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Envisioning a New Era in the Diagnosis and Treatment of Neuro-Ophthalmologic Disorders

Article In Brief

Neuro-ophthalmologists highlight advances in the subspecialty over the past 20 years, including new classifications and treatments for optic neuritis, neuromyelitis optica spectrum disorder, and technological tools that have led to earlier detection of these and other disorders.

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Twenty years ago, neurologists could only directly view the optic nerve and detect any of its abnormal states such as papilledema (shown here) via the direct ophthalmoscope. Now, technological advances have allowed for the development of affordable digital cameras, which provide beautiful photographs of the optic nerve and retina without pharmacologic pupillary dilation.

The new millennium has ushered in extraordinary progress revolutionizing the detection, treatment, and management of neuro-ophthalmologic disorders such as optic neuropathies, papilledema, and visual loss.

“While the exquisite anatomy and physiology of the afferent visual system within the eye and the brain were understood and appreciated far more than 20 years ago, remarkable advances have occurred in the past two decades,” said Nancy J. Newman, MD, FAAN, LeoDelle Jolley Chair in Ophthalmology, director of the section of neuro-ophthalmology, and professor of ophthalmology and neurology at Emory Eye Center in Atlanta. For example, Dr. Newman said, the classification of optic neuritis (inflammation of the optic nerve) has been modified substantially.

Optic Neuritis

Twenty years ago, optic neuritis was either monophasic optic neuritis or multiple sclerosis (MS). A brain MRI and cerebrospinal fluid analysis could usually discern cases of MS. If the results were normal, neurologists usually would observe closely for any new neurological activity—and “if there was none, the diagnosis of monophasic optic neuritis could be made in retrospect,” said Michael Levy, MD, PhD, FAAN, associate professor at Harvard Medical School and director of the neuroimmunology clinic and research laboratory at Massachusetts General Hospital.

“Now, we have more tools for testing, and we are more discriminating in the diagnosis of cases that have relapsing disease,” Dr. Levy said. “It's not just MS anymore.”

Neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) fall under the umbrella of relapsing diseases. For both conditions, there are highly reliable blood tests to make a diagnosis, Dr. Levy said. Moreover, three new therapies approved by the US Food and Drug Administration (FDA) are available for NMOSD, so making the diagnosis allows for effective treatment. MOGAD trials have launched this year, he said.

Neurologists also have a better understanding of MRI and clinical features, genetic backgrounds, and overlapping serologies that help them identify mitochondrial diseases and paraneoplastic syndromes that also can cause neurological vision loss, Dr. Levy said.

“What has changed is our ability to accurately detect the start of relapsing diseases after the first attack of optic neuritis,” he said. “We also have new therapies that allow us to prevent relapses.”

Neurologists now know there are several different diseases that cause optic neuritis, each with their own characteristics in terms of severity, prognosis and likelihood for recurrence.

“Testing after optic neuritis has improved our ability to prevent recurrent attacks,” Dr. Levy said. “Educational activities on this topic have helped to spread awareness and about who to test and when to refer for preventive treatment.”

The greatest advances have occurred in the development of immune modulating medications to prevent attacks. There are more than 18 new FDA approved drugs in MS and three in neuromyelitis optica spectrum disorder (NMOSD), and more are expected to gain approval for MOGAD, Dr. Levy said.

“NMOSD and MOGAD are antigen-specific diseases—that is, we know what the immune system is targeting,” he said. “That allows us to look upstream in the disease pathogenesis at why the disease is occurring and how we may be able to specifically switch the immune system off to those antigens.”

But what hasn't changed is “the diagnosis of monophasic optic neuritis to provide patients with reassurance about their prognosis,” Dr. Levy said. “We still have to wait for a few years and make the diagnosis in retrospect if all was quiet.” Another drawback is the lack of treatments to help in the regeneration of optic nerve tissue after inflammatory damage, he said.

Advances in Technology

Meanwhile, technology also has accelerated by leaps and bounds. Twenty years ago, neurologists could only directly view the optic nerve and detect any of its abnormal states such as papilledema via the direct ophthalmoscope, a clinical examination instrument rarely and poorly used.

“Over the past two decades, technological advances have allowed for the development of easy to use and affordable digital cameras, which provide beautiful photographs of the optic nerve and retina without pharmacologic pupillary dilation,” Dr. Newman said.

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“Using OCT, one can determine if there is damage to the optic nerve as demonstrated by thinning of this layer. Furthermore, one can determine which aspects of the optic nerve (superior versus inferior, for example) have been damaged, by inspecting which sectors of the retinal nerve fiber layer have thinned. If a patient presents with a superior visual field defect, for example, the practitioner can use the OCT to look for corresponding inferior thinning of the retinal nerve fiber layer.”—DR. MARK DINKIN

This equipment facilitates appropriate diagnosis by the non-ophthalmologist and results in an informed referral to an ophthalmologist only when necessary. “Additionally, new advances in artificial intelligence deep learning systems have made immediate automated interpretation of these photographs a reality,” she said. “Obviously, these clinical examination advances are changing the focus of medical and neurologic education of students and trainees now and into the future.”

One of the most important technological advancements has been the incorporation of optical coherence tomography (OCT) in the evaluation of optic neuropathies. This technology uses low coherent light to measure the thickness of the retinal nerve fiber layer (RNFL)—the layer of axons along the inner surface of the retina that become the optic nerve, said Marc Dinkin, MD, director of neuro-ophthalmology and associate professor of ophthalmology at Weill Cornell Medical College and New York-Presbyterian Hospital.

“Using OCT, one can determine if there is damage to the optic nerve as demonstrated by thinning of this layer,” Dr. Dinkin said. “Furthermore, one can determine which aspects of the optic nerve (superior versus inferior, for example) have been damaged, by inspecting which sectors of the retinal nerve fiber layer have thinned. If a patient presents with a superior visual field defect, for example, the practitioner can use the OCT to look for corresponding inferior thinning of the retinal nerve fiber layer.”

However, he added, “One caveat is that recent damage to the optic nerve in a more posterior location will not affect the thickness of these fibers for several weeks or months, until retrograde degeneration sets in. Furthermore, demyelination of the optic nerve as may occur in optic neuritis will not necessarily cause thinning unless there is accompanying axonal loss.”

Dr. Newman said the application of OCT imaging to neurologic disorders, particularly those of the anterior visual pathways (the optic nerves and chiasm), has revolutionized diagnosis. It has helped differentiate retinal from optic nerve disease and establish the chronicity of a process affecting the optic nerve. In addition, she said, OCT has been instrumental in ruling out optic nerve damage in a patient with visual loss, influencing the timing and degree of neurosurgical intervention in compressive lesions of the optic nerves and chiasm, and determining the extent of follow-up and repeat intervention.

“OCT of the optic nerve and retina, especially the ganglion cells in the macular region, is now also used to provide objective endpoints in clinical trials of multiple sclerosis and neurologic degenerative disorders where it can provide surrogate markers for disease progression, and perhaps even diagnosis,” Dr. Newman said.

Disc edema also can be quantified using OCT. The neuro-ophthalmologist can either measure the optic disc volume or assess the RNFL, which is typically thicker when there is edema, Dr. Dinkin said.

“Twenty years ago, before the advent of OCT, a neuro-ophthalmologist would still be able to assess the structure of the optic nerve by looking for either pallor or cupping, both of which can indicate optic nerve atrophy,” he said. “Inspection of the optic nerve head is still a very important part of the neuro-ophthalmologist exam, but is dependent on subjective qualitative observation, and does not allow precise quantitative measurements to detect change from one visit to another.”

MRI also has come a long way. It now allows for dedicated high resolution orbital imaging that is more sensitive for inflammatory optic neuropathies (typically showing enhancement of the nerve) or for optic nerve atrophy. More subtle tumors, such as small optic nerve sheath meningiomas, are also more likely to be detected by modern MRI imaging, Dr. Dinkin said.

Acute retinal arterial ischemia—ophthalmic artery occlusion, central retinal artery occlusion, branch retinal artery occlusion and transient monocular visual loss of retinal arterial origin—is now recognized as a neurologic emergency requiring urgent referral to an acute stroke center, Dr. Newman said. Immediate diagnostic evaluation for underlying cause is needed along with initiation of treatment and secondary prevention of stroke. This change in behavior has been difficult to accomplish and is still an ongoing effort, especially among eye-care providers.

In addition, Dr. Newman said, “new treatments for genetic disorders of the optic nerve are beginning to become a reality, with clinical trials showing some efficacy of idebenone and gene therapy for the blinding maternally-inherited Leber hereditary optic neuropathy.”

Changing Demographics of Disorders

The landscape of a few disorders also has evolved with the changing demographics of the nation's population. For example, Dr. Newman said, idiopathic intracranial hypertension (IIH)—a disorder of elevated intracranial pressure of unknown cause, which especially affects young obese women of child-bearing age—has been recognized for centuries,” she said. However, “the incidence of this potentially blinding disease from the papilledema that ensues has skyrocketed in parallel with the obesity epidemic in developed countries worldwide.”

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“What has changed is our ability to accurately detect the start of relapsing diseases after the first attack of optic neuritis. We also have new therapies that allow us to prevent relapses.”—DR. MICHAEL LEVY

Neurologists' understanding of IIH has progressed over the last two decades, Dr. Dinkin said. The recognition of venous sinus stenosis at the junction of the transverse and sigmoid sinus in the majority of IIH patients has implicated venous hypertension as a contributing factor to the disease pathophysiology. It also has led to the use of venous sinus stenting as a surgical alternative to cerebrospinal fluid shunting for medically refractory patients, he said. The stenting is investigational at this point and is being researched in studies and used off-label.

Despite significant research demonstrating a role of the cytokine IL-6 in its pathophysiology, giant cell arteritis (GCA) “remains of cryptic origin,” Dr. Dinkin said, adding, “Some pathological studies have suggested an infectious etiology, specifically related to varicella zoster infection, but subsequent studies have not confirmed this.”

However, there has been a revolution in the management of GCA. Evidence from the GiACTA trial reveals that the IL-6 inhibitor tocilizumab results in the need for lower cumulative doses of corticosteroids. “Twenty years ago, steroids were the only treatment, with occasional experimental use of methotrexate,” Dr. Dinkin said.

Unfortunately, neurologists' knowledge about the etiology and treatment of non-arteritic anterior ischemic optic neuropathy has not changed significantly in the last 20 years. “After an ambitious multicenter trial using a neuroprotective agent did not produce clear-cut results, there remains no proven treatment for the disease,” Dr. Dinkin said. “However, it is expected that much will be learned about the natural history and epidemiology of the disease from the data in that trial.”

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“New treatments for genetic disorders of the optic nerve are beginning to become a reality, with clinical trials showing some efficacy of idebenone and gene therapy for the blinding maternally-inherited Leber hereditary optic neuropathy.”—DR. NANCY J. NEWMAN

Even with the many technological advances in neuro-ophthalmology, “the core principles of neuro-anatomical localization remain unchanged, as do the primary steps of the neuro-ophthalmic examination: Check visual acuity, color vision, visual fields, and eye movements, and perform fundoscopy,” he said.

Disclosures

Dr. Newman has received fees for consulting for GenSight, Chiesi, Neurophoenix, and Stoke. Dr. Levy has received fees for serving on the advisory boards of Alexion, Genentech, and Horizon. Dr. Dinkin had no disclosures.

Link Up for More Information

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