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Objectives: The pathophysiology of multiple sclerosis (MS) involves inflammatory neurodegeneration in the brainstem, cerebellum, and retina. The clinical relevance of oculomotor involvement in MS, however, remains uncertain. Methods: In this cross-sectional study, we evaluated heterophoria as a (sub)clinical tool in 54 MS patients and 55 age-matched healthy controls (HCs). We quantified heterophoria in prism diopters for distance and near range with orthoptic examination. Our primary outcome was high degrees of horizontal heterophoria (HDHH) defined as measurements beyond ±2 standard deviations from the mean prism diopter of heterophoria of our HCs. Results: More than one-third (37%, n=20/54) of MS patients but only 11% (n=6/55) of HCs were classified as HDHH [distance, MS=9% (n=5/54) versus HC=6% (n=3/55); near, MS=19% (n=10/54) versus HC=5% (n=3/55)]. Our MS patients presented more combined vertical and horizontal deviations at near range [MS 19% (n=10/54) versus for HC 7% (n=4/55)]. We observed the combination of HDHH both at distance and at near testing in 9% (n=5/54) of MS patients but not at all in HCs (n=0/55). Discussion: Despite the high prevalence of heterophoria, HDHH may be an additional (sub)clinical tool of subclinical involvement in MS. Thus, orthoptic examination may be an additional tool to improve MS diagnostic procedures.
Assuntos
Esclerose Múltipla , Humanos , Estudos Transversais , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Estrabismo , Estudos de Casos e Controles , Estudo de Prova de ConceitoRESUMO
Protein translation is an essential cellular process and dysfunctional protein translation causes various neurodevelopmental disorders. The eukaryotic translation elongation factor 1A (eEF1A) delivers aminoacyl-tRNA to the ribosome, while the eEF1B complex acts as a guanine exchange factor (GEF) of GTP for GDP indirectly catalyzing the release of eEF1A from the ribosome. The gene EEF1D encodes the eEF1Bδ subunit of the eEF1B complex. EEF1D is alternatively spliced giving rise to one long and three short isoforms. Two different homozygous, truncating variants in EEF1D had been associated with severe intellectual disability and microcephaly in two families. The published variants only affect the long isoform of EEF1D that acts as a transcription factor of heat shock element proteins. By exome sequencing, we identified two different homozygous variants in EEF1D in two families with severe developmental delay, severe microcephaly, spasticity, and failure to thrive with optic atrophy, poor feeding, and recurrent aspiration pneumonia. The EEF1D variants reported in this study are localized in the C-terminal GEF domain, suggesting that a disturbed protein translation machinery might contribute to the neurodevelopmental phenotype. Pathogenic variants localized in both the alternatively spliced domain or the GEF domain of EEF1D cause a severe neurodevelopmental disorder with microcephaly and spasticity.
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Microcefalia , Transtornos do Neurodesenvolvimento , Humanos , Guanina , Fatores de Troca do Nucleotídeo Guanina/genética , Transtornos do Neurodesenvolvimento/genética , Isoformas de Proteínas/genética , Fator 1 de Elongação de PeptídeosRESUMO
INTRODUCTION: Optic neuritis leads to degeneration of retinal ganglion cells whose axons form the optic nerve. The standard treatment is a methylprednisolone pulse therapy. This treatment slightly shortens the time of recovery but does not prevent neurodegeneration and persistent visual impairment. In a phase II trial performed in preparation of this study, we have shown that erythropoietin protects global retinal nerve fibre layer thickness (RNFLT-G) in acute optic neuritis; however, the preparatory trial was not powered to show effects on visual function. METHODS AND ANALYSIS: Treatment of Optic Neuritis with Erythropoietin (TONE) is a national, randomised, double-blind, placebo-controlled, multicentre trial with two parallel arms. The primary objective is to determine the efficacy of erythropoietin compared to placebo given add-on to methylprednisolone as assessed by measurements of RNFLT-G and low-contrast visual acuity in the affected eye 6 months after randomisation. Inclusion criteria are a first episode of optic neuritis with decreased visual acuity to ≤ 0.5 (decimal system) and an onset of symptoms within 10 days prior to inclusion. The most important exclusion criteria are history of optic neuritis or multiple sclerosis or any ocular disease (affected or non-affected eye), significant hyperopia, myopia or astigmatism, elevated blood pressure, thrombotic events or malignancy. After randomisation, patients either receive 33,000 international units human recombinant erythropoietin intravenously for 3 consecutive days or placebo (0.9% saline) administered intravenously. With an estimated power of 80%, the calculated sample size is 100 patients. The trial started in September 2014 with a planned recruitment period of 30 months. ETHICS AND DISSEMINATION: TONE has been approved by the Central Ethics Commission in Freiburg (194/14) and the German Federal Institute for Drugs and Medical Devices (61-3910-4039831). It complies with the Declaration of Helsinki, local laws and ICH-GCP. TRIAL REGISTRATION NUMBER: NCT01962571.
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Protocolos Clínicos , Eritropoetina/administração & dosagem , Neurite Óptica/tratamento farmacológico , Retina/fisiopatologia , Acuidade Visual , Adolescente , Adulto , Método Duplo-Cego , Eritropoetina/efeitos adversos , Feminino , Alemanha , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: To investigate the benefit of adding bevacizumab to intravitreal recombinant tissue plasminogen activator (rTPA) and gas as initial therapy in subretinal hemorrhage and choroidal neovascularization because of age-related macular degeneration. METHODS: Thirty-eight consecutive patients with recent (1-31 days) subretinal hemorrhage who were treated with intravitreal rTPA and gas (26 patients) or with intravitreal bevacizumab, rTPA, and gas (12 patients) were included in this retrospective analysis. In all patients, a standardized antivascular endothelial growth factor therapy was followed. Testing of best-corrected visual acuity, biomicroscopy, and fundus examination were performed at 4 weeks and 7 months. RESULTS: The mean pretreatment best-corrected visual acuity in the rTPA/gas group was 0.08 ± 0.09 and 0.12 ± 0.13 in the bevacizumab/rTPA/gas group. After 4 weeks, it was significantly higher in the bevacizumab/rTPA/gas group (0.25 ± 0.26) than in the rTPA/gas (0.08 ± 0.1) group (P < 0.05). Also, after 7 months, best-corrected visual acuity was significantly higher in the bevacizumab/rTPA/gas group (0.07 ± 0.07 vs. 0.24 ± 0.35; P < 0.05). Reading vision could be restored in 0% (rTPA/gas) versus 50% (bevacizumab/rTPA/gas). Stabilization (0 ± 2 lines) or improvement of best-corrected visual acuity was obtained in 62% (rTPA/gas) versus 84% (bevacizumab/rTPA/gas). CONCLUSION: From our retrospective pilot study, there is a strong indication that the addition of intravitreal bevacizumab is safe and superior to the displacement of submacular hemorrhages alone with rTPA and gas.
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Inibidores da Angiogênese/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Neovascularização de Coroide/tratamento farmacológico , Gases/administração & dosagem , Macula Lutea , Degeneração Macular/complicações , Hemorragia Retiniana/tratamento farmacológico , Inibidores Teciduais de Metaloproteinases/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Bevacizumab , Neovascularização de Coroide/etiologia , Neovascularização de Coroide/fisiopatologia , Quimioterapia Combinada , Óculos , Feminino , Gases/efeitos adversos , Humanos , Injeções Intraoculares , Degeneração Macular/fisiopatologia , Masculino , Projetos Piloto , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Hemorragia Retiniana/etiologia , Hemorragia Retiniana/fisiopatologia , Estudos Retrospectivos , Inibidores Teciduais de Metaloproteinases/efeitos adversos , Resultado do Tratamento , Acuidade Visual/efeitos dos fármacos , Corpo VítreoRESUMO
AIMS: The use of the chemotherapeutic cytosine arabinoside (Ara-C) causes an ocular toxic reaction, characterized by aspecific keratopathy. We examined the pathway of the damaged cells by in vivo confocal microscopy. METHODS: Prospective study of 11 patients with acute myeloic leukemia treated with high-dose Ara-C. Ten eyes developed fluorescein-negative punctate keratopathy, and were examined by slit lamp and in vivo confocal biomicroscopy at days 1, 3-4 and 9-14 after the beginning of ocular symptoms. RESULTS: In vivo confocal microscopy revealed disseminated highly reflective granular irregular intraepithelial elements in the central cornea, which affected about 3% of epithelial cells. At day 1 of symptoms, these elements were present only in the basal epithelial layer (median 275.5/mm(2)), at days 3-4 they were mainly found in the basal (187.5/mm(2)) but also in the apical layers (96/mm(2)), at days 9-14 they mainly presented in more superficial layers (115/mm(2) apically vs. 15.5/mm(2) in the basal layers). DISCUSSION: The intraepithelial distribution of cells with a granular cytosolic signal evolved over time, reflecting the migration of the necrotic basal cells to the wing cell layer and finally to apical epithelial layers. The desquamation of the necrotic cells is related to the resolution of symptoms, according to the period of the epithelial cell turnover. By confocal microscopy, we could follow the intraepithelial route of cells damaged by Ara-C in vivo.