Author Of 5 Presentations
P0499 - The epidemiology of optic neuritis in the United Kingdom and implications for consensus diagnostic criteria for multiple sclerosis. (ID 409)
Abstract
Background
The epidemiology of optic neuritis (ON) has been studied less carefully than the epidemiology of multiple sclerosis (MS). The association of ON with many other diseases poses one of several challenges for inclusion of ON in consensus diagnostic criteria for MS.
Objectives
To investigate current trends in ON incidence, prevalence and associations with systemic and neurological diseases in the United Kingdom (UK).
Methods
We used The Health Improvement Network (THIN), a nationally representative primary care records database to conduct a retrospective cross-sectional and population cohort study (1997-2018), and matched case-control and cohort study (1995-2020) (matched 4:1 on age, sex, region and Townsend Deprivation Index[TDI]).
Results
We included 11,086,469 patients with 75 million patient-years of follow-up. Amongst 2,895 incident cases with ON, 69.5%(n=2011) were female (mean age at diagnosis 41.6 (sd15.6)), 92.5% (n=1,227/1,326) were white and 24.9% were in TDI quintile 1 (no deprivation). The annual point prevalence (per 100,000 people) steadily increased from 69.3 (95%CI 57.2-81.3) in 1997 to 114.8 (95%CI 111.0-118.6) in 2018. The annual incidence rate was stable over 22 years, at 3.7 (95% CI 3.6-3.9) per 100,000 person-years. Highest risk of incident ON was associated with female sex, obesity, reproductive age, mixed or South Asian ethnicity, smoking, and Scottish residence; compared to children ≤10 years at cohort entry, adjusted incident rate ratio was >6-fold higher in women aged 21-40 years (p<0.001). In multivariable logistic regression, ON cases had significantly higher odds of prior diagnosis of MS (17.3%, OR 98.2, 95%CI 65.4-147.5), syphilis (0.2%, OR 5.8, 95%CI 1.4-23.7), mycoplasma (0.2%, OR3.90,1.09-13.93), vasculitis(0.5%, OR3.70,1.68-8.15), sarcoidosis(0.5%, OR2.50,1.21-5.18), Epstein Barr virus(3.8% OR2.29,1.80-2.92), Crohn’s disease(0.7%, OR1.97,1.13-3.43), and psoriasis(4.3%, OR1.28,1.03-1.58). ON patients had significantly higher hazard of incident MS(adjusted HR285.0,167.9-483.8), Behçet’s disease(HR17.4,1.6-195.5), sarcoidosis(HR14.8,4.9-45.1), vasculitis(HR4.9,1.8-13.1), Sjögren’s syndrome(HR3.5,1.4-8.8), and herpetic infection (HR1.7,1.2-2.3).
Conclusions
This large, population-representative study reveals stable incidence of ON in the UK over a 22-year period, and provides evidence-based guidance for investigation of MS and non-MS ON. Careful exclusion of non-MS ON patients, a sizable proportion, will be relevant for future revision of consensus MS diagnostic criteria, to minimize misdiagnosis.
P0763 - A longitudinal study validating the optical coherence tomography inter-eye difference as a robust diagnostic test in multiple sclerosis (ID 1383)
Abstract
Background
Dissemination in space is one of two conceptional columns on which consensus diagnostic criteria of multiple sclerosis (MS) rests. Consistently cross-sectional data has demonstrated that optical coherence tomography (OCT) can be used to reveal the inter-eye difference of retinal layers as an additional para-clinical test in this context.
Objectives
To test the validity of the inter-eye difference of retinal layers as a diagnostic test in multiple sclerosis longitudinally.
Methods
Patients with multiple sclerosis and healthy controls who were longitudinally followed up at the Multiple Sclerosis Centre Amsterdam underwent OCT assessment at baseline and two year follow-up. We calculated the inter-eye percentage difference (IEPD) for the macular ganglion-cell inner plexiform layer (mGCIPL). Previously published cut-off levels (IMSVISUAL) were used to calculate diagnostic sensitivity and specificity levels.
Results
We included 199 participants of which 39 were healthy controls (HC). Patients with multiple sclerosis either had never experienced a clinical attack of optic neuritis (Non-MSON, n=81), suffered from unilateral MSON (n=48) or bilateral MSON (n=31). Longitudinal progression on the EDSS was less marked in these groups compared to longitudinal progression of mGCIPL atrophy. At baseline the diagnostic sensitivity and specificity values for the IEPD of the mGCIPL for comparing HC with unilateral MSON were 70%/97%, and with bilateral MSON 86%/97%. At two year follow-up the respective diagnostic sensitivity and specificity levels were 71%/97% and 83%/97%.
Conclusions
The inter-eye difference of the mGCIPL could be validated as a robust para-clinical test for multiple sclerosis longitudinally. These data were based on presence of a clinical episode of either unilateral or bilateral MSON. Extension of this approach to consider asymptomatic optic nerve pathology is warranted to further increase diagnostic sensitivity levels.
P0764 - A prognostically relevant functional-structural relationship in acute optic neuritis (ID 1569)
Abstract
Background
In the setting of acute optic neuritis (ON) it can be difficult to accurately predict clinical recovery and differentiate between the various associated syndromes.
Objectives
To prospectively investigate if comprehensive electrodiagnostic testing in acute optic neuritis (ON) can predict functional recovery or identify differences between ON subtypes.
Methods
Patients presenting with acute typical demyelinating ON and controls underwent pattern visual evoked potentials (PVEP), pattern electroretinography (PERG) and optical coherence tomography (OCT) within 14 days of symptom onset. OCT and visual acuity evaluation were repeated after approximately 3 months.
Results
We recruited 25 ON patients (11 isolated ON, 9 multiple sclerosis associated ON and 6 myelin-oligodendrocyte glycoprotein (MOG) seropositive ON) and 5 controls. All subjects were included acutely, with investigations done on average 6.7 days from first symptoms. Nine patients had conduction block at baseline. PVEP peak times were increased and amplitudes were decreased in ON. The PERGs showed that N95 and P50 amplitudes as well as P50 peak times were decreased in ON. None of the PVEP and PERG measures differed across the ON subtypes. A PVEP amplitude reduction was related to more severe GCL loss and thinner pRNFL layer at follow up (r=-0.58; p=0.008 and r=0.72; p=0.021). No such correlation existed at baseline. PVEP peak times and PERG measures were not similarly prognostic for structural outcome.
Conclusions
These data suggest that in acute ON, reduced neuronal function, as indirectly assessed by the reduced PVEP amplitudes, is predictive of subsequent neuronal loss. PVEP amplitudes may be helpful in guiding treatment decisions in acute ON.
P0769 - Saccadic eye movements reflect functional connectivity of the oculomotor brain network in MS patients (ID 1108)
Abstract
Background
Eye movement is controlled by a widespread network of cortical and subcortical areas, the oculomotor brain network, thus accurate measurement of these movements could represent a non-invasive method to reflect (dys)functioning of these interconnected areas. This is especially relevant for diseases in which network disruption is known to represent a key pathological feature, as in multiple sclerosis (MS).
Objectives
To investigate the association between saccadic eye movements and functional connectivity of the oculomotor brain network in patients with MS.
Methods
Subjects were included from the prospective Amsterdam MS cohort. A validated standardized infrared oculography protocol (DEMoNS) was used for quantifying pro-saccades and anti-saccades (reflexive and voluntary saccadic eye movements, respectively). After resting-state magnetoencephalography (MEG) measurement, data pre-processing and beamforming of the MEG data to source space, 73 oculomotor regions of the Brainnetome atlas were included based on previous literature (i.e. the FOcuS atlas). The phase lag index (PLI) was used as a measure of functional connectivity (FC) between all regions within the oculomotor network (and it’s subnetworks) for the six conventional frequency bands. The relationship between saccadic parameters and mean FC was analyzed using multivariate linear regression models adjusted for sex, age and disease type. Effect size modification by sex was additionally investigated.
Results
The 183 included patients with MS showed altered saccadic eye movements compared to the 58 included healthy controls. Regarding pro-saccades, worse saccadic eye movement performance was mainly related to a higher FC in theta and gamma bands and a lower connectivity in alpha and beta bands. Strongest relations with FC were found for peak velocity and the parietal eye field (theta band, β -2.1 E-4, p=0.006), gain and the precuneus (gamma band, β -1.3 E-4, p=0.003) and gain and the inferior frontal eye field (theta band, β -21.0 E-4, p<0.001). For anti-saccades, the strongest associations were found between the proportion of errors and the thalamus (beta band, β 8.0 E-4, p=0.006) and error of the final eye position and the precuneus (theta band, β -6.2 E-4, p=0.004). For female MS patients the proportion of errors was also strongly related to the supplementary eye field (gamma band, β 6.4 E-4, p=0.003) and for male patients the latency of a correct response to the cingulate eye field (delta band, β 5.3 E-4, p=0.006).
Conclusions
Saccadic eye movements were related to altered functional connectivity of fronto-parietal brain regions and the thalamus in patients with MS. Furthermore, there was evidence for a relevant sex difference in patterns of functional damage of the oculomotor brain network. This network approach provides an additional backing for the future use of eye movement measurement as an easy applicable tool for monitoring or predicting the disease MS.
P0772 - The optic nerve as a 5th location for dissemination in space for multiple sclerosis criteria: a role for optical coherence tomography (ID 410)
Abstract
Background
The diagnosis of multiple sclerosis (MS) is based on a combination of clinical and para-clinical tests to demonstrate dissemination in time and space. The potential of optical coherence tomography (OCT) to demonstrate optic nerve involvement as a 5th location for dissemination in space has been recognised.
Objectives
To test the feasibility of OCT measures of retinal asymmetry as a diagnostic test for MS at the community level. To test for a broad range of comorbidities typically present in a general population. To carefully evaluate ophthalmological co-morbidities and test the relevance of intraocular pressures and refraction.
Methods
Community based study (72,120 subjects). Calculation of the inter-eye difference of inner retinal OCT data for MS using the UK Biobank data. The inter-eye percentage difference (IEPD) and inter-eye absolute difference (IEAD) were calculated for the macular retinal nerve fibre layer (mRNFL), ganglion-cell inner plexiform layer complex (mGCIPL) and ganglion cell complex (mGCC). Area under the receiver operating characteristic curve (AUC) comparisons were followed by univariate and multivariable comparisons accounting for a large range of diseases and comorbidities. Cutoff levels were optimized by ROC and the Youden index.
Results
The prevalence of MS was 0.002 (95%CI 0.0013-0.0031). Overall the discriminatory power of diagnosing MS with the IEPD (AUC 0.71, 95%CI 0.67-0.76) and IEAD (0.71, 95%CI 0.67-0.75) for the mGCIPL were significantly higher if compared to the mGCC (IEPD AUC 0.64, 95%CI 0.59-0.69, p=0.0017; IEAD AUC 0.63, 95%CI 0.58-0.68, p<0.0001) and mRNFL (IEPD AUC 0.59, 95%CI 0.54-0.63, p<0.0001; IEAD AUC 0.55, 95%CI 0.50-0.59, p<0.0001). Screening sensitivity levels for the mGCIPL IEPD (4% cut-off) were 51.7% and for the IEAD (4 μm cut-off) 43.5%. Specificity levels were 82.8% and 86.8%. The number of co-morbidities was important. There was a stepwise decrease of the AUC from 0.72 in control subjects to 0.66 in more than nine co-morbidities or presence of neuromyelitis optica spectrum disease. In the multivariable analyses greater age, diabetes mellitus and a non-white ethnic background were relevant confounders. For most interactions the effect sizes were large (partial omega square > 0.14) with very narrow CIs.
Conclusions
The OCT GCIPL IEPD and IEAD may be considered as a supportive diagnostic test for MS diagnostic criteria in a young person without relevant co-morbidity. Importantly, previously discussed comorbidities such as need for refraction (> +/-5dpt) were not relevant.
Presenter Of 2 Presentations
P0499 - The epidemiology of optic neuritis in the United Kingdom and implications for consensus diagnostic criteria for multiple sclerosis. (ID 409)
Abstract
Background
The epidemiology of optic neuritis (ON) has been studied less carefully than the epidemiology of multiple sclerosis (MS). The association of ON with many other diseases poses one of several challenges for inclusion of ON in consensus diagnostic criteria for MS.
Objectives
To investigate current trends in ON incidence, prevalence and associations with systemic and neurological diseases in the United Kingdom (UK).
Methods
We used The Health Improvement Network (THIN), a nationally representative primary care records database to conduct a retrospective cross-sectional and population cohort study (1997-2018), and matched case-control and cohort study (1995-2020) (matched 4:1 on age, sex, region and Townsend Deprivation Index[TDI]).
Results
We included 11,086,469 patients with 75 million patient-years of follow-up. Amongst 2,895 incident cases with ON, 69.5%(n=2011) were female (mean age at diagnosis 41.6 (sd15.6)), 92.5% (n=1,227/1,326) were white and 24.9% were in TDI quintile 1 (no deprivation). The annual point prevalence (per 100,000 people) steadily increased from 69.3 (95%CI 57.2-81.3) in 1997 to 114.8 (95%CI 111.0-118.6) in 2018. The annual incidence rate was stable over 22 years, at 3.7 (95% CI 3.6-3.9) per 100,000 person-years. Highest risk of incident ON was associated with female sex, obesity, reproductive age, mixed or South Asian ethnicity, smoking, and Scottish residence; compared to children ≤10 years at cohort entry, adjusted incident rate ratio was >6-fold higher in women aged 21-40 years (p<0.001). In multivariable logistic regression, ON cases had significantly higher odds of prior diagnosis of MS (17.3%, OR 98.2, 95%CI 65.4-147.5), syphilis (0.2%, OR 5.8, 95%CI 1.4-23.7), mycoplasma (0.2%, OR3.90,1.09-13.93), vasculitis(0.5%, OR3.70,1.68-8.15), sarcoidosis(0.5%, OR2.50,1.21-5.18), Epstein Barr virus(3.8% OR2.29,1.80-2.92), Crohn’s disease(0.7%, OR1.97,1.13-3.43), and psoriasis(4.3%, OR1.28,1.03-1.58). ON patients had significantly higher hazard of incident MS(adjusted HR285.0,167.9-483.8), Behçet’s disease(HR17.4,1.6-195.5), sarcoidosis(HR14.8,4.9-45.1), vasculitis(HR4.9,1.8-13.1), Sjögren’s syndrome(HR3.5,1.4-8.8), and herpetic infection (HR1.7,1.2-2.3).
Conclusions
This large, population-representative study reveals stable incidence of ON in the UK over a 22-year period, and provides evidence-based guidance for investigation of MS and non-MS ON. Careful exclusion of non-MS ON patients, a sizable proportion, will be relevant for future revision of consensus MS diagnostic criteria, to minimize misdiagnosis.
P0772 - The optic nerve as a 5th location for dissemination in space for multiple sclerosis criteria: a role for optical coherence tomography (ID 410)
Abstract
Background
The diagnosis of multiple sclerosis (MS) is based on a combination of clinical and para-clinical tests to demonstrate dissemination in time and space. The potential of optical coherence tomography (OCT) to demonstrate optic nerve involvement as a 5th location for dissemination in space has been recognised.
Objectives
To test the feasibility of OCT measures of retinal asymmetry as a diagnostic test for MS at the community level. To test for a broad range of comorbidities typically present in a general population. To carefully evaluate ophthalmological co-morbidities and test the relevance of intraocular pressures and refraction.
Methods
Community based study (72,120 subjects). Calculation of the inter-eye difference of inner retinal OCT data for MS using the UK Biobank data. The inter-eye percentage difference (IEPD) and inter-eye absolute difference (IEAD) were calculated for the macular retinal nerve fibre layer (mRNFL), ganglion-cell inner plexiform layer complex (mGCIPL) and ganglion cell complex (mGCC). Area under the receiver operating characteristic curve (AUC) comparisons were followed by univariate and multivariable comparisons accounting for a large range of diseases and comorbidities. Cutoff levels were optimized by ROC and the Youden index.
Results
The prevalence of MS was 0.002 (95%CI 0.0013-0.0031). Overall the discriminatory power of diagnosing MS with the IEPD (AUC 0.71, 95%CI 0.67-0.76) and IEAD (0.71, 95%CI 0.67-0.75) for the mGCIPL were significantly higher if compared to the mGCC (IEPD AUC 0.64, 95%CI 0.59-0.69, p=0.0017; IEAD AUC 0.63, 95%CI 0.58-0.68, p<0.0001) and mRNFL (IEPD AUC 0.59, 95%CI 0.54-0.63, p<0.0001; IEAD AUC 0.55, 95%CI 0.50-0.59, p<0.0001). Screening sensitivity levels for the mGCIPL IEPD (4% cut-off) were 51.7% and for the IEAD (4 μm cut-off) 43.5%. Specificity levels were 82.8% and 86.8%. The number of co-morbidities was important. There was a stepwise decrease of the AUC from 0.72 in control subjects to 0.66 in more than nine co-morbidities or presence of neuromyelitis optica spectrum disease. In the multivariable analyses greater age, diabetes mellitus and a non-white ethnic background were relevant confounders. For most interactions the effect sizes were large (partial omega square > 0.14) with very narrow CIs.
Conclusions
The OCT GCIPL IEPD and IEAD may be considered as a supportive diagnostic test for MS diagnostic criteria in a young person without relevant co-morbidity. Importantly, previously discussed comorbidities such as need for refraction (> +/-5dpt) were not relevant.