PHOMS in MS is due to intermittently raised intracranial pressure or an otherwise impaired "glymphatic" outflow from eye to brain. ANN NEUROL 2020;88:309-319.

A model for interrogating the clinico-radiological paradox in multiple sclerosis: Internuclear ophthalmoplegia.

BACKGROUND AND PURPOSE: The clinico-radiological paradox in multiple sclerosis (MS) is well recognized, relevant and yet poorly understood. The suitability of an in vivo model for the clinico-radiological paradox was tested, using internuclear ophthalmoplegia (INO) and the medial longitudinal fasciculus (MLF). METHODS: In this cross-sectional study lesions of the MLF were rated by an experienced MS neuroradiologist blinded to all other information. The presence of an INO was objectively determined by a validated infrared oculography protocol (DEMoNS). Clinical information, including the National Eye Institute Visual Function Questionnaire, was obtained. RESULTS: This study included 202 patients with MS. The clinico-radiological paradox occurred in 50 patients (25%). This consisted of 45 patients having an INO without an MLF lesion and five patients with an MLF lesion but without an INO. The visual function overall score was related to the presence of an INO (p = 0.016), but not to MLF lesions seen on magnetic resonance imaging (MRI) (p = 0.207). A consensus list of potential causes for the clinico-radiological paradox was compiled and the MRI images were deposited in a repository. CONCLUSION: This study provides an objective and quantitative model to investigate the clinico-radiological paradox. Our data suggest that pathology of the MLF is more frequently detected and more clinically relevant by infrared oculography than by MLF lesion rating on MRI.

Infratentorial and spinal cord lesions: Cumulative predictors of long-term disability?

OBJECTIVE: The objective of the study was to determine whether early infratentorial and/or spinal cord lesions are long-term cumulative predictors of disability progression in multiple sclerosis (MS). METHODS: We selected 153 MS patients from the longitudinal Amsterdam MS cohort. Lesion analysis was performed at baseline and year 2. Disability progression after 6 and 11 years was measured using the Expanded Disability Status Scale (EDSS) and EDSS-plus (including 25-foot walk and 9-hole peg test). Patients with spinal cord or infratentorial lesions were compared for the risk of 6- and 11-year disability progression to patients without spinal cord or infratentorial lesions, respectively. Subsequently, patients with lesions on both locations were compared to patients with only spinal cord or only infratentorial lesions. RESULTS: Baseline spinal cord lesions show a higher risk of 6-year EDSS progression (odds ratio (OR): 3.6, p = 0.007) and EDSS-plus progression (OR: 2.5, p = 0.028) and 11-year EDSS progression (OR: 2.8, p = 0.047). Patients with both infratentorial and spinal cord lesions did not have a higher risk of 6-year disability progression than patients with only infratentorial or only spinal cord lesions. CONCLUSION: The presence of early spinal cord lesions seems to be a dominant risk factor of disability progression. Simultaneous presence of early infratentorial and spinal cord lesions did not undisputedly predict disability progression.

Monitoring retinal changes with optical coherence tomography predicts neuronal loss in experimental autoimmune encephalomyelitis.

BACKGROUND: Retinal optical coherence tomography (OCT) is a clinical and research tool in multiple sclerosis, where it has shown significant retinal nerve fiber (RNFL) and ganglion cell (RGC) layer thinning, while postmortem studies have reported RGC loss. Although retinal pathology in experimental autoimmune encephalomyelitis (EAE) has been described, comparative OCT studies among EAE models are scarce. Furthermore, the best practices for the implementation of OCT in the EAE lab, especially with afoveate animals like rodents, remain undefined. We aimed to describe the dynamics of retinal injury in different mouse EAE models and outline the optimal experimental conditions, scan protocols, and analysis methods, comparing these to histology to confirm the pathological underpinnings. METHODS: Using spectral-domain OCT, we analyzed the test-retest and the inter-rater reliability of volume, peripapillary, and combined horizontal and vertical line scans. We then monitored the thickness of the retinal layers in different EAE models: in wild-type (WT) C57Bl/6J mice immunized with myelin oligodendrocyte glycoprotein peptide (MOG35-55) or with bovine myelin basic protein (MBP), in TCR2D2 mice immunized with MOG35-55, and in SJL/J mice immunized with myelin proteolipid lipoprotein (PLP139-151). Strain-matched control mice were sham-immunized. RGC density was counted on retinal flatmounts at the end of each experiment. RESULTS: Volume scans centered on the optic disc showed the best reliability. Retinal changes during EAE were localized in the inner retinal layers (IRLs, the combination of the RNFL and the ganglion cell plus the inner plexiform layers). In WT, MOG35-55 EAE, progressive thinning of IRL started rapidly after EAE onset, with 1/3 of total loss occurring during the initial 2 months. IRL thinning was associated with the degree of RGC loss and the severity of EAE. Sham-immunized SJL/J mice showed progressive IRL atrophy, which was accentuated in PLP-immunized mice. MOG35-55-immunized TCR2D2 mice showed severe EAE and retinal thinning. MBP immunization led to very mild disease without significant retinopathy. CONCLUSIONS: Retinal neuroaxonal damage develops quickly during EAE. Changes in retinal thickness mirror neuronal loss and clinical severity. Monitoring of the IRL thickness after immunization against MOG35-55 in C57Bl/6J mice seems the most convenient model to study retinal neurodegeneration in EAE.

The clinical value of the patient-reported multiple sclerosis neuropsychological screening questionnaire.

BACKGROUND: Cognitive problems are difficult to identify in patients with multiple sclerosis (MS). OBJECTIVE: To investigate the clinical applicability of the patient-reported MS Neuropsychological Screening Questionnaire (MSNQ-P). METHODS: Cut-off scores were determined to differentiate between cognitively impaired (n = 90), mildly cognitively impaired (n = 115), and cognitively preserved (n = 147) MS patients using receiver operating characteristic analyses. RESULTS: We could not define specific and sensitive cut-off scores. Higher scores (≥27) did indicate cognitive impairment. Among patients with a higher education, lower scores (<12) indicated intact cognition. CONCLUSION: Certain scores can indicate intact or impaired cognitive function. Still, MSNQ-P scores should be interpreted with caution.

Retinal atrophy in relation to visual functioning and vision-related quality of life in patients with multiple sclerosis.

BACKGROUND: Inner retinal layer atrophy in patients with multiple sclerosis (MS) has been validated as a structural imaging biomarker for neurodegeneration. OBJECTIVE: To determine how retinal layer thickness relates to high-contrast visual acuity (HCVA), low-contrast visual acuity (LCVA) and vision-related quality of life (QoL) and to investigate the effect of previous episodes on MS-associated optic neuritis (MSON). METHODS: Spectral-domain optical coherence tomography (SD-OCT) was performed in 267 patients with MS. Images were segmented for the peripapillary retinal nerve fiber layer (pRNFL) and the macular ganglion cell inner plexiform layer (GCIPL). Ophthalmological evaluations included history of MSON, HCVA, LCVA, and vision-related QoL. RESULTS: Independent of MSON, HCVA and LCVA were significantly associated with pRNFL and GCIPL thicknesses. Vision-related QoL was positively associated with pRNFL (ß = 0.92, p = 0.06) and GCIPL (ß = 0.93, p = 0.02) thicknesses. These associations were independent of MSON. Not only binocular but also monocular atrophy of the inner retinal layers was associated with lower vision-related QoL. CONCLUSION: This study showed that retinal atrophy has a significant impact on visual functioning in patients with MS. OCT may therefore provide useful insight to patients with visual dysfunction, and our findings support including OCT and vision-related QoL measures into optic neuritis treatment trials.

Cognitive impairment in patients with multiple sclerosis is associated with atrophy of the inner retinal layers.

BACKGROUND: Inner retinal layer (IRL) atrophy is a potential biomarker for neurodegeneration in multiple sclerosis (MS). OBJECTIVE: To investigate the relationship between cognitive impairment and IRL atrophy in MS. METHODS: Cross-sectional study design, including 217 patients and 59 healthy controls. Subjects were investigated clinically, underwent retinal optical coherence tomography (OCT) and comprehensive cognitive assessments. The association between these modalities was evaluated by regression analyses. RESULTS: Of the patients, 44.2% were cognitively impaired. In the absence of multiple sclerosis-associated optic neuritis (MSON), cognitively impaired patients had a significantly lower mean peripapillary retinal nerve fiber layer (pRNFL, Δ: 8.13 µm, p < 0.001) and mean macular ganglion cell-inner plexiform layer (mGCIPL, Δ: 11.50 µm, p < 0.001) thickness compared to cognitively preserved patients. There was a significant association between the presence of cognitive impairment and pRNFL (odds ratio (OR): 1.11, 95% confidence interval (CI): 1.04-1.18, p = 0.001) and mGCIPL (OR = 1.11, 95% CI = 1.05-1.18, p < 0.001) atrophy. This association was masked by the severe IRL atrophy seen following MSON. CONCLUSION: The strong relationship between cognitive impairment across multiple cognitive domains and atrophy of the pRNFL and mGCIPL in patients who never suffered from MSON suggests that OCT is useful in assessing central nervous system neurodegeneration in MS.

Switching natalizumab to fingolimod within 6 weeks reduces recurrence of disease activity in MS patients.

BACKGROUND: Natalizumab is an effective treatment in relapsing-remitting multiple sclerosis (MS). Mainly because of the risk of progressive multifocal leukoencephalopathy (PML), a substantial proportion of John Cunningham (JC) virus-positive patients switch to fingolimod. Previous reports show a clear benefit when the duration of a washout (WO) period of natalizumab is 0-3 months in comparison to longer WO periods. However, there is no consensus regarding the optimal duration of a WO period under 3 months. OBJECTIVE: We compared MS disease activity after different WO periods. In addition, we investigated several factors that possibly influence recurrence of disease activity, including serum natalizumab concentration and lymphocyte counts. METHODS: From a prospective observational cohort study of natalizumab-treated patients, we selected 52 patients who switched to fingolimod. We divided the patients in three groups (<6 weeks, 6-8 weeks, >8 weeks WO). Serum natalizumab concentration and lymphocyte count were assessed during and after natalizumab treatment. RESULTS: Patients with a WO period of >8 weeks had a significant higher recurrence of disease activity (odds ratio, 6.8; 95% confidence interval, 1.4-32.8) compared to patients with a WO period of <6 weeks. Serum natalizumab concentration and lymphocyte count did not predict recurrence of disease activity. INTERPRETATION: A short WO period decreases the risk of recurrence of disease activity. The possible impact of a short WO period on the risk of carry-over PML in JC virus-positive patients remains uncertain.

The International Multiple Sclerosis Visual System Consortium: Advancing Visual System Research in Multiple Sclerosis.

BACKGROUND: The International Multiple Sclerosis Visual System Consortium (IMSVISUAL) was formed in November 2014 with the primary goal of improving research, care, and education regarding the role of the visual system in multiple sclerosis (MS) and related disorders. METHODS: In this review, we describe the formation, goals, activities, and structure of IMSVISUAL, as well as the relationship of IMSVISUAL with the Americas Committee for Treatment and Research in MS (ACTRIMS). Finally, we provide an overview of the work IMSVISUAL has completed to date, as well as an outline of research projects ongoing under the auspices of IMSVISUAL. RESULTS: IMSVISUAL has 140 members worldwide and continues to grow. Through IMSVISUAL-related research, optical coherence tomography (OCT)-derived peripapillary retinal nerve fiber layer (pRNFL) thinning has been established as a predictor of future disability in MS. IMSVISUAL has also developed guidelines for reporting OCT studies in MS. Moreover, a systematic review performed by IMSVISUAL found that not only are pRNFL and ganglion cell + inner plexiform layer (GCIPL) thicknesses reduced in patients with MS (particularly in eyes with prior optic neuritis [ON]), but that inner nuclear layer measures may be higher among MS ON eyes, relative to healthy control eyes. Currently, there are several ongoing IMSVISUAL projects that will establish a role for visual outcomes in diagnosing MS and quantifying the effects of emerging therapies in clinical trials. CONCLUSIONS: The development of IMSVISUAL represents a major collaborative commitment to defining the role of visual outcomes in high-quality, large-scale studies that generate definitive and instructive findings in the field of MS. As a consortium, IMSVISUAL has completed several international collaborative projects, is actively engaged in numerous ongoing research studies, and is committed to expanding the role of vision research in MS and related disorders.

Cortical atrophy patterns in multiple sclerosis are non-random and clinically relevant.

Grey matter atrophy is common in multiple sclerosis. However, in contrast with other neurodegenerative diseases, it is unclear whether grey matter atrophy in multiple sclerosis is a diffuse 'global' process or develops, instead, according to distinct anatomical patterns. Using source-based morphometry we searched for anatomical patterns of co-varying cortical thickness and assessed their relationships with white matter pathology, physical disability and cognitive functioning. Magnetic resonance imaging was performed at 3 T in 208 patients with long-standing multiple sclerosis (141 females; age = 53.7 ± 9.6 years; disease duration = 20.2 ± 7.1 years) and 60 age- and sex-matched healthy controls. Spatial independent component analysis was performed on cortical thickness maps derived from 3D T1-weighted images across all subjects to identify co-varying patterns. The loadings, which reflect the presence of each cortical thickness pattern in a subject, were compared between patients with multiple sclerosis and healthy controls with generalized linear models. Stepwise linear regression analyses were used to assess whether white matter pathology was associated with these loadings and to identify the cortical thickness patterns that predict measures of physical and cognitive dysfunction. Ten cortical thickness patterns were identified, of which six had significantly lower loadings in patients with multiple sclerosis than in controls: the largest loading differences corresponded to the pattern predominantly involving the bilateral temporal pole and entorhinal cortex, and the pattern involving the bilateral posterior cingulate cortex. In patients with multiple sclerosis, overall white matter lesion load was negatively associated with the loadings of these two patterns. The final model for physical dysfunction as measured with Expanded Disability Status Scale score (adjusted R(2) = 0.297; P < 0.001) included the predictors age, overall white matter lesion load, the loadings of two cortical thickness patterns (bilateral sensorimotor cortex and bilateral insula), and global cortical thickness. The final model predicting average cognition (adjusted R(2) = 0.469; P < 0.001) consisted of age, the loadings of two cortical thickness patterns (bilateral posterior cingulate cortex and bilateral temporal pole), overall white matter lesion load and normal-appearing white matter integrity. Although white matter pathology measures were part of the final clinical regression models, they explained limited incremental variance (to a maximum of 4%). Several cortical atrophy patterns relevant for multiple sclerosis were found. This suggests that cortical atrophy in multiple sclerosis occurs largely in a non-random manner and develops (at least partly) according to distinct anatomical patterns. In addition, these cortical atrophy patterns showed stronger associations with clinical (especially cognitive) dysfunction than global cortical atrophy.

Multi-parametric structural magnetic resonance imaging in relation to cognitive dysfunction in long-standing multiple sclerosis.

BACKGROUND: Cognitive deficits are common in multiple sclerosis. Most previous studies investigating the imaging substrate of cognitive deficits in multiple sclerosis included patients with relatively short disease durations and were limited to one modality/brain region. OBJECTIVE: To identify the strongest neuroimaging predictors for cognitive dysfunction in a large cohort of patients with long-standing multiple sclerosis. METHODS: Extensive neuropsychological testing and multimodal 3.0T MRI was performed in 202 patients with multiple sclerosis and 52 controls. Cognitive scores were compared between groups using Z-scores. Whole-brain, white matter, grey matter, deep grey matter and lesion volumes; cortical thickness, (juxta)cortical and cerebellar lesions; and extent and severity of diffuse white matter damage were measured. Stepwise linear regression was used to identify the strongest predictors for cognitive dysfunction. RESULTS: All cognitive domains were affected in patients. Patients showed extensive atrophy, focal pathology and damage in up to 75% of the investigated white matter. Associations between imaging markers and average cognition were two times stronger in cognitively impaired patients than in cognitively preserved patients. The final model for average cognition consisted of deep grey matter DGMV volume and fractional anisotropy severity (adjusted R²=0.490; p<0.001). CONCLUSION: From all imaging markers, deep grey matter atrophy and diffuse white matter damage emerged as the strongest predictors for cognitive dysfunction in long-standing multiple sclerosis.

Functional brain networks: linking thalamic atrophy to clinical disability in multiple sclerosis, a multimodal fMRI and MEG study.

Thalamic atrophy is known to be one of the most important predictors for clinical dysfunction in multiple sclerosis (MS). As the thalamus is highly connected to many cortical areas, this suggests that thalamic atrophy is associated with disruption of cortical functional networks. We investigated this thalamo-cortical system to explain the presence of physical and cognitive problems in MS. Functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG) were performed in 86 MS patients and 21 healthy subjects. We computed cortical functional networks for fMRI and MEG by respectively the Pearson's correlation coefficient and the phase lag index using the same automated anatomical labeling atlas for both modalities. Thalamo-cortical functional connectivity was only estimated using fMRI. We computed conventional network metrics such as clustering coefficient and path length and analyzed the minimum spanning tree (MST), a subnetwork and backbone of the original network. MS patients showed reduced thalamic volumes and increased thalamo-cortical connectivity. MEG cortical functional networks showed a lower level of integration in MS in terms of the MST, whereas fMRI cortical networks did not differ between groups. Lower integration of MEG cortical functional networks was both related to thalamic atrophy as well as to increased thalamo-cortical functional connectivity in fMRI and to worse cognitive and clinical status. This study demonstrated for the first time that thalamic atrophy is associated with global disruption of cortical functional networks in MS and this global disruption of network activity was related to worse cognitive and clinical function in MS. Hum Brain Mapp 36:603-618, 2015. © 2014 Wiley Periodicals, Inc.

Toward the use of proxy reports for estimating long-term patient-reported outcomes in multiple sclerosis.

BACKGROUND: Assessment of disease impact in multiple sclerosis (MS) is usually driven by information obtained directly from patients using patient-reported outcomes. However, when patients' response in longitudinal studies is less reliable or missing, proxy respondents may be used. OBJECTIVE: The objective of this paper is to evaluate whether long-term patient scores can be reliably estimated using scores obtained from proxies. METHODS: Baseline, six-month and two-year data were collected from 155 patients and proxies on the physical scale of the Multiple Sclerosis Impact Scale (MSIS-29). Linear regression analyses were performed with the patient two-year scores as outcome, proxy two-year scores as predictor and other variables that could contribute to a better prediction of the patient follow-up score. RESULTS: The patient follow-up score could be predicted rather accurately (R(2) = 0.74) using the patient baseline score and the proxy follow-up score. The correlation between observed and predicted scores was 0.86. The model performed well in different follow-up durations and even better in an external cohort. CONCLUSION: A simple model of a constant value (intercept), the patient baseline score and the proxy follow-up score can predict patients' follow-up score on the physical impact of MS.

Disruption of structural and functional networks in long-standing multiple sclerosis.

Both gray matter atrophy and disruption of functional networks are important predictors for physical disability and cognitive impairment in multiple sclerosis (MS), yet their relationship is poorly understood. Graph theory provides a modality invariant framework to analyze patterns of gray matter morphology and functional coactivation. We investigated, how gray matter and functional networks were affected within the same MS sample and examined their interrelationship. Magnetic resonance imaging and magnetoencephalography (MEG) were performed in 102 MS patients and 42 healthy controls. Gray matter networks were computed at the group-level based on cortical thickness correlations between 78 regions across subjects. MEG functional networks were computed at the subject level based on the phase-lag index between time-series of regions in source-space. In MS patients, we found a more regular network organization for structural covariance networks and for functional networks in the theta band, whereas we found a more random network organization for functional networks in the alpha2 band. Correlation analysis revealed a positive association between covariation in thickness and functional connectivity in especially the theta band in MS patients, and these results could not be explained by simple regional gray matter thickness measurements. This study is a first multimodal graph analysis in a sample of MS patients, and our results suggest that a disruption of gray matter network topology is important to understand alterations in functional connectivity in MS as regional gray matter fails to take into account the inherent connectivity structure of the brain.

What explains gray matter atrophy in long-standing multiple sclerosis?

PURPOSE: To identify the measures of focal and diffuse white matter (WM) abnormalities that are related to whole-brain, deep, and cortical gray matter (GM) atrophy in long-standing multiple sclerosis (MS). MATERIALS AND METHODS: The institutional review board approved the study; all subjects gave written informed consent. Magnetic resonance (MR) imaging was performed at 3 T in 208 patients with MS of long-standing duration (disease duration ≥ 10 years) and in 60 healthy control subjects. Normalized GM volume (NGMV), normalized WM volume (NWMV), normalized deep GM volume (NDGMV), cortical thickness, and normalized lesion volume (NLV) were quantified. Tissue integrity of normal-appearing WM (NAWM) and lesions was measured by using diffusion-tensor MR imaging. Multivariate associations between measures of GM atrophy and WM abnormalities were assessed in the patient group by using multiple linear regression. RESULTS: NGMV, NDGMV, and cortical thickness were reduced in patients with MS (all P < .001). The final model for NGMV consisted of NWMV, NLV, and patient age and sex (adjusted R(2) = 0.58, P < .001). NWMV, NLV, and patient sex were the explanatory variables for NDGMV (adjusted R(2) = 0.75, P < .001). The model for cortical thickness consisted of fractional anisotropy of NAWM, NLV, and patient age and sex (adjusted R(2) = 0.32, P < .001). The relationship between GM atrophy and WM abnormalities was weaker in primary and secondary progressive disease than in relapsing-remitting disease. CONCLUSION: Whole-brain and deep GM atrophy were particularly explained by WM atrophy and lesion volume, while cortical atrophy was associated with NAWM integrity loss. The weaker relationship between GM atrophy and WM abnormalities in patients with progressive disease might indicate a more independent neurodegenerative disease process in these patients.

Do patient and proxy agree? Long-term changes in multiple sclerosis physical impact and walking ability on patient-reported outcome scales.

BACKGROUND: Patient-reported outcome scales (PROs) are useful in monitoring changes in multiple sclerosis (MS) over time. Although these scales are reliable and valid measures in longitudinal studies in MS patients, it is unknown what the impact is when obtaining longitudinal data from proxies. OBJECTIVE: The objective of this paper is to compare longitudinal changes in patient and proxy responses on PROs assessing physical impact of MS and walking ability. METHODS: In a prospective observational study, data on the Multiple Sclerosis Impact Scale (MSIS-29 physical) and Multiple Sclerosis Walking Scale (MSWS-12) were obtained from 137 patient-proxy couples at baseline and at two-year follow-up. Demographic and disease-related variables explaining agreement or disagreement between patients and proxies were investigated using linear regression analyses. RESULTS: Full agreement was found in 56% (MSIS) and 62% (MSWS) of the patient-proxy couples. Complete disagreement was very rare for both scales (2% MSIS, 5% MSWS). When patients were more positive than proxies, a higher age, longer disease duration, longer patient-proxy relationship and increased levels of depression, anxiety and caregiver burden in proxies were observed. CONCLUSION: In the majority of the patient-proxy couples there was agreement. Proxies can serve as a valuable source of information, but caution remains essential when using scores from proxies.

Mean upper cervical cord area (MUCCA) measurement in long-standing multiple sclerosis: relation to brain findings and clinical disability.

BACKGROUND: The majority of patients with multiple sclerosis (MS) present with spinal cord pathology. Spinal cord atrophy is thought to be a marker of disease severity, but in long-disease duration its relation to brain pathology and clinical disability is largely unknown. OBJECTIVE: Our aim was to investigate mean upper cervical cord area (MUCCA) in patients with long-standing MS and assess its relation to brain magnetic resonance imaging (MRI) measures and clinical disability. METHODS: MUCCA was measured in 196 MS patients and 55 healthy controls using 3DT1-weighted cervical images obtained at 3T MRI. Clinical disability was measured using the Expanded Disability Status Scale (EDSS), Nine-Hole-Peg test (9-HPT), and 25 feet Timed Walk Test (TWT). Stepwise linear regression was performed to assess the association between MUCCA and MRI measures, and between MUCCA and clinical disability. RESULTS: MUCCA was smaller (mean 11.7%) in MS patients compared with healthy controls (72.56±9.82 and 82.24±7.80 mm2 respectively; p<0.001), most prominently in male patients. MUCCA was associated with normalized brain volume, and number of cervical cord lesions. MUCCA was independently associated with EDSS, TWT, and 9-HPT. CONCLUSION: MUCCA was reduced in MS patients compared with healthy controls. It provides a relevant marker for clinical disability in long-standing disease, independent of other MRI measures.

Clinical relevance of serum natalizumab concentration and anti-natalizumab antibodies in multiple sclerosis.

BACKGROUND: Antibodies against natalizumab have been found in 4.5-14.1% of natalizumab-treated multiple sclerosis (MS) patients. If antibodies persist, they are associated with an adverse effect on treatment response. However, it has proved to be difficult to standardize anti-drug antibody measurements. OBJECTIVES: The purpose of this study was to evaluate the clinical and radiological impact of serum natalizumab concentrations and their relation with anti-natalizumab antibodies in MS patients. METHODS: In this prospective observational cohort study of 73 consecutive patients treated with natalizumab, we measured serum natalizumab levels and antibody titers before the start of natalizumab treatment, at weeks 12 and 24 and annually after natalizumab initiation. Antibodies against natalizumab were measured by radioimmunoassay and serum natalizumab concentrations using a newly developed enzyme linked immunosorbent assay (ELISA). Magnetic resonance imaging (MRI) scan and clinical evaluation were performed before the start of natalizumab treatment and subsequently every year. RESULTS: Antibodies were detected in 58% of the natalizumab-treated patients. All patients developed their antibodies before week 24. The large majority of these patients reverted to neutralizing antibody (NAb) negative status during follow-up. The presence of antibodies was inversely correlated with serum natalizumab concentration (p<0.001). Only high antibody titers are associated with very low or undetectable serum natalizumab concentration. Both high antibody titers and low serum natalizumab concentrations are associated with relapses and gadolinium-enhancing lesions on MRI. CONCLUSIONS: Our data show that both low natalizumab serum concentration and high antibody titers are associated with a lack of efficacy of natalizumab. Measuring serum natalizumab, using a highly specific assay, might lead to more enhanced precision using natalizumab in individual patients.

The Role of Optical Coherence Tomography Criteria and Machine Learning in Multiple Sclerosis and Optic Neuritis Diagnosis.

BACKGROUND AND OBJECTIVES: Recent studies have suggested that intereye differences (IEDs) in peripapillary retinal nerve fiber layer (pRNFL) or ganglion cell + inner plexiform (GCIPL) thickness by spectral domain optical coherence tomography (SD-OCT) may identify people with a history of unilateral optic neuritis (ON). However, this requires further validation. Machine learning classification may be useful for validating thresholds for OCT IEDs and for examining added utility for visual function tests, such as low-contrast letter acuity (LCLA), in the diagnosis of people with multiple sclerosis (PwMS) and for unilateral ON history. METHODS: Participants were from 11 sites within the International Multiple Sclerosis Visual System consortium. pRNFL and GCIPL thicknesses were measured using SD-OCT. A composite score combining OCT and visual measures was compared individual measurements to determine the best model to distinguish PwMS from controls. These methods were also used to distinguish those with a history of ON among PwMS. Receiver operating characteristic (ROC) curve analysis was performed on a training data set (2/3 of cohort) and then applied to a testing data set (1/3 of cohort). Support vector machine (SVM) analysis was used to assess whether machine learning models improved diagnostic capability of OCT. RESULTS: Among 1,568 PwMS and 552 controls, variable selection models identified GCIPL IED, average GCIPL thickness (both eyes), and binocular 2.5% LCLA as most important for classifying PwMS vs controls. This composite score performed best, with area under the curve (AUC) = 0.89 (95% CI 0.85-0.93), sensitivity = 81%, and specificity = 80%. The composite score ROC curve performed better than any of the individual measures from the model (p < 0.0001). GCIPL IED remained the best single discriminator of unilateral ON history among PwMS (AUC = 0.77, 95% CI 0.71-0.83, sensitivity = 68%, specificity = 77%). SVM analysis performed comparably with standard logistic regression models. DISCUSSION: A composite score combining visual structure and function improved the capacity of SD-OCT to distinguish PwMS from controls. GCIPL IED best distinguished those with a history of unilateral ON. SVM performed as well as standard statistical models for these classifications. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that SD-OCT accurately distinguishes multiple sclerosis from normal controls as compared with clinical criteria.

Clinico-radiological dissociation of disease activity in MS patients: frequency and clinical relevance.

OBJECTIVE: To investigate the prevalence and clinical relevance regarding disability progression in multiple sclerosis patients with a dissociation in clinical and radiological disease expression. METHODS: We prospectively selected patients with early relapsing-remitting multiple sclerosis (MS) or a clinically isolated syndrome (CIS) from the Amsterdam MS cohort. Patients underwent clinical examination at baseline, after 2 years, 6 years and a subset also after 11 years, including the Expanded Disability Status Scale (EDSS), 25-foot walk test (25-FWT) and 9-hole peg test (9-HPT). Brain and spinal cord MRI scans were obtained at baseline and after 2 years. Two years after baseline, patients with dissociation in their clinical and radiological disease progression were identified as: (1) patients with high clinical disease activity (defined by relapses) and low radiological disease activity (defined by white-matter lesions on T2-weighted imaging); or (2) patients with low clinical disease activity and high radiological disease activity. Binary logistic regression analyses were performed to predict disability progression after 6 and 11 years of follow-up. Patients with low clinical and low radiological disease activity were used as the reference group. RESULTS: The prevalence of clinico-radiological dissociation was low (6.4% had high clinical and low radiological disease activity and 5.1% had a combination of low clinical and high radiological disease activity) compared to 88.5% of patients without a dissociation. Patients with a dissociation of clinical and radiological disease activity did not show a statistically significant difference in risk of disability progression after 6 and 11 years. CONCLUSIONS: A clinico-radiological dissociation is rather a rare phenomenon in MS patients. The clinical relevance of such a dissociation regarding the prediction of disability progression is questionable.