Optic neuritis: the eye as a window to the brain

Jenkins, Thomas M.; Toosy, Ahmed

doi:10.1097/wco.0000000000000414

Cited by 46 publications

(33 citation statements)

References 58 publications

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“…Although previously thought to be a consequence of inflammatory mediated myelin loss, neurodegeneration independent of demyelination has been observed in both murine models of MS [2, 3] and human post-mortem retinal tissue [4]. Neurodegeneration in the afferent visual pathway is prevalent in MS, most frequently following optic neuritis (ON; an inflammation of the optic nerve) and often resulting in functional visual impairment that can persist even after treatment [5, 6]. Damage from the optic nerve can propagate into the retina, by processes of retrograde degeneration, contributing to visual impairment observed in MS [7].…”

Section: Introductionmentioning

confidence: 99%

Retinal pathology in experimental optic neuritis is characterized by retrograde degeneration and gliosis

Manogaran

Samardzija

Schad

et al. 2019

acta neuropathol commun

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The exact mechanisms and temporal sequence of neurodegeneration in multiple sclerosis are still unresolved. The visual pathway including its unmyelinated retinal axons, can serve as a prototypic model of neurodegeneration in experimental optic neuritis. We conducted a longitudinal study combining retinal imaging through optical coherence tomography (OCT) with immunohistochemical analyses of retinal and optic nerve tissue at various time points in experimental autoimmune encephalomyelitis (EAE). Inner retinal layer (IRL) thickness was measured in 30 EAE and 14 healthy control C57BL/6 J mice using OCT. Distribution of marker proteins was assessed by immunofluorescence staining and retinal mRNA levels were assayed using real-time PCR. Histological morphology was evaluated on light and electron microscopy images. Signs of inflammatory edema 11 days post immunisation coincided with IRL thickening, while neuro-axonal degeneration throughout the disease course contributed to IRL thinning observed after 20 days post immunisation. Retinal pathology, including axonal transport impairment, was observed early, prior to cellular infiltration (i.e. T-cells) in the optic nerve 11 days post immunisation. Yet, the effects of early retinal damage on OCT-derived readouts were outweighed by the initial inflammatory edema. Early microglial activation and astrocytosis was detected in the retina prior to retinal ganglion cell loss and persisted until 33 days post immunisation. Müller cell reactivity (i.e. aquaporin-4 and glutamine synthetase decrease) presented after 11 days post immunisation in the IRL. Severe neuro-axonal degeneration was observed in the optic nerve and retina until 33 days post immunisation. Initial signs of retinal pathology subsequent to early glial activity, suggests a need for prophylactic treatment of optic neuritis. Following early inflammation, Müller cells possibly respond to retinal pathology with compensatory mechanisms. Although the majority of the IRL damage observed is likely due to retrograde degeneration following optic neuritis, initial pathology, possibly due to gliosis, may contribute further to IRL thinning. These results add morphological substrate to our OCT findings. The extent and rapid onset of axonal and neuronal damage in this model appears relevant for testing interventions scaled to human optic neuritis. Electronic supplementary material The online version of this article (10.1186/s40478-019-0768-5) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Retinal pathology in experimental optic neuritis is characterized by retrograde degeneration and gliosis

Manogaran

Samardzija

Schad

et al. 2019

acta neuropathol commun

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“…Papilledema and a relative afferent pupillary defect give diagnostic clues in ophthalmic examination [ 7 , 9 ]. Recovery from optic neuritis is common, yet residual deficits can remain and impact quality of life [ 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Laquinimod protects the optic nerve and retina in an experimental autoimmune encephalomyelitis model

Wilmes

Reinehr

Kühn

et al. 2018

J Neuroinflammation

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BackgroundThe oral immunomodulatory agent laquinimod is currently evaluated for multiple sclerosis (MS) treatment. Phase II and III studies demonstrated a reduction of degenerative processes. In addition to anti-inflammatory effects, laquinimod might have neuroprotective properties, but its impact on the visual system, which is often affected by MS, is unknown. The aim of our study was to investigate potential protective effects of laquinimod on the optic nerve and retina in an experimental autoimmune encephalomyelitis (EAE) model.MethodsWe induced EAE in C57/BL6 mice via MOG35–55 immunization. Animals were divided into an untreated EAE group, three EAE groups receiving laquinimod (1, 5, or 25 mg/kg daily), starting the day post-immunization, and a non-immunized control group. Thirty days post-immunization, scotopic electroretinograms were carried out, and mice were sacrificed for histopathology (HE, LFB), immunohistochemistry (MBP, Iba1, Tmem119, F4/80, GFAP, vimentin, Brn-3a, cleaved caspase 3) of the optic nerve and retina, and retinal qRT-PCR analyses (Brn-3a, Iba1, Tmem119, AMWAP, CD68, GFAP). To evaluate the effect of a therapeutic approach, EAE animals were treated with 25 mg/kg laquinimod from day 16 when 60% of the animals had developed clinical signs of EAE.ResultsLaquinimod reduced neurological EAE symptoms and improved the neuronal electrical output of the inner nuclear layer compared to untreated EAE mice. Furthermore, cellular infiltration, especially recruited phagocytes, and demyelination in the optic nerve were reduced. Microglia were diminished in optic nerve and retina. Retinal macroglial signal was reduced under treatment, whereas in the optic nerve macroglia were not affected. Additionally, laquinimod preserved retinal ganglion cells and reduced apoptosis. A later treatment with laquinimod in a therapeutic approach led to a reduction of clinical signs and to an improved b-wave amplitude. However, no changes in cellular infiltration and demyelination of the optic nerves were observed. Also, the number of retinal ganglion cells remained unaltered.ConclusionFrom our study, we deduce neuroprotective and anti-inflammatory effects of laquinimod on the optic nerve and retina in EAE mice, when animals were treated before any clinical signs were noted. Given the fact that the visual system is frequently affected by MS, the agent might be an interesting subject of further neuro-ophthalmic investigations.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1208-3) contains supplementary material, which is available to authorized users.

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“…During embryonic development, the retina and optic nerve extend from the diencephalon thus, the retina has been considered an extension of the central nervous system (CNS) [27][28][29][30][31]. The unmyelinated axons in the retinal ganglion cell layer converge toward the optic disc and form the optic nerve at the back of the eye.…”

Section: Retina An Extension To the Central Nervous Systemmentioning

confidence: 99%

A Retinal Biophysical Biomarker for Amyotrophic Lateral Sclerosis (ALS)

Amin¹

2021

Preprint

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Amyotrophic lateral sclerosis (ALS) is an incurable motor neuron disease with no current valid diagnostic imaging biomarkers. The retina is an extension of the central nervous system and axonal transport defects have been documented in various neurodegenerative diseases. This study reports evidence of axonal pathology in the retina of ALS patients using an interdisciplinary approach that includes the neuropathological study of retinal sections in ALS patients expanded to the optical characteristics of the whole retina preparations using eye imaging technology. The histopathological examination of retina sections revealed round profiles in the retinal nerve fibre layer in 10 out 10 ALS patients and in 4 out of 10 age-matched control patients. All 10 ALS patients showed increased phosphorylated neurofilament immunoreactivity in the retinal nerve fibre layer compared to all 10 control patients. Retinal imaging of whole globes and retina flat-mounts by blue reflectance retinal funduscopy and optical coherence tomography revealed hyper-reflective profiles in the retinal nerve fibre layer. For the first time, approximately 1µm retinal ganglion cells axons were visualized in immunofluorescence stained retina flat-mounts using near-infrared retina fundus imaging and Image Mapping Spectrometer. These findings suggest axonal pathology in retinal ganglion cells and its potential use as a novel non-invasive ocular imaging biomarker for ALS.

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Optic neuritis: the eye as a window to the brain

Cited by 46 publications

References 58 publications

Retinal pathology in experimental optic neuritis is characterized by retrograde degeneration and gliosis

Retinal pathology in experimental optic neuritis is characterized by retrograde degeneration and gliosis

Laquinimod protects the optic nerve and retina in an experimental autoimmune encephalomyelitis model

A Retinal Biophysical Biomarker for Amyotrophic Lateral Sclerosis (ALS)

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