Optical coherence tomography angiography measurements in multiple sclerosis: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVES: Recent literature on multiple sclerosis (MS) demonstrates the growing implementation of optical coherence tomography-angiography (OCT-A) to discover potential qualitative and quantitative changes in the retina and optic nerve. In this review, we analyze OCT-A studies in patients with MS and examine its utility as a surrogate or precursor to changes in central nervous system tissue. METHODS: PubMed and EMBASE were systematically searched to identify articles that applied OCT-A to evaluate the retinal microvasculature measurements in patients with MS. Quantitative data synthesis was performed on all measurements which were evaluated in at least two unique studies with the same OCT-A devices, software, and study population compared to controls. A fixed-effects or random-effects model was applied for the meta-analysis based on the heterogeneity level. RESULTS: The study selection process yielded the inclusion of 18 studies with a total of 1552 evaluated eyes in 673 MS-associated optic neuritis (MSON) eyes, 741 MS without optic neuritis (MSNON eyes), and 138 eyes without specification for the presence of optic neuritis (ON) in addition to 1107 healthy control (HC) eyes. Results indicated that MS cases had significantly decreased whole image superficial capillary plexus (SCP) vessel density when compared to healthy control subjects in the analyses conducted on Optovue and Topcon studies (both P < 0.0001). Likewise, the whole image vessel densities of deep capillary plexus (DCP) and radial peripapillary capillary (RPC) were significantly lower in MS cases compared to HC (all P < 0.05). Regarding optic disc area quadrants, MSON eyes had significantly decreased mean RPC vessel density compared to MSNON eyes in all quadrants except for the inferior (all P < 0.05). Results of the analysis of studies that used prototype Axsun machine revealed that MSON and MSNON eyes both had significantly lower ONH flow index compared to HC (both P < 0.0001). CONCLUSIONS: This systematic review and meta-analysis of the studies reporting OCT-A measurements of people with MS confirmed the tendency of MS eyes to exhibit reduced vessel density in the macular and optic disc areas, mainly in SCP, DCP, and RPC vessel densities.

A Randomized Prospective Trial Comparing Repository Corticotropin Injection and Intravenous Methylprednisolone for Neuroprotection in Acute Optic Neuritis.

BACKGROUND: Repository corticotrophin injection (RCI, Acthar Gel) and intravenous methylprednisolone (IVMP) improve the rate but not the extent of visual recovery following acute optic neuritis. RCI has adrenal-stimulating and melanocortin receptor-stimulating properties that may endow it with unique anti-inflammatory properties relative to IVMP. METHODS: Individuals with acute optic neuritis of less than 2 weeks duration were prospectively enrolled and randomized 1:1 to receive either RCI or IVMP. Peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell plus inner plexiform layer thickness (GC + IPL) were serially evaluated by OCT. In addition, patient-reported outcomes (PROs) for changes in fatigue, mood, visual function, depression, and quality of life (QOL) were measured, and high and low contrast visual acuity were recorded. RESULTS: Thirty-seven subjects were enrolled (19 RCI; 18 IVMP); the average time from symptom to treatment was 8.8 days. At 6 months, there was no difference in the primary outcome: loss of average pRNFL thickness in the affected eye (RCI vs IVMP: -13.1 vs -11.7 µm, P = 0.88) 6 months after randomization. Additional outcomes also showed no difference between treatment groups: 6-month attenuation of GC + IPL thickness (RCI vs IVMP: -13.8 vs -12.0 µm, P = 0.58) and frequency of pRNFL swelling at 1 month (RCI vs IVMP: 63% vs 72%, P = 0.73) and 3 months (RCI vs IVMP: 26% vs 31%, P = 0.99). Both treatments resulted in improvement in visual function and PROs. CONCLUSIONS: Treatment of acute optic neuritis with RCI or IVMP produced no clinically meaningful differences in optic nerve structure or visual function.

Alterations in the retinal vasculature occur in multiple sclerosis and exhibit novel correlations with disability and visual function measures.

BACKGROUND: The retinal vasculature may be altered in multiple sclerosis (MS), potentially acting as a biomarker of disease processes. OBJECTIVE: To compare retinal vascular plexus densities in people with MS (PwMS) and healthy controls (HCs), and examine correlations with visual function and global disability. METHODS: In this cross-sectional study, 111 PwMS (201 eyes) and 50 HCs (97 eyes) underwent optical coherence tomography angiography (OCTA). Macular superficial vascular plexus (SVP) and deep vascular plexus (DVP) densities were quantified, and poor quality images were excluded according to an artifact-rating protocol. RESULTS: Mean SVP density was 24.1% (SD = 5.5) in MS eyes (26.0% (SD = 4.7) in non-optic neuritis (ON) eyes vs. 21.7% (SD = 5.5) in ON eyes, p < 0.001), as compared to 29.2% (SD = 3.3) in HC eyes (p < 0.001 for all MS eyes and multiple sclerosis optic neuritis (MSON) eyes vs. HC eyes, p = 0.03 for MS non-ON eyes vs. HC eyes). DVP density did not differ between groups. In PwMS, lower SVP density was associated with higher levels of disability (expanded disability status scale (EDSS): R2 = 0.26, p = 0.004; multiple sclerosis functional composite (MSFC): R2 = 0.27, p = 0.03) and lower letter acuity scores (100% contrast: R2 = 0.29; 2.5% contrast: R2 = 0.40; 1.25% contrast: R2 = 0.31; p < 0.001 for all). CONCLUSIONS: Retinal SVP density measured by OCTA is reduced across MS eyes, and correlates with visual function, EDSS, and MSFC scores.

Preserved canonicality of the BOLD hemodynamic response reflects healthy cognition: Insights into the healthy brain through the window of Multiple Sclerosis.

The hemodynamic response function (HRF), a model of brain blood-flow changes in response to neural activity, reflects communication between neurons and the vasculature that supplies these neurons in part by means of glial cell intermediaries (e.g., astrocytes). Intact neural-vascular communication might play a central role in optimal cognitive performance. This hypothesis can be tested by comparing healthy individuals to those with known white-matter damage and impaired performance, as seen in Multiple Sclerosis (MS). Glial cell intermediaries facilitate the ability of neurons to adequately convey metabolic needs to cerebral vasculature for sufficient oxygen and nutrient perfusion. In this study, we isolated measurements of the HRF that could quantify the extent to which white-matter affects neural-vascular coupling and cognitive performance. HRFs were modeled from multiple brain regions during multiple cognitive tasks using piecewise cubic spline functions, an approach that minimized assumptions regarding HRF shape that may not be valid for diseased populations, and were characterized using two shape metrics (peak amplitude and time-to-peak). Peak amplitude was reduced, and time-to-peak was longer, in MS patients relative to healthy controls. Faster time-to-peak was predicted by faster reaction time, suggesting an important role for vasodilatory speed in the physiology underlying processing speed. These results support the hypothesis that intact neural-glial-vascular communication underlies optimal neural and cognitive functioning.

Brain and retinal atrophy in African-Americans versus Caucasian-Americans with multiple sclerosis: a longitudinal study.

On average, African Americans with multiple sclerosis demonstrate higher inflammatory disease activity, faster disability accumulation, greater visual dysfunction, more pronounced brain tissue damage and higher lesion volume loads compared to Caucasian Americans with multiple sclerosis. Neurodegeneration is an important component of multiple sclerosis, which in part accounts for the clinical heterogeneity of the disease. Brain atrophy appears to be widespread, although it is becoming increasingly recognized that regional substructure atrophy may be of greater clinical relevance. Patient race (within the limitations of self-identified ancestry) is regarded as an important contributing factor. However, there is a paucity of studies examining differences in neurodegeneration and brain substructure volumes over time in African Americans relative to Caucasian American patients. Optical coherence tomography is a non-invasive and reliable tool for measuring structural retinal changes. Recent studies support its utility for tracking neurodegeneration and disease progression in vivo in multiple sclerosis. Relative to Caucasian Americans, African American patients have been found to have greater retinal structural injury in the inner retinal layers. Increased thickness of the inner nuclear layer and the presence of microcystoid macular pathology at baseline predict clinical and radiological inflammatory activity, although whether race plays a role in these changes has not been investigated. Similarly, assessment of outer retinal changes according to race in multiple sclerosis remains incompletely characterized. Twenty-two African Americans and 60 matched Caucasian Americans with multiple sclerosis were evaluated with brain MRI, and 116 African Americans and 116 matched Caucasian Americans with multiple sclerosis were monitored with optical coherence tomography over a mean duration of 4.5 years. Mixed-effects linear regression models were used in statistical analyses. Grey matter (-0.9%/year versus -0.5%: P =0.02), white matter (-0.7%/year versus -0.3%: P =0.04) and nuclear thalamic (-1.5%/year versus -0.7%/year: P =0.02) atrophy rates were approximately twice as fast in African Americans. African Americans also exhibited higher proportions of microcystoid macular pathology (12.1% versus 0.9%, P =0.001). Retinal nerve fibre layer (-1.1% versus -0.8%: P =0.02) and ganglion cell+ inner plexiform layer (-0.7%/year versus -0.4%/year: P =0.01) atrophy rates were faster in African versus Caucasian Americans. African Americans on average exhibited more rapid neurodegeneration than Caucasian Americans and had significantly faster brain and retinal tissue loss. These results corroborate the more rapid clinical progression reported to occur, in general, in African Americans with multiple sclerosis and support the need for future studies involving African Americans in order to identify individual differences in treatment responses in multiple sclerosis.

New Ways of "Seeing" the Mechanistic Heterogeneity of Multiple Sclerosis Plaque Pathogenesis.

BACKGROUND: Over the past few decades, we have witnessed a transformation with respect to the principles and pathobiological underpinnings of multiple sclerosis (MS). From the traditional rubric of MS as an inflammatory and demyelinating disorder restricted to central nervous system (CNS) white matter, our contemporary view has evolved to encompass a broader understanding of the variable mechanisms that contribute to tissue injury, in a disorder now recognized to affect white and grey matter compartments. EVIDENCE ACQUISITION: A constellation of inflammation, ion channel derangements, bioenergetic supply: demand mismatches within the intra-axonal compartment, and alterations in the dynamics and oximetry of blood flow in CNS tissue compartments are observed in MS. These findings have raised questions regarding how histopathologic heterogeneity may influence the diverse clinical spectrum of MS; and, accordingly, how individual treatment needs vary from 1 patient to the next. RESULTS: We are now on new scaffolding in MS; one that promises to translate key clinical and laboratory observations to the application of emerging patient-centered therapies. CONCLUSIONS: This review highlights our current knowledge of the underlying disease mechanisms in MS, explores the inflammatory and neurodegenerative consequences of tissue damage, and examines physiologic factors that contribute to bioenergetic homeostasis within the CNS of affected patients.

Optimal Intereye Difference Thresholds in Retinal Nerve Fiber Layer Thickness for Predicting a Unilateral Optic Nerve Lesion in Multiple Sclerosis.

BACKGROUND: The optic nerve is a frequent site for involvement in multiple sclerosis (MS). Optical coherence tomography (OCT) detects thinning of the retinal nerve fiber layer (RNFL) in eyes of patients with MS and in those meeting criteria for clinically or radiologically isolated demyelinating syndromes. Current international diagnostic criteria for MS do not include the optic nerve as an imaging lesion site despite the high prevalence of acute optic neuritis (ON), or occult optic neuropathy, among early MS and clinically isolated syndrome patients; as well as most MS patients over the course of the disease. We sought to determine optimal thresholds for intereye difference in peripapillary RNFL thickness that are most predictive of a unilateral optic nerve lesion. METHODS: We analyzed spectral domain OCT data of 31 healthy volunteers and 124 patients with MS at a single center as part of an ongoing collaborative investigation of visual outcomes. Intereye differences in peripapillary (360°) RNFL thickness were calculated as the absolute value of the difference. First, we determined the 95th percentile value of intereye difference for the healthy volunteers. This value was applied to the convenience sample group of MS patients as a validation cohort determining how well this threshold could distinguish patients with vs without a history of unilateral ON. The relation of intereye differences in peripapillary RNFL thickness to binocular low-contrast letter acuity scores was also examined. RESULTS: Among healthy volunteer participants (n = 31), the 95th percentile value for intereye difference (upper boundary of expected for normal controls) was 6.0 µm. This value was applied to the convenience sample group of MS patients (n = 124, validation cohort). Positive predictive value, negative predictive value, sensitivity, and specificity for identifying MS patients with a history of unilateral ON were calculated for the 6-µm threshold value in a 2 × 2 table analysis with the application of χ tests (P < 0.0001). The 6-µm threshold was predictive of worse binocular low-contrast acuity scores at 2.5% (P = 0.03) and 1.25% (P = 0.002 by linear regression analyses). A receiver operating characteristic curve analysis demonstrated an optimal intereye difference threshold of 5 µm for identifying unilateral ON in the MS cohort. CONCLUSIONS: An intereye difference of 5-6 µm in RNFL thickness is a robust structural threshold for identifying the presence of a unilateral optic nerve lesion in MS.

Calibrated imaging reveals altered grey matter metabolism related to white matter microstructure and symptom severity in multiple sclerosis.

Multiple sclerosis (MS) involves damage to white matter microstructures. This damage has been related to grey matter function as measured by standard, physiologically-nonspecific neuroimaging indices (i.e., blood-oxygen-level dependent signal [BOLD]). Here, we used calibrated functional magnetic resonance imaging and diffusion tensor imaging to examine the extent to which specific, evoked grey matter physiological processes were associated with white matter diffusion in MS. Evoked changes in BOLD, cerebral blood flow (CBF), and oxygen metabolism (CMRO2 ) were measured in visual cortex. Individual differences in the diffusion tensor measure, radial diffusivity, within occipital tracts were strongly associated with MS patients' BOLD and CMRO2 . However, these relationships were in opposite directions, complicating the interpretation of the relationship between BOLD and white matter microstructural damage in MS. CMRO2 was strongly associated with individual differences in patients' fatigue and neurological disability, suggesting that alterations to evoked oxygen metabolic processes may be taken as a marker for primary symptoms of MS. This work demonstrates the first application of calibrated and diffusion imaging together and details the first application of calibrated functional MRI in a neurological population. Results lend support for neuroenergetic hypotheses of MS pathophysiology and provide an initial demonstration of the utility of evoked oxygen metabolism signals for neurology research. Hum Brain Mapp 38:5375-5390, 2017. © 2017 Wiley Periodicals, Inc.

Cerebellar Control of Eye Movements.

BACKGROUND: The cerebellum plays a central role in the online, real-time control, and long-term modulation of eye movements. EVIDENCE ACQUISITION: We reviewed the latest (fifth) edition of Leigh and Zee's textbook, The Neurology of Eye Movements, and literature in PUBMED using the following terms: cerebellum, flocculus, paraflocculus, vermis, oculomotor vermis, dorsal vermis, caudal fastigial nucleus, fastigial oculomotor region, uvula, nodulus, ansiform lobule, eye movements, saccades, ipsipulsion, contrapulsion, smooth pursuit, vergence, convergence, divergence, gaze-holding, down beat nystagmus, vestibulo-ocular reflex (VOR), angular VOR, translational VOR, skew deviation, velocity storage. RESULTS: The cerebellum is vital in optimizing the performance of all classes of gaze-shifting and gaze-stabilizing reflexes. The flocculus-paraflocculus are crucial to VOR gain and direction, pulse-step matching for saccades, pursuit gain, and gaze-holding. The ocular motor vermis and caudal fastigial nuclei are essential in saccadic adaptation and accuracy, and pursuit gain. The nodulus and ventral uvula are involved in processing otolothic signals and VOR responses, including velocity storage. CONCLUSIONS: The cerebellum guarantees the precision of ocular movements to optimize visual performance and occupies a central role in all classes of eye movements both in real-time control and in long-term calibration and learning (i.e., adaptation).

Retinal damage and vision loss in African American multiple sclerosis patients.

OBJECTIVE: To determine whether African American (AA) multiple sclerosis (MS) patients exhibit more retinal damage and visual impairment compared to Caucasian American (CA) MS patients. METHODS: A total of 687 MS patients (81 AAs) and 110 healthy control (HC) subjects (14 AAs) were recruited at 3 academic hospitals between 2008 and 2012. Using mixed effects regression models, we compared high- and low-contrast visual acuity (HCVA and LCVA) and high-definition spectral domain optical coherence tomography measures of retinal architecture between MS patients of self-identified AA and CA ancestry. RESULTS: In HCs, baseline peripapillary retinal nerve fiber layer (RNFL) thickness was 6.1µm greater in AAs (p = 0.047), whereas ganglion cell/inner plexiform layer (GCIP) thickness did not differ by race. In MS patients, baseline RNFL did not differ by race, and GCIP was 3.98µm thinner in AAs (p = 0.004). AAs had faster RNFL and GCIP thinning rates compared to CAs (p = 0.004 and p = 0.046, respectively). AA MS patients had lower baseline HCVA (p = 0.02) and worse LCVA per year of disease duration (p = 0.039). Among patients with an acute optic neuritis (AON) history, AAs had greater loss of HCVA than CA patients (p = 0.012). INTERPRETATION: This multicenter investigation provides objective evidence that AA MS patients exhibit accelerated retinal damage compared to CA MS patients. Self-identified AA ancestry is associated with worse MS-related visual disability, particularly in the context of an AON history, suggesting a more aggressive inflammatory disease course among AA MS patients or a subpopulation therein.

An update on neuro-ophthalmology of multiple sclerosis: the visual system as a model to study multiple sclerosis.

PURPOSE OF REVIEW: The purpose of this review is to familiarize the reader with the landscape of current neuro-ophthalmology research in the field of multiple sclerosis and to highlight important findings, directions of future research and advances in the clinical management of visual and ocular motor manifestations of multiple sclerosis. RECENT FINDINGS: Research pertaining to the visual system in multiple sclerosis has identified new biomarkers of disease and is contributing to a better understanding of disease mechanisms. Progress has been made in the symptomatic management of visual manifestations of multiple sclerosis and visual outcome measures are now being included in clinical trials, with important quality of life ramifications. Perhaps the most prominent contribution from neuro-ophthalmology research in multiple sclerosis has been the establishment of the visual system as a model to study disease pathogenesis, and for the systematic, objective, and longitudinal detection and monitoring of protective and restorative neurotherapeutic strategies. The emergence of these sophisticated capabilities has been in large part due to the application of high speed, high definition, and objective methods for the elucidation of both the structure and function of visual system networks. SUMMARY: Advances in neuro-ophthalmology research in multiple sclerosis have led to the establishment of the visual system as a model to objectively study disease pathogenesis, and for the identification of novel neurotherapeutic capabilities. With the prospects of myelin repair and neuroprotective agents increasingly becoming recognized as achievable goals, the validation and utility of new visual outcome measures quantifying changes in axonal integrity, myelin protection, and repair will likely prove invaluable.

Individual Prognostication of Disease Activity and Disability Worsening in Multiple Sclerosis With Retinal Layer Thickness z Scores.

BACKGROUND AND OBJECTIVES: Retinal optical coherence tomography (OCT) provides promising prognostic imaging biomarkers for future disease activity in multiple sclerosis (MS). However, raw OCT-derived measures have multiple dependencies, supporting the need for establishing reference values adjusted for possible confounders. The purpose of this study was to investigate the capacity for age-adjusted z scores of OCT-derived measures to prognosticate future disease activity and disability worsening in people with MS (PwMS). METHODS: We established age-adjusted OCT reference data using generalized additive models for location, scale, and shape for peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell-inner plexiform layer (GCIP) thicknesses, involving 910 and 423 healthy eyes, respectively. Next, we transformed the retinal layer thickness of PwMS from 3 published studies into age-adjusted z scores (pRNFL-z and GCIP-z) based on the reference data. Finally, we investigated the association of pRNFL-z or GCIP-z as predictors with future confirmed disability worsening (Expanded Disability Status Scale score increase) or disease activity (failing of the no evidence of disease activity [NEDA-3] criteria) as outcomes. Cox proportional hazards models or logistic regression analyses were applied according to the original studies. Optimal cutoffs were identified using the Akaike information criterion as well as location with the log-rank and likelihood-ratio tests. RESULTS: In the first cohort (n = 863), 172 PwMS (24%) had disability worsening over a median observational period of 2.0 (interquartile range [IQR]:1.0-3.0) years. Low pRNFL-z (≤-2.04) were associated with an increased risk of disability worsening (adjusted hazard ratio (aHR) [95% CI] = 2.08 [1.47-2.95], p = 3.82e-5). In the second cohort (n = 170), logistic regression analyses revealed that lower pRNFL-z showed a higher likelihood for disability accumulation at the two-year follow-up (reciprocal odds ratio [95% CI] = 1.51[1.06-2.15], p = 0.03). In the third cohort (n = 78), 46 PwMS (59%) did not maintain the NEDA-3 status over a median follow-up of 2.0 (IQR: 1.9-2.1) years. PwMS with low GCIP-z (≤-1.03) had a higher risk of showing disease activity (aHR [95% CI] = 2.14 [1.03-4.43], p = 0.04). Compared with raw values with arbitrary cutoffs, applying the z score approach with optimal cutoffs showed better performance in discrimination and calibration (higher Harrell's concordance index and lower integrated Brier score). DISCUSSION: In conclusion, our work demonstrated reference cohort-based z scores that account for age, a major driver for disease progression in MS, to be a promising approach for creating OCT-derived measures useable across devices and toward individualized prognostication.

Targeting Neuroinflammation to Alleviate Chronic Olfactory Dysfunction in Long COVID: A Role for Investigating Disease-Modifying Therapy (DMT)?

Chronic olfactory dysfunction after SARS-CoV-2 infection occurs in approximately 10% of patients with COVID-19-induced anosmia, and it is a growing public health concern. A regimen of olfactory training and anti-neuroinflammatory therapy with co-ultramicronized palmitoylethanolamide with luteolin (um-PEA-LUT) has shown promising results in clinical trials; however, approximately 15% of treated patients do not achieve full recovery of a normal olfactory threshold, and almost 5% have no recovery. Disease-modifying therapies (DMTs), which are used to treat autoimmune neuroinflammation in multiple sclerosis (MS), have not been studied for treating persistent inflammation in refractory post-COVID-19 smell disorder. This study evaluated COVID-19-related smell loss and MS-related smell loss, comparing the responses to different therapies. Forty patients with MS and 45 reporting post-COVID-19 olfactory disorders were included in the study. All patients underwent nasal endoscopy and were evaluated by using validated Sniffin' Sticks testing. The patients with long COVID were treated for three months with um-PEA-LUT plus olfactory training. The patients with MS were treated with DMTs. Olfactory functions before and after treatment were analyzed in both groups. At the experimental endpoint, 13 patients in the COVID-19 group treated with um-PEA-LUT had residual olfactory impairment versus 10 patients in the MS group treated with DMTs. The severity of the persistent olfactory loss was lower in the MS group, and the patients with MS treated with IFN-beta and glatiramer acetate had the preservation of olfactory function. These data provide a rationale for considering prospective trials investigating the efficacy of DMTs for post-COVID-19 olfactory disorders that are refractory to um-PEA-LUT with olfactory training. This study is the first to consider the role of DMT in treating refractory post-viral olfactory loss in patients with long COVID.

Recurrent Optic Neuritis and Perineuritis Followed by an Unexpected Discovery: From the National Multiple Sclerosis Society Case Conference Proceedings.

We describe a woman with a history of relapsing acute optic neuritis and perineuritis. Testing failed to confirm a specific diagnosis; hence, she was diagnosed with seronegative neuromyelitis optica spectrum disorder and treated with the immunotherapy rituximab, later in conjunction with mycophenolate mofetil. She achieved a durable remission for 9 years until she presented with paresthesia affecting her left fifth digit, right proximal thigh, and left foot, while also reporting a 25-pound weight loss over the prior 3 months. New imaging demonstrated a longitudinally extensive and enhancing optic nerve, in conjunction with multifocal enhancing lesions within the spinal cord, in a skip-like distribution. The differential diagnosis is discussed.

MOG Antibody-Associated Disease and Thymic Hyperplasia: From the National Multiple Sclerosis Society Case Conference Proceedings.

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a recently described CNS inflammatory disorder that may manifest with optic neuritis, myelitis, seizures, and/or acute disseminated encephalomyelitis. While MOG-specific antibodies in patients with MOGAD are IgG1, a T-cell-dependent antibody isotype, immunologic mechanisms of this disease are not fully understood. Thymic hyperplasia can be associated with certain autoimmune diseases. In this report we describe a case of MOGAD associated with thymic hyperplasia in a young adult.

Multiple Sclerosis Followed by Neuromyelitis Optica Spectrum Disorder: From the National Multiple Sclerosis Society Case Conference Proceedings.

A woman presented at age 18 years with partial myelitis and diplopia and experienced multiple subsequent relapses. Her MRI demonstrated T2 abnormalities characteristic of multiple sclerosis (MS) (white matter ovoid lesions and Dawson fingers), and CSF demonstrated an elevated IgG index and oligoclonal bands restricted to the CSF. Diagnosed with clinically definite relapsing-remitting MS, she was treated with various MS disease-modifying therapies and eventually began experiencing secondary progression. At age 57 years, she developed an acute longitudinally extensive transverse myelitis and was found to have AQP4 antibodies by cell-based assay. Our analysis of the clinical course, radiographic findings, molecular diagnostic methods, and treatment response characteristics support the hypothesis that our patient most likely had 2 CNS inflammatory disorders: MS, which manifested as a teenager, and neuromyelitis optica spectrum disorder, which evolved in her sixth decade of life. This case emphasizes a key principle in neurology practice, which is to reconsider whether the original working diagnosis remains tenable, especially when confronted with evidence (clinical and/or paraclinical) that raises the possibility of a distinctively different disorder.

Hearing abnormalities in multiple sclerosis: clinical semiology and pathophysiologic mechanisms.

Auditory manifestations from multiple sclerosis (MS) are not as common as the well-recognized sentinel exacerbations of optic neuritis, partial myelitis, motor weakness, vertiginous episodes, heat intolerance, and eye movement abnormalities. This paper discusses four cases of auditory changes, secondary to MS, and describes the first case, to our knowledge, of palinacousis, the perseveration of hearing, despite cessation of the sound stimulus. For each we characterize the initial complaint, the diagnostic work up, and ultimately, underscore the individualized treatment interventions, that allowed us to achieve a remission in all four cases. Individually codifying the treatment regimens served to mitigate, if not to abolish, the clinical derangements in hearing. Special attention is focused upon examination of the clinical manifestations and the pathophysiologic mechanisms which are responsible for them. We further emphasize the differential diagnostic considerations, and physical exam findings, along with the results of laboratory testing, neuro-imaging sequences, and lesion localization. Taken together, such information is germane to organizing cogently coherent strategic treatment plan(s). We believe that this small case series represents a clinically pragmatic example of 'precision medicine'; a principal theme and goal throughout this paper, the achievement of such in MS, but also as an illustration for the assessment and management schema for neuroimmunologic disorders in general.

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.

Functional treatments in multiple sclerosis.

PURPOSE OF REVIEW: This review focuses on recent advances in the understanding and management of symptoms and dysfunctions associated with multiple sclerosis (MS). RECENT FINDINGS: A broad spectrum of dysfunctions associated with MS are under investigation. Research published in the past year and a half addresses gait dysfunction, exercise training, fatigue, bowel/bladder and sexual dysfunction, and sleep disruption. Functional electrical stimulation and strength training have been validated for improvement in gait and motor function. Exercise training has been shown to benefit mood and quality of life scores and to reduce circulating inflammatory cytokine levels. Fatigue remains a challenging problem with incremental improvements in understanding of underlying causes and effective drug therapies offered by recent work. Treatment of bowel, bladder and sexual dysfunction utilizing a variety of modalities has been investigated with some progress. SUMMARY: In the absence of treatments to reverse neurologic injury due to MS, effective symptom management and functional improvement remain essential to mitigate disability and maintain quality of life. Basic research, as well as controlled clinical trials, in this realm offers promising insights and solutions.