Multifocal visual evoked potentials in demyelinating diseases of the visual pathway

Multifocal visual evoked potentials (mfVEP) provide an objective functional measure of the integrity of the visual pathway. This thesis constitutes a comprehensive assessment of mfVEP changes in demyelinating diseases of the visual pathway. The efficacy of the mfVEP technique was compared to full-field pattern-reversal visual evoked potential and the results illustrate a superiority of the mfVEP in detecting focal visual field defects in patients with different visual pathway disorders. The evolution of mfVEP parameters’ changes following acute optic neuritis (ON) was assessed in a longitudinal study of affected and fellow eyes in a large cohort of patients during the first 12 months after attack. The results indicated that mfVEP amplitude can be used as an early predictor of post-ON axonal loss. Additionally, the apparently more severe involvement of ON eyes in the MS subgroup may be due to subclinical inflammation along the visual pathway. The analysis of latency delay in fellow eyes in ON patients indicated that the observed changes are most likely due to subclinical demyelination in the visual pathway and a reflection of the burden of disease in MS patients rather than a result of adaptive cortical plasticity to compensate for delayed transmission of visual information. The last study evaluated the relationship between mfVEP latency and posterior visual pathway lesions in MS patients which demonstrated a significant evidence linking the mfVEP changes with retro-geniculate inflammatory demyelinating lesions

Fingolimod after a first unilateral episode of acute optic neuritis (MOVING) - preliminary results from a randomized, rater-blind, active-controlled, phase 2 trial

BACKGROUND: Neuroprotection and promotion of remyelination represent important therapeutic gaps in multiple sclerosis (MS). Acute optic neuritis (ON) is a frequent MS manifestation. Based on the presence and properties of sphingosine-1-phosphate receptors (S1PR) on astrocytes and oligodendrocytes, we hypothesized that remyelination can be enhanced by treatment with fingolimod, a S1PR modulator currently licensed for relapsing-remitting MS. METHODS: MOVING was an investigator-driven, rater-blind, randomized clinical trial. Patients with acute unilateral ON, occurring as a clinically isolated syndrome or MS relapse, were randomized to 6 months of treatment with 0.5 mg oral fingolimod or subcutaneous IFN-β 1b 250 μg every other day. The change in multifocal visual evoked potential (mfVEP) latency of the qualifying eye was examined as the primary (month 6 vs. baseline) and secondary (months 3, 6 and 12 vs. baseline) outcome. In addition, full field visual evoked potentials, visual acuity, optical coherence tomography as well as clinical relapses and measures of disability, cerebral MRI, and self-reported visual quality of life were obtained for follow-up. The study was halted due to insufficient recruitment (n = 15), and available results are reported. RESULTS: Per protocol analysis of the primary endpoint revealed a significantly larger reduction of mfVEP latency at 6 months compared to baseline with fingolimod treatment (n = 5; median decrease, 15.7 ms) than with IFN-β 1b treatment (n = 4; median increase, 8.15 ms) (p <  0.001 for interaction). Statistical significance was maintained in the secondary endpoint analysis. Descriptive results are reported for other endpoints. CONCLUSION: Preliminary results of the MOVING trial argue in support of a beneficial effect of fingolimod on optic nerve remyelination when compared to IFN-β treatment. Interpretation is limited by the small number of complete observations, an unexpected deterioration of the control group and a difference in baseline mfVEP latencies. The findings need to be confirmed in larger studies. TRIAL REGISTRATION: The trial was registered as EUDRA-CT 2011-004787-30 on October 26, 2012 and as NCT01647880 on July 24, 2012

Multimodal diagnostics in multiple sclerosis: predicting disability and conversion from relapsing-remitting to secondary progressive disease course - protocol for systematic review and meta-analysis

Background The number of patients diagnosed with multiple sclerosis (MS) has increased significantly over the last decade. The challenge is to identify the transition from relapsing-remitting to secondary progressive MS. Since available methods to examine patients with MS are limited, both the diagnostics and prognostication of disease progression would benefit from the multimodal approach. The latter combines the evidence obtained from disparate radiologic modalities, neurophysiological evaluation, cognitive assessment and molecular diagnostics. In this systematic review we will analyse the advantages of multimodal studies in predicting the risk of conversion to secondary progressive MS. Methods and analysis We will use peer-reviewed publications available in Web of Science, Medline/PubMed, Scopus, Embase and CINAHL databases. In vivo studies reporting the predictive value of diagnostic methods will be considered. Selected publications will be processed through Covidence software for automatic deduplication and blind screening. Two reviewers will use a predefined template to extract the data from eligible studies. We will analyse the performance metrics (1) for the classification models reflecting the risk of secondary progression: sensitivity, specificity, accuracy, area under the receiver operating characteristic curve, positive and negative predictive values; (2) for the regression models forecasting disability scores: the ratio of mean absolute error to the range of values. Then, we will create ranking charts representing performance of the algorithms for calculating disability level and MS progression. Finally, we will compare the predictive power of radiological and radiomical correlates of clinical disability and cognitive impairment in patients with MS. Ethics and dissemination The study does not require ethical approval because we will analyse publicly available literature. The project results will be published in a peer-review journal and presented at scientific conferences. PROSPERO registration number CRD42022354179

Evaluation of hemifield sector analysis protocol in multifocal visual evoked potential (MFVEP) objective perimetry for the diagnosis and early detection of glaucomatous field defects

Visual field assessment is a core component of glaucoma diagnosis and monitoring, and the Standard Automated Perimetry (SAP) test is considered up until this moment, the gold standard of visual field assessment. Although SAP is a subjective assessment and has many pitfalls, it is being constantly used in the diagnosis of visual field loss in glaucoma. Multifocal visual evoked potential (mfVEP) is a newly introduced method used for visual field assessment objectively. Several analysis protocols have been tested to identify early visual field losses in glaucoma patients using the mfVEP technique, some were successful in detection of field defects, which were comparable to the standard SAP visual field assessment, and others were not very informative and needed more adjustment and research work. In this study, we implemented a novel analysis approach and evaluated its validity and whether it could be used effectively for early detection of visual field defects in glaucoma. OBJECTIVES: The purpose of this study is to examine the effectiveness of a new analysis method in the Multi-Focal Visual Evoked Potential (mfVEP) when it is used for the objective assessment of the visual field in glaucoma patients, compared to the gold standard technique. METHODS: 3 groups were tested in this study; normal controls (38 eyes), glaucoma patients (36 eyes) and glaucoma suspect patients (38 eyes). All subjects had a two standard Humphrey visual field HFA test 24-2 and a single mfVEP test undertaken in one session. Analysis of the mfVEP results was done using the new analysis protocol; the Hemifield Sector Analysis HSA protocol. Analysis of the HFA was done using the standard grading system. RESULTS: Analysis of mfVEP results showed that there was a statistically significant difference between the 3 groups in the mean signal to noise ratio SNR (ANOVA p<0.001 with a 95% CI). The difference between superior and inferior hemispheres in all subjects were all statistically significant in the glaucoma patient group 11/11 sectors (t-test p<0.001), partially significant 5/11 (t-test p<0.01) and no statistical difference between most sectors in normal group (only 1/11 was significant) (t-test p<0.9). sensitivity and specificity of the HAS protocol in detecting glaucoma was 97% and 86% respectively, while for glaucoma suspect were 89% and 79%. DISCUSSION: The results showed that the new analysis protocol was able to confirm already existing field defects detected by standard HFA, was able to differentiate between the 3 study groups with a clear distinction between normal and patients with suspected glaucoma; however the distinction between normal and glaucoma patients was especially clear and significant. CONCLUSION: The new HSA protocol used in the mfVEP testing can be used to detect glaucomatous visual field defects in both glaucoma and glaucoma suspect patient. Using this protocol can provide information about focal visual field differences across the horizontal midline, which can be utilized to differentiate between glaucoma and normal subjects. Sensitivity and specificity of the mfVEP test showed very promising results and correlated with other anatomical changes in glaucoma field loss

Diagnóstico de esclerosis múltiple mediante análisis de registros de tomografía de coherencia óptica y redes neuronales convolucionales entrenadas con imágenes sintéticas

Antecedentes: La Esclerosis Múltiple (EM) es una enfermedad del sistema nervioso central altamente discapacitante y que se presenta con frecuencia en adultos jóvenes. Para su diagnóstico se utilizan los criterios de McDonald, basados principalmente en evidencias de resonancia magnética, estudio del líquido cefalorraquídeo y el estado clínico del paciente. Sin embargo es conveniente investigar nuevos biomarcadores que permitan un diagnóstico fiable y no invasivo en las primeras fases de la enfermedad, permitiendo de este modo el uso de tratamientos modificadores de la enfermedad, ya que puede suponer una mejor evolución de los pacientes. Objetivos: El objetivo general de la presente tesis doctoral es investigar nuevos métodos de procesamiento y clasificación de imágenes de espesores de diferentes estructuras de la retina, obtenidas mediante Tomografía de Coherencia Óptica de fuente de barrido (SS-OCT) para conseguir un diagnóstico precoz de EM. Métodos: Se dispone de imágenes de espesores de las siguientes estructuras de la retina: retina completa, RNFL, GCL+, GCL++ y coroides, adquiridas por un equipo SS-OCT, en una base de datos formada por 48 sujetos de control y 48 pacientes con EM de diagnóstico reciente. Para la identificación de las estructuras y de las regiones con mayor capacidad discriminante se utiliza el método Relieff de categorización de características. Como clasificador, se utiliza una Red Neuronal Convolucional (RNC), y para evitar problemas de sobreajuste, se generan imágenes sintéticas con Redes Generativas Antagónicas. La comprobación de los métodos de clasificación se realiza mediante validación cruzada dejando uno fuera. Resultados: No existe diferencia significativa entre el grupo de control y el grupo de pacientes ni en edad ni en distribución entre sexos. Los pacientes han tenido un diagnóstico reciente (7,35 ± 1,95 meses). La aplicación del método Relieff detecta que las tres estructuras con mayor capacidad discriminante son GCL+, GCL++ y el espesor de la retina completa. Mediante las Redes Generativas Antagónicas se generan 100 imágenes SS-OCT sintéticas de sujetos de control y 100 imágenes SS-OCT de pacientes EM. Utilizando las imágenes originales en el clasificador RNC se obtiene una precisión de 0,968; en imágenes filtradas con el método Relieff la precisión de es 1,0 y utilizando las imágenes sintéticas para el entrenamiento de la RNC también es 1,0. Si se dispone únicamente del 50% de las imágenes originales, se comprueba la ventaja de disponer datos sintéticos para el entrenamiento de la RNC: la precisión aumenta de 0,66 a 0,96. Conclusiones: Las alteraciones estructurales neurorretinianas en las primeras fases de la EM son adecuadas para implementar un sistema de ayuda al diagnóstico mediante una red neuronal convolucional con un excelente nivel de precisión

Afferent Visual Pathway Assessment in an Exploratory Trial of Autologous Mesenchymal Stem Cells in Multiple Sclerosis

There is a considerable need for treatments in MS for preventing progressive neurological disability. Assessment of the afferent visual pathway shows potential in investigating new therapies in MS. Mesenchymal Stem Cells exhibit properties of potential therapeutic relevance in progressive MS. A phase I/IIA trial of adult autologous mesenchymal stem cells as a potential therapy for Multiple Sclerosis [MSCIMS] was designed as an open label, pre (up to 20 months) vs. post treatment (up to 10 months) (single intravenous administration of autologous bone marrow derived mesenchymal stem cells) comparison study in ten secondary progressive MS patients. Primary end points were adverse events and secondary end points were efficacy measures. All 10 patients had previous history of clinical optic neuritis: this was in order to enable longitudinal structural and functional assessments of the disease-affected afferent visual pathway. Piecewise linear mixed models were used to assess the change in gradients over time at the point of intervention. All 10 patients tolerated the trial assessments and intervention. No significant or serious adverse events were seen. Improvement after treatment was seen in visual acuity and visual evoked response latency, along with an increase in optic nerve cross-sectional area. The results suggest that autologous mesenchymal stem cells are safe and could possibly promote endogenous repair mechanisms such as remyelination, although a definitive conclusion of this cannot be made from this small study. While MSCIMS was a proof of concept study only, based on the encouraging experience derived from it, there would seem to be potential value in future, larger placebo controlled, double-blinded, randomised therapeutic phase IIb/III trials that could (i) more definitively investigate stem cells as a therapy and (ii) use the visual pathway disease model for investigating the efficacy of potential neuroprotective and reparative therapeutic agents

The investigation of acute optic neuritis: a review and proposed protocol

Optic neuritis is an inflammatory optic neuropathy that affects many patients with multiple sclerosis (MS) at some point during their disease course. Differentiation of acute episodes of MS-associated optic neuritis from other autoimmune and inflammatory optic neuropathies is vital for treatment choice and further patient management, but is not always straightforward. Over the past decade, a number of new imaging, laboratory and electrophysiological techniques have entered the clinical arena. To date, however, no consensus guidelines have been devised to specify how and when these techniques can be most rationally applied for the diagnostic work-up of patients with acute optic neuritis. In this article, we review the literature and attempt to formulate a consensus for the investigation of patients with acute optic neuritis, both in standard care and in research with relevance to clinical treatment trials

Structural and functional investigations of vigabatrin toxicity

The purpose of this thesis was to investigate visual dysfunction arising from vigabatrin (VGB) toxicity: structural investigation utilising optical coherence tomography (OCT) and functional investigation using multifocal electrophysiology. OCT of the retinal nerve fibre layer (RNFL) based upon a fixed diameter circle scan and enabling reference to the manufacturers' large proprietary normative database, revealed a specific finding associated with vigabatrin-attributed visual field loss (VAVFL) namely, a characteristic pattern of nasal quadrant attenuation with a normal temporal quadrant thickness. This was present in all 11 individuals (including 2 learning-disabled adults) with VAVFL. A further 4 of 16 (including 3 learning- disabled adults and three children) VGB-exposed individuals with normal visual fields (VGB-E) also manifested this pattern as did two of three individuals (one learning-disabled adult and two children) exposed to VGB but unable to undertake perimetry. The pattern was absent in all 13 individuals treated with non-gabaergic anti-epileptic drugs manifesting normal fields and in 9 normal children. OCT is readily achievable in children as young as 3 years and in learning-disabled adults and should be essential for identifying VAVFL. A re-analysis of RNFL thickness for quadrant/sector differences by OCT and by scanning laser ophthalmoscopy (Heidelberg Retinal Tomography (HRT)) on 13 individuals with VAVFL, 8 VGB-E and 21 normal individuals previously published (Wild et al., 2006) confirmed the abnormal nasal/normal temporal pattern of attenuation. Four children, exposed to VGB in utero, from three mothers (two with VAVFL and nasal RNFL attenuation) yielded normal visual fields and RNFL thicknesses. The amplitudes and implicit times of the mfERG waveform were normal in all 5 VAVFL and in 9 VGB-E, when compared to 13 normal individuals. This suggests that neither bipolar cell nor photoreceptor cell dysfunction, respectively, is implicated in VGB toxicity. The mfVEP amplitudes were normal in all 5 VAVFL and in all 9 VGB-E, when compared to 16 normal individuals. The lack of abnormality may arise from the mismatch between cortical functional topography and the characteristics of VAVFL and the technical limitations associated with the monocular analysis of the mfVEP