Progressive Functional and Neuroretinal Affectation in Patients With Multiple Sclerosis Treated With Fingolimod.

BACKGROUND: To evaluate the effect of fingolimod in visual function and neuroretinal structures in patients with multiple sclerosis (MS) for a period of 1 year. METHODS: This longitudinal and observational cohort study included 78 eyes of 78 patients with MS treated with fingolimod. All subjects were evaluated every 3 months during 12 months and compared with 32 patients treated with interferon beta. All patients were examined for high-contrast and low-contrast (2.5% and 1.25%) visual acuity (VA), contrast sensitivity vision (CSV) (using Pelli-Robson and CSV-1000E tests), color vision (Farnsworth D-15 and L'Anthony D-15 desaturated tests), and retinal structural measurements (retinal nerve fiber layer [RNFL] and ganglion cell layer [GCL] thickness) using optical coherence tomography (OCT) technology. RESULTS: Patients with MS treated with fingolimod for a period of 1 year showed significant reduction in 100% and 1.25% contrast VA (P = 0.009 and 0.008, respectively), an alteration of contrast sensitivity and color perception (Pelli-Robson test, CSV-1000E test, Farnsworth D-15 desaturated test, and L'Anthony D-15 desaturated test; P < 0.001), GCL thickness reduction (P = 0.007), and an average macular central thickness increase of 2.6 µm (P = 0.006). Patients with MS treated with interferon beta did not show significant changes in visual function tests neither in macular thickness measurements, but they showed a significant reduction in GCL and RNFL thicknesses. The reduction in neuroretinal structures observed by OCT was significantly higher in the interferon-beta group, but patients treated with fingolimod showed a significant increase in macular central thickness and a reduction in low contrast vision (P < 0.001). CONCLUSIONS: Patients with MS treated with fingolimod and with no clinically observable macular edema show a significant change in visual function parameters and average macular central thickness increase compared with those treated with interferon beta. These findings are probably due to subclinical macular edema produced by fingolimod, which might be considered as an indicator for pharmacovigilance of sphingosine-1-phosphate inhibitors to be improved.

Perception of stigma in patients with primary progressive multiple sclerosis.

Stigma associated with neurological disorders may contribute to a poor health-related quality of life. However, limited information is available in primary progressive multiple sclerosis. We investigated the presence and impact of stigma in patients with primary progressive multiple sclerosis. A non-interventional, cross-sectional study was conducted. A total of 55 primary progressive multiple sclerosis patients were studied (mean age 55.8±9.5 years, 56.4% male). The median Expanded Disability Status Scale score was 5.5 (4.0-6.5). Stigma prevalence was 78.2% (n=43). Twenty-four patients (43.6%) were classified as depressed. Scores on the eight-item Stigma Scale for Chronic Illness correlated with physical (rho=0.464, p<0.001) and psychological (rho=0.358, p=0.007) 29-item Multiple Sclerosis Impact Scale subscores. Stigma predicted concurrent depression (odds ratio=1.13; p=0.046). Stigma was highly prevalent with a detrimental effect on quality of life and mood in primary progressive multiple sclerosis.

Changes in peripapillary choroidal thickness in patients with multiple sclerosis.

PURPOSE: To study peripapillary choroidal thickness (PPCT) around the optic disc and establish zones using a new swept source optical coherence tomography (SS-OCT) device. To evaluate PPCT differences between patients with multiple sclerosis (MS) and age- and sex-matched healthy controls. METHODS: A total of 102 healthy subjects and 51 patients with MS were consecutively recruited. Healthy subjects were divided into teaching (n = 51, used to establish choroidal zones) and validating (n = 51, used to compare measurements with MS patients) populations. An optic disc 6.0 × 6.0-mm three-dimensional scan was obtained using SS-OCT Triton. A 26 × 26 cube-grid centred on the optic disc was generated automatically to measure PPCT. Four choroidal zones were established and used to compare PPCT between healthy controls and patients with MS. RESULTS: Peripapillary choroidal thickness (PPCT) was significantly thinner in patients in all concentric zones (p ≤ 0.0001): 134.02 ± 16.59 µm in MS group versus 171.56 ± 12.43 µm in the control group in zone 2; 182.23 ± 20.52 versus 219.03 ± 17.99 µm, respectively, in zone 3; and 223.52 ± 10.70 versus 259.99 ± 10.29 µm, respectively, in zone 4. The choroidal thinning in the MS group tended to decrease as we distanced from the optic nerve head. Peripapillary choroidal thickness (PPCT) had a similar pattern in controls and MS; it was thicker in the superior region, followed by temporal, nasal and inferior regions. CONCLUSION: Patients with MS showed peripapillary choroidal thinning when compared with healthy subjects in all zones around the optic disc. Peripapillary choroidal tissue shows a concentric pattern, increasing in thickness when increasing the distance from the optic nerve. The new SS-OCT could be useful for evaluating choroidal thinning in clinical practice.

Relación entre homocisteinemia y respuesta simpaticocutánea en la enfermedad de Parkinson / Relationship between homocysteinaemia and sympathetic skin response in Parkinson's disease

Introducción. En la enfermedad de Parkinson (EP) se han observado niveles elevados de homocisteína en relación con el tratamiento con levodopa. Nuestro objetivo ha sido valorar su influencia y la de otras variables relacionadas con la propia EP sobre la respuesta simpaticocutánea. Pacientes y métodos. Estudio observacional, transversal, en el que se incluyó de forma consecutiva a pacientes con EP. Se valoró la respuesta simpaticocutánea de forma unilateral en los miembros superiores, y se determinó la influencia de la gravedad de la EP según la Unified Parkinson Disease Rating Scale, y las escalas de Hoehn y Yahr y de Schwab y England, y de los niveles sanguíneos de homocisteína, vitamina B12 y ácido fólico sobre la latencia y amplitud de la respuesta simpaticocutánea. Resultados. Se incluyó a 78 pacientes. La respuesta simpaticocutánea se obtuvo en todos ellos. En el análisis bivariante, la latencia se correlacionó significativamente con la edad, con la edad de inicio de la EP y con los niveles de homocisteína. La presencia de hiperhomocisteinemia se relacionó con una latencia más prolongada. La amplitud sólo se correlacionó con la puntuación en la escala de Schwab y England. En el análisis multivariante, la edad fue la única variable que demostró una asociación significativa tanto con la duración de la latencia como con los niveles de homocisteína. Conclusión. No pudo establecerse una asociación directa entre el aumento de homocisteinemia y la disfunción de la respuesta simpaticocutánea. Los resultados del análisis multivariante sugieren que la prolongación de la latencia en los pacientes de una mayor edad podría deberse a que éstos presentan unos mayores niveles sanguíneos de homocisteína (AU)

Introduction. High levels of homocysteine linked to treatment with levodopa have been observed in patients with Parkinson's disease (PD). Our aim was to assess the influence of serum homocysteine levels and other PD-related on the sympathetic skin response. Patients and methods. An observational, cross-sectional study was conducted that consecutively included patients with PD. We unilaterally assessed the sympathetic skin response in the upper limbs. We measured the influence of PD severity (measured by the Hoehn & Yahr and the Schwab & England scales, and the Unified Parkinson Disease Rating Scale) and blood homocysteine, vitamin B12 and folic acid levels on the latency and amplitude of the sympathetic skin response. Results. A total of 78 patients were enrolled, and all achieved a sympathetic skin response. In the bivariate analysis, latency was significantly correlated with age, age at PD onset and homocysteinaemia levels. The presence of hyperhomocysteinemia was associated with a longer latency. The amplitude was only correlated with the score on the Schwab & England scale. In the multivariate analysis, age was the only variable that showed a significant association with the latency duration and homocysteine levels. Conclusion. A direct association could not be established between the increase in homocysteinaemia levels and sympathetic skin response dysfunction in PD. The results of the multivariate analysis suggest that latency prolongation in elderly patients could be due to the fact that these patients have higher blood levels of homocysteinaemia (AU)

Retinal and Optic Nerve Degeneration in Patients with Multiple Sclerosis Followed up for 5 Years.

PURPOSE: To quantify retinal nerve fiber layer (RNFL) changes in patients with multiple sclerosis (MS) and healthy controls with a 5-year follow-up and to analyze correlations between disability progression and RNFL degeneration. DESIGN: Observational and longitudinal study. PARTICIPANTS: One hundred patients with relapsing-remitting MS and 50 healthy controls. METHODS: All participants underwent a complete ophthalmic and electrophysiologic exploration and were re-evaluated annually for 5 years. MAIN OUTCOME MEASURES: Visual acuity (Snellen chart), color vision (Ishihara pseudoisochromatic plates), visual field examination, optical coherence tomography (OCT), scanning laser polarimetry (SLP), and visual evoked potentials. Expanded Disability Status Scale (EDSS) scores, disease duration, treatments, prior optic neuritis episodes, and quality of life (QOL; based on the 54-item Multiple Sclerosis Quality of Life Scale score). RESULTS: Optical coherence tomography (OCT) revealed changes in all RNFL thicknesses in both groups. In the MS group, changes were detected in average thickness and in the mean deviation using the GDx-VCC nerve fiber analyzer (Laser Diagnostic Technologies, San Diego, CA) and in the P100 latency of visual evoked potentials; no changes were detected in visual acuity, color vision, or visual fields. Optical coherence tomography showed greater differences in the inferior and temporal RNFL thicknesses in both groups. In MS patients only, OCT revealed a moderate correlation between the increase in EDSS and temporal and superior RNFL thinning. Temporal RNFL thinning based on OCT results was correlated moderately with decreased QOL. CONCLUSIONS: Multiple sclerosis patients exhibit a progressive axonal loss in the optic nerve fiber layer. Retinal nerve fiber layer thinning based on OCT results is a useful marker for assessing MS progression and correlates with increased disability and reduced QOL.

Optical Coherence Tomography as a Biomarker for Diagnosis, Progression, and Prognosis of Neurodegenerative Diseases.

Neurodegenerative diseases present a current challenge for accurate diagnosis and for providing precise prognostic information. Developing imaging biomarkers for multiple sclerosis (MS), Parkinson disease (PD), and Alzheimer's disease (AD) will improve the clinical management of these patients and may be useful for monitoring treatment effectiveness. Recent research using optical coherence tomography (OCT) has demonstrated that parameters provided by this technology may be used as potential biomarkers for MS, PD, and AD. Retinal thinning has been observed in these patients and new segmentation software for the analysis of the different retinal layers may provide accurate information on disease progression and prognosis. In this review we analyze the application of retinal evaluation using OCT technology to provide better understanding of the possible role of the retinal layers thickness as biomarker for the detection of these neurodegenerative pathologies. Current OCT analysis of the retinal nerve fiber layer and, specially, the ganglion cell layer thickness may be considered as a good biomarker for disease diagnosis, severity, and progression.

Artificial neural network techniques to improve the ability of optical coherence tomography to detect optic neuritis.

PURPOSE: To analyze the ability of Spectralis optical coherence tomography (OCT) to detect multiple sclerosis (MS) and to distinguish MS eyes with antecedent optic neuritis (ON). To analyze the capability of artificial neural network (ANN) techniques to improve the diagnostic precision. METHODS: MS patients and controls were enrolled (n = 217). OCT was used to determine the 768 retinal nerve fiber layer thicknesses. Sensitivity and specificity were evaluated to test the ability of OCT to discriminate between MS and healthy eyes, and between MS with and without antecedent ON using ANN. RESULTS: Using ANN technique multilayer perceptrons, OCT could detect MS with a sensitivity of 89.3%, a specificity of 87.6%, and a diagnostic precision of 88.5%. Compared with the OCT-provided parameters, the ANN had a better sensitivity-specificity balance. CONCLUSIONS: ANN technique improves the capability of Spectralis OCT to detect MS disease and to distinguish MS eyes with or without antecedent ON.

Mitochondrial complex enzyme activities and cytochrome C expression changes in multiple sclerosis.

Blood platelets have been widely proposed as biomarkers in studies of mitochondrial function and aging-related and neurodegenerative diseases. Defects in mitochondrial function were found not only in the substantia nigra of Parkinson's disease patients but also in their blood platelets. Similarly, it has also been described in the blood platelet mitochondria of Alzheimer's disease patients. To study mitochondrial aerobic metabolism function and protein expression in platelets of multiple sclerosis (MS) patients and control subjects, mitochondrial aconitase, mitochondrial superoxide dismutases 1 and 2 (SOD1 and SOD2), and respiratory complex enzyme activities in platelets of MS patients and control subjects were determined. Likewise, mitochondrial lipid peroxidation and mitochondrial SOD1 and cytochrome c expressions were investigated. Mitochondrial aconitase activity was higher in MS patients than in controls (P < 0.05). A significant increase on all respiratory complex activities in MS patients was observed (P < 0.05). Mitochondrial lipid peroxidation was significantly higher in MS patients than in controls (P < 0.05). Significant changes of cytochrome c and mitochondrial SOD1 expressions were detected (P < 0.05), with a decrease of 44 ± 5 % and an increase of 46 ± 6 %, respectively. Our study reveals that significant changes in mitochondrial aerobic metabolism function and mitochondrial SOD1 and cytochrome c expressions are produced in platelets of MS patients.

Retinal layer segmentation in patients with multiple sclerosis using spectral domain optical coherence tomography.

PURPOSE: To evaluate the thickness of the 10 retinal layers in the paramacular area of patients with multiple sclerosis (MS) compared with healthy subjects using the new segmentation technology of spectral domain optical coherence tomography (OCT). To examine which layer has better sensitivity for detecting neurodegeneration in patients with MS. DESIGN: Observational, cross-sectional study. PARTICIPANTS: Patients with MS (n = 204) and age-matched healthy subjects (n = 138). METHODS: The Spectralis OCT system (Heidelberg Engineering, Inc., Heidelberg, Germany) was used to obtain automated segmentation of all retinal layers in a parafoveal scan in 1 randomly selected eye of each participant, using the new segmentation application prototype. MAIN OUTCOME MEASURES: The thicknesses of 512 parafoveal points in the 10 retinal layers were obtained in each eye, and the mean thickness of each layer was calculated and compared between patients with MS and healthy subjects. The analysis was repeated, comparing patients with MS with and without previous optic neuritis. Correlation analysis was performed to evaluate the association between each retinal layer mean thickness, duration of disease, and functional disability in patients with MS. A logistic regression analysis was performed to determine which layer provided better sensitivity for detecting neurodegeneration in patients with MS. RESULTS: All retinal layers, except the inner limiting membrane, were thinner in patients with MS compared with healthy subjects (P < 0.05). Greater effects were observed in the inner retinal layers (nerve fiber, ganglion cells, inner plexiform, and inner nuclear layers) of eyes with previous optic neuritis (P < 0.05). The retinal nerve fiber layer and ganglion cell layer thicknesses were inversely correlated with the functional disability score in patients with MS. The ganglion cell layer and inner plexiform layer thicknesses could predict axonal damage in patients with MS. CONCLUSIONS: Analysis based on the segmentation technology of the Spectralis OCT revealed retinal layer atrophy in patients with MS, especially of the inner layers. Reduction of the ganglion cell and inner plexiform layers predicted greater axonal damage in patients with MS.

Diagnostic ability of a new method for measuring haemoglobin levels in the optic nerve head in multiple sclerosis patients.

AIMS: To evaluate a new method for measuring haemoglobin (Hb) levels and quantifying the colour changes in the optic nerve head of multiple sclerosis (MS) patients to detect axonal loss and consequently optic disc atrophy. MATERIAL AND METHODS: 40 MS patients and 40 age and sex-matched healthy subjects were included in this prospective cross-sectional study and underwent a full ophthalmological examination, including three photographs of the optic disc. The Laguna ONhE ('optic nerve hemoglobin'; Insoft SL, Tenerife, Spain) software was used to obtain the Hb analysis in each of the 24 sectors and average Hb of optic disc photographs acquired. Reproducibility of measurements provided by Laguna ONhE program was analysed. RESULTS: MS patients showed significant reduction of optic disc Hb percentages in average Hb (58.99% in MS, 65.39% in healthy subjects; p<0.001) and in almost all analysed sectors with the largest differences in temporal sectors. Laguna ONhE program showed good reproducibility measuring Hb percentages in MS patients and healthy subjects. CONCLUSIONS: Measurements of optic disc Hb levels obtained with Laguna ONhE software had good ability detecting optic atrophy and axonal loss in MS patients. This method had good reliability and is easy to implement in routine clinical practice.

Neural networks to identify multiple sclerosis with optical coherence tomography.

PURPOSE: To compare axonal loss in ganglion cells detected with spectral-domain optical coherence tomography (OCT) in eyes of patients with multiple sclerosis (MS) versus healthy control subjects using an artificial neural network (ANN). To analyse the capability of the ANN technique to improve the detection of retinal nerve fibre layer (RNFL) damage in patients with multiple sclerosis. METHODS: Patients with multiple sclerosis (n = 106) and age-matched healthy subjects (n = 115) were enrolled. The Spectralis OCT system was used to obtain the circumpapillary RNFL thickness in both eyes. The 768 RNFL thickness measurements provided by the Spectralis OCT were performed to obtain thickness measurements from 24 uniformly divided locations around the peripapillary RNFL. The performance of the ANN technique for identifying RNFL loss in patients with multiple sclerosis was evaluated. Receiver-operating characteristic (ROC) curves were used to display the ability of the test to discriminate between MS and healthy eyes in our population. ROC curves obtained using ANN and parameters provided by OCT (mean and 6 sector thicknesses) were compared. RESULTS: The capability of the ANN technique to detect RNFL loss in patients with multiple sclerosis compared with healthy subjects was good. The area under the ROC curve was 0.945. Compared with the OCT-provided parameters, the ANN had the largest area under the ROC curve. CONCLUSIONS: Measurements of RNFL thickness obtained with Spectralis OCT have a good ability to differentiate between healthy and individuals with multiple sclerosis. Based on the area under the ROC curve, the ANN performed better than any single OCT parameter.

Neuro-ophthalmologic evaluation, quality of life, and functional disability in patients with MS.

OBJECTIVE: To evaluate correlations between longitudinal changes in neuro-ophthalmologic measures and quality of life (QOL) and disability in patients with multiple sclerosis (MS), using optical coherence tomography (OCT), visual evoked potentials (VEP), and visual field examination. METHODS: Fifty-four patients with relapsing-remitting MS were enrolled in this study and underwent Multiple Sclerosis Quality of Life questionnaire (54 items) (MSQOL-54) and Expanded Disability Status Scale (EDSS) evaluation, as well as complete neuro-ophthalmologic examination including visual field testing and retinal nerve fiber layer (RNFL) measurements using Cirrus and Spectralis OCT and VEP. All patients were re-evaluated at 12, 24, and 36 months. Logistical regression was performed to analyze which measures, if any, could predict QOL. RESULTS: Overall, RNFL thickness results at the baseline evaluation were significantly different from those at 3 years (p ≤ 0.05), but there were no differences in functional measures (visual acuity, contrast sensitivity, color vision, visual field, and VEP). A reduced MSQOL-54 score was associated with an increase in EDSS score and a decrease in both functional and structural parameters. Patients with longer MS duration presented with a lower MSQOL-54 score (reduction in QOL). CONCLUSIONS: Patients with progressive axonal loss as seen in RNFL results had a lower QOL and more functional disability.

Progressive degeneration of the retinal nerve fiber layer in patients with multiple sclerosis.

PURPOSE: To quantify changes in the retinal nerve fiber layer (RNFL) of patients with multiple sclerosis (MS) over 3 years and to evaluate whether treatment protects against RNFL degeneration. METHODS: Ninety-four MS patients and 50 healthy subjects were followed-up over 3 years. All subjects underwent a complete ophthalmic examination, which included assessment of visual acuity (Snellen chart), color vision (Ishihara pseudoisochromatic plates), visual field examination, optical coherence tomography (OCT), and visual evoked potentials (VEPs). All patients were reevaluated at 12, 24, and 36 months to quantify changes in the RNFL. RESULTS: Changes were detected in RNFL thickness at the 36-month follow-up. Significant decreases (P < 0.05, t-test) were observed in the mean, superior, inferior, and temporal RNFL thicknesses, and macular volume provided by OCT, and in the P100 latency of VEP of the MS group, but only in the mean and inferior RNFL thicknesses of the healthy control group. Greater changes in the superior and inferior RNFL thicknesses during follow-up were detected in the MS group. Differences between treatments were not detected, but untreated patients had higher degeneration in the mean and superior RNFL thicknesses during the follow-up (P = 0.040 and P = 0.19, respectively). CONCLUSIONS: Progressive axonal loss can be detected in the optic nerve fiber layer of MS patients. Analysis of the RNFL by OCT can be useful for evaluating MS progression and efficacy of treatment as a neuroprotective factor against axonal degeneration.

Risk factors for progressive axonal degeneration of the retinal nerve fibre layer in multiple sclerosis patients.

AIM: To quantify structural and functional degeneration in the retinal nerve fibre layer (RNFL) of patients with multiple sclerosis (MS) over a 2-year time period, and to analyse the effect of prior optic neuritis (ON) as well as the duration and incidence of MS relapses. METHODS: 166 MS patients and 120 healthy controls underwent assessment of visual acuity and colour vision, visual field examination, optical coherence tomography, scanning laser polarimetry and visual evoked potentials (VEPs). All subjects were re-evaluated after a period of 12 and 24 months. RESULTS: Changes in the optic nerve were detected by structural measurements but not by functional assessments. Changes registered in MS patients were greater than changes in healthy controls (p<0.05). Eyes with previous ON showed a greater reduction of parameters in the baseline evaluation, but RNFL atrophy was not significantly greater in the longitudinal study. Patients with MS relapses showed a greater reduction of RNFL thickness and VEP amplitude compared with non-relapsing cases. Patients with and without treatment showed similar measurement reduction, but the non-treated group had a significantly higher increase in Expanded Disability Status Scale (p=0.029). CONCLUSIONS: MS causes progressive axonal loss in the optic nerve, regardless of a history of ON. This ganglion cell atrophy occurs in all eyes but is more marked in MS eyes than in healthy eyes.

Increased serum interleukin-17 levels in patients with myasthenia gravis.

It has been suggested that interleukin-17 (IL-17) plays a crucial role in the development of several autoimmune diseases. However, there are no data about the relationship between myasthenia gravis and IL-17. The aim of this study was to measure the concentration of IL-17 and determine whether levels depend on the severity of MG. Serum IL-17 concentrations were measured in 25 patients. IL-17 concentrations were higher in generalized MG compared with controls and correlated with anti-acetylcholinesterase receptor antibody titers.

Progressive changes in the retinal nerve fiber layer in patients with multiple sclerosis.

PURPOSE: To quantify changes in the retinal nerve fiber layer (RNFL) of patients with multiple sclerosis (MS) over a 1-year time period and to compare the ability of noninvasive diagnostic imaging devices and visual evoked potentials (VEP) to detect axonal loss in these patients. METHODS: Eighty-one patients with MS underwent a complete ophthalmic examination that included assessment of visual acuity and color vision, refractive evaluation, visual field examination, optical coherence tomography (OCT), scanning laser polarimetry (GDx), and measurement of VEP. All the patients were re-evaluated after a period of 12 months in order to quantify any change in the RNFL. Only one randomly chosen eye from each patient was included in the study. RESULTS: Statistically significant differences between the 2 examinations were recorded for the overall mean and inferior RNFL thickness and the macular volume, as assessed by OCT, as well as for the temporal-superior-nasal-inferior-temporal average standard deviation provided by GDx. The greatest differences were obtained for the mean RNFL thickness (90.46 microm vs 85.96 microm). Changes in the optic nerve were detected by structural measurements but not by functional assessments. CONCLUSIONS: Axonal loss in the optic nerve of patients with MS is greater than that expected in healthy subjects, regardless of the presence of a previous optic neuritis.