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OBJECTIVE: Retrograde trans-synaptic neuroaxonal degeneration is considered a key pathological factor of subclinical retinal neuroaxonal damage in multiple sclerosis (MS). We aim to evaluate the longitudinal association of optic radiation (OR) lesion activity with retinal neuroaxonal damage and its role in correlations between retinal and brain atrophy in people with clinically isolated syndrome and early MS (pweMS). METHODS: Eighty-five pweMS were retrospectively screened from a prospective cohort (Berlin CIS cohort). Participants underwent 3T magnetic resonance imaging (MRI) for OR lesion volume and brain atrophy measurements and optical coherence tomography (OCT) for retinal layer thickness measurements. All pweMS were followed with serial OCT and MRI over a median follow-up of 2.9 (interquartile range: 2.6-3.4) years. Eyes with a history of optic neuritis prior to study enrollment were excluded. Linear mixed models were used to analyze the association of retinal layer thinning with changes in OR lesion volume and brain atrophy. RESULTS: Macular ganglion cell-inner plexiform layer (GCIPL) thinning was more pronounced in pweMS with OR lesion volume increase during follow-up compared to those without (Difference: -0.82 µm [95% CI:-1.49 to -0.15], p = 0.018). Furthermore, GCIPL thinning correlated with both OR lesion volume increase (ß [95% CI] = -0.27 [-0.50 to -0.03], p = 0.028) and brain atrophy (ß [95% CI] = 0.47 [0.25 to 0.70], p < 0.001). Correlations of GCIPL changes with brain atrophy did not differ between pweMS with or without OR lesion increase ( η p 2 = 5.92e-7 , p = 0.762). INTERPRETATION: Faster GCIPL thinning rate is associated with increased OR lesion load. Our results support the value of GCIPL as a sensitive biomarker reflecting both posterior visual pathway pathology and global brain neurodegeneration.
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Doenças do Sistema Nervoso Central , Esclerose Múltipla , Humanos , Esclerose Múltipla/patologia , Células Ganglionares da Retina/patologia , Estudos Prospectivos , Estudos Retrospectivos , Doenças do Sistema Nervoso Central/complicações , Atrofia/patologiaRESUMO
BACKGROUND: In the demyelinating disease multiple sclerosis (MS), chronic-active brain inflammation, remyelination failure and neurodegeneration remain major issues despite immunotherapy. While B cell depletion and blockade/sequestration of T and B cells potently reduces episodic relapses, they act peripherally to allow persistence of chronic-active brain inflammation and progressive neurological dysfunction. N-acetyglucosamine (GlcNAc) is a triple modulator of inflammation, myelination and neurodegeneration. GlcNAc promotes biosynthesis of Asn (N)-linked-glycans, which interact with galectins to co-regulate the clustering/signaling/endocytosis of multiple glycoproteins simultaneously. In mice, GlcNAc crosses the blood brain barrier to raise N-glycan branching, suppress inflammatory demyelination by T and B cells and trigger stem/progenitor cell mediated myelin repair. MS clinical severity, demyelination lesion size and neurodegeneration inversely associate with a marker of endogenous GlcNAc, while in healthy humans, age-associated increases in endogenous GlcNAc promote T cell senescence. OBJECTIVES AND METHODS: An open label dose-escalation mechanistic trial of oral GlcNAc at 6 g (n = 18) and 12 g (n = 16) for 4 weeks was performed in MS patients on glatiramer acetate and not in relapse from March 2016 to December 2019 to assess changes in serum GlcNAc, lymphocyte N-glycosylation and inflammatory markers. Post-hoc analysis examined changes in serum neurofilament light chain (sNfL) as well as neurological disability via the Expanded Disability Status Scale (EDSS). RESULTS: Prior to GlcNAc therapy, high serum levels of the inflammatory cytokines IFNγ, IL-17 and IL-6 associated with reduced baseline levels of a marker of endogenous serum GlcNAc. Oral GlcNAc therapy was safe, raised serum levels and modulated N-glycan branching in lymphocytes. Glatiramer acetate reduces TH1, TH17 and B cell activity as well as sNfL, yet the addition of oral GlcNAc dose-dependently lowered serum IFNγ, IL-17, IL-6 and NfL. Oral GlcANc also dose-dependently reduced serum levels of the anti-inflammatory cytokine IL-10, which is increased in the brain of MS patients. 30% of treated patients displayed confirmed improvement in neurological disability, with an average EDSS score decrease of 0.52 points. CONCLUSIONS: Oral GlcNAc inhibits inflammation and neurodegeneration markers in MS patients despite concurrent immunomodulation by glatiramer acetate. Blinded studies are required to investigate GlcNAc's potential to control residual brain inflammation, myelin repair and neurodegeneration in MS.
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Encefalite , Esclerose Múltipla , Humanos , Animais , Camundongos , Acetilglucosamina/uso terapêutico , Interleucina-17 , Acetato de Glatiramer , Interleucina-6 , Esclerose Múltipla/tratamento farmacológico , Inflamação/tratamento farmacológico , CitocinasRESUMO
Purpose: Idiopathic intracranial hypertension (IIH) leads to optic nerve head swelling and optic atrophy if left untreated. We wanted to assess an easy to perform volumetric algorithm to detect and quantify papilledema in comparison to retinal nerve fiber layer (RNFL) analysis using optical coherence tomography (OCT). Methods: Participants with and without IIH underwent visual acuity testing at different contrast levels and static perimetry. Spectralis-OCT measurements comprised standard imaging of the peripapillary RNFL and macular ganglion cell layer (GCL). The optic nerve head volume (ONHV) was determined using the standard segmentation software and the 3.45 mm early treatment diabetic retinopathy study (ETDRS) grid, necessitating manual correction within Bruch membrane opening. Three neuro-ophthalmologists graded fundus images according to the Frisén scale. A mixed linear model (MLM) was used to determine differences between study groups. Sensitivity and specificity was evaluated using the area under the receiver-operating characteristic (ROC). Results: Twenty-one patients with IIH had an increased ONHV of 6.46 ± 2.36 mm3 as compared to 25 controls with 3.20 ± 0.25 mm3 (P < 0.001). The ONHV cutoff distinguishing IIH from controls was 3.97 mm3 (i.e. no patient with IIH had an ONHV below and no healthy individual above this value). The area under the curve (AUC) for ONHV was 0.99 and for the RNFL at 3.5 mm 0.90. The Frisén scale grading correlated higher with the ONHV (r = 0.90) than with the RNFL thickness (r = 0.68). ONHV measurements were highly reproducible in both groups (coefficient of variation <0.01%). Conclusions: OCT-based volumetry of the optic nerve head discriminates very accurately between individuals with and without IIH. It may serve as a useful adjunct to the rating with the subjective and ordinal Frisén scale. Translational Relevance: A simple OCT protocol run on the proprietary software of a commercial OCT device can reliably discriminate between normal optic nerve heads or pseudo-papilledema and true papilledema while being highly reproducible. Our normative data and OCT preset may be used in further clinical studies.
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Disco Óptico , Papiledema , Pseudotumor Cerebral , Humanos , Fibras Nervosas , Disco Óptico/diagnóstico por imagem , Papiledema/diagnóstico , Pseudotumor Cerebral/complicações , Células Ganglionares da Retina , Tomografia de Coerência ÓpticaRESUMO
Retinal changes and visual symptoms are present in several inflammatory, degenerative and tumorous disorders of the central nervous system (CNS). Optical coherence tomography (OCT) is a method that can be used in clinical practice to detect and quantify the structural correlates of these visual symptoms in neurological disorders. OCT is a non-invasive imaging technique, based on interferometry, which can create high-resolution images of the retina and measure the thickness and volume of the different retinal layers. The combined ganglion cell- and inner plexiform layer (GCIPL) and the peripapillary retinal nerve fibre layer (pRNFL) are of particular interest in the field of neurological disorders, since they contain the neuronal bodies (ganglion cells) and their axons that form the optic nerve. In acute optic neuritis (ON), initial swelling of the pRNFL can be detected by OCT and this may contribute to the diagnosis and differential diagnosis of ON; moreover, the extent of the GCIPL-thinning within the first 4 weeks after an acute ON can contribute to the prediction of the long-term visual recovery. However, the role of OCT in the field of multiple sclerosis (MS) is not restricted in patients with ON, since even eyes without an ON-history show mild thinning of the pRNFL and GCIPL. This thinning seems to be associated with neurodegenerative processes in the entire CNS. Several studies showed correlations between these OCT-parameters and a higher risk of clinical deterioration (disability progression), cognitive deficits and disease activity in patients with MS. However, it is often still unclear how these correlations can be useful in the management of the individual patient. In recent years, OCT has been applied to a greater extent to neurodegenerative diseases, such as Parkinson's disease, amyotrophic lateral sclerosis (ALS) and various forms of dementia. However, routine clinical use is still further away than for inflammatory CNS diseases, since the role of OCT in the diagnosis, differential diagnosis and prediction of the clinical course of neurodegenerative diseases is still unclear. This review article offers a summary of the available study results on OCT parameters and their role in inflammatory, degenerative and tumorous diseases of the central nervous system (CNS).
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Doenças do Sistema Nervoso Central/diagnóstico por imagem , Neurite Óptica , Tomografia de Coerência Óptica , Humanos , Nervo Óptico , Retina , Células Ganglionares da Retina , Tomografia de Coerência Óptica/métodosRESUMO
BACKGROUND: The International Multiple Sclerosis Visual System Consortium (IMSVISUAL) was formed in November 2014 with the primary goal of improving research, care, and education regarding the role of the visual system in multiple sclerosis (MS) and related disorders. METHODS: In this review, we describe the formation, goals, activities, and structure of IMSVISUAL, as well as the relationship of IMSVISUAL with the Americas Committee for Treatment and Research in MS (ACTRIMS). Finally, we provide an overview of the work IMSVISUAL has completed to date, as well as an outline of research projects ongoing under the auspices of IMSVISUAL. RESULTS: IMSVISUAL has 140 members worldwide and continues to grow. Through IMSVISUAL-related research, optical coherence tomography (OCT)-derived peripapillary retinal nerve fiber layer (pRNFL) thinning has been established as a predictor of future disability in MS. IMSVISUAL has also developed guidelines for reporting OCT studies in MS. Moreover, a systematic review performed by IMSVISUAL found that not only are pRNFL and ganglion cell + inner plexiform layer (GCIPL) thicknesses reduced in patients with MS (particularly in eyes with prior optic neuritis [ON]), but that inner nuclear layer measures may be higher among MS ON eyes, relative to healthy control eyes. Currently, there are several ongoing IMSVISUAL projects that will establish a role for visual outcomes in diagnosing MS and quantifying the effects of emerging therapies in clinical trials. CONCLUSIONS: The development of IMSVISUAL represents a major collaborative commitment to defining the role of visual outcomes in high-quality, large-scale studies that generate definitive and instructive findings in the field of MS. As a consortium, IMSVISUAL has completed several international collaborative projects, is actively engaged in numerous ongoing research studies, and is committed to expanding the role of vision research in MS and related disorders.
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Pesquisa Biomédica/normas , Gerenciamento Clínico , Oftalmopatias , Esclerose Múltipla/terapia , Oftalmologia , Guias de Prática Clínica como Assunto , Acuidade Visual , Oftalmopatias/diagnóstico , Oftalmopatias/etiologia , Oftalmopatias/terapia , Humanos , Esclerose Múltipla/complicações , Esclerose Múltipla/diagnósticoRESUMO
Background: Diffusion Tensor Imaging (DTI) can evaluate microstructural tissue damage in the optic radiation (OR) of patients with clinically isolated syndrome (CIS), early relapsing-remitting multiple sclerosis and neuromyelitis optica spectrum disorders (NMOSD). Different post-processing techniques, e.g. tract-based spatial statistics (TBSS) and probabilistic tractography, exist to quantify this damage. Objective: To evaluate the capacity of TBSS-based atlas region-of-interest (ROI) combination with 1) posterior thalamic radiation ROIs from the Johns Hopkins University atlas (JHU-TBSS), 2) Juelich Probabilistic ROIs (JUEL-TBSS) and tractography methods using 3) ConTrack (CON-PROB) and 4) constrained spherical deconvolution tractography (CSD-PROB) to detect OR damage in patients with a) NMOSD with prior ON (NMOSD-ON), b) CIS and early RRMS patients with ON (CIS/RRMS-ON) and c) CIS and early RRMS patients without prior ON (CIS/RRMS-NON) against healthy controls (HCs). Methods: Twenty-three NMOSD-ON, 18 CIS/RRMS-ON, 21 CIS/RRMS-NON, and 26 HCs underwent 3â¯T MRI. DTI data analysis was carried out using JUEL-TBSS, JHU-TBSS, CON-PROB and CSD-PROB. Optical coherence tomography (OCT) and visual acuity testing was performed in the majority of patients and HCs. Results: Absolute OR fractional anisotropy (FA) values differed between all methods but showed good correlation and agreement in Bland-Altman analysis. OR FA values between NMOSD and HC differed throughout the methodologies (p-values ranging from pâ¯<â¯0.0001 to 0.0043). ROC-analysis and effect size estimation revealed higher AUCs and R2 for CSD-PROB (AUCâ¯=â¯0.812; R2â¯=â¯0.282) and JHU-TBSS (AUCâ¯=â¯0.756; R2â¯=â¯0.262), compared to CON-PROB (AUCâ¯=â¯0.742; R2â¯=â¯0.179) and JUEL-TBSS (AUCâ¯=â¯0.719; R2â¯=â¯0.161). Differences between CIS/RRMS-NON and HC were only observable in CSD-PROB (AUCâ¯=â¯0.796; R2â¯=â¯0.094). No significant differences between CIS/RRMS-ON and HC were detected by any of the methods. Conclusions: All DTI post-processing techniques facilitated the detection of OR damage in patient groups with severe microstructural OR degradation. The comparison of distinct disease groups by use of different methods may lead to different - either false-positive or false-negative - results. Since different DTI post-processing approaches seem to provide complementary information on OR damage, application of distinct methods may depend on the relevant research question.
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Doenças Desmielinizantes/patologia , Cápsula Interna/patologia , Esclerose Múltipla Recidivante-Remitente/patologia , Neuromielite Óptica/patologia , Substância Branca/patologia , Adulto , Anisotropia , Imagem de Tensor de Difusão/métodos , Feminino , Humanos , Cápsula Interna/fisiopatologia , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Fibras Nervosas/patologia , Neuromielite Óptica/fisiopatologia , Substância Branca/fisiopatologiaRESUMO
The objectives of the study were to investigate the value of optical coherence tomography in detecting papilledema in patients with idiopathic intracranial hypertension (IIH), a disease which is difficult to monitor and which can lead to permanent visual deficits; to analyze retinal changes over time. In this non-interventional case-control study, spectral-domain optical coherence tomography (SD-OCT) was used to analyze the retinal and optic nerve head (ONH) morphology of 21 patients with IIH and 27 age- and sex-matched healthy controls over time. We analyzed the ONH volume using a custom-made algorithm and employed semi-automated segmentation of macular volume scans to assess the macular retinal nerve fiber layer (RNFL) and ganglion cell layer and inner plexiform layer complex as well as the total macular volume. In IIH patients, the ONH volume was increased and correlated with cerebrospinal fluid (CSF) pressure. The ONH volume decreased after the initiation of treatment with acetazolamide. The macular RNFL volume decreased by 5% in 3.5 months, and a stepwise multivariate regression analysis identified CSF pressure as the main influence on macular RNFL volume at diagnosis. The only factor predicting macular RNFL volume loss over time was ONH volume. SD-OCT can non-invasively monitor changes in retinal and ONH morphology in patients with IIH. Increased ONH volume leads to retinal atrophy in the form of macular RNFL volume loss, presumably due to mechanic jamming of the optic nerve at the disc and subsequent axonal loss.
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Nervo Óptico/diagnóstico por imagem , Pseudotumor Cerebral/diagnóstico por imagem , Retina/diagnóstico por imagem , Tomografia de Coerência Óptica , Acetazolamida/uso terapêutico , Adulto , Algoritmos , Atrofia , Inibidores da Anidrase Carbônica/uso terapêutico , Estudos de Casos e Controles , Progressão da Doença , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Nervo Óptico/efeitos dos fármacos , Tamanho do Órgão , Reconhecimento Automatizado de Padrão , Estudos Prospectivos , Pseudotumor Cerebral/tratamento farmacológico , Retina/efeitos dos fármacos , Tomografia de Coerência Óptica/métodos , Resultado do Tratamento , Ultrassonografia , Acuidade VisualRESUMO
OBJECTIVE: To investigate the association of Epstein-Barr virus (EBV) nuclear antigen-1 (EBNA-1) and viral capsid antigen (VCA) immunoglobulin (Ig)G antibodies in serum as well as EBV DNA load in saliva with radiological and clinical disease activity in patients with clinically isolated syndrome (CIS) and early relapsing-remitting MS (RRMS). METHODS: EBNA-1 and VCA immunoglobulin (Ig)G antibodies were determined in serum of 100 patients with CIS/early RRMS and 60 healthy controls. EBV DNA load was measured in saliva of 48 patients and 50 controls. Patients underwent clinical assessment with the Expanded Disability Status Scale (EDSS) and 3 Tesla magnetic resonance imaging at baseline and after a median of 20 months of follow-up (n = 63 for MRI, n = 71 for EDSS). The association of EBV parameters with occurrence of a second relapse, indicating conversion to clinically definite MS (CDMS), was evaluated over a median of 35 months of follow-up after the first clinical event (n = 89). RESULTS: EBNA-1 IgG antibody frequency (p = 0.00005) and EBNA-1 and VCA IgG antibody levels (p<0.0001 for both) were higher in patients than in controls. EBV DNA load in saliva did not differ between groups. Neither EBV antibody levels nor DNA load in saliva were associated with baseline or follow-up number or volume of T2-weighted (T2w) or contrast enhancing lesions, number of Barkhof criteria or the EDSS, or with the number of new T2w lesions, T2w lesion volume change or EDSS change on follow-up. Likewise, levels of EBV IgG antibodies in serum and DNA load in saliva were not associated with conversion to CDMS. CONCLUSIONS: While these findings confirm the association of EBV infection with early MS, neither EBNA-1 nor VCA IgG antibodies in serum nor EBV DNA load in saliva were associated with radiological or clinical disease activity in patients with CIS/early RRMS. These data are compatible with the concept that EBV may be a trigger for MS acting very early during the development of the disease.
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Anticorpos Antivirais/sangue , DNA Viral/metabolismo , Herpesvirus Humano 4/imunologia , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/patologia , Saliva/metabolismo , Adulto , Biomarcadores/sangue , Biomarcadores/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/virologia , Adulto JovemRESUMO
BACKGROUND: Myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) are present in a subset of aquaporin-4 (AQP4)-IgG-negative patients with optic neuritis (ON) and/or myelitis. Little is known so far about brainstem involvement in MOG-IgG-positive patients. OBJECTIVE: To investigate the frequency, clinical and paraclinical features, course, outcome, and prognostic implications of brainstem involvement in MOG-IgG-positive ON and/or myelitis. METHODS: Retrospective case study. RESULTS: Among 50 patients with MOG-IgG-positive ON and/or myelitis, 15 (30 %) with a history of brainstem encephalitis were identified. All were negative for AQP4-IgG. Symptoms included respiratory insufficiency, intractable nausea and vomiting (INV), dysarthria, dysphagia, impaired cough reflex, oculomotor nerve palsy and diplopia, nystagmus, internuclear ophthalmoplegia (INO), facial nerve paresis, trigeminal hypesthesia/dysesthesia, vertigo, hearing loss, balance difficulties, and gait and limb ataxia; brainstem involvement was asymptomatic in three cases. Brainstem inflammation was already present at or very shortly after disease onset in 7/15 (47 %) patients. 16/21 (76.2 %) brainstem attacks were accompanied by acute myelitis and/or ON. Lesions were located in the pons (11/13), medulla oblongata (8/14), mesencephalon (cerebral peduncles; 2/14), and cerebellar peduncles (5/14), were adjacent to the fourth ventricle in 2/12, and periaqueductal in 1/12; some had concomitant diencephalic (2/13) or cerebellar lesions (1/14). MRI or laboratory signs of blood-brain barrier damage were present in 5/12. Cerebrospinal fluid pleocytosis was found in 11/14 cases, with neutrophils in 7/11 (3-34 % of all CSF white blood cells), and oligoclonal bands in 4/14. Attacks were preceded by acute infection or vaccination in 5/15 (33.3 %). A history of teratoma was noted in one case. The disease followed a relapsing course in 13/15 (87 %); the brainstem was involved more than once in 6. Immunosuppression was not always effective in preventing relapses. Interferon-beta was followed by new attacks in two patients. While one patient died from central hypoventilation, partial or complete recovery was achieved in the remainder following treatment with high-dose steroids and/or plasma exchange. Brainstem involvement was associated with a more aggressive general disease course (higher relapse rate, more myelitis attacks, more frequently supratentorial brain lesions, worse EDSS at last follow-up). CONCLUSIONS: Brainstem involvement is present in around one third of MOG-IgG-positive patients with ON and/or myelitis. Clinical manifestations are diverse and may include symptoms typically seen in AQP4-IgG-positive neuromyelitis optica, such as INV and respiratory insufficiency, or in multiple sclerosis, such as INO. As MOG-IgG-positive brainstem encephalitis may take a serious or even fatal course, particular attention should be paid to signs or symptoms of additional brainstem involvement in patients presenting with MOG-IgG-positive ON and/or myelitis.
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Tronco Encefálico/fisiopatologia , Imunoglobulina G/sangue , Glicoproteína Mielina-Oligodendrócito/imunologia , Neuromielite Óptica/sangue , Neuromielite Óptica/diagnóstico por imagem , Adolescente , Adulto , Fatores Etários , Barreira Hematoencefálica/patologia , Tronco Encefálico/diagnóstico por imagem , Estudos de Coortes , Avaliação da Deficiência , Encefalite/sangue , Encefalite/diagnóstico por imagem , Encefalite/imunologia , Feminino , Humanos , Interferon beta/uso terapêutico , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mielite/sangue , Mielite/imunologia , Mielite/patologia , Neuromielite Óptica/tratamento farmacológico , Neuromielite Óptica/imunologia , Rituximab/uso terapêutico , Adulto JovemRESUMO
BACKGROUND: Muscular weakness in myasthenia gravis (MG) is commonly assessed using Quantitative Myasthenia Gravis Score (QMG). More objective and quantitative measures may complement the use of clinical scales and might detect subclinical affection of muscles. We hypothesized that muscular weakness in patients with MG can be quantified with the non-invasive Quantitative Motor (Q-Motor) test for Grip Force Assessment (QGFA) and Involuntary Movement Assessment (QIMA) and that pathological findings correlate with disease severity as measured by QMG. METHODS: This was a cross-sectional pilot study investigating patients with confirmed diagnosis of MG. Data was compared to healthy controls (HC). Subjects were asked to lift a device (250 and 500 g) equipped with electromagnetic sensors that measured grip force (GF) and three-dimensional changes in position and orientation. These were used to calculate the position index (PI) and orientation index (OI) as measures for involuntary movements due to muscular weakness. RESULTS: Overall, 40 MG patients and 23 HC were included. PI and OI were significantly higher in MG patients for both weights in the dominant and non-dominant hand. Subgroup analysis revealed that patients with clinically ocular myasthenia gravis (OMG) also showed significantly higher values for PI and OI in both hands and for both weights. Disease severity correlates with QIMA performance in the non-dominant hand. CONCLUSION: Q-Motor tests and particularly QIMA may be useful objective tools for measuring motor impairment in MG and seem to detect subclinical generalized motor signs in patients with OMG. Q-Motor parameters might serve as sensitive endpoints for clinical trials in MG.
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Força da Mão/fisiologia , Debilidade Muscular/diagnóstico , Debilidade Muscular/fisiopatologia , Miastenia Gravis/fisiopatologia , Estudos de Casos e Controles , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dinamômetro de Força Muscular , Projetos PilotoRESUMO
Autosomal dominant ataxia type 14 (SCA14) is a rare usually adult-onset progressive disorder with cerebellar neurodegeneration caused by mutations in protein kinase C gamma. We set out to examine cerebellar and extracerebellar neurochemical changes in SCA14 by MR spectroscopy. In 13 SCA14 patients and 13 healthy sex- and age-matched controls, 3-T single-voxel brain proton MR spectroscopy was performed in a cerebellar voxel of interest (VOI) at TE = 30 ms to obtain a neurochemical profile of metabolites with short relaxation times. In the cerebellum and in additional VOIs in the prefrontal cortex, motor cortex, and somatosensory cortex, a second measurement was performed at TE = 144 ms to mainly extract the total N-acetyl-aspartate (tNAA) signal besides the signals for total creatine (tCr) and total choline (tCho). The cerebellar neurochemical profile revealed a decrease in glutathione (6.12E-06 ± 2.50E-06 versus 8.91E-06 ± 3.03E-06; p = 0028) and tNAA (3.78E-05 ± 5.67E-06 versus 4.25E-05 ± 5.15E-06; p = 0023) and a trend for reduced glutamate (2.63E-05 ± 6.48E-06 versus 3.15E-05 ± 7.61E-06; p = 0062) in SCA14 compared to controls. In the tNAA-focused measurement, cerebellar tNAA (296.6 ± 42.6 versus 351.7 ± 16.5; p = 0004) and tCr (272.1 ± 25.2 versus 303.2 ± 31.4; p = 0004) were reduced, while the prefrontal, somatosensory and motor cortex remained unaffected compared to controls. Neuronal pathology in SCA14 detected by MR spectroscopy was restricted to the cerebellum and did not comprise cortical regions. In the cerebellum, we found in addition to signs of neurodegeneration a glutathione reduction, which has been associated with cellular damage by oxidative stress in other neurodegenerative diseases such as Parkinson's disease and Friedreich's ataxia.
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Cerebelo/metabolismo , Córtex Cerebral/metabolismo , Glutationa/metabolismo , Espectroscopia de Prótons por Ressonância Magnética/métodos , Ataxias Espinocerebelares/metabolismo , Adulto , Idoso , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Creatina/metabolismo , Feminino , Ácido Glutâmico/metabolismo , Glutationa/deficiência , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: To investigate posterior visual pathway damage in multiple sclerosis using ultrahigh-field magnetic resonance imaging (MRI) at 7 Tesla (7 T), and to determine its correlation with visual disability and retinal fibre layer (RNFL) damage detectable by optic coherence tomography (OCT). METHODS: We studied 7 T MRI, OCT, functional acuity contrast testing (FACT), and visually evoked potentials (VEP, n = 16) in 30 patients (including 26 relapsing-remitting MS and four clinically isolated syndrome patients) and 12 healthy controls to quantify RNFL thickness, optic radiation lesion volume, and optic radiation thickness. RESULTS: Optic radiation lesion volume was associated with thinning of the optic radiation (p < 0.001), delayed VEP (p = 0.031), and visual disability indicated by FACT (p = 0.020). Furthermore, we observed an inverse correlation between optic radiation lesion volume and RNFL thickness (p < 0.001), including patients without previous optic neuritis (p < 0.001). CONCLUSIONS: Anterior visual pathway damage, but also (subclinical) optic radiation integrity loss detectable by 7 T MRI are common findings in MS that are mutually affected. Given the association between optic radiation damage, visual impairment, and increased VEP latency in this exploratory study of a limited sample size, clinicians should be aware of acute lesions within the optic radiation in patients with (bilateral) visual disturbances. KEY POINTS: ⢠Focal destruction of the optic radiation is detectable by 7 T MRI. ⢠Focal optic radiation damage is common in MS. ⢠Optic radiation damage is associated with RNFL thinning, detectable by OCT. ⢠Optic radiation damage is associated with delayed VEP and visual dysfunction. ⢠RNFL thickness in non-optic neuritis eyes correlates with optic radiation demyelination.
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Esclerose Múltipla Recidivante-Remitente/patologia , Neurite Óptica/patologia , Transtornos da Visão/etiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Potenciais Evocados Visuais , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Fibras Nervosas/patologia , Músculos Oculomotores/patologia , Projetos Piloto , Estudos Prospectivos , Doenças Retinianas/patologia , Tomografia de Coerência Óptica , Transtornos da Visão/patologia , Adulto JovemRESUMO
BACKGROUND: Microcystic macular edema (MME) and inner nuclear layer thickening (INL) were described in multiple sclerosis (MS) and neuromyelitis optica (NMO) patients using optical coherence tomography (OCT). The cause of these findings is currently unknown and a relation to inflammatory or degenerative processes in the optic nerve is discussed. OBJECTIVE: The aim of our study was to investigate whether INL thickening and MME are related to optic neuritis (ON) in various neuro-inflammatory disorders causingON: MS, NMO and chronic inflammatory optic neuropathy. METHODS: We retrospectively analyzed data from 216 MS patients, 39 patients with a clinically isolated syndrome, 20 NMO spectrum disorder patients, 9 patients with chronic inflammatory optic neuropathy and 121 healthy subjects. Intra-retinal layer segmentation was performed for the eyes of patients with unilateral ON. Scanning laser ophthalmoscopy (SLO) images were reviewed for characteristic ocular fundus changes. RESULTS: Intra-retinal layer segmentation showed that eyes with a history of ON displayed MME independent INL thickening compared to contralateral eyes without previous ON. MME was detected in 22 eyes from 15 patients (5.3% of all screened patients), including 7 patients with bilateral edema. Of these, 21 had a prior history of ON (95%). The SLO images of all 22 MME-affected eyes showed crescent-shaped texture changes which were visible in the perifoveal region. A second grader who was blinded to the results of the OCT classified all SLO images for the presence of these characteristic fundus changes. All MME eyes were correctly classified (sensitivityâ=â100%) with high specificity (95.2%). CONCLUSION: This study shows that both MME and INL thickening occur in various neuro-inflammatory disorders associated with ON. We also demonstrate that detection and analysis of MME by OCT is not limited to B-scans, but also possible using SLO images.
Assuntos
Edema Macular/complicações , Esclerose Múltipla/complicações , Neurite Óptica/complicações , Retina/patologia , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Edema Macular/diagnóstico , Edema Macular/patologia , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/patologia , Oftalmoscopia , Neurite Óptica/diagnóstico , Neurite Óptica/patologia , Estudos Retrospectivos , Tomografia de Coerência Óptica , Adulto JovemRESUMO
OBJECTIVE: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune encephalitis with a characteristic neuropsychiatric syndrome and severe and prolonged clinical courses. In contrast, standard clinical magnetic resonance imaging (MRI) remains normal in the majority of patients. Here, we investigated structural and functional brain changes in a cohort of patients with anti-NMDAR encephalitis. METHODS: Twenty-four patients with established diagnosis of anti-NMDAR encephalitis and age- and gender-matched controls underwent neuropsychological testing and multimodal MRI, including T1w/T2w structural imaging, analysis of resting state functional connectivity, analysis of white matter using diffusion tensor imaging, and analysis of gray matter using voxel-based morphometry. RESULTS: Patients showed significantly reduced functional connectivity of the left and right hippocampus with the anterior default mode network. Connectivity of both hippocampi predicted memory performance in patients. Diffusion tensor imaging revealed extensive white matter changes, which were most prominent in the cingulum and which correlated with disease severity. In contrast, no differences in T1w/T2w structural imaging and gray matter morphology were observed between patients and controls. INTERPRETATION: Anti-NMDAR encephalitis is associated with characteristic alterations of functional connectivity and widespread changes of white matter integrity despite normal findings in routine clinical MRI. These results may help to explain the clinicoradiological paradox in anti-NMDAR encephalitis and advance the pathophysiological understanding of the disease. Correlation of imaging abnormalities with disease symptoms and severity suggests that these changes play an important role in the symptomatology of anti-NMDAR encephalitis.
Assuntos
Encefalite Antirreceptor de N-Metil-D-Aspartato/patologia , Encefalite Antirreceptor de N-Metil-D-Aspartato/fisiopatologia , Adulto , Encefalite Antirreceptor de N-Metil-D-Aspartato/metabolismo , Feminino , Neuroimagem Funcional , Hipocampo/metabolismo , Hipocampo/patologia , Hipocampo/fisiopatologia , Humanos , Leucoencefalopatias/metabolismo , Leucoencefalopatias/patologia , Leucoencefalopatias/fisiopatologia , Imageamento por Ressonância Magnética/instrumentação , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Rede Nervosa/metabolismo , Rede Nervosa/patologia , Rede Nervosa/fisiopatologia , Testes Neuropsicológicos , Índice de Gravidade de Doença , Adulto JovemRESUMO
OBJECTIVE: To evaluate 3D spectral domain optical coherence tomography (SDOCT) volume scans as a tool for quantification of optic nerve head (ONH) volume as a potential marker for treatment effectiveness and disease progression in idiopathic intracranial hypertension (IIH). DESIGN AND PATIENTS: Cross-sectional pilot trial comparing 19 IIH patients and controls matched for gender, age and body mass index. Each participant underwent SDOCT. A custom segmentation algorithm was developed to quantify ONH volume (ONHV) and height (ONHH) in 3D volume scans. RESULTS: Whereas peripapillary retinal nerve fiber layer thickness did not show differences between controls and IIH patients, the newly developed 3D parameters ONHV and ONHH were able to discriminate between controls, treated and untreated patients. Both ONHV and ONHH measures were related to levels of intracranial pressure (ICP). CONCLUSION: Our findings suggest 3D ONH measures as assessed by SDOCT as potential diagnostic and progression markers in IIH and other disorders with increased ICP. SDOCT may promise a fast and easy diagnostic alternative to repeated lumbar punctures and could therefore ease monitoring of treatment or disease progression.
Assuntos
Disco Óptico/fisiopatologia , Doenças do Nervo Óptico/fisiopatologia , Pseudotumor Cerebral/fisiopatologia , Tomografia de Coerência Óptica/métodos , Adulto , Estudos de Coortes , Estudos Transversais , Progressão da Doença , Feminino , Humanos , Imageamento Tridimensional/métodos , Pressão Intraocular/fisiologia , Masculino , Pessoa de Meia-Idade , Fibras Nervosas/patologia , Fibras Nervosas/fisiologia , Doenças do Nervo Óptico/diagnóstico , Projetos Piloto , Pseudotumor Cerebral/diagnóstico , Adulto JovemRESUMO
BACKGROUND: Xenotropic murine leukemia virus-related virus (XMRV), a novel human retrovirus originally identified in prostate cancer tissues, has recently been associated with chronic fatigue syndrome (CFS), a disabling disease of unknown etiology affecting millions of people worldwide. However, several subsequent studies failed to detect the virus in patients suffering from these illnesses or in healthy subjects. Here we report the results of efforts to detect antibody responses and viral sequences in samples from a cohort of German CFS and relapsing remitting multiple sclerosis (MS) patients with fatigue symptoms. METHODOLOGY: Blood samples were taken from a cohort of 39 patients fulfilling the Fukuda/CDC criteria (CFS), from 112 patients with an established MS diagnosis and from 40 healthy donors. Fatigue severity in MS patients was assessed using the Fatigue Severity Scale (FSS). Validated Gag- and Env-ELISA assays were used to screen sera for XMRV antibodies. PHA-activated PBMC were cultured for seven days in the presence of IL-2 and DNA isolated from these cultures as well as from co-cultures of PBMC and highly permissive LNCaP cells was analyzed by nested PCR for the presence of the XMRV gag gene. In addition, PBMC cultures were exposed to 22Rv1-derived XMRV to assess infectivity and virus production. CONCLUSION: None of the screened sera from CFS and MS patients or healthy blood donors tested positive for XMRV specific antibodies and all PBMC (and PBMC plus LNCaP) cultures remained negative for XMRV sequences by nested PCR. These results argue against an association between XMRV infection and CFS and MS in Germany. However, we could confirm that PBMC cultures from healthy donors and from CFS patients can be experimentally infected by XMRV, resulting in the release of low levels of transmittable virus.
Assuntos
Síndrome de Fadiga Crônica/sangue , Síndrome de Fadiga Crônica/virologia , Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla Recidivante-Remitente/virologia , Vírus Relacionado ao Vírus Xenotrópico da Leucemia Murina/genética , Adulto , Linhagem Celular Tumoral , Estudos de Coortes , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Alemanha , Humanos , Técnicas In Vitro , Leucócitos Mononucleares/virologia , Masculino , Microscopia de Fluorescência/métodos , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase/métodosRESUMO
Understanding the immune response in the central nervous system (CNS) is crucial for the development of new therapeutic concepts in chronic neuroinflammation, which differs considerably from other autoimmune diseases. Special immunologic properties of inflammatory processes in the CNS, which is often referred to as an immune privileged site, imply distinct features of CNS autoimmune disease in terms of disease initiation, perpetuation, and therapeutic accessibility. Furthermore, the CNS is a stress-sensitive organ with a low capacity for self-renewal and is highly prone to bystander damage caused by CNS inflammation. This leads to neuronal degeneration that contributes considerably to the phenotype of the disease. In this chapter, we discuss recent findings emphasizing the predominant role of the adaptive immune system in the pathogenesis of chronic neuroinflammation, that is, multiple sclerosis (MS) in patients and experimental autoimmune encephalomyelitis (EAE) in rodents. In addition, we report on efforts to translate these findings into clinical practice with the aim of developing selective treatment regimens.