Measuring and predicting the effect of remyelinating therapy in multiple sclerosis: a randomised controlled trial protocol (RESTORE).

INTRODUCTION: Remyelination failure hampers symptomatic recovery in multiple sclerosis (MS), underlining the importance of developing remyelinating therapies. Optic neuritis is currently the most established method of measuring remyelination in MS trials. Complementary more generalisable methods of measuring remyelination are required to confirm treatment efficacy. Measuring internuclear ophthalmoplegia (INO) with infrared oculography provides such a method. Moreover, this method can be expanded with a test for selecting likely treatment responders by using fampridine. The aim of this trial is to investigate the (long-term) remyelinating effects of clemastine fumarate in patients with MS and INO and to evaluate if treatment response can be predicted using fampridine. METHODS AND ANALYSIS: RESTORE is a single-centre double-blind randomised placebo-controlled trial of clemastine fumarate versus placebo. Prior to clemastine treatment improvement in oculographic features of INO after a single 10 mg dose of fampridine is measured in all participants and used to predict the treatment response to clemastine. Eighty individuals with MS and INO will be 1:1 randomised to 4 mg of clemastine fumarate two times a day for 6 months or equivalent placebo. Our primary outcome is improvement in the Versional Dysconjugacy Index-area under the curve, measured by infrared oculography after 6 months of treatment. Participants are assessed for persistent treatment effects 6, 18 and 30 months after end of treatment. Secondary outcome measures include other oculography parameters including double-step saccades, retinal imaging, visual acuities, physical disability, cognition and patient-reported outcomes. ETHICS AND DISSEMINATION: Clemastine is a registered and very well-established drug with well-known safety and side effects. The protocol was approved by the medical ethical committee of the Amsterdam UMC, location VUMC and the Dutch Central Committee on Research Involving Human Subject. Written informed consent is obtained from all participants. The results will be published in peer-reviewed medical scientific journals. TRIAL REGISTRATION NUMBER: EudraCT: 2021-003677-66, ClinicalTrials.gov: NCT05338450.

Clinical review of retinotopy.

Two observations made 29 years apart are the cornerstones of this review on the contributions of Dr Gordon T. Plant to understanding pathology affecting the optic nerve. The first observation laid the anatomical basis in 1990 for the interpretation of optical coherence tomography (OCT) findings in 2009. Retinal OCT offers clinicians detailed in vivo structural imaging of individual retinal layers. This has led to novel observations which were impossible to make using ophthalmoscopy. The technique also helps to re-introduce the anatomically grounded concept of retinotopy to clinical practise. This review employs illustrations of the anatomical basis for retinotopy through detailed translational histological studies and multimodal brain-eye imaging studies. The paths of the prelaminar and postlaminar axons forming the optic nerve and their postsynaptic path from the dorsal lateral geniculate nucleus to the primary visual cortex in humans are described. With the mapped neuroanatomy in mind we use OCT-MRI pairings to discuss the patterns of neurodegeneration in eye and brain that are a consequence of the hard wired retinotopy: anterograde and retrograde axonal degeneration which can, within the visual system, propagate trans-synaptically. The technical advances of OCT and MRI for the first time enable us to trace axonal degeneration through the entire visual system at spectacular resolution. In conclusion, the neuroanatomical insights provided by the combination of OCT and MRI allows us to separate incidental findings from sinister pathology and provides new opportunities to tailor and monitor novel neuroprotective strategies.

A novel eye-movement impairment in multiple sclerosis indicating widespread cortical damage.

In multiple sclerosis, remyelination trials have yet to deliver success like that achieved for relapse rates with disease course modifying treatment trials. The challenge is to have a clinical, functional outcome measure. Currently, there are none that have been validated, other than visual evoked potentials in optic neuritis. Like vision, quick eye movements (saccades) are heavily dependent on myelination. We proposed that it is possible to extrapolate from demyelination of the medial longitudinal fasciculus in the brainstem to quantitative assessment of cortical networks governing saccadic eye movements in multiple sclerosis. We have developed and validated a double-step saccadic test, which consists of a pair of eye movements towards two stimuli presented in quick succession (the demonstrate eye movement networks with saccades protocol). In this single-centre, cross-sectional cohort study we interrogated the structural and functional relationships of double-step saccades in multiple sclerosis. Data were collected for double-step saccades, cognitive function (extended Rao's Brief Repeatable Battery), disability (Expanded Disability Status Scale) and visual functioning in daily life (National Eye Institute Visual Function Questionnaire). MRI was used to quantify grey matter atrophy and multiple sclerosis lesion load. Multivariable linear regression models were used for analysis of the relationships between double-step saccades and clinical and MRI metrics. We included 209 individuals with multiple sclerosis (mean age 54.3 ± 10.5 years, 58% female, 63% relapsing-remitting multiple sclerosis) and 60 healthy control subjects (mean age 52.1 ± 9.2 years, 53% female). The proportion of correct double-step saccades was significantly reduced in multiple sclerosis (mean 0.29 ± 0.22) compared to controls (0.45 ± 0.22, P < 0.001). Consistent with this, there was a significantly larger double-step dysmetric saccadic error in multiple sclerosis (mean vertical error -1.18 ± 1.20°) compared to controls (-0.54 ± 0.86°, P < 0.001). Impaired double-step saccadic metrics were consistently associated with more severe global and local grey matter atrophy (correct responses-cortical grey matter: ß = 0.42, P < 0.001), lesion load (vertical error: ß = -0.28, P < 0.001), progressive phenotypes, more severe physical and cognitive impairment (correct responses-information processing: ß = 0.46, P < 0.001) and visual functioning. In conclusion, double-step saccades represent a robust metric that revealed a novel eye-movement impairment in individuals with multiple sclerosis. Double-step saccades outperformed other saccadic tasks in their statistical relationship with clinical, cognitive and visual functioning, as well as global and local grey matter atrophy. Double-step saccades should be evaluated longitudinally and tested as a potential novel outcome measure for remyelination trials in multiple sclerosis.

Retinal inter-eye difference and atrophy progression in multiple sclerosis diagnostics.

BACKGROUND: The visual system could be included in the diagnostic criteria for multiple sclerosis (MS) to demonstrate dissemination in space (DIS) and dissemination in time (DIT). OBJECTIVE: To investigate the diagnostic value of retinal asymmetry in MS. METHODS: A prospective, longitudinal study in individuals with MS (n=151) and healthy controls (n=27). Optical coherence tomography (OCT) was performed at 0, 2 and 4 years. Macular ganglion cell and inner plexiform layer (mGCIPL) thickness was determined as well as measures for retinal asymmetry: the inter-eye percentage difference (IEPD) and inter-eye absolute difference (IEAD). Receiver operator characteristics curves were plotted and the area under the curve (AUC) was calculated for group comparisons of the mGCIPL, IEPD, IEAD and atrophy rates. RESULTS: The diagnostic accuracy of both the IEPD and IEAD for differentiating bilateral and unilateral MS optic neuritis was high and stable over time (AUCs 0.88-0.93). The IEPD slightly outperformed the IEAD. Atrophy rates showed low discriminatory abilities for differentiating MS from controls (AUC 0.49-0.58). CONCLUSION: The inter-eye differences of the mGCIPL have value for demonstration of DIS but in individuals with longstanding MS not for DIT. This may be considered as a test to detect DIS in future diagnostic criteria. Validation in a large prospective study in people presenting with symptoms suggestive of MS is required.

Artificial intelligence extension of the OSCAR-IB criteria.

Artificial intelligence (AI)-based diagnostic algorithms have achieved ambitious aims through automated image pattern recognition. For neurological disorders, this includes neurodegeneration and inflammation. Scalable imaging technology for big data in neurology is optical coherence tomography (OCT). We highlight that OCT changes observed in the retina, as a window to the brain, are small, requiring rigorous quality control pipelines. There are existing tools for this purpose. Firstly, there are human-led validated consensus quality control criteria (OSCAR-IB) for OCT. Secondly, these criteria are embedded into OCT reporting guidelines (APOSTEL). The use of the described annotation of failed OCT scans advances machine learning. This is illustrated through the present review of the advantages and disadvantages of AI-based applications to OCT data. The neurological conditions reviewed here for the use of big data include Alzheimer disease, stroke, multiple sclerosis (MS), Parkinson disease, and epilepsy. It is noted that while big data is relevant for AI, ownership is complex. For this reason, we also reached out to involve representatives from patient organizations and the public domain in addition to clinical and research centers. The evidence reviewed can be grouped in a five-point expansion of the OSCAR-IB criteria to embrace AI (OSCAR-AI). The review concludes by specific recommendations on how this can be achieved practically and in compliance with existing guidelines.

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.

Quantification of Visual Fixation in Multiple Sclerosis.

Purpose: Eye movement abnormalities are common in multiple sclerosis (MS), and infrared oculography is a noninvasive method for quantification. This study aims to describe and classify abnormalities of visual fixation and their clinical relevance in MS. Methods: A validated standardized infrared oculography protocol, Demonstrate Eye Movement Networks with Saccades, was used for quantifying gaze stability during a fixation task in MS patients and healthy controls. Saccadic intrusions, gaze drift, and stability of fixation around the drift line were used to subclassify MS patients by performing receiver operating characteristic analyses of different parameters. The relationship between the presence of abnormalities of fixation and visual functioning was analyzed using logistic regression models, which was adjusted for possible confounders. Results: This cross-sectional study included 213 subjects with MS and 57 healthy controls. Square wave jerk abnormalities were present in 24% of MS patients. The prevalence was higher in more disabled subjects. The presence of larger square wave jerks (with a higher amplitude) in the MS patients was related to complaints of focusing on stationary objects (odds ratio, 2.2; P = 0.035) and a lower vision-related quality of life (odds ratio, 2.56; P = 0.012). Conclusions: This study provided a comprehensive overview of the characteristics of problems with visual fixation in subjects with MS. The most important and most common finding was the presence of larger square wave jerks during fixation, which was related to visual functioning in daily life.

Treatment of internuclear ophthalmoparesis in multiple sclerosis with fampridine: A randomized double-blind, placebo-controlled cross-over trial.

AIM: To examine whether the velocity of saccadic eye movements in internuclear ophthalmoparesis (INO) improves with fampridine treatment in patients with multiple sclerosis (MS). METHODS: Randomized, double-blind, placebo-controlled, cross-over trial with fampridine in patients with MS and INO. Horizontal saccades were recorded at baseline and at multiple time points post-dose. Main outcome measures were the change of peak velocity versional dysconjugacy index (PV-VDI) and first-pass amplitude VDI (FPA-VDI). Both parameters were compared between fampridine and placebo using a mixed model analysis of variance taking patients as their own control. Pharmacokinetics was determined by serial blood sampling. RESULTS: Thirteen patients had a bilateral and 10 had a unilateral INO. One patient had an INO of abduction (posterior INO of Lutz) and was excluded. Fampridine significantly reduced both PV-VDI (-17.4%, 95% CI: -22.4%, -12.1%; P < 0.0001) and FPA-VDI (-12.5%, 95% CI: -18.9%, -5.5%; P < 0.01). Pharmacokinetics demonstrated that testing coincided with the average tmax at 2.08 hours (SD 45 minutes). The main adverse event reported after administration of fampridine was dizziness (61%). CONCLUSION: Fampridine improves saccadic eye movements due to INO in MS. Treatment response to fampridine may gauge patient selection for inclusion to remyelination strategies in MS using saccadic eye movements as primary outcome measure.

The Pulfrich Phenomenon: Practical Implications of the Assessment of Cases and Effectiveness of Treatment.

The Pulfrich phenomenon, originally described in normal observers, is a treatable disorder of the perception of movement in depth in cases of unilateral or asymmetric optic neuropathy. Treatment is highly bespoke and factors influencing treatment response and failure remain unclear. We assessed 25 adults with suspected Pulfrich phenomenon due to a range of conditions in two tertiary referral centres. Monocularly tinted spectacles were successful in reducing symptoms of the Pulfrich phenomenon under daylight conditions in nine subjects, eight of whom had optic neuritis. These spectacles were not effective at night and in patients with visual field defects due to ischaemic optic neuropathy, glaucoma, optic disc drusen or severe peripapillary retinal nerve fibre loss on optical coherence tomography.

The role of optical coherence tomography and infrared oculography in assessing the visual pathway and CNS in multiple sclerosis.

In this review, a current overview is provided of how optical coherence tomography and infrared oculography can aid in assessing the visual system and CNS in multiple sclerosis (MS). Both afferent and efferent visual disorders are common in MS and visual complaints can have a tremendous impact on daily functioning. Optical coherence tomography and infrared oculography can detect and quantify visual disorders with high accuracy, but could also serve as quantitative markers for inflammation, neurodegeneration and network changes including cognitive decline in MS patients. The assessment of the efferent and afferent visual pathways is relevant for monitoring and predicting the disease course, but is also potentially valuable as an outcome measure in therapeutic trials.

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.

Recovery to Preinterventional Functioning, Return-to-Work, and Life Satisfaction After Treatment of Unruptured Aneurysms.

BACKGROUND AND PURPOSE: The eventual goal of preventive treatment of unruptured intracranial aneurysms is to increase the number of life years with high life satisfaction. Insight in the time with reduced functioning, working capacity, and life satisfaction after aneurysm treatment is pivotal to balance the pros and cons of preventive aneurysm occlusion. METHODS: We sent a questionnaire on time-to-recovery to preintervention functioning and return-to-work and life satisfaction to patients treated for an unruptured aneurysm between 2000 and 2013. Changes in life satisfaction before treatment, during recovery, and at follow-up were assessed with Wilcoxon signed-rank tests. RESULTS: The questionnaire was sent to 159 patients of whom 110 (69%) responded. The mean follow-up time after aneurysm treatment was 6 years (SD 4). Fifty-four patients had endovascular and 56 had microsurgical occlusion. Complete recovery to preintervention functioning was reported by 81% (95% confidence interval [CI], 74-88) of patients, with a median time-to-recovery of 3 months (range 0-48). Complete work recovery was reported by 78% (95% CI, 66-87) of patients. The proportion of patients with high life satisfaction reduced from 76% (95% CI, 67-84) before treatment to 52% (95% CI, 43-61) during the period of recovery (P<0.01) and restored largely at long-term follow-up (67% [95% CI, 59-76], P=0.08). CONCLUSION: Life satisfaction is significantly reduced during the period of recovery after treatment of unruptured aneurysms. In the long-term, ≈1 out of 5 patients reports incomplete recovery. These treatment effects should be kept in mind when considering preventive aneurysm treatment. Prospective studies are needed to better compare these losses in patients treated for unruptured aneurysms with those who had subarachnoid hemorrhage.

Rapid Systematic Review of the Epley Maneuver for Treating Posterior Canal Benign Paroxysmal Positional Vertigo.

OBJECTIVE: The aim of this study was to compare watchful waiting to the Epley maneuver as a management option for patients with posterior canal benign paroxysmal positional vertigo (p-BPPV) regarding symptom relief. DATA SOURCES: PubMed, Embase, and The Cochrane Library. METHODS: A systematic search was conducted. Studies reporting original study data were included. Relevance and risk of bias (RoB) of the selected articles were assessed. Studies with low relevance, high RoB, or both were excluded. Absolute risk differences and their 95% confidence intervals (CIs) were extracted for the included studies. RESULTS: A total of 1448 unique studies were retrieved. Eight of these satisfied the eligibility criteria. At 1-week follow-up, all included studies reported a clinically relevant effect in favor of the Epley maneuver regarding symptom relief (absolute risk differences ranging from 20% [95% CI, 5%-37%] to 59% [95% CI, 32%-76%]) or conversion to a negative Dix-Hallpike (absolute risk differences ranging from 17% [95% CI, -5%-37%] to 64% [95% CI, 29%-79%]). At 1-month follow-up, the results of the included studies diverged further. Absolute risk differences ranged from 6% (95% CI, -24%-35%) more symptom relief in favor of watchful waiting to 79% (95% CI, 56%-88%) in favor of the Epley maneuver. CONCLUSION AND RECOMMENDATIONS: All data of the selected studies show a benefit in favor of the Epley maneuver at 1-week follow-up in the management of p-BPPV. The Epley maneuver should be considered in all patients with p-BPPV.