Physicians should hospitalize ON patients to prevent blindness, possible death.
Reviewed by Robert C. Sergott, MD.
Recognizing that there is much that is new about an old disease is pivotal to the practice of comprehensive ophthalmology, said Robert C. Sergott, MD, describing the new optic neuritis (ON) paradigm.
Sergott is director of the Neuro-Ophthalmology Service at Wills Eye Hospital and founding director and CEO of the Annesley EyeBrain Center at Thomas Jefferson University in Philadelphia, Pennsylvania.
“Neuromyelitis optica [NMO] was a subject touched on briefly when I was in medical school and was extremely difficult to diagnose quickly,” he said. “Now it may be diagnosed easily and quickly because of a blood test for anti–aquaporin-4 antibodies. Every time this happens in medicine, what were thought previously to be rare diseases become more commonplace.”
The difference between multiple sclerosis (MS) and NMO with ON is that the prognosis of the latter is much worse and can result in a stroke to the retina because of an immunologically mediated vasculitis immunologic basis.
“Ophthalmologists must assume that every case of ON is NMO until the diagnostic study results are received,” he advised. Because of the risk of NMO with ON proceeding to ischemic damage in the retina, treatment with high-dose corticosteroids is time-sensitive.
This immunologic disease was once thought to be rare, occurring with simultaneous bilateral ocular involvement and the presence of spinal cord symptoms of myelopathy. However, the opposite is true, with the disease developing unilaterally and with or without spinal cord symptoms. Anti–myelin-associated oligodendrocyte glycoprotein (anti-MOG) is a similar disorder that also must be recognized quickly.
Similar to ON and MS, NMO is far more common in women, and the incidence rates are 2 to 3 times higher in Black and Asian patients. Also, NMO is more active during and immediately after pregnancy. The median age of onset is 40 years, and the worse the visual loss, the more likely it is a diagnosis of NMO.
Gastrointestinal symptoms, including hiccups, weight loss, and itchiness, may help in the differential diagnosis of NMO. However, the only current definitive tests are anti–aquaporin-4 and anti-MOG blood tests. Patients may have the classic findings of NMO but negative antibody titers, and they are now classified as seronegative NMO. Delays in the availability of testing results necessitate the assumption that the patient has NMO until proven otherwise. “Treat first and establish the diagnosis afterward,” Sergott said. Not treating rapidly can result in an immunologically mediated ischemic optic neuropathy and/or central retinal artery occlusion.
A 29-year-old man with a 1-week history of right eyebrow pain, ocular pain, and pain with ocular movement reported decreased vision in his right eye with a visual acuity (VA) of 20/50; the VA in the fellow eye was 20/20. The respective IOPs were 25 and 22 mm Hg. He started latanoprost bilaterally. With no improvement, he presented to the emergency department at Wills Eye Hospital. The patient’s history was unremarkable. The VA was counting fingers and there was an afferent pupillary defect in the right eye. An MRI showed enhancement of the optic nerve in the right eye and an enlarged nerve in the left eye extending to the chiasm. No white matter lesions indicative of MS were seen.
“This long segment of an enhancing optic nerve lesion and a normal brain increases our clinical suspicion for NMO , but it is not specific for the diagnosis,” Sergott said.
An aggressive treatment approach is mandatory in NMO as is collaboration with other specialists. Ophthalmologists are advised to quickly refer patients to the emergency department for neuroimaging of the optic nerves, brain, and spinal cord. There should be admission to the hospital, administration of intravenous (IV) steroids, and collaboration with neurology or neuro-ophthalmology while awaiting the NMO titer results.
NMO has gone through a major therapeutic advance, Sergott pointed out. NMO is related to ophthalmology through the retinal blood vessels and those in and around the optic nerve. Research has indicated that B cells are stimulated to produce high concentrations of antibodies to aquaporin-4. Aquaporin 4 is highly localized to the astrocytic footplates that contact the retinal arterioles. The bottom line is that antibodies to aquaporin-4 are the pathogenesis of the periarterial inflammation in NMO compared with MS in which the extravasation of immunologically active cells emerge in perivenular location. Complement activation and increased levels of IL-6 also develop.
He explained, based upon the elegant neuro-immunopathogenesis research of Claudia Lucchinetti, MD, of Mayo Clinic in Rochester, Minnesota, and others, that the current therapies are based on the following sequencing: first, IV methylprednisolone; second, plasmapheresis; and then either B-cell depletion, anti–IL-6 therapy, or complement inhibition.
Histopathologic studies have shown that NMO may produce ischemic damage, “strokes” in the spinal cord correlating very well with what can develop in the central retinal artery and its branches.
In patients with spinal cord disease, 83% do poorly; in contrast, 67% of patients with ON do poorly. “This is much worse than the ON with MS,” Sergott said.
NMO attacks can result in blindness, paralysis, and death from neurogenic respiratory failure. Incomplete recovery from attacks is the typical course that can result in cumulative disability. Within 5 years of NMO onset, more than 50% of patients are blind in 1 or both eyes or require ambulatory assistance, he noted.
Three medications have received FDA approval for treating NMO: Uplizna (inebilizumab-cdon, Viela Bio) for B-cell depletion; Soliris (eculizumab, Alexion Pharmaceuticals Inc.) for complement inhibition; and Enspryng (satralizumab, Chugai Pharmaceutical) for anti–IL-6 activity. Sergott pointed out that ophthalmologists must recognize ON quickly and move in a different paradigm than before.
“It is no longer an option to wait to perform imaging,” he said. “All ON patients should be hospitalized. NMO and MS cannot be differentiated clinically, and NMO must be treated to prevent strokes in the optic nerve and retina.”
Specifically, Sergott advised treating with IV methylprednisolone upon admission to the hospital, followed by MRI, a serologic work-up, and lumbar puncture for NMO, Lyme disease, syphilis, and anti-MOG antibodies. If the vision does not improve with IV steroid treatment, plasmapheresis should be performed quickly. If unsuccessful, it should be followed by B-cell depletion, complement inhibition, or anti–IL-6 therapy.
A neuroradiologic clue to NMO involves the area postrema in the distal brainstem; when it is inflamed, hiccups, vomiting, and weight loss develop. Another clue is that the lesions in the spinal cord are longer than in MS and can span 3 or more contiguous vertebral segments of the spinal cord and involve the central gray matter, with the lesions generally localized to the cervical and upper thoracic cord, Sergott said.
“In 2021, we have a new paradigm for ON. Ophthalmologists should think NMO first and MS second. ON is NMO until proven otherwise to prevent strokes to the optic nerve and retina,” Sergott concluded.