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 (β = 0.92, p = 0.06) and GCIPL (β = 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

Multiple sclerosis and drug discovery:A work of translation

Multiple sclerosis (MS) is after trauma the most important neurological disease in young adults, affecting 1 per 1000 individuals. With currently available medications, most of these targeting the immune system, satisfactory results have been obtained in patients with relapsing MS, but these can have serious adverse effects. Moreover, despite some promising developments, such as with B cell targeting therapies or sphingosine-1-phosphate modulating drugs, there still is a high unmet need of safe drugs with broad efficacy in patients with progressive MS. Despite substantial investments and intensive preclinical research, the proportion of promising lead compounds that reaches the approved drug status remains disappointingly low. One cause lies in the poor predictive validity of MS animal models used in the translation of pathogenic mechanisms into safe and effective treatments for the patient. This disturbing situation has raised criticism against the relevance of animal models used in preclinical research and calls for improvement of these models. This publication presents a potentially useful strategy to enhance the predictive validity of MS animal models, namely, to analyze the causes of failure in forward translation (lab to clinic) via reverse translation (clinic to lab). Through this strategy new insights can be gained that can help generate more valid MS models

Asymptomatic spinal cord lesions do not predict the time to disability in patients with early multiple sclerosis

BACKGROUND: The presence of asymptomatic spinal cord (SC) lesions in patients with clinically isolated syndrome (CIS) or relapsing-remitting multiple sclerosis (RRMS) predicts conversion to clinically definite multiple sclerosis (CDMS). The relation between asymptomatic SC abnormalities and disability progression warrants further investigation. OBJECTIVE: To determine the prognostic value of asymptomatic SC lesions in CIS and early RRMS with respect to the time to disability development. METHODS: Clinical and demographic data, brain and SC magnetic resonance imaging (MRI) were collected of CIS or early RRMS patients. Two main analyses were performed. For the first analysis, patients were divided into two groups: (1) patients with asymptomatic SC lesions and (2) patients without SC lesions and patients with symptomatic SC lesions. The second analysis excluded patients with symptomatic SC lesions. Incidence curves were used to analyse differences between these groups in time to the development of disability and time to a second relapse. RESULTS: A total of 178 patients were included, and 42 patients (23.6%) had asymptomatic SC lesions. No significant differences were found on the time to disability development or the time to a second event. CONCLUSION: Asymptomatic SC lesions early in the disease course do not predict the time to disability development in patients diagnosed with CIS or early RRMS

The Physiological Variation of the Retinal Nerve Fiber Layer Thickness and Macular Volume in Humans as Assessed by Spectral Domain-Optical Coherence Tomography

Purpose.: With the introduction of spectral domain–optical coherence tomography (SD-OCT), changes in retinal nerve fiber layer (RNFL) thickness and macular volume (MV) can be detected with high precision. The aim of this study was to determine whether there is a physiological quantifiable degree of variation of these structures in humans. Methods.: This study took place during a 10-km charity run at VU University Medical Center Amsterdam. Weight, height, hydration status, RNFL thickness (ring scan, 12° around the optic nerve head), and MV (20° × 20°) were assessed in 69 subjects (44 runners, 25 controls) using SD-OCT with eye-tracking function. The SD-OCT scans were assessed before running (normal status), after running (more dehydrated status), and 1 to 1.5 hours after finishing the run (rehydrated status). Controls were measured at the same time intervals as the runners but did not participate in the running event. Changes over time were assessed by general linear models, correcting for repeated measurements. Results.: In runners, a significant increase in both RNFL thickness (94.4 μm [baseline] to 95.2 μm [rehydration], P = 0.04) and MV (288.9 μm [baseline] to 291.0 μm [rehydration], P < 0.001) over time was observed. Controls did not show significant changes over time. Anatomically, the physiological change of RNFL thickness was most marked in the nasal sectors. Conclusions.: This prospective study demonstrated a significant physiological variation of the RNFL thickness and MV at a proportion that, on an individual patient level, may be relevant for longitudinal studies in neurodegenerative diseases

Cerebral rituximab uptake in multiple sclerosis: A (89)Zr-immunoPET pilot study

Previous studies have demonstrated that the chimeric monoclonal antibody rituximab significantly reduces clinical and radiological disease activity in relapsing-remitting multiple sclerosis as early as 4 weeks after the first administration. The exact mechanisms leading to this rapid effect have not yet been clarified. The aim of this positron emission tomography study was to assess central nervous system penetration as a possible explanation, using zirconium-89-labelled rituximab. No evidence was found for cerebral penetration of [(89)Zr]rituximab

Cerebrospinal fluid anti-myelin antibodies are related to magnetic resonance measures of disease activity in multiple sclerosis

0.001), together constituting 85% of all positive CSF samples. In contrast, elevated anti-myelin IgG antibody reactivity was present in a minority of IND patients (21%), marginally present in controls (5%) and absent in OND patients (0%). Most strikingly, anti-myelin IgG antibody reactivity was related to the number of T2 lesions (r = 0.31, p = 0.041) and gadolinium enhancing T1 lesions (r = 0.37, p = 0.016) on brain MRI in CIS and relapse onset MS patients. Conclusion: CSF anti-myelin IgG antibodies are promising specific biomarkers in CIS and relapse onset MS and correlate with MR measures of disease activit

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

Concomitant granule cell neuronopathy in patients with natalizumab-associated PML

Granule cell neuronopathy (GCN) is a rare JC virus infection of the cerebellar granule cell neurons in immunocompromised patients. On brain imaging, GCN is characterized by cerebellar atrophy which can be accompanied by infratentorial white matter lesions. The objective of this study is to investigate the prevalence of MRI findings suggestive of GCN in a large natalizumab-associated progressive multifocal leukoencephalopathy (PML) cohort. MRI scans from before, at the time of, and during follow-up after diagnosis of PML in 44 natalizumab-treated MS patients, and a control group of 25 natalizumab-treated non-PML MS patients were retrospectively reviewed for imaging findings suggestive of GCN. To assess and quantify the degree of cerebellar atrophy, we used a 4 grade rating scale. Three patients in the PML group showed imaging findings suggestive of GCN and none in the control group. In two of these PML patients, cerebellar atrophy progressed from grade 0 at the time of diagnosis of isolated supratentorial PML to grade 1 and 2 after 2.5 and 3 months, respectively, in the absence of infratentorial white mater lesions. The third patient had grade 1 cerebellar atrophy before diagnosis of infra- and supratentorial PML, and showed progression of cerebellar atrophy to grade 2 in the 3 months following PML diagnosis. None of the other eight patients with infratentorial PML lesions developed cerebellar atrophy suggestive of GCN. Three cases with imaging findings suggestive of GCN were detected among 44 natalizumab-associated PML patients. GCN may, therefore, be more common than previously considered in natalizumab-associated PML patients

Upper cervical cord atrophy is independent of cervical cord lesion volume in early multiple sclerosis: A two-year longitudinal study

Background: Upper cervical cord atrophy and lesions have been shown to be associated with disease and disability progression already in early relapsing-remitting multiple sclerosis (RRMS). However, their longitudinal relationship remains unclear. Objective: To investigate the cross-sectional and longitudinal relation between focal T2 cervical cord lesion volume (CCLV) and regional and global mean upper cervical cord area (UCCA), and their relations with disability. Methods: Over a two-year interval, subjects with RRMS (n = 36) and healthy controls (HC, n = 16) underwent annual clinical and MRI examinations. UCCA and CCLV were obtained from C1 through C4 level. Linear mixed model analysis was performed to investigate the relation between UCCA, CCLV, and disability over time. Results: UCCA at baseline was significantly lower in RRMS subjects compared to HCs (p = 0.003), but did not decrease faster over time (p ≥ 0.144). UCCA and CCLV were independent of each other at any of the time points or cervical levels, and over time. Lower baseline UCCA, but not CCLV, was related to worsening of both upper and lower extremities function over time. Conclusion: UCCA and CCLV are independent from each other, both cross-sectionally and longitudinally, in early MS. Lower UCCA, but not CCLV, was related to increasing disability over time

Real-world keystroke dynamics are a potentially valid biomarker for clinical disability in multiple sclerosis

Background: Clinical measures in multiple sclerosis (MS) face limitations that may be overcome by utilising smartphone keyboard interactions acquired continuously and remotely during regular typing. Objective: The aim of this study was to determine the reliability and validity of keystroke dynamics to assess clinical aspects of MS. Methods: In total, 102 MS patients and 24 controls were included in this observational study. Keyboard interactions were obtained with the Neurokeys keyboard app. Eight timing-related keystroke features were assessed for reliability with intraclass correlation coefficients (ICCs); construct validity by analysing group differences (in fatigue, gadolinium-enhancing lesions on magnetic resonance imaging (MRI), and patients vs controls); and concurrent validity by correlating with disability measures. Results: Reliability was moderate in two (ICC = 0.601 and 0.742) and good to excellent in the remaining six features (ICC = 0.760–0.965). Patients had significantly higher keystroke latencies than controls. Latency between key presses correlated the highest with Expanded Disability Status Scale (r = 0.407) and latency between key releases with Nine-Hole Peg Test and Symbol Digit Modalities Test (ρ = 0.503 and r = −0.553, respectively), ps < 0.001. Conclusion: Keystroke dynamics were reliable, distinguished patients and controls, and were associated with clinical disability measures. Consequently, keystroke dynamics are a promising valid surrogate marker for clinical disability in MS