Optic neuritis in the era of biomarkers

doi:10.1016/j.survophthal.2019.08.001

Survey of Ophthalmology

Volume 65, Issue 1, January–February 2020, Pages 12-17

https://doi.org/10.1016/j.survophthal.2019.08.001 Get rights and content

Abstract

The Optic Neuritis Treatment Trial, a landmark study completed in 1991, stratified the risk of multiple sclerosis in patients with optic neuritis. Since that time, unique biomarkers for optic neuritis have been found. The antibody against aquaporin-4 (AQP4)-immunoglobulin G (IgG) discovered in 2004 was found to be both the pathologic cause and a reliable biomarker for neuromyelitis optica spectrum disorders. This finding enabled an expanded definition of the phenotype of neuromyelitis optica spectrum disorder and improved treatment of the disease. Subsequently, myelin oligodendrocyte glycoprotein (MOG) IgG was recognized to be a marker for MOG-IgG-associated disorder, a central demyelinating disease characterized by recurrent optic neuritis, prominent disk edema, and perineural optic nerve enhancement on magnetic resonance imaging. Most multiple sclerosis disease-modifying agents are ineffective for AQP4-IgG-positive neuromyelitis optica spectrum disorder and MOG-IgG-associated disorder. Because there are crucial differences in treatment and prognosis between multiple sclerosis, AQP4-IgG-positive neuromyelitis optica spectrum disorder, and MOG-IgG-associated disorder, ophthalmologists should be aware of these new biomarkers of optic neuritis and incorporate their testing in all patients with atypical optic neuritis.

Introduction

In the strictest sense of the word, optic neuritis (ON) connotes an inflammatory infectious or noninfectious process affecting the optic nerve; however, in clinical parlance, ON implies an inflammatory demyelinating condition. In the past decades, substantial strides have been made in better understanding ON, beginning with the Optic Neuritis Treatment Trial (ONTT)³ and more recently with the discovery of unique biomarkers of ON. The ONTT aimed to understand the association of ON to multiple sclerosis (MS) and the role of corticosteroids in managing ON,⁴ thereby setting a standard of care in its evaluation and treatment.²² The ONTT found that brain magnetic resonance imaging (MRI) was crucial for stratifying the future risk of developing MS.⁷ In addition, it showed that high-dose intravenous methylprednisolone (IVMP) accelerated the recovery of vision, but did not change the ultimate visual outcome. In addition, low-dose oral prednisone at 1 mg/kg/day alone had no effect on visual recovery, but rather surprisingly increased the risk of another attack of ON for reasons that remain unclear.³ It is incontrovertible that the ONTT provided invaluable guidance on the evaluation and management of “typical” ON, which is usually from MS or is idiopathic. The ONTT found that MS developed in 50% of patients with ON within 15 years.⁷ There are atypical cases of ON, however, that were previously unclassifiable until the recent discovery of autoantibody biomarkers of ON: aquaporin-4 (AQP4) immunoglobulin G (IgG) and myelin oligodendrocyte glycoprotein (MOG) IgG (Table 1).

Section snippets

Recent advances

A true sea change occurred in the arena of central nervous system (CNS) autoimmune inflammatory demyelinating disease in 2004 when an IgG biomarker was described by Lennon and colleagues from the Mayo Clinic as a diagnostic aid for neuromyelitis optica (NMO).²⁵ Classically, NMO is characterized by ON (either unilateral or bilateral, and often recurrent and severe) and transverse myelitis (usually spanning 3 or more vertebral segments). Identification of a target autoantigen, AQP4, a principal

Conclusions

Introduction of reliable serologic testing for AQP4-IgG and MOG-IgG has expanded our understanding and treatment options for ON, enabling earlier and more accurate diagnosis and determination of prognosis. Although screening for AQP4-IgG and MOG-IgG may not be necessary for patients presenting with typical ON, it is strongly recommended in the workup of patients with “atypical ON” (Fig. 2). Seropositivity will often change the treatment recommendations, especially in the setting of

Method of literature search

A literature search was performed using PubMed/Medline using the following terms: 1) optic neuritis, 2) neuromyelitis optica spectrum disorder (NMOSD), 3) aquaporin-4 antibodies (AQP4-IgG), 4) myelin oligodendrocyte glycoprotein antibodies (MOG-IgG). All relevant articles were included. Reference lists from the selected articles were checked to obtain further relevant articles not included in the electronic database.

Disclosures

J.J. Chen has no disclosures. E.P. Flanagan receives research support from MedImmune but has not received personal compensation. S.J. Pittock is a named inventor on filed patents that relate to functional AQP4/NMO-IgG assays and NMO-IgG as a cancer marker; consulted for Alexion and Medimmune; and received research support from Grifols, Medimmune, and Alexion; all compensation for consulting activities is paid directly to Mayo Clinic. V.A. Lennon receives royalties for technology relating to

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Cited by (53)

Visual Outcomes Following Plasma Exchange for Optic Neuritis: An International Multicenter Retrospective Analysis of 395 Optic Neuritis Attacks
2023, American Journal of Ophthalmology
To evaluate the effectiveness of plasma exchange (PLEX) for optic neuritis (ON).
We conducted an international multicenter retrospective study evaluating the outcomes of ON following PLEX. Outcomes were compared to raw data from the Optic Neuritis Treatment Trial (ONTT) using a matched subset.
A total of 395 ON attack treated with PLEX from 317 patients were evaluated. The median age was 37 years (range 9-75), and 71% were female. Causes of ON included multiple sclerosis (108), myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD) (92), aquaporin-4-IgG–positive neuromyelitis optica spectrum disorder (AQP4+NMOSD) (75), seronegative-NMOSD (34), idiopathic (83), and other (3). Median time from onset of vision loss to PLEX was 2.6 weeks (interquartile range [IQR], 1.4-4.0). Median visual acuity (VA) at the time of PLEX was count fingers (IQR, 20/200-hand motion), and median final VA was 20/25 (IQR, 20/20-20/60) with no differences among etiologies except MOGAD-ON, which had better outcomes. In 81 (20.5%) ON attacks, the final VA was 20/200 or worse. Patients with poor outcomes were older (P = .002), had worse VA at the time of PLEX (P < .001), and longer delay to PLEX (P < .001). In comparison with the ONTT subset with severe corticosteroid-unresponsive ON, a final VA of worse than 20/40 occurred in 6 of 50 (12%) PLEX-treated ON vs 7 of 19 (37%) from the ONTT treated with intravenous methylprednisolone without PLEX (P = .04).
Most ON attacks improved with PLEX, and outcomes were better than attacks with similar severity in the ONTT. The presence of severe vision loss at nadir, older age, and longer delay to PLEX predicted a worse outcome whereas MOGAD-ON had a more favorable prognosis. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.
Neuro-Ophthalmic Complications of COVID-19 Infection and Vaccination
2023, Advances in Ophthalmology and Optometry
Shot in the dark
2023, Survey of Ophthalmology
A 43-year-old woman presented with decreased vision in the right eye associated with painful eye movements 10 days after receiving her first dose of Pfizer-BioNTech coronavirus disease 2019 (COVID-19) vaccine (Pfizer Inc, New York, NY). Two days later she developed painful loss of vision in the left eye. Clinical presentation and magnetic resonance imaging findings were consistent with bilateral optic perineuritis transitioning to optic neuritis. Extensive evaluation including aquaporin-4 immunoglobin G (IgG), myelin oligodendrocyte glycoprotein IgG, and lumbar puncture was unrevealing. Visual acuity at nadir was counting fingers in both eyes, but after receiving intravenous steroids and plasma exchange vision eventually improved to 20/20 in each eye, although she was left with inferior visual field defects and bilateral optic disc pallor. This case highlights the diagnostic challenge in the evaluation of atypical optic neuritis with a review of post-COVID-19 vaccination-associated optic neuritis.
The case report of AQP4 and MOG IgG double positive NMOSD treated with subcutaneous Ofatumumab
2023, Journal of Neuroimmunology
Neuromyelitis optica spectrum disorders (NMOSD) is an autoimmune demyelinating disease with IgG against aquaporin 4 (AQP4) in more than two thirds of patients. Anti-myelin-oligodendrocyte glycoprotein (MOG) antibody is found in some AQP4-negative NMOSD patients and MOG antibody-associated disease (MOGAD) is thought to be distinct from NMOSD. Due to the high disabling nature of NMOSD, treatment strategy on first attack is crucial for good prognosis. Rituximab (RTX), an anti-CD20 monoclonal antibody (mAb), is the first-line treatment for NMOSD. However, RTX can be limited by the relatively high rate of systemic allergic reaction. Herein, we reported a rare case of AQP4 and MOG-IgG double positive NMOSD patient effectively and safely treated with ofatumumab (OFA), a novel fully humanized anti-CD20 mAb.
Neurological involvement of sarcoidosis: current diagnostic and therapeutic strategies
2023, Revue de Medecine Interne
La neurosarcoïdose est une manifestation rare mais potentiellement grave de la sarcoïdose, associée à une morbidité et mortalité significatives. Dans les différentes études, la mortalité était d’environ 10 % à 10 ans avec plus de 30 % des patients qui avaient un handicap significatif à la fin du suivi. Les atteintes les plus fréquentes sont les atteintes encéphaliques (50–60 %) avec en particulier une atteinte des paires crâniennes (nerfs VII le plus fréquemment puis nerfs optiques, oculomoteurs et vestibulaire), médullaires (20–30 %) et plus rarement du système nerveux périphérique (10–15 % environ). Tout l’enjeu du diagnostic est d’éliminer les diagnostics différentiels. Les présentations atypiques peuvent faire discuter la nécessité de biopsie cérébrale afin de mettre en évidence la présence de lésions granulomateuses tout en éliminant les diagnostics alternatifs notamment infectieux et tumoraux. La prise en charge thérapeutique repose sur la corticothérapie et les immunomodulateurs. Il n’y a pas d’étude prospective comparative permettant de statuer clairement sur le choix de l’immunosuppresseur en première intention et dans les formes réfractaires. Les immunosuppresseurs conventionnels tels que le méthotrexate, le mycophénolate mofétil et le cyclophosphamide sont couramment employés. Les données sont de plus en plus nombreuses sur l’utilisation des anti-TNFα (notamment l’infliximab) dans les formes réfractaires et/ou sévères. Des données supplémentaires sont nécessaires pour évaluer leur intérêt en première ligne chez les patients ayant une atteinte sévère et associée à un risque non négligeable de rechute.
Neurosarcoidosis (NS) is a rare but severe form of sarcoidosis. NS is associated with significant morbidity and mortality. Mortality is about 10% at 10 years with more than 30% of patients who have a significant disability. The most frequent features are cranial neuropathy (the facial and optic nerve most commonly affected), cranial parenchymal lesions, meningitis, spinal corn abnormalities (20–30%) and more rarely peripheral neuropathy (approximately 10–15%). The challenge of diagnosis is to eliminate other diagnoses. Atypical presentations should make to discuss the need for cerebral biopsy in order to highlight the presence of granulomatous lesions while eliminating alternative diagnosis. Therapeutic management is based on corticosteroid therapy and immunomodulators. There are no comparative prospective study to allow us to define the first-line immunosuppressive treatment and the therapeutic strategy in refractory patients. Conventional immunosuppressants such as methotrexate, mycophenolate mofetil and cyclophosphamide are commonly used. Data on the efficacy of anti-TNFα (including infliximab) in refractory and/or severe forms are increasing during the last ten years. Additional data is necessary to assess their interest in first line in patients with severe involvement and a significant risk of relapse.
Identification of double-stranded DNA in the cerebrospinal fluid of patients with acute neuromyelitis optica spectrum disorder
2023, Journal of Clinical Neuroscience
Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory disease of the central nervous system (CNS) characterized by severe myelitis and optic neuritis. Double-stranded DNA (dsDNA) is involved in the pathogenesis of various autoimmune diseases, such as systemic lupus erythematosus. However, its role in NMOSD remains unclear. In this study, the concentration of dsDNA in the cerebrospinal fluid (CSF) was quantified in 23 patients with NMOSD and 16 patients with other neurological diseases (ONDs). CSF dsDNA levels in patients with NMOSD (median: 0.03 ng/µL) were significantly higher than those in patients with ONDs (median: 0.01 ng/μl). CSF dsDNA levels showed no significant difference before and after treatment. Elevation of CSF dsDNA levels may suggest its essential role in the augmentation of CNS inflammation in patients with NMOSD.

View all citing articles on Scopus

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Major reviewOptic neuritis in the era of biomarkers

Abstract

Introduction

Section snippets

Recent advances

Conclusions

Method of literature search

Disclosures

Ophthalmology

Am J Ophthalmol

J Neurol Sci

Ophthalmology

Lancet

Treatment of acute relapses in neuromyelitis optica: Steroids alone versus steroids plus plasma exchange

Mult Scler

MRI and retinal abnormalities in isolated optic neuritis with myelin oligodendrocyte glycoprotein and aquaporin-4 antibodies: a comparative study

J Neurol Neurosurg Psychiatry

A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. The Optic Neuritis Study Group

N Engl J Med

Antimyelin antibodies as a predictor of clinically definite multiple sclerosis after a first demyelinating event

N Engl J Med

Plasma exchange in severe attacks of neuromyelitis optica

Mult Scler Int

Multiple sclerosis risk after optic neuritis - Final optic neuritis treatment trial follow-up

Arch Neurol

Do myelin oligodendrocyte glycoprotein antibodies represent a distinct syndrome?

J Neuroophthalmol

Evaluation of treatment response in adults with relapsing MOG-Ab-associated disease

J Neuroinflammation

Clinical, radiologic, and prognostic features of myelitis associated with myelin oligodendrocyte glycoprotein autoantibody

JAMA Neurol

Neuromyelitis optica spectrum disorders: Spectrum of MR imaging findings and their differential diagnosis

Radiographics

Disease course and treatment responses in children with relapsing myelin oligodendrocyte glycoprotein antibody-associated disease

JAMA Neurol

Screening for MOG-IgG and 27 other anti-glial and anti-neuronal autoantibodies in 'pattern II multiple sclerosis' and brain biopsy findings in a MOG-IgG-positive case

Mult Scler

MOG encephalomyelitis: International recommendations on diagnosis and antibody testing

J Neuroinflammation

MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 2: Epidemiology, clinical presentation, radiological and laboratory features, treatment responses, and long-term outcome

J Neuroinflammation

MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 1: Frequency, syndrome specificity, influence of disease activity, long-term course, association with AQP4-IgG, and origin

J Neuroinflammation

MOG-IgG in primary and secondary chronic progressive multiple sclerosis: a multicenter study of 200 patients and review of the literature

J Neuroinflammation

Major review
Optic neuritis in the era of biomarkers