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Hi, I’m Bobbi Pritt, Director of the Clinical Parasitology Lab and Vice Chair of Education in the Department of Laboratory Medicine and Pathology at Mayo Clinic. Antibodies to aquaporin-4 and myelin oligodendrocyte glycoprotein (MOG) are recently described biomarkers seen in a subset of atypical optic neuritis which have revolutionized our understanding of optic neuritis. In this “Hot Topic,” my colleague, Dr. John Chen, will review these advances and how they impact the clinical care of our patients with optic neuritis.
I hope you enjoy this month’s Hot Topic, and I want to personally thank you for allowing Mayo Clinic the opportunity to be a partner in your patient’s health care.
Hello, I’m Dr. John Chen, one of the neuro-ophthalmologists at Mayo Clinic in Rochester, Minnesota. I would like to talk to you today about optic neuritis in the era of biomarker discovery.
I have no financial disclosures to report.
As a background, optic neuritis is an inflammation of the optic nerve, which is typically caused by demyelination. It is the most common cause of optic neuropathy in young patients. Patients with optic neuritis present with subacute monocular vision loss with the nadir of vision loss typically occurring within a few days. Vision loss can range from near-normal vision to no light perception. Ninety percent of patients will have eye pain that is worsened with eye movements. Patients also often have dyschromatopsia, where colors are not as vibrant as they once were. The optic nerve appearance is normal two-thirds of the time because it is often retrobulbar. If there is disc edema, it is typically mild, similar to the photo on the right.
Much of what we know about the treatment and natural history of optic neuritis comes from the landmark Optic Neuritis Treatment Trial (ONTT) that was completed in 1991. In this study, patients with acute optic neuritis were randomized to IV steroids, oral steroids, or placebo. This study found that all cases of optic neuritis tended to recover with or without treatment. An improvement to 20/40 or better was seen in 92% of patients. However, not all cases improved, with 3% remaining 20/200 or worse. Interestingly, treatment with IV steroids led to a quicker recovery, but did not change the ultimate visual outcome. Low-dose oral prednisone actually led to an increased risk of relapse and is therefore not recommended for the treatment of acute optic neuritis.
The differential diagnosis of optic neuritis is broad, as you can see from this slide. Most cases of optic neuritis in the Western world are caused by multiple sclerosis or are idiopathic. At the time of the ONTT, this was the main dichotomy and remains so for typical optic neuritis.
The ONTT found that at 15 years, 50% of patients with optic neuritis will develop multiple sclerosis. The MRI brain at the time of the optic neuritis helps stratify this risk, with 72% of patients developing multiple sclerosis (MS) if there are white-matter lesions, as shown here on this slide. The risk is only 25% if there are no white-matter lesions.
The ONTT did a wonderful job of providing guidance for cases of typical optic neuritis. However, there were cases of atypical optic neuritis that were unexplained until more recently. We now have biomarkers of optic neuritis, which are offered by the Mayo Clinic Neuroimmunology Laboratory, that help explain many cases of atypical optic neuritis, such as severe optic neuritis with poor recovery, bilateral optic neuritis, prominent disc edema, and relapsing optic neuritis.
The first antibody-mediated demyelinating disease discovered was neuromyelitis optica (NMO). The initial series of NMO was first described by Devic and Gault in 1894. Patients with NMO classically present with severe optic neuritis with poor recovery, which can be bilateral and recurrent, often leading to blindness, and can also present with severe transverse myelitis. A classic patient is shown here who previously had optic neuritis in the right eye with residual pallor and “count fingers” vision, who then presented with acute optic neuritis in the left eye with poor vision. The MRI shows enhancement of the left optic nerve, but there are no periventricular white-matter lesions on the FLAIR MRI, which supports NMO as opposed to MS. Patients with NMO often also have transverse myelitis extending more than three segments, as shown in this image, compared to transverse myelitis lesions in MS, which are typically short.
For over a century, there was debate as to whether NMO was a subtype of MS or a separate entity. In 2004, Vanda Lennon, M.D., Ph.D., and colleagues at Mayo Clinic found that the antibody against aquaporin 4 (AQP4) is both a biomarker and pathologic cause of NMO, which cemented NMO as a distinct entity from MS. AQP4 is a water-channel protein expressed in the brain, spinal cord, and optic nerves, which are the areas affected by NMO. Binding of the AQP4-IgG to AQP4 causes complement activation and astrocytic injury.
In addition, knowledge of AQP4-IgG expanded the phenotype of NMO beyond optic neuritis and transverse myelitis. This is now termed neuromyelitis optica spectrum disorder (NMOSD), which also includes area postrema syndrome, where patients present with intractable nausea and vomiting from dorsal medullary lesions, as shown in this picture, or acute brainstem syndrome, symptomatic narcolepsy from diencephalon lesions, and symptomatic cerebral syndrome.
This entity is important to diagnose because the prognosis and treatment is much different than MS. The attacks are severe and tend to have poor recovery. Optic neuritis will lead to legal blindness of 20/200 or worse in one eye in about 50% of patients affected by optic neuritis from NMO. Optic neuritis from NMOSD tends to relapse more commonly, affect both eyes, and also affect the chiasm. Transverse myelitis can lead to paraplegia. Brainstem and diencephalon lesions can cause hiccups, nausea and vomiting, and respiratory failure. Mortality rates range between 6 and 32%. The higher numbers were from earlier studies. Now that we have better treatments, the mortality rates have been improving, but it can still be a fatal disease.
Because the attacks are severe, early plasma exchange therapy is often used in addition to IV steroids for acute attacks. In addition, these patients need to be on chronic, lifelong immunotherapy to prevent relapse, with rituximab typically being the first-line agent. A recent, randomized, double-blinded, placebo-controlled trial showed eculizumab, a C5 complement inhibitor, led to a significant reduction in relapses, which was published in the New England Journal of Medicine and will undoubtedly be used more in the future. It is important to note that most MS disease-modifying agents are not only ineffective for NMOSD, but may actually worsen the disease process, which stresses the importance of correctly identifying patients with AQP4-IgG-positive NMOSD.
AQP4 antibody testing is done at Mayo Clinic with a fluorescence-activated cell sorting (FACS) cell-based assay, which remains the gold standard in terms of sensitivity and specificity. A schematic of the FACS cell-based assay is shown here. HEK-293 cells are transiently transfected with AQP4 and a GFP marker. These cells are then exposed to human serum samples. Samples with AQP4 antibodies will bind to the AQP4-transfected HEK-293 cells, which are detected by flow cytometry using an IgG1-specific secondary antibody conjugated to AlexaFluor 647 fluorescent dye. The AQP4-IgG antibody is 76% sensitive and >99% specific for NMOSD. The serum is more sensitive than cerebrospinal fluid (CSF). However, this means that roughly 25% of NMOSD are negative for AQP4-IgG, suggesting there were other biomarkers that were not yet discovered in cases of AQP4-IgG-negative NMOSD.
More recently, antibodies against myelin oligodendrocyte glycoprotein (MOG)-IgG have been discovered, which is the newest biomarker for a subset of patients with optic neuritis and several other demyelinating phenotypes. MOG is a transmembrane protein found on the surface of oligodendrocytes. In the early 2000s, MOG antibody was erroneously thought to be a marker of MS based on non-specific older generation assays with MOG in its non-conformational form. However, with recent transfected cell-based assays with MOG in its native conformational form, there is general agreement that the MOG antibody is a biomarker for a distinct demyelinating disease process—MOG-associated disorders—which is different from both MS and AQP4-IgG seropositive NMOSD.
The Mayo Clinic Neuroimmunology Lab was the first CLIA-approved lab to offer MOG antibody testing in the US, which became commercially available in the fall of 2017 after several years of testing and optimization. The assay is similar to the AQP4-IgG cell-based FACS assay, but uses MOG as the antigen that is transfected in the HEK-293 cells. The results for a positive and negative MOG-IgG patient are shown here. As can be seen from the figure, the binding index, which is the ratio of the fluorescence of the GFP-positive transfected cells over the fluorescence of the GFP-negative non-transfected cells is markedly elevated in our MOG-IgG-positive patient and close to one for the negative patient. If a patient is positive, the sample undergoes serial dilutions to determine the titer.
Patients with MOG autoimmunity present with a diverse phenotype, which includes optic neuritis, transverse myelitis, acute demyelinating encephalomyelitis, and brainstem encephalitis. A subset of MOG-IgG-positive patients meets the current NMOSD criteria. In fact, MOG-IgG is positive in approximately a third of patients with AQP4-seronegative NMOSD. However, despite some overlap in clinical features, MOG-associated disorder is a different disease entity than AQP4-IgG-NMOSD and MS. The MOG antibody and AQP4 antibodies very rarely coexist, and patients with classic MS are not typically positive for the MOG antibody.
The most common symptom of MOG-IgG-associated disorder is optic neuritis. Features favoring MOG optic neuritis diagnosis include optic disc edema, bilateral optic neuritis, and recurrent optic neuritis. Optic disc edema can be severe, as shown in this figure. Recurrent optic neuritis occurs in about 50% of patients, with some cases being both steroid responsive and steroid dependent, resembling what has been termed chronic relapsing inflammatory optic neuropathy (CRION). MRI of the optic nerve often shows long segments of optic nerve enhancement. In addition, up to 50% of cases can show optic nerve sheath enhancement with extension to the peribulbar fat, as shown in this figure, which is also a fairly specific sign of MOG-IgG-related optic neuritis. Vision loss is usually severe at nadir, but fortunately the recovery is typically better than seen with AQP4-IgG optic neuritis. Only 6–10% of patients with MOG-IgG optic neuritis have a final visual outcome worse than 20/200 compared to 50% of patients with AQP4-IgG optic neuritis.
Acute treatment for MOG-IgG optic neuritis is with IV methylprednisolone for 3 to 5 days. We recommend a longer oral prednisone taper over 1 to 3 months because of the higher potential to relapse compared to other forms of optic neuritis. If there is no recovery at 1 to 2 weeks and the vision loss is severe, one could consider plasma exchange or IVIG.
If patients have relapsing disease with residual deficits, patients should be treated with chronic immunotherapy. The optimal treatment for MOG-IgG-associated disorder is still being determined. Similar to AQP4-IgG-positive NMOSD, MS disease-modifying agents do not appear to be effective and, therefore, this entity is important to be distinguished from MS. In patients with relapsing disease, the first-line treatment is typically rituximab, azathioprine, or mycophenolate. Monthly IVIG may be efficacious for severe relapsing disease, but future randomized clinical trials will be required to confirm the best treatment.
One question we are often asked is, when should we test for AQP4 and MOG antibodies? We believe that these antibodies should be checked for any case of atypical optic neuritis, which includes severe visual impairment, bilateral or recurrent optic neuritis, poor visual recovery, prominent disc edema, perineural optic nerve enhancement, or co-existing extra-optic nerve CNS demyelinating lesions suggestive of MOG-IgG or AQP4-IgG disease. It is important to differentiate MOG-IgG and AQP4-IgG disease from MS because the outcomes are different, and more importantly the treatment is different.
It is also important to note that not all assays for these antibodies are equal. A false positive can be just as detrimental as a false negative because it can lead to an incorrect diagnosis and unnecessary treatments. These antibodies should all be run on cell-based assays, as done by the Mayo Clinic Neuroimmunology Lab, because this provides the best combination of sensitivity and specificity. For both AQP4-IgG and MOG-IgG, serum is more sensitive and specific than CSF.
It is an exciting time to be a neuro-ophthalmologist because of the availability of these new biomarkers for optic neuritis. We are able to better diagnose diseases that were previously thought to be idiopathic, which allows us to better prognosticate outcomes and provide better treatments. An understanding of the pathogenesis of these disease processes ultimately leads to directed therapies. For example, knowledge that AQP4-IgG activates complement causing astrocyte lysis led to the recent groundbreaking trial confirming the efficacy of eculizumab. A better understanding of MOG-IgG-associated disorder will likely yield similar promising new therapies.
Based on this Hot Topic, I hope you were able to appreciate the importance of checking for AQP4 and MOG antibodies in cases of atypical optic neuritis because their presence will alter the expected prognosis and optimal treatment. This is just the beginning foray into biomarkers for optic neuritis. Other antibodies will be discovered that will help explain currently idiopathic cases of optic neuritis.
If you are uncertain about a patient’s diagnosis or testing, our neuroimmunologists, including Dr. Sean Pittock, Director of the Neuroimmunology Lab, Dr. Andrew McKeon, Co-Director, among several other wonderful neuroimmunologists, and I, would be happy to discuss the case with you.
Thank you for watching this Hot Topic on optic neuritis in the era of biomarkers.